Process Validation

7.A Official requirements

Here you will find answers to the following questions:

What are the purpose and the objective of process validation?

What are the effects of process-analytical technologies (PAT) on validation?
What is the significance of process design for validation; how is design space
established?
Who is responsible for ensuring that process validation is carried out in
accordance with regulations?
What is the procedure regarding process validation in a manufacturing contract?
What is the object of process validation?
Which requirements apply to prospective, concurrent and retrospective process
validation?
When and how should a revalidation be carried out?
How can continuous validation be carried out?

7.A.1 Regulative Aspects

Process validation is a fundamental component of the quality assurance system used by
pharmaceutical manufacturers. It should verify that the procedures and processes used in
drug product manufacturing are suitable for their purposes and guarantee that the process
used to produce the drug product will consistently meet its pre-determined specifications
and quality characteristics. A procedure is an established way of carrying out an activity.
A process is a set of methods and actions that interact to convert inputs to outputs.
Process validation is a basic factor for drug product safety and quality.
7.A.1.1 Legal requirements for drug products
The holder of a manufacturing authorization must ensure that manufacturing and
analysis are carried out in line with the most recent developments in science and
technology. Moreover, he or she must also operate a quality management system that
includes good manufacturing practice, in line with the type and scale of the activities.
The EU guidelines for good manufacturing procedure for medicinal products must be
consulted whenever the foundations for good manufacturing practice are laid out. This
gives the EU guidelines for good manufacturing practice a high regulatory binding
character. Bear in mind that methods other than those described in the EU guidelines may
also be suitable for implementing the goals of the quality assurance principles. The EU
guidelines for good manufacturing practice for drug products do not in any way intend to
restrict the development of new concepts or technologies providing that these are

validated and ensure a level of quality assurance that is at least equal to that described in
the EU guidelines. The EU guidelines, therefore, have the character of prefabricated
expertise representing modern scientific and technological standards for drug product
manufacturing and testing.
Materials produced in or for the United States are expected to meet the Current Good
Manufacturing Practices for Finished Pharmaceuticals as defined in 21CFR Parts 210 and
211. While the USA and EU have similar GMP requirements, they are not identical as
some expectations may differ. However, compliance with one area's GMP will generally
be found to be in reasonable compliance with the others.
In accordance with article 10 para. 3 of Directive 2003/94/EC and the CGMP regulations
of the USA, it is incumbent upon all European and United States manufacturers to
validate new manufacturing procedures and other significant changes.
The procedures applied in manufacturing must be validated in line with modern scientific
and technological standards. Critical phases in a manufacturing procedure must be
revalidated on a regular basis. When test preparations are used, the manufacturing
process must be validated as a whole as far as this is indicated, and the production
development phase must be allowed for; critical processing steps must always be
validated. All steps taken for the design and development of the manufacturing process
must be documented in full.
7.A.1.2 Responsibilities
In Europe, the head of production is responsible for validating the manufacturing area.
In accordance with 2.5 and 2.7 EU GMP Guide, he or she must ensure that the
necessary manufacturing procedure validations are carried out. The written procedures
and operating procedures (batch production records) for which he or she is responsible
for creating form the basis of validation, and must conform to the marketing
authorization/registration documents. Responsibilities should be clearly defined, if other
internal areas (e.g. Engineering, Research & Development) are involved in the validation.
A written contract must be drawn up between the contract giver and the contract
acceptor, in accordance with EU GMP Guide 7.1, if the task of process validation is
transferred to third parties. The contract must clearly define the responsibilities of both
sides, and in particular regulate compliance with good manufacturing practice. The
contract giver must ensure that the contract acceptor carries out the task in line with the
instructions given. Transferring the task of process validation to external service
providers does not change regulations concerning responsibility in line with EU GMP
Guide in any way: the head of manufacturing can transfer the execution of, but not the
responsibility for process validation. This means that he or she retains the legal and
public responsibility for completing all validation work in line with regulations in his or
her area.

The holder of the manufacturing authorization is responsible for ensuring that function
owners under public law are able to carry out their duties in accordance with the
regulations. In accordance with EU GMP Guide 2.2, he or she must bestow sufficient
authority on staff in leading or responsible roles to enable them to meet the demands of
their tasks. He or she must, therefore, make the necessary organizational arrangements
(organizational diagrams and job descriptions) and provide the necessary utilities.
For compliance under United States laws and regulations, the firm holding the approvals
and filings is legally responsible. The expectations and general requirements for
validation are similar to the EU with the exception that the specific person responsible for
performing the validation is more flexible. The head of the appropriate organizational
unit is responsible for assuring that validations are conducted and properly documented
with the documented review and approval of the quality unit. The president or most
senior manager/director of the firm is ultimately held accountable for all CGMP
compliance requirements.
7.A.1.3 GMP Requirements
Detailed regulations on the aims and execution of process validation can be found in the
EU guidelines for good manufacturing practice for medicinal products. According to
chapter 5.22, when new batch production records or processing methods are introduced,
proof of their suitability for routine operation should be established. It should be
demonstrated that the defined process using the established materials and equipment will
consistently produce a product that is of the required quality.
In the USA, validation has been a legal requirement for more than 30 years. References
in the GMP regulations from Section 211.100 are the historical basis for what today is
commonly referred to by FDA as the foundation of validation.
"There shall be written procedures for production and process control designed to assure
that drug products have the identity, strength, quality and purity they purport or are
represented to possess ... these written procedures, including any changes, shall be
drafted, reviewed, and approved by the appropriate organizational units and reviewed and
approved by the quality control unit". "Designed to assure" can be interpreted as the
beginning of the concept for "Validation".
The process for executing validation is described in Annex 15 of the EU guidelines for
good manufacturing practice for medicinal products. As Annex 15 contains only the
principles of qualification and validation, the PIC/S document PI 006 Recommendations
on Validation Master Plan, Installation and Operational Qualification, Non-Sterile
Process Validation, Cleaning Validation can assist with the interpretation and the
implementation. This document applies primarily to inspectorates in the PIC/S member
states, for whom it is intended as instruction for preparing an inspection, and as an
advanced training aid for qualification/validation.

As, for PIC/S purposes, this reflects the latest scientific and technological developments,
valuable information regarding the implementation of the specifications in Annex 15 may
also be found here for the industry (see chapter C.6.15 Annex 15 Final Version Qualification and validation and chapter F.1 Recommendations on Validation Master
Plan Installation and Operational Qualification Non-Sterile Process Validation Cleaning
Validation (PIC/S PI 006)).
The USA has similar documents, which can be referred to for guidance when
implementing validation activities and practices. Some of these are included in File 4
Chapter D of this manual (chapter D USA: CFR and FDA Guidelines). Attention should
be paid to the Inspection Guides and Guidances issued by FDA as they provide greater
detail in acceptable validation practices than can be found in regulations issued by FDA.
It is also suggested that www.fda.gov be periodically searched for new information being
considered (draft) or issued by the FDA on relevant subjects. Since the United States, the
EU, and Japan all participate in ICH as equal partners, any ICH issued guidances can also
be seen as important reference documents.
The US FDA Compliance Program Guidance Manual can also provide invaluable
information about what can be expected by the FDA. These Compliance programs were
written for FDA personnel, and provide manufacturers with greater insight into what the
FDA expects. It is suggested that the FDA website should be searched for applicable
inspection guides such as Program Numbers: 7346.832 (Pre-Approval
Inspections/Investigations), 7346.843 (Post-Approval Audit Inspections), 7356.002 (Drug
Manufacturing Inspections), and 7356.002A (Sterile Drug Process Inspections).
Figure 7.A-1 gives an overview of relevant text passages in the regulations.
Figure 7.A-1 Regulations relating to process validation
Regulations relating to process validation
Directive 2003/94/EC, article 10
Validation of new manufacturing procedures and
para. 3
all important changes
EU guidelines for good
When new batch production records or processing
manufacturing practice for medicinal methods are introduced, proof of their suitability
products, chapter 5.22
for routine operation should be established. It
should be demonstrated that, when the established
materials and equipment are used, the defined
process will consistently produce a product that is
of the required quality.
Annex 15 of EU guidelines for good Description of the validation process
manufacturing practice for medicinal
products
PIC/S document PI 006
"Recommendations on Validation
Master Plan, Installation and

As interpretation and implementation aid for

Annex 15 of the EU GMP Guideline

Operational Qualification, NonSterile Process Validation, Cleaning

Validation"
United States CGMP Regulations 21 Establishes requirements for validation under USA
CFR Parts 210 and 211
law. Care must be exercised by readers of these
regulations, since the word "Validation" is not
always specifically mentioned or referenced in
every case where the regulations are expecting
validation. See Section 211.100.
US Guideline on General Principles Provides guidance for consideration by
of Process Validation
manufacturers.
7.A.1.4 Aspects regarding marketing authorization
Process validation must thereby take into account the critical parameters that can
influence product quality or process reliability. Determining critical parameters already
forms a part of the development phase and the improvement phase of the process. The
manufacturing methods should be founded in these phases and a description of the
necessary in-process controls should be given.
Information regarding the evidence required for new drug approval with respect to the
development of a drug product and its relevant production processes can be found in the
Note For Guidance on Pharmaceutical Development (EMEA/CHMP/ 167068/2004, the
document is the same as the ICH Q8 document), and the EMEA Note For Guidance on
Development Pharmaceutics (CPMP/QWP/ 155/96) among other places. In these
guidelines, it is clearly emphasized that the process development studies form the basis
for later validation inspections (see figure 7.A-2).
In this respect, development studies carried out before marketing authorization may also
be the subject of official controls in a GMP inspection.
Figure 7.A-2 Relationship between process development and validation
Relationship between process development and validation
The selection, control and any improvements to the production process that are to be
described in chapter 3.2.P.3.3 of the submission file for marketing authorization
(Common Technical Document) must be explained in further detail. The critical
characteristics of the formulation, as well as the process options available should be
taken into account in order to give reasons for the selection of the manufacturing
procedure and the formulation components. The suitability of the equipment used for the
product should be demonstrated. Process development studies should form the basis for
process optimization, process validation and continuous process verification.
(In accordance with the EMEA Note For Guidance on Pharmaceutical Development,
EMEA/CHMP/ 167068/2004). The US FDA has also had a long history of expecting

similar requirements and evaluations to be established to support validation activities.

With regard to amendments that become necessary later on during process improvements,
the applicant can ensure maximum flexibility in the future as early as during the
authorization process: he should describe the measuring equipment available for
continuous process monitoring and state how the end point in sub processes can be
controlled and reviewed. This can also be evaluated as evidence that he or she
understands the process, if monitoring data from the development phase is summarized
meaningfully. His or her ability to control critical process parameters should also be
proven by these means.
The process robustness and its ability to produce reproducible quality should be proven
by means of risk evaluations, among other methods.
The applicant should submit a full description of the manufacturing procedure, on the
basis of the critical product and process attributes determined the development phase.
The requirements for this are described in the EMEA Note for guidance on manufacture
of the finished dosage form (CPMP/QWP/486/95). The significance of in-process
controls and the procedure with regard to process optimization should also be addressed
in this description.
The reason for omitting certain batch-related quality controls must be provided by means
of data from the process evaluation or validation.
See the chapter E.6.A ICH Q6A: Specifications: Test Procedures and Acceptance Criteria
for New Drug Substances and New Drug Products: Chemical Substances for more
information.
A process description and the proof that the finished product conforms to its
specifications are by themselves no guarantees that the manufacturing process is suitable.
For this reason, the applicant is increasingly expected to present data regarding the
validity of the manufacturing process as early as during the authorization process. The
scope of the data to be presented depends on the complexity of the product and the
relevant manufacturing process. The EMEA Note for Guidance on Process Validation
(CPMP/QWP/848/96) indicates the required data volume that should routinely be
presented in the authorization process.
The applicant's job is made significantly easier by the fact that the Note for Guidance on
Process Validation for marketing authorization of the drug product does not require proof
of the three validation batches on a commercial scale that are otherwise customary in
validation. This also applies for all standard manufacturing procedures in which the data
regarding the pilot batches (see below) allows validity on a commercial scale to be
predicted. The Validation on a commercial scale is then executed in the manufacturing
facility after approval has been issued, and reviewed by the local GMP inspectorate. It is
important to note that it is illegal in the USA to distribute for commercial use any drug

product prior to it being fully validated, properly documented, and finally approved by
the quality unit.
Whenever deviations from standard manufacturing procedures are found, proof of the
validation on a commercial scale must also be recorded in the application for marketing
authorization. Annex II of the Note for Guidance on Process Validation clarifies which
cases are considered non-standard manufacturing procedures (see figure 7.A-3). The
active substance used, type of drug product, the process itself and the manufacturer's
production experience all play a part in deciding whether a manufacturing procedure is
a non-standard manufacturing procedure.
Figure 7.A-3 Non-standard manufacturing procedures in accordance with Annex II of the
Note for Guidance on Process Validation
Non-standard manufacturing procedures in accordance
with Annex II of the Note for Guidance on Process Validation

The manufacture of special pharmaceutical dosage forms, such as:

o Metered dose inhalers
o Liquid disperse systems (suspensions, emulsions)
o Products with delayed release
o Individual forms in which the content of active substance is <2 % of
composition
o Other special dosage forms (e.g. parenteral depot drugs based on
biodegradable polymers, liposomes, micellar preparations)
Recording new technologies in conventional processes e.g. new drying
techniques
(Highly) specialized new technologies or conventional processes known to be
complex, which require increased concentration, e.g.
o Processes with critical steps, such as freeze drying or microencapsulation
o Processes in which the physicochemical properties of the active substance
or an excipient (e.g. lubricants, film-forming agents) cause problems with
up-scaling or stability problems
Non-standard sterilization methods, e.g.
o Autoclave sterilization procedures that differ from pharmacopoeia
requirements
o Radiation sterilization procedure with small 25 KGy
o Aseptic processes that are not otherwise stated
o Standard sterilization procedure with parametric release (see EMEA Note
for Guidance on Parametric Release, CPMP/QWP/3015/99)

The Note for Guidance on Process Validation assumes that the applicant is in a position
to establish a relationship between the data in the development phase (laboratory and
pilot batches), and the results of later process validation on a commercial scale:

An initial inspection of the suitability of the procedure and its in-process controls
should be carried out in the earlier development phase by manufacturing batches
on a laboratory scale (laboratory batches: 1/100 to 1/1000 of the later market
size). The laboratory batches are usually used to develop bulk manufacturing
and packaging procedures. These batches can also be used in preclinical or
clinical studies. The manufacture of laboratory batches is an effective means of
determining critical product and process parameters. This is the stage at which
suitable reasons should be given for the selection of the manufacturing procedure.
Figure 7.A-4 Validation diagram in accordance with Annex I of the Note for
Guidance on Process Validation
Validation diagram in accordance with
Annex I of the Note for Guidance on Process Validation

Brief process description with a summary of the critical process

levels or critical variables to be investigated during the validation

Specifications of the finished product

Cross reference to analytical methods in the submission file for

marketing authorization

In-process controls and acceptance criteria

Additional tests to be carried out (with acceptance criteria and

evidence of validation of analytical methods)

Sampling planning: where, when and how will the samples be

taken?

Data on the record type and assessment of results

Time planning

Following on from this, pilot batches are manufactured as part of the process
improvement phase, with a batch size at least 10 % of the later commercial
batches. In the case of solid oral dosage forms, the batch size must be at least
10 % or 100,000 units, whichever is larger. (Exception: in the case of veterinary
medicaments, the batch size may also be below 100,000 units). The pilot batches
thereby form an intermediate stage between the small scale of the laboratory batch
at the development level and the large scale of the commercial batch in routine
production. This intermediate stage serves to predict the feasibility of
manufacturing on a commercial scale. With the pilot batches, the ability to control
the critical parameters in the manufacturing process should be reviewed under
conditions similar to the routine. It is also important to determine which
equipment is suitable for manufacture on a commercial scale. Like laboratory
batches, these batches can be used in preclinical or clinical studies. They also act
as a sample for stability testing.
The transition from laboratory scale to pilot batch size to commercial scale (scaleup) should verify that the batch size can be enlarged without impairing product
quality. To this end, a diagram of the process validation to be carried out later on
a commercial scale should be submitted with the application for marketing

authorization, indicating in particular how the critical parameters detected in the

development phase should be reviewed at the commercial batch level. The
validation diagram should be submitted with the application for marketing
authorization and should contain, as a minimum, the information displayed in
figure 7.A-4.
Once validation has been completed in line with the diagram above, a validation report
should be created that contains the information listed in figure 7.A-5, as a minimum. The
regulatory authorities and authorities responsible must be informed immediately, if
significant deviations from the results expected have been determined at validation. In
such cases, corrective action must be proposed. An amendment must be submitted to the
regulatory authorities, if this results in any changes to the manufacturing procedure being
necessary.
Figure 7.A-5 Validation report in accordance with Annex I of the Note for Guidance on
Process Validation
Validation report in accordance with
Annex I of the Note for Guidance on Process Validation

Manufacture and test records for the validation batches

Certificates of analysis
Reports of any deviations determined or necessary modifications/changes
Conclusions

It is important to note that differences between the EU and USA Marketing Authorization
policies and practices exist. Harmonization in this area has yet to be accomplished. As a
result, the FDA and its website should be consulted to assure that practices expected for
drug products being produced for USA distribution and/or consumption are indeed being
properly implemented.

7.A.2 Principles of process validation

The lack of understanding of the purpose and aim of process validation and incorrect
interpretation of the regulatory basics have in the past overwhelmingly caused process
validation to be mutated into a documentation exercise, in which three validation batches
are manufactured on the basis of fixed mostly average parameters without risks and
process limits being identified.
The validation documentation is archived and not usually used again. This procedure
cannot lead to success with regard to the process reliability that is to be expected, and
today it no longer complies with the understanding of a proper process validation. The
manufacturer should be able to assure the validity of his processes on an ongoing and
permanent basis, not only at the start and at certain points in the process.

The manufacturing systems and equipment used for the in-process control must have
been qualified before validation is executed. The personnel that conducts (i.e. controls or
supervises) the manufacturing process must have been trained appropriately in the tasks
to be carried out. All documents used (operating instructions, records, checklists) should
be checked, approved and implemented in advance.
Acceptance criteria for validation should be derived from the work carried out in the
research and development phase. An acceptance criterion is an established requirement
that must be met for validation to be completed successfully. Acceptance criteria can be
set as both process-related parameters and product-related specifications.
Acceptance criteria must be created and documented before validation is carried out as
they are core elements of every validation protocol. For example, it is possible to utilize
requirements from batch production records, application documentation or risk analyses,
when establishing acceptance criteria.
Figure 7.A-6 gives an overview of the most important principles of process validation.

Figure 7.A-6 Principles of process validation

Principles of process validation
The process is defined.
The product must meet predetermined specifications.
The scope and depth of the validation investigations are based on a risk
assessment.
The process is managed and reproducible.
Evidence is provided that previously-defined acceptance criteria have been met.
The validation results are documented in full, correctly and traceably.
For the USA, the validation is approved by the appropriate organizational units
and the Quality control unit.

7.A.2.1 Process understanding

In order to be able to validate processes, you have to understand them. You need to know
how and by what they are influenced in order to be able to control processes adequately.
This kind of risk-based approach must be pursued throughout the entire lifecycle of the
process, starting with development and optimization and continuing to routine production
and change control. The trend in process validation is, therefore, clearly towards a
continuous process validation. This means that processes are not simply validated once
and then their suitability not reviewed for a long period, but they are continually
monitored and evaluated. Statistical tools such as quality control cards play an
important role in this.
The work carried out in the development and improvement phase of a drug product (see
chapter 7.I.1 Process development) forms the basis for process understanding. Already

identified critical parameters in the development and improvement phase, should be taken
into account when process validation is carried out. This data is also subject to inspection
by the authorities, if they are incorporated into process validation. Therefore,
development and optimization, including all changes implemented during these phases,
must be carefully documented so that the compilation of the process design is traceable.
Validation is consequently founded on the development and improvement phase and
represents a fundamental part of the life cycle of the process (see figure 7.A-7).
Figure 7.A-7 Life cycle of processes

to enlarge, click here!

7.A.2.2 Type and scope of process validation
"It is impossible to state categorically when and how qualification/validation should be
carried out, as the size and complexity of production processes and facilities vary
considerably" (PIC/S document PI 006, chapter 2.5.5)
The expenditure required for process validation depends on the type of manufacturing
procedure and the nature of the products. In the same way, a distinction should be made
according to application, e.g. whether the data is to be ascertained for the approval of a
drug product with a new or known active pharmaceutical ingredient, for confirmation of a
change that has been carried out or for a routine revalidation.
Each process validation is based on an interpretation of a base of representative data.
Validation must be carried out in such a way that the type and scope of the data received
allows sufficient evidence to be provided of the reproducibility of the process. This
presupposes that the basic data is complete, correct and has been recorded using
calibrated measuring equipment. The interpretation always begins with the raw data upon
which all processing and transfers are based.
Figure 7.A-8 Statement by EMEA and FDA on continuous validation
Statement by EMEA on continuous validation

Question

Would EMEA consider a validation strategy, which eliminates the need for
product equivalence validation (e.g. PQ with 3 batches), if the product/process
signature would be qualified at the development stage?

Answer

We are prepared to accept that where a product is subject to enhanced process

understanding and monitoring that a state of continuous validation could be
achieved. The validation strategy should be adequately justified.

(EMEA homepage, Q/A on PAT)

Statement by FDA on continuous validation
Advanced pharmaceutical science and engineering principles and manufacturing control
technologies can provide a high level of process understanding and control capability.
Use of these advanced principles and control technologies can provide a high assurance
of quality by continuously monitoring, evaluating, and adjusting every batch using
validated in-process measurements, tests, controls, and process endpoints. For
manufacturing processes developed and controlled in such a manner, it may not be
necessary for a firm to manufacture multiple conformance batches prior to initial
distribution. Agency staff (field and center) should discuss the need for conformance
batches prior to distribution with the designated agency contacts when inspecting firms
employing these advanced pharmaceutical science and engineering principles and control
technologies.
(FDA Compliance Policy Guide CPG 7132c.08, 2004)
Processes in which the interaction between critical process parameters and the variable
properties of the starting material is not known exactly can only be reproduced rigidly, on
the basis of established manufacturing instructions. The manufacturing instructions
usually follow from the process descriptions specified in the marketing authorization. The
process description is subject to a risk analysis, the results of which determine the scope
and depth of the validation (see EU GMP Guideline, chapter C.6.15 Annex 15 Final
Version - Qualification and validation, no. 1). Even if process validations for standard
processes (that is, all conventional, well-established manufacturing procedures apart from
the non-standard processes in figure 7.A-3) are usually carried out only after approval has
been granted, the prospective validation using these validation batches must still be
carried out (see chapter 7.A.3.1 Prospective validation). This means that a drug product
may be put into circulation only once the relevant manufacturing procedure has been
confirmed as valid.
If, however, the manufacturer is in a position to continuously evaluate a process, e.g. by
using process-analytical technologies (see chapter 7.J Process Analytical Technology
(PAT)) as well as process control and evaluation by means of control cards (see chapter

7.A.5.3 Quality control cards), and can give evidence of the process understanding
required for this, he or she has reached a status that can be labeled continuous validation.
Where possible, this should be proven as early as in the approval procedure (see chapter
7.A.1.4 Aspects regarding marketing authorization). In such cases, regulations can be
simplified; a prospective validation using three validation batches on a commercial scale
can be omitted. The concrete evidence that must be presented in individual cases for a
continuous validation status to be assumed has not yet been substantiated by the
authorities. Both the European (EMEA) and American pharmaceutical authorities (FDA)
have, however, declared that they would, in cases where extensive process understanding
has been proven, be prepared to dispense with the need for evidence of the three
validation batches (see figure 7.A-8). Yet, in the USA, most field investigators would
expect to observe multiple lots validations as historically performed by industry. The
FDA's willingness to dispense with this normal expectation can be and is currently
subject to FDA headquarter review and approval.
7.A.2.3 Traceability of validation investigations
Validation investigations should deal in particular with the critical product and process
attributes that were determined during the manufacturing procedure's risk analysis and
development work. As a result, manufacturing procedure, risk analysis and scope of
validation very closely related.
Consequently, the type and scope of the validation investigations carried out are traceable
only, if this relationship is also clear in the documentation. Criticism is often heard in
GMP inspections to the effect that the risk analysis does not take the entire manufacturing
process into account, and the scope of validation cannot be harmonized with the results of
the risk analysis. Setting up a comparative process matrix (traceability matrix) has
proven useful in making it possible to prove the traceability of the validation results to
the results of the risk analysis and the functionality of the manufacturing process (see
figure 7.A-9).
Figure 7.A-9 Traceability matrix as a means of linking documents
to enlarge,
click here!

7.A.2.4 Manufacturing under routine conditions

Process validation should be carried out under conditions that are as close as possible to
reality, and should take into account the following factors, among others:

Raw materials from different suppliers/manufacturers used, in particular in

different synthesis procedures/impurity profiles of active pharmaceutical
ingredients
Validation batches manufactured by different personnel (insofar as manual
influences are critical)
Routine production equipment used (different facilities/lines should also be
compared where it is relevant and critical)
Validation batches manufactured in different market sizes (providing the batch
size is a critical parameter)
Seasonal, climatic influences taken into account (insofar as e.g. temperature and
humidity may affect the product or process)

7.A.2.5 Bracketing (product group formation)

Depending on the product range and type of production, it is possible to combine groups
of products or procedures (bracketing), which reduces the total expenditure required.
The principle behind bracketing and the classification of individual products or
procedures into one group must be justified. The validation object selected from the
group does not need to be representative of the entire group, but should represent the
Worst Case. The Worst Case is usually the manufacturing procedure that is hardest to
control - a selection which must be justified based on a risk analysis.
7.A.2.6 Challenge tests
Also, in the framework of process validation, proof should be established of the
suitability of sampling procedures and in-process testing regarding their significance for
process reliability. Usual procedures to do this are challenge tests, which are intended to
prove that errors are discovered and rectified or prevented by means of existing control
measures (e.g. the inspection to ascertain whether a camera-assisted blister control
system is capable of determining incorrectly filled blisters).
The aim of these challenge tests is not to determine margins of error (proven-acceptable
ranges, PAR). This is a subject addressed in the development stage. The validation is
executed under standard conditions, not extreme conditions that do not conform to
reality. Challenge tests under worst-case conditions do not mean that a number of
validation batches must be manufactured in consideration of all possible combinations of
critical parameters. (If only five parameters each have three test values, it basically means
that 35 = 243 validation batches are manufactured on a commercial scale.) In other words,
the standard conditions that are the least favorable for the process and product when all
circumstances are taken into account are those that are selected as the result of a risk
assessment.

As evidence that the specifications have been fulfilled, all required quality controls
should also be carried out on the finished product.
7.A.2.7 Deviations
Each process validation must be documented completely and in a such way that it is
traceable. Changes in the test procedure must be noted. If batch data has not been
considered, this must be explained and documented.
Deviations during the validation (e.g. deviations from acceptance criteria, the procedure
or specifications) must always be documented. The cause of the deviation must be
determined and the consequences evaluated. During validation investigations, deviations
can occur if the design of the process that is being checked was not suitable, or the
process was not optimized sufficiently with respect to the control parameters. Inadequate
process development or optimization must be rectified later. However, this subsequent
improvement must not, however, be made by means of the validation since it is not the
aim of validation to develop or improve, but to provide evidence that the product is, since
development and optimization, suitable in accordance with previously specified
acceptance criteria. It follows that it is prohibited to make any alteration to a previously
established sequence of operation or acceptance criteria in the context of finalizing a
validation protocol. In these cases, the optimization of the process should first be halted,
appropriate change control procedures carried out and validation begun.

7.A.3 Types of validation

7.A.3.1 Prospective validation
In principle, it is assumed that process validation is completed before the first routine
commercial lots of a drug product are manufactured and distributed (prospective
validation). In the case of standard manufacturing procedures, this usually takes place
after approval has been granted; for non-standard manufacturing procedures, validation
must already have been proven in the approval procedure (see chapter 7.A.1.4 Aspects
regarding marketing authorization).
The requirement is for three consecutive batches conforming to specification to be
manufactured, to confirm that a prospective validation has been carried out in accordance
with the regulations. The batch size should correspond to the normal commercial scale.
The manufacturer must justify testing on smaller validation batches and simultaneously
provide evidence that the results can be transposed to the commercial scale. If this is the
case, it should be justified in detail in the validation protocol. Finally, evidence of the
validity of the process must be recorded even if batch size is reduced.
The validation batches manufactured may only be put into circulation if a positive
validation result has been recorded. Similarly, no commercial batches may be put into
circulation until validation has been successfully completed. Since stock for sales or for
other forms of disposal meets the conditions of placing on the market, it is permissible to

begin routine manufacturing for pharmaceutical purposes only once validation has been
successfully completed (figure 7.A-10).
Of course, all requirements established in the submission file for marketing authorization
must be met. Prospective validation should be documented by a validation protocol and
a validation report.
Figure 7.A-10 Prospective validation in accordance with Annex 15 of the EU GMP
guidelines
Prospective validation in accordance with Annex 15 of the EU GMP guidelines
Short description of the process
Overview of the critical processing steps tested
Equipment/premises (including measuring, monitoring and recording
instruments) and the calibration status of these instruments
Specifications for the approval of the finished product
Listing of the analytical techniques if necessary
In-process controls including acceptance criteria
Additional tests that are to be carried out, where necessary, including acceptance
criteria and validation of the analytical techniques
Sampling plan
Methods for recording and evaluating results
Description of tasks and allocation of responsibilities
Suggested schedule

The points listed in figure 7.A-10 should be the minimum contents of a prospective
validation, and should be included as points listed in accordance with Annex 15 of the
EU guidelines for good manufacturing practice for drug products (chapter C.6.15 Annex
15 Final Version - Qualification and validation). For the USA, Validation guidelines
issued by the FDA can be referenced; however, US authorities allow flexibility in what
needs to exist as long as the equivalent of what is sought in a USA Guidance exists as a
minimum, and is properly documented and approved by the Quality unit.
It is generally acknowledged that the three prospective validation batches that are usually
accepted have little statistical significance regarding process reliability. Therefore, it is
not the rigid reproduction of three batches that is decisive within the framework of
prospective validation. The number of times a process is run should rather be sufficient
for considering variability in routine production, showing possible trends and obtaining
sufficient data for a meaningful interpretation. It is important for USA compliance, that at
least 3 consecutive batches are produced for validation to even be considered acceptable.
The validation should be repeated for at least 3 more consecutive batches, if a batch
needs to be discarded or not included in the validation run.
7.A.3.2 Concurrent validation

When manufacturing procedures are validated, the prospective course of action is the
norm. In exceptional cases, validation of the process during routine manufacture may be
required (concurrent validation). The significant difference here is the option of putting
validation batches into circulation even though validation is not complete and no
conclusive evidence exists that the process is indeed suitable. This represents a risk for
drug product safety and consumer health protection. For this reason, concurrent
validation must be used only in justified exceptional cases. The decision to take this
course of action must be well-founded, documented and approved by an authorized
person.
An important condition for concurrent validation is that the process is already well
managed. Evidence may, among other methods, be provided by means of quality control
cards (see chapter 7.A.5.3 Quality control cards) and statistical investigations into
relevant process parameters, e.g. by determining the process capability index (CpK, see
chapter 7.A.5.4 Process capability investigation). Development and optimization data,
data from the scale-up phase or comparable production data from other plants, for
instance, may be used as data sources.
Prerequisites for concurrent validation include:

The premises and equipment used for the process are conclusively qualified.
A carefully conducted risk analysis has been presented and evaluated.
The execution of concurrent validation is described in a validation protocol,
which takes into account the critical parameters determined in the risk analysis
and determines acceptance criteria.

If these prerequisites are met, concurrent validation is permissible, e.g. in the following
cases:

Transfer of a validated process to another plant (e.g. to a contract manufacturer)

Modification of an existing process (e.g. dosage or tablet shape are different from
the validated procedure)

Concurrent validation is prohibited for all non-standard manufacturing procedures (see

figure 7.A-3).

In the USA, the FDA's Compliance Policy Guides Manual Chapter 4 (CPG
7132c.08) states that: For some products, the completion of the initial
conformance batch phase of process validation before the distribution of any one
batch would require the manufacture of unneeded batches (e.g., certain orphan
drug products), which would not be in the interest of public health. In addition,
the completion of multiple batches before first distribution may also be
impractical for a product with a very short shelf life or that is intended for limited
use (e.g., some radiopharmaceuticals). Therefore, the need to manufacture
multiple conformance batches in advance of initial product distribution may not
be needed under these circumstances. In such cases, product distribution may

have occurred concurrently with the release (or approval for release) of each
conformance batch.
The agency's evaluation of a firm's decision to release batches concurrent with the
manufacture of the initial conformance batches should include review and/or audit
and assessment of:
o the firm's basis for justifying the distribution of individual batches prior to
completion of the initial conformance batches (to include review of the
product/process development effort);
o the firm's protocol/plan and available data to verify that there are adequate
batch controls and testing prior to release for distribution of each batch,
and provides for adequate and timely assessment of the validity of the
process once all initial conformance batches have been manufactured;
o and the firm's program for monitoring distributed batches and provisions
for a rapid response to information suggesting the process is not under
control (e.g., subsequent batch failures, production problems related to
process design or equipment performance, complaints). Documentation,
monitoring, and controls systems are expected to be more comprehensive
whenever concurrent validation is being exercised.
7.A.3.3 Retrospective validation
Processes that already exist that have not been validated prospectively or concurrently
can, in accordance with Annex 15 of the EU GMP guidelines, be validated
retrospectively on the basis of historical manufacturing data (retrospective validation).
Validation of manufacturing procedures has been a legal requirement for many years. In
the 21st century, it is hardly imaginable or acceptable for a manufacturer not to have
validated an existing manufacturing procedure. For this reason, the principle of
retrospective validation can largely be revoked. Nevertheless, if manufacturers decide to
use this procedure, they are advised to coordinate it with the supervisory authorities
responsible.
If retrospective validation is carried out, the data must enable process reliability to be
evaluated within defined acceptance criteria. Reliable data from a defined time period
should be evaluated using an experience report to determine whether the manufacturing
procedure in question has fulfilled the established requirements based on a validation
protocol, and whether it will fulfill these requirements in future (see figure 7.A-11).
Figure 7.A-11 Experience report for retrospective validation
Data sources for an experience report for retrospective validation
Equipment logbooks with documented process data
Batch documentation (manufacturing and test records)
Training documentation (in particular with manual procedures)
Change history (change control reports)
Results from the ongoing stability program
Deviation reports

Product quality reviews

Quality control cards, process capability investigations

In the United States, retrospective validation of drug products is generally not acceptable.
It is strongly suggested that FDA be contacted, if a firm is going to attempt to perform a
retrospective validation for products being produced for future USA distribution.
Annex 15 of the EU guidelines for good manufacturing practice for drug products allows
retrospective validation only for established processes that have not undergone any
critical changes (e.g. product composition, process parameters, process sequence) during
the period under observation .
Retrospective validation is then only acceptable if the set of data used as a basis is
sufficiently large (at least ten batches that conform to specifications) and statistically
meaningful. A validation protocol and a validation report should be compiled for the
retrospective process validation documentation, in the same way as for prospective
process validation.
A purely retrospective data analysis is prohibited if:

The raw data used as a basis is missing

The data does not cover the current range of operational parameters
Significant changes have been made in the period of observation
Unresolved deviations or trends have been documented

7.A.4 Revalidation
Periodic revalidation (i.e. repetition of validation at certain time intervals) is prescribed
by German pharmaceutical law: "Critical phases in a manufacturing operation must be
revalidated on a regular basis" (AMWHV 13 para. 5 clause 2). Phases in a
manufacturing procedure that should be classified as critical include in particular those
that may affect the product safety, such as sterilization.
The following is also recorded in the PIC/S document PI 006 that deals with
recommendations for validation: "The qualification and validation do not consist of oneoff activities such as the introduction of a new manufacturing process. The initial
implementation should always be pursued as a continuous programme". (PIC/S document
PI 006, chapter 2.5.12)
The validation status of a manufacturing procedure can be jeopardized by the following,
for example:

Accumulation of minor changes having a negative overall effect

Process instructions not followed correctly
Inadequate training of personnel

Unclear/contradictory instructions
Increasing levels of failures or deviations
Change of general conditions (e.g. laws, GMP guidelines)

Manufacturing procedures should therefore be evaluated at specific intervals to ensure

that they remain in a validated state. A check that provides evidence that the procedure
still satisfies the prescribed requirements fulfils the necessity of a revalidation (review), if
no significant changes have been made to the manufacturing procedure. This check can
be made using quality control cards, process capability investigations, trend analyses or
Product Quality Reviews (see figure 7.A-12), among other methods (see also chapter
15.F Annual product review/ Product quality review).
Figure 7.A-12 Product quality reviews
Product quality reviews as an element of revalidation
"Regular periodic or rolling quality reviews of all licensed medicinal or drug products,
including export only products, should be conducted with the objective of verifying the
consistency of the existing process, the appropriateness of current specifications for both
starting materials and finished product to highlight any trends and to identify product and
process improvements."
(EU GMP Guideline, Chapter 1.5).
The schedule and/or process to be used for revalidation determination should be given in
a validation master plan (VMP, see chapter 7.A.4.1 Validation master plan).
In addition to the periodic validation, a revalidation must be carried out for critical
changes too. According to Annex 15 of the EU guidelines for good manufacturing
practice for drug products, it is incumbent upon the manufacturer, as part of his change
control program (see chapter 19.C Change control) to evaluate all changes with regard
to their effects on product quality or process reliability and carry out a revalidation if
necessary.
Figure 7.A-13 mentions some examples of changes for which revalidation are
compulsory.
Figure 7.A-13 Revalidation following critical changes
Changes which may make a revalidation necessary:

Changes to the product composition

Changes to the primary packaging material (e.g. replacing glass with plastic)
Changing the manufacturer of the starting material or the process used to produce
the starting material(s)
Changes to the sequence of operation
Expansion or widening of the acceptance criteria defined for critical process
parameters

Changes to the equipment and supply systems

Change of manufacturing site
Conspicuous trends or deviations (= unintentional changes)

The revalidation of critical changes should provide evidence that changes to a process
and/or the process environment do not negatively affect process attributes and product
quality (cf. PIC/S document PI 006, chapter 6.6.1).
It is not absolutely necessary to requalify a process from scratch just because a specific
aspect has been modified. However, it is important to carefully assess the type of change
(risk analysis) to identify possible repercussions and to establish the precise scope of the
revalidation (cf. FDA, CDER, 1987 chapter D.2 Guideline on General Principles of
Process Validation).
The documentation requirements for revalidation are the same as those for initial
validation and similar documents may, therefore, be used in many cases (cf. PIC/S
document PI 006, Chapter 6.6.3).
US FDA expects to see a written "quality assurance system in place which requires
revalidation whenever there are changes in packaging, formulation, equipment, or
processes which could impact on product effectiveness or product characteristics, and
whenever there are changes in product characteristics. Furthermore, when a change is
made in raw material supplier, the manufacturer should consider subtle, potentially
adverse differences in the raw material characteristics. A determination of adverse
differences in raw material indicates a need to revalidate the process." (See chapter D.2
Guideline on General Principles of Process Validation.)
The main documents for validation are the validation master plan, and the related
validation protocols with the closing validation reports. In general, the GMP
documentation requirements (see chapter 15.B GMP-conforming documentation) apply
to the design and compilation of documents for validation.
7.A.4.1 Validation master plan
A unit's current validation projects must, in accordance with Annex 15 of the EU
guidelines for good manufacturing practice for drug products, be described in a validation
master plan (see figure 7.A-14).
Figure 7.A-14 Contents of the VMP in accordance with Annex 15
Contents of the validation master plan (VMP)
Organization and responsibilities
Definitions, basic procedures, documentation formats
Principles for setting up acceptance criteria
Relevant premises, equipment and procedures

Risk analysis and bracketing procedures

Scheduling, estimated personnel and material outlay

The manufacturer can use this to establish the principles and procedure relevant to the
process validation and estimate the resources required. In this respect, the timing and
sequence of the individual validation projects is an important component within the
validation master plan. Moreover, the validation master plan enables the GMP
investigator to understand the company approach towards process validation as well as
towards determining and organizing the required activities. When the validation master
plan is compiled, reference may be made to existing documents. In the case of large
projects, it is possible and permissible to compile several validation master plans.
The FDA's Guide to Inspections of Validation Documentation (see chapter D.6 Guide to
Inspections of Validation Documentation) discusses Validation Master Plans and
provides some insight into FDA thinking. This guide is no longer available on the FDA
site, and is therefore not considered to exist as a current FDA Guide. However, it does
provide insight that can be valuable to manufacturers of drugs for use in the USA.
7.A.4.2 Validation protocol and report
The detailed rules for performing the validations should be established in directions based
on procedure ("validation protocol" according to Annex 15, no. 6) and checked and
authorized by the persons responsible. In particular, in terms of their content, they should
specify the critical steps and state the acceptance criteria.
A validation protocol should contain the points shown in figure 7.A-15 in accordance
with PIC/S document PI 006, chapter 6.3.3. The reference to the FDA shown above in
Section 7.A.4.1 can also be used to help understand FDA expectations for various
documentation issues.
Figure 7.A-15 Contents of the validation protocol in accordance with PIC/S document PI
006, chapter 6.3.3
Contents of the validation protocol in accordance with PIC/S document PI 006
Description of the process
Description of validation investigations
Details of the equipment and facilities to be used (including measuring and
recording instruments) and the calibration status of these instruments.
Variables to be investigated
Sampling (where, when, how, how much)
Product characteristics to be tested and the relevant test methods
Acceptance criteria
Time schedule
Responsibilities
Details of recording and evaluation methods including statistical analysis

procedure

The execution of individual validation projects should be documented in a report that

corresponds to the validation protocol ("validation report" in accordance with Annex 15,
no. 7, see figure 7.A-16), in line with specifications.
Figure 7.A-16 Contents of the validation report in accordance with PIC/S document PI
006, chapter 6.3.9
Contents of the validation report in accordance with PIC/S document PI 006

Description of the process, the batch and packaging documents with details of the
critical processing steps
Detailed summary of the analytical results from the in-process controls and the
tests carried out on the final product (including data from failed tests). If the raw
data is omitted, a reference to the corresponding sources must be included.
Data on additional work carried out (including formal reasoning) and other
deviations from the validation protocol
Analysis of the results obtained and comparison with the expected results
Formal authorization or rejection of the validation by the team or person
responsible (after remedial actions or repeated operations have been completed)

The report should contain an overview of the results cross-referenced with the validation
protocol. Deviations observed and the conclusions drawn from them (including necessary
changes) should be listed. Deviations from the plan should also be evaluated.
Recommendations for continuing investigations (e.g. trend analyses, monitoring) and the
in-process controls necessary for routine production should accompany the evaluation of
the report.
As previously noted, approvals by the appropriate organizational units, final reviews, and
approval by the Quality unit is expected in the USA.
7.A.4.3 Archiving
Archiving should be performed according to EU national law or USA requirements (as
appropriate). All validation records must be retained according to applicable
requirements. Archiving regulations are applicable to validation documentation and the
archiving period is calculated from the last batch manufactured using the validated
procedure. Records must be archived in a suitable area within the premises established by
the authorization in line with national law. Suitable measures must be taken to restrict
access to the records to authorized persons only. If the manufacturing company or testing
operation in which the documentation is stored is shut down, the pharmaceutical
manufacturer must take measures to ensure that the documentation is archived for the full
period required.

All raw data accrued in connection with validation should be archived together with the
validation report or as an annex to it. In no circumstances may raw data be destroyed
before the archiving period has expired. Original documents must be stored. Summaries
of raw data, e.g. in Excel tables, cannot be viewed as a replacement. In exceptional cases,
copies may be archived instead of original documents if legibility cannot otherwise be
guaranteed for the duration of the archiving period (e.g. if data is printed on thermal
paper). Certified copies should be made in such cases. This approach may be valuable for
use during an FDA review, but must be properly documented along with the justified
reason for not maintaining the original data.
If raw data is accrued electronically, it is particularly important to consider creating
legible printouts after several years have passed. This may mean that the data format or
storage medium has to be changed during the archiving period. Transferring data to a
new media or a different format must not alter the raw data in any way. The authenticity
of the data once it has been transferred must, therefore, be ensured by means of a
validated procedure.

7.A.5 Maintaining the validation status

7.A.5.1 General conditions and prerequisites
Classic approaches to validation, whether they are carried out prospectively, concurrently
or retrospectively, all have the same shortcoming: they provide only a snapshot of the
validation status of a procedure/process. However, for reasons of drug product safety it is
important to demand that the suitability of procedures and processes be ensured on a
permanent and continuous basis. The manufacturer should therefore take all the necessary
measures to ensure that the suitability of his processes is continuously reviewed,
confirmed, and verified (continuous validation/verification).
Basic principles for suitable processes include:

Established control measures

An understanding of the connection between critical process parameters and
product quality attributes
Qualified and continuously-maintained premises, equipment and supply systems
for process operation
Qualified personnel, trained in process control and documentation
Effective change control programs that establish and monitor the measures
required for implementing critical process changes
Self-inspections to review the effectiveness of the quality assurance system
A documented system to deal with deviations
Measuring systems in particular are critical elements of the equipment required
for suitable data analysis. It could cause inappropriate decisions to be made, if
such systems display a high spread in relation to the overall process spread.
Measuring systems must, therefore, be stable and not contribute significantly to
overall data spread. They must deliver correct results, which should be ensured by

carrying out calibration on a regular basis. In classic manufacturing processes

suitability is confirmed predominantly by means of conclusions from random
sampling on intermediate and final products, data recording from a specific time
period can only be evaluated retrospectively. Process measures are, however, then
only efficient and effective, if they are used to prevent faults and deviations, i.e.,
the aim of these measures is for critical process and product attributes to conform
to the specified acceptance criteria. This keeps the spread of finished products
within the tolerance limits. In the case of processes for which a Design Space (
chapter 7.I.2 Design space) has been described and which are monitored by means
of process-analytical technologies (see chapter 7.J Process Analytical Technology
(PAT), the manufacturer continuously receives data from which he can directly
derive the suitability of the process.
7.A.5.2 Principles of statistical process control
Statistical process control, in which statistical procedures are used for planning and
evaluation, helps control and steer production processes (cf. DIN 58936 Quality
management in laboratory medicine - Part 1: Basic terminology).
Product batches and production processes are never exactly the same, as every product
and process is exposed to different influences, which cause varying measurement values
for the quality attributes in question. Under spread, different measured values are
summarized in the descriptive statistics to estimate the dispersion of sample values
around their mean.
The following measured values are used for the spread:

Spread
(Inter) quartile interval
Average deviation
Average absolute deviation
Variance and standard deviation

The causes of spreads that can be determined relating to one feature by observing
processes may be manifold. Random and systematic influences must also be considered:

Random influences represent the constant total of many small individual

influences. They are always present, stable over time and, therefore, predictable.
Systematic influences have a non-random, frequently consistent cause. This may
be a missing verification, for instance, replaced components, external influences,
ageing or fatigue. They often change the measuring signal in the same direction
only. Systematic influences can be traced back to a large main influence or a few
influences that occur irregularly and, therefore, render the process unstable and
unpredictable. In rare cases, this changes the process to such an extent that it
benefits the process products. Then, the systematic influences can be identified
and introduced in the long term. However, as a rule systematic influences are

undesirable, as they change the process distribution so significantly that the

products no longer conform to specifications. As a result, harmful systematic
influences must be identified and rectified.
Processes that display a stable and repeatable distribution and are, as a result, free of
troublesome systematic influences, are also known as managed processes (see figure
7.A-17).
Figure 7.A-17 Definition of a "managed process"
Managed process A process in which the parameters do not change the distribution of the
characteristic process values, or the extent to which they are changed is known or within
known limits.
Figure 7.A-18 From unmanaged to managed process

to enlarge, click here!

The two upper examples in figure 7.A-18 show an unmanaged process in which the cause
of spread can be attributed to both random and systematic influences. Providing that the
project range remains within the tolerance limits as shown in the second example,
products that conform to specifications will still be produced. However, as the process is
not managed, the result of even the next batch cannot be predicted, and the process
conditions may breach the tolerance limits. In both of these cases, systematic spread
influences must first be eliminated so that the process is manageable.
Both of the lower examples in figure 7.A-18 show processes in which conditions remain
largely unchanged, which can be attributed to constant statistical characteristic values
(mean, standard deviation, range). The managed process that does not, however, conform
to specifications (third example in figure 7.A-18) still needs to be optimized (to reduce
random spread influences) to ensure that all units conform to specifications.
The aim of statistical process control is to control a process in such a way that systematic
influences are excluded and the process adheres to the established acceptance criteria.

Figure 7.A-19 also reflects the procedure in process control:

Figure 7.A-19 Process control

to enlarge, click here!

The first measure in process control is aimed at aligning the process with a
standard value (centering it).
In order to reduce the proportion of products above and below the specification
limit, random spread influences must also be reduced (second measure). This
increases the yield of products that conform to specifications.
An acceptable (capable) process is characterized by the fact that its internal spread
is lower than the specified tolerances. In the example diagram, the tolerance
conforms to the interval between the upper specification limit (USL) and lower
specification limit (LSL).

Since a managed process can generally be described by means of a predictable

distribution, this distribution can be used to estimate the number of products that conform
to specifications. Providing that the statistical characteristic values of a process do not
change significantly, i.e. the process is managed, it can be assumed that it will generate a
consistent number of products that conform to specifications
7.A.5.3 Quality control cards
Dr. Walter Shewhart distinguished between process data that is controlled and
uncontrolled, that is between processes subject to random and systematic influences, as
early as 1931 in his book Economic Control of Quality of Manufactured Product.
Shewhart used a graph, the quality control card, to develop a way of identifying and
counterbalancing changes in the process flow at an early stage, using sampling data. The
testing data from the random sample, such as tablet weight, is shown in graph form on a
quality control card QCC (see figure 7.A-20).
Figure 7.A-20 The quality control card

to enlarge, click here!

The alert and action limits plotted on the quality control cards indicate the values at
which an early warning of a possible deviation from normal operational parameters could
occur and immediate corrective action as well as further clarification is required.
Alert and action limits allow any development (trends) towards defective products to be
identified in good time, before a faulty part or product is produced. This enables you to
intervene in the process early enough to prevent defective products from being
manufactured. The quality control card is, therefore, an indicator of a process's ability to
supply products that conform to specifications. Quality control cards can be set up for
both quantitative (measurable variables) and qualitative features (attributive properties)
(see figure 7.A-21).
Figure 7.A-21 Measurable features of control cards
Control cards for quantitative features
Control cards for qualitative features
Tablet weight
Pigment marks on sugar-coated tables
Filling quantity in tubes
Distribution of a lyophilized cake
Release rate
Tablet surface
Disintegration time
Color of solutions

Preliminary investigations

Before a quality control card investigation can begin, the uncontrolled process sequence
must be watched in an observation phase, by means of random samples (usually 10
random samples of 5 parts each). This should give a picture of the process spread
behavior. Normally distributed values display a symmetrical distribution pattern on the
quality control card, with the values of the random variables concentrated in the middle
of the distribution and occur more and more sparingly with greater distance to the middle.
As can be seen in figure 7.A-22, 95.5 to 99.7% of all values are concentrated around the
middle value within a limit of 2 to 3 standard deviations. Consequently, in a managed

process, very few values should be found outside these limits. These limits can, therefore,
be regarded as alert or action limits.
Figure 7.A-22 Value frequency at normal distribution

to enlarge, click here!

To be able to construct the quality control card, the statistical identification data mean
and standard deviation is required. This data is determined in preliminary investigations.
The mean is plotted with the relevant 2s and 3s values on the Y-axis (dimension of the
feature result). The 2s values are known as alert limits and the 3s values as action or
intervention limits. It is tolerated, if the alert limit is exceeded once, while it requires
immediate corrective action, if the action or intervention limit is exceeded. The testing
results are entered on the X-axis in chronological order. The probability of the action
limit being exceeded is 0.3 %, which means that should it occur, this can safely be
regarded as a deviation.
Control card types

A quality control card can be compiled for every statistical parameter that can be used to
describe a process. In practice, the following types of quality control cards have become
accepted:

Mean card (mean of n units in a random sample): monitors the course of middle
process conditions
Standard deviation card (standard deviation taken from n units in a random
sample): monitors the process spread
Control cards for individual values (original values) and ranges (extreme
values): uses the smallest and largest value in the random sample n in order to
represent infringements of the alert and action limits
Median control cards: an alternative to mean cards

The procedure for specifying limit values can be used to distinguish between the process
control card the acceptance control card:

The process control card is a control card that does not assume specified limits.
The upper and lower alert limit as well as the upper and lower action limit are

defined by means of estimated values or distribution parameters for known and

previously-executed processes. Since further testing data may be gathered during
the course of the process, this is used for new limit value calculations.
The acceptance control card is a control card that is used to calculate the action
and alert limits by means of specified tolerance limit values. The tolerance limit
values indicate the maximum deviations that are permissible in a product.

Sign for error occurrence

The intervention limits are not the only sign that an error has occurred; the arrangement
of the measuring points can also indicate this. As previously mentioned, systematic
deviations are subject to principles. These principles can be deduced from the course of
the measuring points on the quality control card.
This is what is known as a trend (see figure 7.A-23), when 7 measuring points display a
practically linear incline in the direction of a limit. Tool wear may be rapidly increasing,
which would soon cause the intervention or alert limit to be exceeded.
Figure 7.A-23 A "trend" in the quality control card

to enlarge, click here!

A pattern (see figure 7.A-24) is a non-random curve progression, e.g. periodic
"oscillation" around the specified mean. For instance, this could be caused due to
temperature fluctuations, which cause the parts manufactured to be sometimes larger, or
sometimes smaller.
Figure 7.A-24 A "pattern" in the quality control card

to enlarge, click here!

For all intents and purposes, if 7 measuring points fall above or below the specified
mean, it gives rise to a new real mean. This observation is described as a run (see figure
7.A-25) and may indicate that a stamp in a tablet press has become damaged and the
pellet will manufacture larger or smaller products from now on.
Figure 7.A-25 A "run" in the quality control card

to enlarge, click here!

When a quality control card is evaluated, it is essential to distinguish between random
and systematic influences. Random influences cause a spread of testing data on the
quality control card. They are caused by influencing factors such as temperature
fluctuations or the properties of starting materials. Systematic influences lead to a
gradual shift in the testing data on the quality control card, and are caused by influencing
factors such as plant wear or incorrectly adjusted equipment.
Optimum use

To make the best use of quality control cards, it is important to first clarify which
issues/problems are to be dealt with by the quality control card; understanding possible
spread influences also is of some importance here. As a rule, quality control cards
compare the spread within a random sample with the spread between more than one
random sample. ItTherefore, it is important, therefore, for the random samples to be taken
in such a way that allows as many spread influences and sources that could affect process
results as possible to be taken into account. Furthermore, it is very important to record
types of measuring data that allow a real statement about product quality or process
manageability and can be obtained quickly by measuring, so that the process can be
controlled immediately.
7.A.5.4 Process capability investigation
Process validation must verify that the critical parameters of a manufacturing procedure
or a group of manufacturing procedures are managed within established limits
(acceptance criteria). This can be done by statistical investigation of the relevant process
parameters on the basis of manufacturing data, e.g. by determining the process capability
(process capability index (CpK)), see figure 7.A-26).
Figure 7.A-26 Process capability investigation

to enlarge, click here!

This is of particular importance in the case of processes that are complex or hard to
control. It allows a lasting conclusion regarding validity to be drawn, if such processes
are evaluated regularly by means of process capability investigations.
Managed processes with conditions that change only within tolerance limits are labeled
"capable" processes. The degree to which a managed process is able to adhere to
tolerance limits can also be determined by means of process capability investigations.
However, process capability investigations are only useful, if the process has previously
been proven to be managed. Managed processes are predictable processes. Providing
that systematic spread influences can still affect the spread and location of process
distribution, calculating process capability serves no purpose. Process capability
investigations also require the processes to be investigated to have a normal distribution.
Cp and CpK value

In practice, the Cp and CpK values have become established for determining process
capability
The process capability index is a measure of the smallest possible proportion of
defective units in a process arising whenever the characteristic values (centered
manufacturing) are optimally distributed. In fact, the index does not state whether the
distribution of the values is centered.
The Cp value is defined as:

to enlarge, click here!

Since it is not essential for the mean value of a process parameter to conform to the
middle of the specification breath, it is more useful to determine the CpK value. The
process capability index (CpK) is a measure of the proportion of units in a process that
can be expected to be defective - the larger the index, the smaller this proportion.

The CpK is defined from the mean, the corresponding standard deviation and the upper
or lower specification limit (USL; LSL) as follows:

to enlarge, click here!

The higher this value, the more safely all units from the quantity investigated are located
within the specifications.
While the Cp value indicates only the relationship of the process spread to the specified
tolerance, the CpK value also includes the location of the mean in relation to the middle
of the tolerance specified.
As a result, the CpK value is always the same or smaller than the Cp value.

to enlarge, click here!

If CpK = Cp, the mean of the quality attributes (process conditions) is exactly in the
middle of the tolerance. The smaller CpK is in relation to Cp, the further the process
conditions are from the middle of the tolerance. If the CpK value > 1.33, process
capability can be assumed (see figure 7.A-27)
Figure 7.A-27 Process capability in accordance with DIN 55350
Process capability in accordance with DIN 55350
CpK < 1.0

No process capability

1.0 < CpK < 1.33

Limited process capability

CpK > 1.33

Process capability

Summary

Process validation is a component of the quality assurance system and should

verify that the procedure and processes used for drug product manufacturing are
appropriate to their purpose.
The head of production is responsible for process validation in the manufacturing
area. He/she can delegate the execution but not the responsibility. For the USA,
the appropriate organizational units are responsible for the validation with the
review and approval of the Quality unit.
The predetermined acceptance criteria for the critical parameters, which are
determined and established within the scope of process development and
optimization, form the basis of every process validation.
Processes should be set up and monitored in such a way that their suitability can
be proven continuously and on a permanent basis (continuous validation).
Classic process validation is usually carried out prospectively. For existing
processes, a concurrent or retrospective procedure may be chosen in accordance

with determined requirements.

Revalidations should be carried out regularly and after critical changes have
occurred.

Notice

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GMP Publishing
Himmelreichstrasse 5
D-79650 Schopfheim (near Basel)
Tel +49 (0)7622 666 86-70
Fax +49 (0)7622 666 86-77
eMail [email protected]
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7.B Validation - a key element of quality assurance

Here you will find answers to the following questions:

How is validation defined?

What is the significance of validation regarding the quality assurance system?
Which problems usually occur while performing process validation?

Validation is a key element of the quality assurance system in a pharmaceutical

company. For a long time, our understanding of pharmaceutical quality was such that one
relied solely on the control of raw materials and final products. The intermediate process
was guaranteed by established experience and the professional honesty of longtime
employees. Today, our understanding is almost the reverse. Well-tested raw materials
from qualified suppliers are used in a process that must be so well controlled that,
theoretically, absolutely nothing can result other than a product that conforms to the
specifications. In contrast, the place of manufacture and staff carrying out production are
interchangeable, as long as they are qualified.
The new approach is conclusive, reasonable and sensible, since if a serious defect is
identified at the final product quality control, irreparable damage has already occurred.
For drug products, reprocessing is prohibited in most cases or is only possible with a
great deal of additional expenditure (see chapter 11.L Reworking). It is necessary to
avoid the final product being rejected using preventive measures, such as validation,
since modern drug substances and innovative preparations are also becoming ever more
expensive. The assessment of a process within the framework of a validation is
important; moreover, because staff stay with companies for shorter periods of time,
which prevents the gathering of a pool of experience and with it continuity of information
and quality. In addition, it is intended to have production processes that can be relocated
between different manufacturing sites - even worldwide. Therefore, processes must be
validated to guarantee a reproducible quality.
Figure 7.B-1 Definition of validation
Definition of validation:
"Action of proving, in accordance with the principles of Good Manufacturing Practice,
that any procedure, process, equipment, material, activity or system actually leads to the
expected results (see also qualification)."
(EU GMP Guideline)
"Establishing documented evidence that provides a high degree of assurance that a
specific process will consistently produce a product meeting its predetermined
specifications and quality attributes."
(FDA Guideline on General Principles of Process Validation and Guidance for Industry -

Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing

Process)
The term reproducible quality in this context means more than the reproducible
fulfillment of final product specifications (cf. also EMEA Note for Guidance on Process
Validation, paragraph 1). To put it the other way round: even if drug product
specifications are repeatedly complied with, it is still not permissible to conclude that a
process is under control and validated.
Therefore, quality in a product is spoken of in terms of being "produced into" and not
simply "tested into". Quality is the sum of properties of a product, not only those that are
covered in the specifications.
At the same time, process validation is only a part of a broad concept which includes
qualification of equipment, facilities, computers, buildings, building and utility services
engineering, staff and suppliers, and demands systematic documentation, archiving and
change control.
For pharmaceutical manufacturers, validation should be understood not as a
discretionary rule, but as a mandatory requirement with which there must be
compliance. Thus validation is addressed regularly during regulatory inspections as
well as during supplier audits and there are still numerous deficiencies observed:
about 10% of all GMP complaints are in the context of validation - at fourth place
in the ranking for all GMP complaints.
Common deficiencies include:

Validation protocols have not been compiled or are not being followed
Information about the equipment used, the critical process parameters, sampling
data, number of validation batches or acceptance criteria is missing from the
validation documentation
Changes to validated processes are not being addressed

Given the enormous amount of time and effort required for validation activities, it is not
easy, initially, to appreciate that validation should also be a tool for saving materials,
making cost-savings and saving time. The new demand by the PIC (cf. PIC/S PI 006) for
permanent validation seems, therefore, to conflict with international cost reduction efforts
in health care.
However, observing other industries, such as the electronics or automobile industries, one
can ascertain that in these - solely for economic interest - even more wide-ranging
process requirements are fulfilled such that final inspections can be completely waived to
some extent. With the aid of statistical process control (SPC) and Continuous
Improvement Processes (CIP), the manufacturing processes there are not only
permanently monitored, they are also continuously optimized.

By comparison, the concept of validation currently practiced in the pharmaceutical field

is only a small beginning - it is not possible to determine normal process variability or
process capability on the basis of only the required three batches.
Thus, the suggestion of the PIC is understandable: "a series of batches ... should be
produced ... It is generally considered acceptable that three consecutive batches/runs
within the finally agreed parameters, giving product of the desired quality would
constitute a proper validation of the process. In practice, it may take some considerable
time to accumulate this data." (PIC/S PI 006).
Recognizing this fact, appendix 15 of the EU guideline states that; "in theory the number
of process runs carried out ... should be sufficient to allow the normal extent of variation
and trends to be established ... It is generally considered acceptable that three consecutive
batches/runs ... would constitute a validation of the process".
The significance of the process validation has taken on a new emphasis, since over the
past months a series of new rules and regulations on this subject have been published,
notably appendix 15 to the EU GMP Guideline Qualification and validation, the EMEA
Note for Guidance on Process Validation and the aide mmoire from the ZLG (German
central authority of the Laender for health protection regarding medicinal products and
medical devices) "Inspection of qualification and validation in pharmaceutical
manufacture and quality control". Last but not least, chapter 12 of the ICH Q7A
guideline, Good Manufacturing Practice guide for active pharmaceutical ingredients
covers the topic of validation more extensively than most other rules or regulations. For
excipients, the topic of validation is described in the IPEC Good Manufacturing Practices
Guide for Bulk Pharmaceutical Excipients. The concept of validation is an evolving
concept all over the world. The expectation for 3 is a guide and even in the USA can be
challenged. One needs to be prepared to justify the exact number of consecutive lots
selected even when data may indicate a larger or smaller number may be appropriate.
The objective of the EMEA Note for Guidance on Process Validation is standardization
of the validation documents that must be submitted with the submission file for
marketing authorization. This guideline is directed at manufacturers of pharmaceutical
products; to some extent, though, the procedure is also transferable to the manufacture of
active pharmaceutical ingredients, excipients, biotech or blood products.
This paper describes very thoroughly what validation data is expected at the point of
submission of the application file for marketing authorization.
Summary
The validation of processes assures a reproducible quality, i.e. product failures will be
minimized systematically instead of being discovered (or not being discovered) by
accident during testing of finished products. Process validation is compulsory for
pharmaceutical manufacturers.

The current practice of 3 validation batches is only the start. The trend moves towards
permanent control of the process, for example by using SPC or CIP.
Notice

Copyright:
Maas & Peither AG
GMP Publishing
Himmelreichstrasse 5
D-79650 Schopfheim (near Basel)
Tel +49 (0)7622 666 86-70
Fax +49 (0)7622 666 86-77
eMail [email protected]
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7.C Process validation approaches

Here you will find answers to the following questions:

Which approaches are possible for process validation studies?

Under which conditions do they apply?
How many batches must be evaluated during a prospective or retrospective
validation study?
What does "critical parameter" mean?
How can critical parameters be determined?

For carrying out validation studies diversified approaches are possible. The validation
method chosen, or whether there is any option to choose at all, depends on the object of
the validation.

7.C.1 Prospective validation

If a new drug product or new manufacturing procedure is planned to be submitted for
marketing authorization, it must be validated. In these cases, validation activities must be
performed prospectively (for exceptions, see chapter 7.C.3 Concurrent validation). By
this, it is understood that proof is established that a manufacturing procedure using the
process parameters established on the basis of findings from process development,
scaling up / pilot plant leads reliably to a product with the desired or labeled quality on
the production scale. For USA produced drugs, the products must have been validated
before commercial distribution is started unless concurrent validation is approved for
specific reasons.
Occasionally, there are attempts within the framework of validation to make up for what
is definitively a development matter: the determination or also challenging of critical
process parameters - thus, the experimental determination of limits of a process
parameter within which a defined product quality can be obtained (see chapter 7.E.4
Prerequisites for carrying out a validation project). This is a hazardous undertaking at this
stage, taking into account that failure can lead to the write-off of a whole production
batch. Even the legislators and prevailing guidelines, such as the "Inspection of
qualification and validation in pharmaceutical manufacture and quality control" aide
mmoire, continue to emphasize that validation is not development and thus
determination or "challenging" of critical process parameters is not the object of
validation. In contrast, the objective of validation is the confirmation of the normal
operating ranges for the critical parameters in a previously evidenced Proven Acceptable
Range, that is, the range within which a process parameter can be varied without
affecting the quality of the final product (see chapter 7.E.4 Prerequisites for carrying out
a validation project).
Figure 7.C-1 Definition of prospective validation

Definition of prospective validation

A prospective validation is a validation conducted prior to distribution of either a new
product, or product made under a revised manufacturing process, where the revisions
may affect the product quality. A prospective validation should be carried out with at
least three consecutive batches. The three batches must comply with the specifications.
Before planned changes in manufacturing technology are implemented, it must be also
shown, with the help of prospective validation, that the change does not have a negative
impact on product quality.
In the very beginning of a prospective validation project, a risk analysis should be
carried out, which evaluates both, the individual product risk and the process risk. On the
basis of the findings obtained during the risk analysis, the validation protocol is then
compiled. The validation protocol must always refer to specific master production
records, or "master formula" or "manufacturing description" as part of the submission file
for marketing authorization). If several master production records are planned to be
validated simultaneously, for example for several dosages of the same preparation, it can
be done using a bracketing concept (see chapter 7.F.1 Validation matrix). However, the
application of bracketing for a particular instance must be justified. Once a process has
been successfully validated, all basic parameters established in the respective
manufacturing instruction and in the related validation protocol, e.g. relating to batch size
(must correspond to the subsequent production batches; batch sizes which deviate by a
factor of more than 10 must be justified in the validation protocol and the impact on the
validation result must be assessed), facilities/equipment, sampling plans, IPCs, control
procedures and operating ranges, are definitively fixed - i.e. following a successful
validation, every change must be recorded and reassessed in relation to the validity of the
process.
There must be careful coordination with production planning when the validation
protocol is compiled and deadlines are established. In particular, when collaborating with
external consultants or contract manufacturers, ambiguity about the enormous amount of
time needed until full completion of the validation project (which is not earlier than by
the time of approval of the validation report by the responsible person) can lead to false
expectations, time pressure or validation forecasts on the basis of partial results that are
legally inadmissible (see chapter 17.A Contract manufacture).
Figure 7.C-2 Definition of retrospective validation
Definition of retrospective validation
A retrospective validation is the validation of the manufacturing procedure for a product
already in distribution based upon available production, in-process control and quality
control data.
A retrospective validation should be carried out with no fewer than ten batches and must,
generally, be supplemented with "prospective cycles".

7.C.2 Retrospective validation

During retrospective validation, the reliability of the manufacturing process is assessed
and documented on the basis of historical data which was collected in connection with
batches that have already been manufactured.
The procedure initially appears effective and time saving for drug products that have
already been in production for years and about which it has been possible to collect a lot
of knowledge. In practice, retrospective validation often emerges as unexpectedly
laborious and disappointing. The reasons for this are simple: in the past few years, GMP
requirements regarding documentation have increased noticeably. There has been an
ongoing improvement in the quality of records (batch reports, records, etc.) as a result.
Looking at older documents today, one often realizes that the records logged are unusable
for an interpretation, as they are incomplete or not homogeneous and consistent
traceability is not guaranteed.
However, to be able to use historical data in terms of a retrospective validation, the
conditions listed in figure 7.C-3 must be given:
Figure 7.C-3 Requirements for a retrospective validation
Requirements for a retrospective validation

Compilation of a validation protocol with risk analysis, definition of critical

parameters, establishing of acceptance criteria
The facilities and equipment used must be qualified and the measuring points
calibrated
Traceability of sampling (intervals, sample sizes, etc.) for IPC and quality control
Homogeneity of historical records (i.e. all batches considered are manufactured
and tested in accordance with the same authorized manufacturing and test
procedure). In case changes have been made to product composition, instructions
or equipment, the exact timing must be traceable.
Analysis of at least 10 consecutive batches - from the statistical point of view and
from the point of view of some FDA inspectors, at least 20 batches are even
acceptable. FDA would generally be very reluctant to accept a retrospective
validation today. To do so, justification would have to be very convincing as to
why a prospective validation was not performed.
Figure 7.C-4 Documents required for retrospective validation
Documents required for retrospective validation

Batch production records with the results of the in-process control

Authorized master production record
Certificates of analysis and test protocols
Reports on rejected batches, exceptional approvals, releases with restrictions
Authorized testing procedure
Stability data

Log books for the facilities, machines and utilities

Results of the environmental monitoring
Results of trend analyses (if available)

For a retrospective validation, as for a prospective validation, a validation protocol must

first be compiled, in which critical processing steps are defined and acceptance criteria
are established. When doing this, one should not be guided by which parameters were
recorded in the past and are now available as collections of data. It was not always
"critical parameters" that were measured, but often those which could be measured easily.
Critical parameters are those which, if changed slightly, can have a significant effect on
the quality of the product, causing it to fail to meet its established acceptance criteria and
specifications. If a parameter can be graded as non-critical - due to many years of
experience, approval and stability data - it does not require validation. However, it should
be mentioned and justified in the validation protocol that this parameter is non-critical this avoids queries at a later date, e.g. from contractors or during inspections.
In most cases, it will be realized during a retrospective validation that either some of the
critical parameters cannot be justified using the available historical data, or the records
are not homogeneous. In these cases, the data that is missing in retrospect must
subsequently be collected with the help of so-called prospective cycles. This means that concomitant to three consecutive ongoing production batches - the missing process
parameters defined in the validation protocol are validated.
This same applies for qualification: old facilities are often not qualified or inadequately
qualified. Qualification of these facilities must be carried out retroactively during
retrospective validation at the latest (see chapter 6 Qualification). This also includes
reviewing the available equipment documentation, operating instructions, maintenance
procedures, etc. for completeness and checking that they are up to date.
Of course, these facilities can only be qualified in their current state. However, if old log
books, calibration reports or similar records are available, it may be possible to draw
conclusions from them that the apparatus/facilities were also formerly in a controlled
state, so historical process data may be used for a retrospective validation.
In contrast, it is very risky to trust the historical batch records, if there are no historical
documents available which show that and how for example measuring equipment was
calibrated, or when changes to facilities were carried out: in this case it is not evident for
example, whether different drying temperatures that have been documented are due to
different air supply temperatures or are quite simply due to the fact that the thermometer
was not calibrated?
In the event that there are insufficient number of batches to be drawn on for retrospective
interpretation, the missing data must be ascertained within a concurrent validation.

As done for a prospective validation, retrospective validation is concluded with a

validation report that must be approved by the responsible person designated in the VMP,
e.g. the head of production or the Qualified Person, or for the USA, the appropriate
organizational unit and the review and approval of the Quality unit.

7.C.3 Concurrent validation

Under certain conditions it is possible to perform a concurrent validation if the validation
program cannot be concluded before the start of routine production.
The Inspection of qualification and validation in pharmaceutical manufacture and quality
control aide mmoire points out that concurrent validation should only be used in
exceptional cases that must be justified. The same requirements as for prospective
validation apply for carrying out and documenting concurrent validation. Here too, a
minimum of 3 validation batches must be evaluated.
Concurrent validation sets particular requirements for validation planning and
coordination between routine production and validation activities, since the batch release
to the market is often time-critical and must not be delayed by validation activities carried
out in parallel. At the same time, conducting additional sampling and analysis for the
purposes of validation requires longer busy times than are normally scheduled in the
production planning for the respective product.

Figure 7.C-5 Examples for application of the "concurrent validation" approach

Examples for application of the "concurrent validation" approach
Transfer of a validated process to another manufacturing site, e.g. to a contract
manufacturer
Supplementation of missing data within a retrospective validation
Long time interval between the manufacture of consecutive batches
Periodic revalidation
Validation of small changes to already validated processes that are well
controlled (e.g. new dosage or different tablet shape)
Validation of variations in batch sizes (scaling up or down sizing)
Figure 7.C-6 Requirements for concurrent validation
Requirements for concurrent validation
Qualified facilities and equipment
Compilation and authorization of a validation protocol with risk analysis (as for a
prospective validation)
Compilation, verification and approval of the validation report for each individual
batch before the batch is released to the market or for clinical studies.

In the USA, concurrent validation is acceptable under certain specific conditions, which
are described in some detail in ICH Q7A, which is the Guideline for Active
Pharmaceutical Ingredient GMP. Prospective validation, while the norm, is not always
possible to allow health critical products to be distributed.
For this important reason, concurrent validations could be accepted under such
conditions. However, it is highly recommended that such an approach should always be
discussed with FDA.
Summary
Prospective validation is the method of choice for all new manufacturing procedures or
larger process changes. It is affected with at least 3 consecutive, successful validation
batches on the production scale.
For concurrent validation, the validation batches are released for sale when the
specifications are complied with. To apply a concurrent validation, special constraints
must be fulfilled and more comprehensive monitoring may be necessary.
For retrospective validation, the evaluation of production data from at least 10 batches is
expected. Missing data must be retrospectively collected in so-called "prospective
cycles".
Notice

Copyright:
Maas & Peither AG
GMP Publishing
Himmelreichstrasse 5
D-79650 Schopfheim (near Basel)
Tel +49 (0)7622 666 86-70
Fax +49 (0)7622 666 86-77
eMail [email protected]
info http://www.gmp-publishing.com

7.D Revalidation
Here you will find answers to the following questions:

What does revalidation mean?

At what intervals should periodic revalidation be carried out?
What kind of changes makes revalidation necessary?

A validation status once reached is not static, but is subject to everyday dynamics: all
companies develop, undergo restructuring and change their targets. The staff changes,
responsibilities change, SOPs are updated, buildings and equipment are adapted and
maintenance work is carried out, etc. Even if the influence of each individual measure on
the validation status is reviewed as part of a systematic change control program (see
chapter 19.C Change control), a conjunction of various events can nonetheless cause
processes to gradually become "devalidated". Other factors like compliance erosion in
staff, inadequate maintenance work, calibration intervals that are too long due to pressure
for time and economy measures, can also mean that the preconditions for the validity of a
process are no longer met. To prevent this from endangering the product quality, critical
process steps must be revalidated at regular intervals. This means that a completed
validation must not be viewed as a one time exercise, but rather the validation status
should be periodically reviewed according to an established review cycle.
Regardless of the periodic revalidation of critical processes, validations (or parts thereof)
must always be repeated if changes are made to buildings, facilities, equipment,
processes, techniques or at the manufacturing site.
Figure 7.D-1 Definition of revalidation
Definition of revalidation
Revalidation means the repetition (of parts) of the validation

after changes that were found to require validation in accordance with the
decision during the change control,
for critical processes (e.g. sterile or aseptic), at established intervals
as described in a USA quality system document which addresses the subject of
revalidation

7.D.1 Time intervals for periodic revalidations

The legal drug product provisions allow the user a certain amount of leeway for carrying
out revalidation. Chapter 5, paragraph 5.24 of the EU GMP Guideline says the following
on the subject:

"Processes and procedures should undergo periodic critical re-evaluation to ensure that
they remain capable of achieving the intended results." The exact definition of "periodic"
is left to the manufacturer.
The validation master plan is the appropriate document to establish a company's concept
for revalidation. When fixing the revalidation intervals, the following must be taken into
consideration:

the individual process risk and product risk

the number of batches manufactured per year
any other control measures used, e.g. SPC (statistical process control)

Depending on the product, the process and the manufacturing frequency, intervals of
between two and five years may be advisable. If a process is continuously monitored with
other methods, e.g. using statistical process control, then longer intervals may also be
justifiable. If no critical change is made to a process during a period under review, an
interpretation and evaluation of the process and product data for this period can be
accepted as revalidation of the process. The USA FDA would expect the concept of
revalidation to be documented in a written Quality System that provides sufficient details
to define when and how a revalidation should be performed (see chapter D.2 Guideline
on General Principles of Process Validation).

7.D.2 Incidences requiring revalidation

7.D.2.1 Changes to the manufacturing instructions
Process validation is carried out on the basis of approved manufacturing instructions. If at
a later stage these manufacturing instructions are intended to be changed, it is necessary
to check, document and possibly show through revalidation, that this change has no effect
on the product quality (see chapter 19.C Change control). Examples of changes to the
manufacturing instructions are:
Figure 7.D-2 Incidences requiring revalidation
Incidences requiring revalidation

planned changes to the manufacturing instructions

o changes in product composition
o changes in production process or the sequence of operations
o changes in primary packaging material
o changes in batch size by more than a factor of 10
o extension of the ranges of critical process parameters
planned changes of raw material (e.g. drug substance) suppliers
changes in manufacturing sites
significant changes to process equipment
extensive maintenance measures on manufacturing machines
trends observed in IPC or quality control

occurrence of quality problems (e.g. OOS) during manufacturing or quality

control

Changes to the product composition

It can have serious impacts on the reproducibility of the manufacturing process, if

ingredients, like APIs or critical excipients are changed, or even if only their percentage
of quantity is changed: the original validation result is therefore no longer relevant.
Critical excipients are to be understood as those, which are either present in the
formulation in very large proportions, or whose properties (e.g. particle size, density,
moisture) significantly influence the physicochemical behavior of the batch. This
includes excipients that do not have any (or only slight) inherent pharmacological
efficacy, but which have a desired effect in the final product (preservative, anti-oxidants,
complex formers, polymers with retarding effects on the API).
Before such changes are made, it is necessary to carry out prospective validation studies
based on three new batches with the changed product composition. It is important to
know that, even if the validation result is favorable, some of these changes must be
presented to the regulatory authorities before the changes are implemented in routine
production (chapter 19.C.1 Principles of change control).
Changes in production process or the sequence of operation

Just like the formulation for a validated process, the exact sequence of operation for all
subsequent production batches is binding. It must be taken into account in the validation
protocol, if it is already planned from the outset to allow different process or sequence
variants.
In practice and for operational reasons, there may be a subsequent wish for process
changes: for example, it may be suggested, that a drying step is performed in a shelf or
tray dryer, since the required fluid bed dryer is constantly in use. Switching between
different blending methods is a frequent but very delicate problem as well. In any case,
such process changes must be revalidated in the context of a prospective validation.
Apparently harmless variations to be made in the sequence of operation must be
highlighted as equally critical: for example, which phase is placed in the vessel and
which is mixed in afterwards can be crucial for the quality of a cream.
Changing the chronological order of two processing steps is also a change in the
sequence of operation which requires validation (e.g.: first heat then evacuate, or first
evacuate then heat? Is it permissible to mix in a flow regulation medium before interim
storage of the tablet mass or only immediately before producing tablets?).
Likewise, it must first be proven through validation that the quality of a product is not
affected if, for example, a manufacturing step is carried out in three sub-batches on

equipment with smaller dimensions, for capacity reasons, and these three sub-batches are
then combined after successful IPC.
In practice, there are often prolonged holding times for intermediate stages or in-process
material because processing has been delayed for planning reasons. These holding times,
above all the appropriate packaging, storage, and possibly analysis before further
processing, can be critical for sensitive products and therefore require validation.
Changes in primary packaging material

The primary packaging material for which sufficient long term stability data is already
available, is defined in the approved and validated manufacturing instructions. In
practice, it is also usual (but not compulsory) to store long term stability samples from the
three validation batches, in order to support or supplement the available data.
On the one hand, a change in the primary packaging material may influence the
validation status of the packaging process, as the changed packaging material may
require different machine settings and can have different process ability properties (e.g.
changing the film thickness of a blister film or of a sachet bag, changing the dimensions
of ampoules, vials, stoppers, changing the material of films, stoppers, closures, etc.). On
the other hand, the influence on the stability of the product must also be reviewed.
Before such a change is introduced, extensive clarifications are first required which
extend far beyond the scope of revalidation. Ultimately, changes to the primary
packaging materials must be indicated to the regulatory authorities in advance.
Planned changes of raw material suppliers

The quality of the raw materials determines not only the stability of a product, but also
the technological behavior during processing. Unfortunately, it is not yet possible to
exhaustively describe raw materials in the specifications in terms of their quality
attributes and requirements, meaning that there may be some surprises during processing
if the supplier is changed, despite the raw material being in line with the specifications
(see chapter 17.A Contract manufacture).
Qualified raw material suppliers must be defined at the time of validation of an approved
formulation. Since the validation is to be carried out using conditions as close to reality as
possible, it is advisable to use the different suppliers' raw materials in the validation
batches.
If another supplier is to be approved at a later date, he must first be qualified (see chapter
17.A.3.1 Selection of one or more contract acceptors), and the production process
concerned (or sub-step) must be revalidated.
For contract manufacturers, it is also important to obtain the approval of the customer
before the change is implemented.

7.D.2.2 Extension of the ranges of critical process parameters

During a validation study, the operating ranges for critical process parameters within
which the process is valid, are verified. If it is planned to extend these ranges at a later
time, it must be proven that the process still reproducibly leads to a product with the
desired quality. However, justifying the planned extension of the limits soon leads to a
crisis in the line of argumentation - initially the processing step in question was originally
designated as "critical", i.e. a slight change would have a big influence on the product
quality. Now and before extending any ranges, it must be proven and documented that the
processing step is not so critical after all.
As the extension of the acceptance limits for critical processing steps can have a farreaching influence on all subsequent steps, it is generally not sufficient to validate only
the processing step in question - rather, all subsequent processing steps must also be
validated either prospectively or concurrently.
7.D.2.3 Changes in manufacturing site
Revalidation is required if the manufacturing site is changed to a different, possibly
newly constructed manufacturing unit of the same company, for example, or to a
subsidiary or contract manufacturer, as the results of the original validation cannot be
compared with manufacturing conditions in a changed environment. The same facilities
or equipment is not generally available at the new manufacturing site (at best they are
constructed in the same way). In the case of relocation to a new manufacturing hall, the
original equipment will have been disassembled in the meantime, and must be qualified
again and started up at the new site. Not only that, but usually the manufacturing,
sampling and IPC tasks at the new manufacturing site will be carried out by different
staff and possibly different raw materials suppliers will also be permitted.
All these aspects show why a process must be revalidated when the manufacturing site is
changed (prospectively or concurrently if allowable under applicable laws or
regulations).
However, before validation studies are performed, the following basic requirements must
be fulfilled at the new manufacturing site:

Qualification of the facilities and equipment

Calibration and maintenance performed according to standard operating
procedures
GMP training of all staff involved
Environmental monitoring
Effective change control system implemented

7.D.2.4 Serious quality problems

If out of specification results (OOS results) occur during the quality control, the
underlying error must be searched for based on a written, OOS-SOP (see chapter 14.H
Out-of-specification results). If it comes to light that the error occurred during the
manufacturing process, then measures must be taken to prevent the error from occurring
again. In particular, the corresponding manufacturing step can no longer be considered to
be validated, if the same error occurs repeatedly. Corrective measures must therefore be
taken (e.g. changing the manufacturing instructions, adding additional control steps, staff
training, adjusting the frequency of calibrations or maintenance). Validation should then
show that these measures have been successful - namely, that the manufacturing process
is again running in a controlled manner.
The same applies if repeated problems or quality deviations have already been observed
during routine manufacturing, e.g. during IPC. The causes of trends, which are observed
during a retrospective batch assessment (e.g. during the Annual Product Review (see
chapter 15.F Annual product review/ Product quality review)), must also be investigated
critically, even if they have not yet lead to OOS situations. Both point to the fact that
changes in the manufacturing process have occurred, which is why it must be revalidated.
Summary
A completed validation study must not be viewed as a one time exercise, as changes can
occur constantly in everyday manufacturing. Such changes may be planned, in which
case their influence on the validation status must be assessed in the context of a change
control program. Other changes are unintended (e.g. through a conjunction of changes
which are considered to be uncritical), and only come to light through trends or even
deviations from the specifications. In this case, measures must be taken to bring the
process under control again. The effectiveness of these measures must be proven through
revalidation.
Critical manufacturing processes must also be reviewed periodically according to an
internally established cycle.
Notice

7.E Planning of process validation

Here you will find answers to the following questions:

Who is responsible for the process validation? Which are typical tasks of a
validation manager?
Who is responsible for validations that are assigned to third parties?
Who should be member of a validation team?
Which prerequisites must be met before a validation project can be started?
Which aspects must be taken into account during development/scale-up?
What kind of action can be taken if not all prerequisites for carrying out a
validation have been met?
Is it necessary to manufacture a development or pilot batch before a validation
study is carried out?
What arrangements must be made with respect to validation during a product
transfer?
Which is the appropriate point in time to perform a process validation study?
How are those process parameters dealt with, which can not be influenced?
What parameters need to be varied during the validation?
Does the manufacturing process has to be challenged during validation studies?

projects
7.E.1 Responsibilities and task assignment
From a legal point of view, performance of process validation lies within the
responsibility of the "Qualified Person" for EU countries (for other countries, please refer
to the respective local regulatory guidelines). In any case, the responsible person for
process validation must be specified in the individual validation master plan (VMP) of a
company (see chapter 7.F Validation master plan). In practice however, this person will
rarely be able to carry out the complex planning, implementation and documentation
tasks himself. These tasks may for example, be handed over to a validation manager, who
coordinates the overall validation project and maintains an overview of the many subtasks. The validation manager may appoint a validation team made up of representatives
from the specialized departments, who are entrusted with the practical work, e.g.
production, engineering, technical, process engineering, documentation and quality
control units. The GMP approach to this form of delegation always assumes that the
responsible person delegates the task to competent staff and also subsequently ensures
that the task assigned is progressing. Tasks and responsibilities delegated must be
documented in writing, e.g. in the validation master plan or validation protocol,
validation policy or relevant SOPs. The tasks typically performed by the validation
manager are listed in figure 7.E-1.

Figure 7.E-1 Typical tasks of a validation manager

Typical tasks of a validation manager

Management of the validation project

Team leader of the validation team
Performance of a risk analysis (with the validation team).
Definition of critical parameters (with the validation team)
Creation of the validation protocol
Coordination of validation activities
Coordination with external contractors (if relevant)
Recording, evaluation and documentation of changes to the validation protocol
during the validation study
Creation of the validation report
Determining the results of the validation (with the validation team)
Proposals for follow-up activities, if relevant (with the validation team)

It is not difficult to imagine that in the case of large validation projects, e.g. starting up
new manufacturing sites, these tasks are too wide-ranging to be dealt with on top of dayto-day business tasks. The creation of full-time positions for persons responsible for
validation has therefore proven to be an effective approach. Smaller recurring validation
projects (e.g. revalidation) often tend to run more smoothly as well when dealt with
routinely by validation managers rather than if they were added to existing high
management workloads.
All recent rules and regulations for qualification and validation emphasize the importance
of careful, documented planning of validation activities. However, the subject of the
validation dictates how the planning and implementation of the validation is organized.
Does the case in hand concern the handover of a validated procedure with a low level of
technical know-how required and a "low-risk" product (see chapter 7.G Risk analysis) to
another production site, or is it the validation of a new operation that deals with
innovative, technologically highly-complex dosage forms? The organization of the
specific pharmaceutical company must also be taken into account. Ultimately, the
additional structures required to carry out the validation should support normal business
activities and interfere with these as little as possible as otherwise quality would be
affected.
Figure 7.E-2 Arrangements governing the assignment of validation to a third party
Arrangements that must be made when assigning validation activities
to a third party

What terminology is to be used?

Who is to carry out the risk analysis?
Who will be specifying the quality of the raw materials? Who defines and
qualifies suppliers?
Who is responsible for the master production record that is provided or created

from scratch?
Do validated test procedures exist? How will the transfer of methods be
organized?
Who creates the validation protocols? Who defines the acceptance criteria?
Who approves the validation protocols?
Who carries out each validation task? Who is to carry out the analysis?
Who records changes to the validation protocol and who assesses and approves
these?
Who creates the validation report?
Who archives raw data?
Who approves the validation report?
What are the arrangements regarding the flow of information for:
o Communication of the result
o OOS
o Changes (change control procedure)

This is also the reason why no recommendable one-fits-all "standard validation

protocols" exist: each company is organized differently and each validation project is
different to the next. If the manufacturing procedures for two or more products of one
manufacturer are in fact very similar, a joint validation may be undertaken according to a
"matrix concept" (see chapter 7.F Validation master plan). In all other cases a universally
applicable "standard validation concept" - frequently requested by persons not so
experienced in process validation - would carry a high risk: for many products, to work
through a standard plan would result in unnecessary costs and workload without adding
any benefit to the quality of the final product.
Unlike for other products, sticking to the same standard plan might be insufficient - e.g.
for highly-innovative products with complex manufacturing procedures possibly
containing active pharmaceutical ingredients with a narrow therapeutic range. Legal
responsibility for the extent of validation activities is therefore placed firmly in the hands
of pharmaceutical companies - they should know their manufacturing processes and be
able to demonstrate through documentation that they are well controlled.
It is particularly important to clearly define the areas of responsibility if validation tasks
are outsourced (partially or fully) to contract acceptors (see chapter 17.A Contract
manufacture).
In this case, a number of different scenarios are possible:

A pharmaceutical manufacturer that has its own manufacturing authorization

outsources the validation of a manufacturing process (or parts thereof) to an
external company, e.g. a consultant. In this case, the contract giver remains
responsible for the validation.
A pharmaceutical manufacturer that has its own manufacturing authorization
hands a manufacturing process and its validation over to a contract manufacturer.

In this case, a contractual agreement defines whether the contract giver or the
contract manufacturer is responsible for the validation.
A pharmaceutical company (holder of marketing authorization) without its own
manufacturing authorization outsources the validation of a manufacturing process
to a contract manufacturer. The responsibility for this validation lies with the
contract manufacturer.

Where validation tasks are assigned to third parties, the validation manager must rise to
the additional challenge of ensuring effective moderation, clear agreements and a fast
flow of information between the contract giver and the contract acceptor (see figure 7.E2). More often than not, the information and experience at the disposal of both parties is
different and their philosophy and terminology does not correspond. It is therefore
important that both contractual partners have defined their respective intentions (in the
validation master plan) and also agree contractually about what they expect from one
another. To do this, a detailed agreement must be drawn up in writing that defines the
scope of the service to be provided and the general conditions (e.g. GMP, DIN/ISO
9000ff, see chapter 1 Quality Management) the contract acceptor must fulfil.

7.E.2 Validation team

Validation projects are usually planned and executed by a validation team led by a
validation manager (see figure 7.E-3).
Figure 7.E-3 Example of functions involved in a validation project
Structure of the validation team (example):

Technical department, engineering, EDP department

Documentation department, regulatory affairs department
Development department, process engineering
Head of manufacturing/production
Production planning
Head of Quality Control
Control laboratory
Microbiology
Quality assurance

The team can also be assisted by an external consultant if necessary. However, decisions
must ultimately be made by the team or by representatives of the departments involved.
The following departments/functions should be represented on this validation team to
make the aforementioned contributions: (This should be regarded as an example, as the
responsibilities in the departments vary greatly depending on the size of the company and
the manner in which it is organized):

Technical department, engineering, EDP department

Maintenance status of facilities and machines
Status of qualifications
Technical documentation
Computer validation status
Documentation department, regulatory affairs department
Current master production record (conforming with application file for marketing
authorization)
Current test procedure
Current validation master plan
Special regulatory and (if relevant) country-specific requirements
Development department, process technology
Planning of development and pilot batches (if relevant)
Results of development and pilot batches
Head of manufacturing/production
Responsible for implementation of validation
Provision of resources
Approval of validation protocol and validation report
Approval of master production record for routine manufacturing
Manufacturing of validation batches, additional sampling according to sampling
plan
Production planning
Planning in of sufficiently large time windows for use of facilities and machines
Head of Quality Control
Validation status of analytical methods
Approval of analytical methods
Capacity planning for analytical tests
Control laboratory
Implementation of analytical work
Microbiology
Status of environmental monitoring
Assessment of microbial reduction during cleaning validation
Microbiological assessment of holding times
Quality assurance
Approval of validation protocol and validation report
Approval of product specifications
Approval of validation batches for clinical studies, for commercial use or as
registration/application samples (if relevant)
Control of compliance with internal and regulatory guidelines, e.g. through
internal audit (control of equipment documentation, logs, SOPs, sanitizing,
compliance with gowning procedures, ...)
Approval of master production record for routine manufacturing
Change control

7.E.3 Timing of validation

In general, only pharmaceutical products manufactured according to validated

manufacturing processes may be distributed. This means that by the time the product is
launched, the process validation must be complete. The time between the submission of
the file for marketing authorization and the issue of approval is very frequently used for
process validation activities. The EMEA Note for Guidance on Process Validation
provides more detailed information on the validation data for specific products that must
be included in the application file at this stage:
For specific medicinal products manufactured according to standard procedures, it is
sufficient if data from a pilot scale validation and the schedule for the commercial scale
validation are available at the time of submission.
On the other hand, for "non-standard products", such as medicines with modified release,
specific lyophilisates, micro capsules or aseptically manufactured products, it cannot
necessarily be assumed, that processes are easily transferable from pilot scale to
production conditions. It is therefore expected that at least 1 or 2 batches will have been
subjected to a production-scale validation before the files for marketing authorization are
submitted. This data must also be supported by pilot batches and a range of products that
have been consistently manufactured under similar process conditions. For non-standard
sterilization methods and aseptic manufacturing methods, the data from three consecutive
production-scale batches must be submitted as a prerequisite for approval (EMEA Note
for Guidance on Process Validation, paragraph 4.4).
While prospective validation is normally expected to be completed for USA distribution
of commercial products, under specific, but rare circumstances, use of concurrent or even
retrospective validation may be allowed. To determine if such a deviation can be
exercised, discussions should be initiated with FDA headquarters personnel early in the
planning stages for product launch.

7.E.4 Prerequisites for carrying out a validation project

The process validation is not an isolated action in an otherwise unaffected environment.
Instead it has far-reaching consequences that have already been explained in more detail
in "Revalidation" (see chapter 7.D Revalidation). Therefore several important
prerequisites must be met in order to ensure proper implementation of the process
validation concept.
Figure 7.E-4 Prerequisites for carrying out a process validation
Prerequisites for carrying out a process validation

Approved validation master plan which clearly defines the key elements of the
validation program, responsibilities and resources
Developed product and developed, optimized process (production scale)
Documentation based on development in which critical processing steps are
defined
Process data obtained during development from which the range of production

process parameters can be derived

Approved master production record
Approved validation protocol with sampling plan, schedule and assignment of
tasks to responsible departments
Qualified facilities and machines
Validated EDP programs
Maintenance of facilities and machines and calibration of measuring equipment
according to SOPs
Approved and validated test methods
Validated cleaning procedures
GMP-compliant environment (rooms, media, environmental monitoring, access
control, sanitizing)
Trained personnel
Good communication between the departments involved and (if relevant) also
between the contract giver and contract acceptor

This includes:

An approved validation master plan (see chapter 7.F Validation master plan)
A fully developed product and developed, optimized process: In this context,
the pressure to achieve shorter development times due to international
competition unfortunately may have fatal consequences: shortcuts taken in the
early development stages that (apparently) save time mean that badly developed
processes are carried through to the production handover stage. Attempts are
subsequently made during the validation phase to make improvements that should
definitely have been carried out at an earlier stage: in addition to process
optimization, the tasks of specification of critical process parameters,
specification of ranges, determination of margins of error and "challenging" are
tried to be carried out simultaneously. The problems that emerge have a
considerable impact on material and time costs. In addition, these kinds of "last
minute experiments" tend not to instill confidence in the authorities that the
process is well understood and adequately controlled. Finally, it must be
remembered that these kinds of "validation batches" cannot simply be made to
"disappear" if they do not comply with the specifications. These activities and last
minute "experiments" involve a large expenditure of time and money for finding,
eliminating, and documenting errors that must be documented as OOS batches in
the manufacturing history. The three final validation batches must demonstrate
unequivocally that the manufacturing procedure is reproducible.
Likewise the latest recommendations on qualification and validation (EMEA Note
for Guidance on Process Validation, paragraph 3 and ZLG Aide Mmoire entitled
Inspection of qualification and validation in pharmaceutical manufacturing and
quality control, paragraphs 6.1 and 6.3) point out that critical steps and critical
process parameters, challenge tests, proof of suitability (feasibility) and
robustness of the process must be established at the development stage. They are
in fact prerequisites for (and not part and parcel of) the process validation.

Sufficient information from development stage to clearly define critical

process parameters and normal operating ranges: The validation should verify
the normal operating parameters (cf. EMEA Note for Guidance: "within their
specified design parameters") under realistic conditions but should not test the
process to its limits ("challenge"). If "challenge tests are planned within the scope
of the validation, these should not test the process, to its limits. Instead,
effectiveness of control measures, performed in order to detect, eliminate and/or
prevent product failures is to be shown (cf. ZLG Aide Mmoire entitled
"Inspection of qualification and validation in pharmaceutical manufacturing and
quality control", paragraph 6.3.1). Relevant examples are function tests for
detection systems such as automatic cameras used to control level and presence,
or similar systems. Strictly speaking, the purpose of these "challenge tests" - or
function tests - is to qualify operating equipment rather than validate processes.
By the same token, the term worst case is used in conjunction with process
validation. The worst case is defined as "a condition or a set of conditions
encompassing upper and lower processing limits and circumstances, within
standard operating procedures, which pose the greatest chance of product or
process failure when compared to ideal conditions. Such conditions do not
necessarily induce product or process failure" (see PIC/S PI006). In other words:
process validation is expected to cover normal variability under real life
conditions, but it is not necessary to build in "artificial events" or extra risks in
validation runs. Or in the words of the ZLG Aide Mmoire Inspection of
....quality control: validation is to be carried out under conditions "close to
reality". For example, raw materials from the various suppliers (approved for the
specific product) should be used in the three validation batches, which should be
produced and/or packaged by different personnel (e.g. different shifts). The
purpose of this approach is to prevent everything running "perfectly" during the
three validation cycles, where everything is planned with the utmost care in
advance, the most experienced people on hand, no holding times (as the job needs
to be finished quickly), but disregarding production-related variations which will
occur later in "real life".
The operating parameters as well as the PAR (Proven Acceptable Range - range
in which the process parameters may demonstrably fluctuate without affecting the
quality of the final product) must have been established during the course of
development. In practice however, the situation with respect to equipment during
development is sometimes so different from the reality of production that
development data is not directly transferable. In these cases, the data required
must be obtained before the validation is carried out from pilot batches
(production equipment, but with smaller batches).
Figure 7.E-5 Validation of the operating ranges

to enlarge, click here!

In figure 7.E-5, a graphic representation of the correlation between the normal

operating range and the PAR range is shown. The "normal operating range" is the
range that must be validated according to law. This range is also stated in the
application file. For day-to-day operations however, additional stricter "internal
operating ranges" and/or "internal specifications" are often used. This is to ensure
that in case of a deviation from the "operating range", this is still not outside the
validated = approved range (i.e. the product can still be put on the market).
Qualification of facilities and machines used as well as calibration of the
measuring equipment (see chapter 6 Qualification): If facilities and equipment are
not qualified and measuring equipment is not regularly calibrated, the assessment
of machine settings is not reliable at all. If, at a later date, it becomes apparent that
the values read out from the displays do not in fact correspond with the actual
values, this would render the results of the validation invalid and require
revalidation.
The significance of the qualification as a prerequisite for the process validation is
made clear in more recent guidelines on the subject (Appendix 15 to EU GMP
Guideline entitled Qualification and validation, EMEA Note for Guidance on
Process Validation and ZLG Aide Mmoire entitled Inspection of qualification
and validation in pharmaceutical manufacturing and quality control).
A minimum requirement before the process validation can start is successful
completion of the OQ. The PQ data (long-term system-related performance test)
are frequently obtained in tandem with the process validation during the first few
months of routine production.
As nowadays all relevant process data is processed by computer, it is essential to
demonstrate that these files can also be reliably "retrieved", i.e. in a form that can
be read by human beings (see chapter 15 Documentation). Where no parallel
recordings (paper printouts) of data acquired, transmitted and stored electronically
have been made, the accuracy and integrity of the data cannot be subsequently
checked. It is therefore necessary to perform computer validation for all
manufacturing equipment using measuring and control technology or electronic
data processing. Special aspects to consider are in this context access rights,
software updates, incorrect input, influence of physical stresses (vibrations, heat,
solvent vapors, dust, magnetic fields, etc.), archiving, speed of access to data etc.
(See chapter 9 Computer Validation.)

Approved test procedure and validated analytical methods: In order to assess

correctly the test samples collected during the validation runs, the analytical
methods used must be validated. If not, there is a risk, that a variability possibly
observed during process validation runs cannot be traced back unambiguously - it
might be caused by either the process or by variations in the analytics.
The test procedure must be approved by the designated responsible person if the
validation batches are used as clinical trial samples, are stored for long-term
stability studies, or - as is the case with concurrent validations - if they are to be
used as commercial products.
Validated cleaning procedures: If the validation batches are to be used as
clinical trial samples or commercial products (concurrent validation), it must be
ensured that patients are not endangered by contamination, i.e. from residual
semi-finished products or cleaning agents or decomposition products. In this case,
a validated cleaning procedure must exist at the time the process validation is
carried out. If the validation batches are to be stored for long-term stability
studies, a suitable cleaning process must exist as a minimum requirement to
prevent the results being falsified due to contamination and subsequently being
called into question.
GMP compliant general conditions: To carry out a process validation as an
isolated measure would be pointless without qualified rooms, environmental
monitoring, access control, sanitizing, maintenance schedules or a functional
documentation system. The training of all staff - not just the staff that carries out
the validation - as well as functioning change control, documentation, calibration
and maintenance systems is an important prerequisite for the process validation.
Information flow: Good communication between the departments involved, and
also (if relevant) between contract giver and contract acceptor, is indispensable
for the smooth running of validation projects. Generally, the validation
experiences of the participants are very different - this applies particularly for
(new) contractual partners. It is therefore necessary to agree on the terminology at
an early stage and explain the basic procedure to all participants using the
validation master plan. When carrying out the individual validation tasks, a good
flow of information between the various interfaces will assist the timely
achievement of objectives. .
Figure 7.E-6 Validation tasks at the individual development stages

to enlarge, click here!

It will obviously not be possible to lay the foundations listed above shortly before
the process validation is due to begin. Instead the various prerequisites for the
validation must be fulfilled stepwise in tandem with the product development (see
chapter 16 Research and Development). Figure 7.E-6 illustrates schematically the
validation tasks that can be carried out at the individual development stages
7.E.4.1 What action should be taken if not all prerequisites have yet been fulfilled?
For complex validation projects where (for example) a large number of tried-and-tested
but very different preparations are manufactured using different facilities, bottlenecks
will be inevitable as not everything can be qualified and validated simultaneously. To tell
the truth, tasks such as qualification or cleaning validation, have not been finalized in
many companies.
In these cases, the validation master plan has an important role to play: The overall
validation requirements are or can be listed in a "validation matrix" (see chapter 7.F.1
Validation matrix) and priorities are assigned to the individual sub-projects (bracketing
may also be justified). In this case, an underlying rationale with respect to the assignment
of priorities - such as product or process risk, production frequency, capacity of
machines, experience with machines/facilities or error frequency (for example) - must be
evident. This list of priorities must then be linked to a realistic schedule.
For the validation of a specific drug product, the status of the qualifications and cleaning
validations must then be assessed and documented in the validation protocol as part of the
risk analysis.
7.E.4.2 Manufacture of a development or pilot batch in the run-up to a validation
If no data on process parameters acquired during development is available in case the
process was transferred to a contract manufacturer, for example - one or several
development batches (batch size approx. 3-10 kg, depending on dosage form and

equipment) should be manufactured to obtain the missing data. In order to be able to

estimate the transferability of the setting parameters to production equipment and future
batch sizes, at least one pilot batch must then be manufactured (at least 1/10 of
production batch size; pilot batches for veterinary drug products may be smaller if
justifiable in accordance with EMEA Note for Guidance on Process Validation). If the
process has not yet been optimized, one pilot batch is insufficient as the risks associated
with the intended validation of a non-optimized process are extremely high. Ultimately,
the following applies:
All processing steps must be controlled and critical processing steps must be validated.
Summary
In order to be able to satisfactorily master a validation project in a timely and
professional manner, sufficient resources should be made available. The management is
fully responsible for ensuring that the validation is carried out properly - irrespective of
whether this is delegated within a company or outsourced. The distribution of tasks and
the responsibilities must be laid down in writing. The planning and practical
implementation of validation projects is usually carried out by a team led by a validation
manager. Care should be taken when assembling the validation team to ensure that all
departments involved are represented.
A process validation can only be successfully carried out if the necessary general
framework is in place - for example: qualification, calibration and maintenance of
equipment and facilities, cleaning validation, environmental monitoring, change control
and training of staff.
Notice

Copyright:
Maas & Peither AG
GMP Publishing
Himmelreichstrasse 5

7.F Validation master plan

Here you will find answers to the following questions:

What is understood by the term validation master plan'

What different types of validation master plans may be compiled?
What is the benefit of the validation master plan for the management, for the
validation manager/validation team or for externals (contractual partners,
authorities)?
What are the essential elements of a validation master plan?
What does a validation matrix contain?
What is "bracketing"?
What is "matrixing"?
Which reasons may justify process validation of product families (product
groups)?

The validation of processes and the qualification of buildings and apparatus as a

prerequisite for the process validation requires a considerable investment in terms of
personnel, time and money. The tasks at issue should not be carried out as a side job and
require full support from the management board. It is therefore important to determine in
writing the general strategy and philosophy of a company on the topic of validation from
the point of view of the management board, e.g. in the form of a validation policy or
validation philosophy. This rather general declaration of intent demonstrates the general
attitude of a company regarding validation problems internally (management board, staff)
and externally (customers, authorities).
The validation policy can be an independent document, part of a quality assurance
manual or a validation master plan.
Beyond the general declaration of intent, the validation master plan documents the
structured approach of a company to validation projects (see chapter 7.F.2 Example of a
validation master plan). The official rules contain the definitions cited in figure 7.F-1.
Figure 7.F-1 Definition of a validation master plan
Definition of a validation master plan
In accordance with PIC/S PI 006 (4.3.1):
"A validation master plan is a document that summarizes the firms overall philosophy,
intentions and approach to be used for establishing performance adequacy."
In accordance with Annex 15, EU GMP Guideline (2):
"All validation activities should be planned. The key elements of a validation program
should be clearly defined and documented clearly in a validation master plan (VMP) or
equivalent documents.
Similar expectations exist in the USA although there are no specific US regulations

covering VMP. However, it is commonly requested during official inspections.

Figure 7.F-2 Function of the validation master plan
Function of the validation master plan

Obligation of the company's senior management to execute the validations

faultlessly and to provide the required resources (time, people and money)
Company specific definition of terms
Company specific implementation of legal requirements
Definition of a structured approach to qualification and validation projects, (key
elements of the qualification and validation program)
Information about the general organization of validation activities,
responsibilities, delegated tasks, interfaces, controlling bodies
Overview of the individual validation projects, including time and cost planning

Pharmaceutical companies tend to complain that there are no binding guidelines from the
legislator for the procedure of how and when validations are to be carried out, and even
terminology and contents vary. Quite the contrary, this should be considered as
invaluable scientific and corporate freedom. After all, the most varied solution
possibilities are conceivable - and each pharmaceutical company is permitted to define an
individual validation strategy optimized to its own organization and product range: the
validation master plan is the correct place for defining and justifying a company's
individual understanding of validation, as well as company-specific definitions and
contents.
A VMP should also point out that validation is not understood as an isolated task, but
rather as a continuous process, and should explain that (and how) the required GMPenvironment is provided ( e.g. maintenance,, documentation, training, change control).
The type and content of the validation master plan can vary greatly (see chapter 7.F.3
Example for a validation matrix). A validation master plan can for example, give a
general overview of the qualification and validation work for a manufacturing site
planned from scratch. In this case it is a useful planning tool for the project management,
and scope and contents will differ significantly from other VMPs, e.g. a validation
master plan for a manufacturing facility in old buildings, producing a great variety of
drug products already marketed for years, but which have never undergone a formally
documented validation process. This type of validation master plan is primarily used to
define rationales for bracketing, to set priorities and to evaluate the risk for products,
where validation has not yet been performed.
Figure 7.F-3 Various types of validation master plan
Various types of validation master plan (VMP)
VMP as a part of project
e.g. for the setting up and qualification of new
management
manufacturing sites
Cross-project VMP

e.g. for a manufacturing facility with old preparations:

for recording and grouping products

VMP as a global validation
concept of a global corporate
group

Determination of corporate strategies, terminology,

acceptance criteria; additional, local master plans may
be necessary

Product-related VMP

in case of extensive validation work for a product

If there is extensive validation work to be done for one product, it can be advantageous to
write an individual validation master plan for this product in order to "unburden" the
individual validation protocols.
Figure 7.F-4 Elements of the validation master plan
Elements of the validation master plan (in accordance with PIC/S PI 006)

Validation policy
Organization and responsibilities
Company specific definitions
Description of the validation project (manufacturing site, building, facility,
process, product)
List of the individual validation projects ("validation matrix"): building, facility,
control equipment to be qualified, products, processes, systems to be validated
Key acceptance criteria or procedure for determining acceptance criteria
Documentation formats for validation plans and reports
List of relevant SOPs
Schedule and cost estimate, estimate of staffing (including training needs) and
equipment
System for change control

In contrast, a validation master plan for a global corporate group has a completely
different focus: the concepts and strategies valid for all country representations should be
specified here - without being able to go into the local task assignments and
responsibilities in much detail.
Basic elements that each validation master plan should contain are specified in PIC/S PI
006 and appendix 15 to the EU GMP Guideline (chapter C.6.15 Annex 15 Final Version Qualification and validation, see also figure 7.F-4).
The validation master plan should be clear and concise and not repeat the contents of
other documents unnecessarily. Cross-references to existing documents are useful here
instead. A validation master plan should be confirmed and approved by the management.
The VMP as a summarizing document provides external parties (clients, customers or the
authorities) with the possibility of quickly gaining an overview of the validation
strategies of a company. This aspect is particularly interesting for contract manufacturers
because the validation often represents a part of the service provided. For the USA, a

validation plan or validation master plan should exist. If it doesn't exist, it may be
considered a sign that validation may be deficient at the firm (Guide to Inspections of
Validation Documentation 1995, US FDA).

7.F.1 Validation matrix

A validation matrix, as a component of the validation master plan, is a table which lists
all products, processes or systems that have to be qualified or validated and allocates the
required action to be taken:

Scale of the qualification (DQ, IQ, OQ, PQ)

Cleaning validation
Method of process validation (prospective, concurrent, retrospective)
Revalidation activities
Current status, future planning
Group/family formation; bracketing and matrixing

The individual activities in the matrix should be indicated with priorities and
responsibilities and enable an overview of complex validation projects (PIC/S PI 006).
Formation of product families or product groups; bracketing and matrixing

In particular, when a large number of drug products are to be validated, already marketed
for years, it is often necessary for reasons of time and cost to summarize the different
strengths of a product or similar products during the process validation, in order to reduce
the validation effort. In this case, there are various strategies:
Matrixing: By this approach, the manufacturing processes for various strengths of the
same drug product are validated together. The formulations and manufacturing processes
must be the same. If there are differences in the composition or manufacturing processes,
a risk analysis must be carried out to evaluate the effects that this could have on the
validation result. Fewer than three validation batches can be manufactured of each
strength if this is scientifically justified in the validation master plan or in the validation
protocol. It is not advisable, however, to produce no validation batches at all from
individual (e.g. the middle) dosages; because the FDA wants to see the validation of a no exact figures - "minimum number of production batches of each strength".
Family grouping: This concept is intended to create a combined validation protocol for
validating the procedure for different but related drug products.
In this case, it is of particular importance to thoroughly justify why the drug products
grouped together into a product group may be validated together. All variations in the
formulation or method of manufacture must be described and evaluated in detail (risk
analysis). If, however, there are major variations in the equipment used or the procedures
performed, each drug product has to be validated separately.

Bracketing: The bracketing concept considers only extreme cases, e.g. the worst-case
scenario. This may include, for example, preparations with the highest and lowest dosage,
drug substances with the best and worst water solubility, the lowest and highest mixing
load, the best and worst flow capabilities, etc.
To use the bracketing concept for the process validation, note that a well-justified written
reasoning must be submitted to explain why the opinion is that the intermediate strengths,
preparations, loads or other features can be extrapolated from the results for the extreme
cases. Despite this, a minimum number of production batches must be included in the
validation for each drug product and each dosage. This minimum number, however, has
not yet been defined and can be determined and justified individually.
For all three procedures, the pharmaceutical company is obliged to develop and justify a
procedure suitable for the particular case and to consider similarities/differences between
the various strengths or different drug products.

7.F.2 Example of a validation master plan

Pharmaceutical
company
VMP-0815-4711

Validation master plan

P. x of y

Validation master plan for Ixberg

valid from 01.05.2003
site

1. Scope
This validation master plan applies at the Ixberg site for the process validation of solid
dosage forms. It also refers to products manufactured at a contract for other
pharmaceutical companies. Furthermore, it is the basis for the process validation of
products manufactured and validated by contract manufacturers for the Pharmaceutical
company company.
This document is binding for all staff in the GMP area involved directly or indirectly in
the manufacturing of solid dosage forms as well as external consultants on the payroll.
This validation master plan does not apply for bio-technological products manufactured
from 2004 in the new facility B6780. The procedure for these products is regulated in a
separate validation master plan.
This validation master plan does not include the cleaning validation and computer
validation. The procedures for the cleaning validation and computer validation are
defined in separate validation master plans.
2. Key terms
Validation master plan, process validation, validation manager, validation team,
validation matrix, statistical techniques, revalidation, qualification, prospective

validation, retrospective validation, concurrent validation, change control, deviations, raw

material quality, product groups, matrixing, bracketing, contract manufacturers, critical
processing steps, testing schedule, acceptance criteria, risk analysis, failure cause
analysis, product file, annual product review, APR
compiled

(Date/signature Validation manager)

checked

(Date/signature Head of Production)

approved

(Date/signature QA management)

authorized

(Date/signature Managing director)

3. Content
1. Scope page 6
2. Key terms page 6
3. Content page 7
4. Validation policy page 8
5. Organization and responsibilities page 8
6. Company specific definitions page 10
7. Format of documents and archiving page 10
8. Description of project page 11
9. Family grouping, bracketing and matrixing page 11
10. Quality of the raw materials used page 12
11. Qualification status of the facilities and equipment used,
including measuring instruments page 12
12. Validation of analytical methods page 12
13. Risk analysis page 12
14. Critical processing steps and process parameters page 12

15. Determination of the test plan page 13

16. Determination of the acceptance criteria page 13
17. Sampling plan page 14
18. Reference documents page 14
19. Schedule page 15
20. Techniques for test interpretation page 15
21. Changes to the validation protocol page 15
22. Control of changes to validated processes or systems page 16
23. Distribution list page 16
24. Change history page 16
Appendices:
Appendix 1: Validation matrix including schedule and capacity estimate
(see chapter 7.F.3 Example for a validation matrix)
Appendix 2: Test plan
(see chapter 7.F.4 Example for a test plan)
Appendix 3: Distribution list
Maximilian Maier, Marlies Eberl
Uwe Paulus, Elisabeth Ober
4. Validation policy
It is an aim of Pharmaceutical company to exclusively manufacture products for trade
whose manufacturing procedure is reproducible, so that defective batches, overhauls and
waste can be avoided and the health of patients is never put into jeopardy.
An important tool for achieving this aim is the process validation, which is a basic
element of the Pharmaceutical company quality assurance system. The validation process
involves all measures and their documentation which prove that procedures and processes
yield reproducible products that correspond to the previously defined specifications. A
prerequisite is that the building, facilities, equipment, machines, computers, staff and
suppliers of raw material involved are suitable (qualified) for the intended use.
With our concept of process validation, we want to comply with legal requirements and

meet the expectations of our customers with the obligations resulting from our ISO 90012000 certification.
5. Organization and responsibilities
The head of production is responsible for process validation at Pharmaceutical company.
He provides the necessary capacities and guarantees the time frame in production
planning required for the validation. The head of production approves the master
production record to be validated. He delegates coordination and execution of validation
projects to the validation manager responsible. The validation manager appoints projectspecific validation teams, made up of representatives from the relevant departments
(pharmaceutical production, quality control, engineering, regulatory affairs department,
etc.) and a member from QA. These teams can also be assisted by external consultants if
necessary. Decisions are made by the team and approved by the validation manager after
consulting the head of production.
If necessary, each validation project can be divided into further validation projects. Each
individual project can be managed and processed by the corresponding specialized
departments.
All staff involved in the planning and execution of the process validation must be able to
demonstrate profound knowledge in the area of validation - additional to the regular
GMP training (SOP 700-120-03 GMP training plan) - and with regards to validation
master plans and validation protocols at Pharmaceutical company. The validation team is
responsible for identifying training shortfalls and the training coordinator is responsible
for organizing the training.
To guarantee that the resources necessary for planning and executing the validation
projects are provided, the validation master plan is finally authorized by the general
management.
Tasks of the validation team:

to determine the scope and the extent of the validation work

to perform risk analyses
to compile a validation protocol and test plans
to set priorities for execution
to plan time and resources
to suggest changes to the validation protocol where necessary
to carry out validation work or establish sub teams to carry out the validation
work
to evaluate the validation results
to generate the validation report
to suggest possible follow-ups
to identify requirements for training as necessary

Tasks of the validation coordinator:

to compile and update a validation master plan

to appoint validation team(s)
to report to the head of production/customer
to check validation plans/reports and any changes
to define the distribution list for the validation documents
to coordinate validation projects as regards time and capacities
to ensure a smooth procedure and good information flow
to make all departments involved aware of validation plans and any planned
changes before approval
to monitor compliance with schedules
to inform training coordinators of requirements for training

Tasks of the head of production in this context:

to approve the master production record to be validated

to check the validation master plans
to approve validation plans/reports and any changes or suggested follow-ups
to provide capacities for carrying out validation projects and necessary training
to approve/make decisions, e.g. in the case of required changes to the formulation
or process changes
to submit planned changes to validated processes to the validation team for cost
estimation

Tasks of the Qualified Person in this context:

to approve the master production record to be validated

to approve validation master plans/reports and any changes or suggested followups

6. Company specific definitions

Process validation is establishing documented evidence that production or packaging
procedures are highly likely to consistently produce a product compliant with the
specifications. The term "process validation" is not used at Pharmaceutical company for
the cleaning validation or validation of analytical methods or for qualification steps. The
validation process involves all measures and their documentation which prove that
procedures and processes yield reproducible products that correspond to the previously
defined specifications.
Qualification is documented evidence of the suitability of buildings, facilities, equipment,
machines, computers, staff and suppliers of raw materials for the intended use. Successful
qualification is a prerequisite for the execution of process or method validations. The
qualification of buildings, facilities, equipment, machines and computers is a process of
several consecutive steps; the individual steps are described in the qualification master

plan QMP 9907834.

Prospective validation is applied for all new processes or newly developed products. The
general procedure for prospective validation is regulated in the SOP 100-200-01
Prospective validation of a new manufacturing procedure.
Retrospective validation is restricted to those drug products already marketed for long
time, which have never undergone formal documented validation up to now. The
prerequisites to be met and criteria to be fulfilled so that a process validation can be
executed retrospectively are regulated in the SOP 100-210-01 Retrospective validation of
manufacturing procedures for old drug products.
Concurrent validation is only possible in few cases that are to be well justified in writing.
The details are regulated in the SOP 100-230-01 Concurrent validation of manufacturing
procedures for transfer to other sites or in the case of slight changes to the procedures.
Critical" factors, processing steps or parameters are those, where a slight change to this
parameter or its environment has a significant influence on the process reliability or the
quality of the final product. Critical factors are identified with the aid of risk analysis.
For further definitions, see the SOP 200-100-03 Definitions and terms.
7. Format of documents and archiving
All documents created as part of the validation procedure must correspond with the
specifications in the SOP 100-505-02 Creation of validation documents and the
respective current templates in the Intranet under
Pharmafirma\QA\database\templates\Validation. This also applies for validation
documents created by external companies. However, in some cases, it is possible to copy
test plans and test reports from external companies into the validation documentation. A
prerequisite is that these documents have cover sheets in the format used by
Pharmaceutical company. This is the only way to guarantee unique identification and
achievability in the Pharmaceutical company archiving system in accordance with the
SOP 100-510-04 Archiving GMP-relevant documents.
8. Description of project
Each validation protocol must include a precise description of the product and the process
to be validated in the form of a flow chart. A number must be assigned to each processing
step (see SOP 100-505-02 Creation of validation documents) so that this step can be
referenced unambiguously.
This VMP applies for the following four product groups:

Product group 1 - Powder and effervescent granulates: This involves powder

mixtures or wet granulates intended to be dissolved and taken orally and filled in
sachets.

Product group 2 - Tablets, film coated tablets and sugar coated tablets: The tablet
cores in this product group are manufactured by direct compression, dry or wet
granulation. Film coated tablets are coated with a solvent-free coating and sugar
coated tablets are coated with a sugar-free coating.
Product group 3 - Pellets: Pellets are manufactured by means of extrusion and
spheronisation. The pellets for a modified dissolution are coated with a solventfree coating. Pellets are mixed according to the desired release profile and
encapsulated in hard gelatin capsules.
Product group 4 - Hard gelatin capsules: Granulates (manufactured by wet or dry
granulation) and/or pellets are encapsulated in hard gelatin shells.

All process validation projects to be carried out within the scope of this VMP, including
schedules, priorities and capacity estimations are listed in appendix 1 (see chapter 7.F.3
Example for a validation matrix).
9. Family grouping, bracketing and matrixing
In order to reduce validation workload, it is possible to define product groups, equipment
groups or groups with similar production processes. However, there must be a written,
scientific rationale in any case. This approach allows to define and validate the "worst
case" within each group, e.g. the most demanding product, the most complicated
equipment, the most complex manufacturing procedure, the most unfavorable batch size).
It is also possible to address various dosages of a drug product in the same validation
protocol according to a bracketing or matrixing concept, as long as the formulation and
manufacturing procedure are comparable.
Prerequisites for the application of bracketing/matrixing or family grouping:

Evaluation of differences in dosage/formulation/procedure/equipment including

risk analysis
Written justification in the validation protocol
Basically, at least one validation batch must be manufactured for each product
and dosage - also when applying the bracketing/matrixing or product group
concept.

10. Quality of the raw materials used

The specifications of the raw materials to be used and the suppliers approved for each
raw material are documented in the respective validation protocol. For common raw
materials, the specifications and suppliers usually used at Pharmaceutical company
should be preferred. If it is necessary in some cases to define exceptional specifications
or suppliers for a particular validation project, this must be justified in the validation
protocol. The suppliers listed in the validation protocol must be qualified.
11. Qualification status of the facilities and equipment used, including measuring

instruments
The validation protocol must list in detail all machines, facilities, measuring instruments
and recording instruments used. The exact equipment type and, if necessary, size must be
fixed because the result of the process validation is always only valid for the facilities and
machines used in the validation runs. Transferability to similar or other equipment must
be proven, where necessary, with revalidation. The qualification status of each of these
pieces of equipment must be documented in the validation protocol. The calibration
status of the measuring instruments should also be noted.
If alternative equipment is permitted for certain processing steps, e.g. different types of
blenders, this must be explained in the validation protocol. The validation must be
planned in such a way that suitable data material is collected for all specified types of
blenders. In this case even more than three validation batches may be required.
12. Validation of analytical methods
Valid analytical methods must be prepared for the testing defined in the validation
protocol. The validation status of the analytical methods is documented in the validation
protocol.
13. Risk analysis
(At least) one risk analysis is carried out before or during the creation of a validation
protocol. As part of this risk analysis, possible deviations/failures are identified for each
processing step and the significance of the effect of these deviations on the quality of the
final product is assessed. The processing steps and critical process parameters identified
in this way must be validated. For more details see SOP 100-640-01 Carrying out risk
analyses. The results of the risk analysis are documented as described in the SOP and are
part of the validation protocol as an appendix.
14. Critical processing steps and process parameters
As a result of risk analysis, the processing steps are divided into noncritical and critical.
Critical processing steps require validation. A test plan, including testing criteria, a
sampling plan and acceptance criteria must be created for each critical processing step.
15. Compilation of test plans
A test plan for each critical processing step is appended to the validation protocol, with
detailed descriptions of the tests to be carried out as part of the validation (see chapter
7.F.4 Example for a test plan). These are basically investigations that are carried out for
validation purposes in addition to the normal in-process controls specified in the
manufacturing instructions.
Tests may include:

more frequent monitoring of process parameters

more frequent in-process controls
additional examinations, e.g. content uniformity or particle size distribution
Control tests after intentionally built in events, e.g. prolonged holding times,
reduced/increased production speeds. However, intentional process faults are
avoided for reasons of cost and environmental protection.

The test plan must also establish:

the frequency of tests

sampling where necessary (amount, intended use)
test methods
acceptance limits

16. Determination of the acceptance criteria

The validation protocol and test plan list the expected results and acceptable ranges of
variations. If the validation runs do not comply with these acceptance criteria, this may be
a hint to the fact, that the process in not under control. Acceptance criteria must always
be defined in advance, prior to the start of the first validation run. The appropriate
selection of acceptance criteria is crucial for the outcome of the validation project and is
therefore a core element of the validation protocol.
When drawing up acceptance criteria, the following must be taken into consideration:

Manufacturing instruction
Application dossier for marketing authorization
Product specifications
Experiences and results from scaling-up, from the pilot plant and from
development

17. Sampling plan

When planning the process validation, particular attention must be paid to the generation
of detailed sampling plans and to correct sampling because unsuitable sampling rarely
leads to a meaningful test result. For critical manufacturing levels in particular, it is of
vital importance that there are precise explanations for whether, for example, samples are
taken regularly during a manufacturing operation or from different places in the
container. Required details in the sampling plan (cf. SOP 300-240-02 Sampling
instructions and plans):

Place (where? top - middle - bottom)

Time (when? time, frequency or start-middle-end)
Type (how? using which instrument?)
Quantity (how many g, ml or pieces per sample?)
Number of samples (how many samples at each sampling point?)

Use (for uniformity of content, physical determination, residual moisture, etc.)

Packaging and storage (in the case of laboratory investigations)
Labeling (traceability of sample series)

The intended use must be noted for all samples. Samples must not be taken "just in case".
In contrast, the test plan can allow for specific testing (e.g. content uniformity), e.g. 40
samples to be taken according to the plan, only 20 of which are to be tested initially and
the other samples only to be analyzed in a predetermined case (e.g. standard deviation
exceeds xyz).
18. Reference documents
For a better understanding and clarity, each validation protocol and report must list the
relevant reference documents, for example, standard operating procedures, development
reports, reports about pilot batches, IQ/OQ/PQ reports, etc.
The following documents are valid together with this validation master plan:
1. the qualification master plan QMP 9907834
2. the following SOPs (the current versions):
o
o
o
o
o
o
o
o
o
o
o
o
o

SOP 100-200-01 Prospective validation of new manufacturing procedures

SOP 100-210-01 Retrospective validation of manufacturing procedures for old
drug products
SOP 100-230-01 Concurrent validation of manufacturing procedures for transfer
to other sites or in the case of slight changes to the procedures
SOP 100-500-02 Annual product review, APR
SOP 100-505-02 Creation of validation documents
SOP 100-510-04 Archiving GMP-relevant documents
SOP 100-640-01 Carrying out risk analyses
SOP 200-100-03 Definitions and terms
SOP 300-240-02 Sampling instructions and plans
SOP 400-500-02 Handling of OOS (out-of-specification)-results
SOP 400-600-03 Reporting, evaluating and carrying out planned changes
(Change control)
SOP 700-120-03 GMP training plan
SOP 900-330-02 Statistical techniques for test evaluation

19. Schedule
Manufacturing validation batches takes considerably more time than routine production.
It is important to take this aspect into consideration when scheduling production and to
draw up a detailed schedule to prevent misunderstandings and bottlenecks. The three
validation batches must be scheduled for manufacture on different days, with different

staff or during different shifts, if possible, to make this as realistic as possible.

The schedule and capacity estimate for this VMP are found in appendix 1 (see chapter
7.F.3 Example for a validation matrix).
20. Techniques for interpretation of test results
In order to prevent validation results from being subsequently influenced by choice of
questionable statistical techniques, the validation protocol and test plan must establish the
methods and statistical testing to be used for the interpretation of the test results (cf. SOP
900-330-02 Statistical techniques for test evaluation).
The use of outlier tests is generally not permitted (exception: biological and
microbiological tests in accordance with SOP 007-014-02). Significantly different test
results are subject to the OOS procedure in accordance with the SOP 400-500-02
Handling of OOS (out-of-specification)-results. However, if this concerns deviations
from the targets as part of the process validation rather than deviations from
specifications, a written failure cause analysis is performed instead.
21. Changes to the validation protocol
If changes to originally planned procedures are necessary during the process validation,
the validation protocol must be modified. Either the relevant test plan can be revised
(new version number, reason for change), or a new version of the validation protocol can
be composed, e.g. in the case of considerable changes.
Each change must be approved before being implemented. All staff involved in the
validation work must be informed about the changes.
Planned changes to the formulation, process, facilities, buildings and analytical methods
are also subject to the change control procedure in accordance with the SOP 400-600-03
Reporting, evaluating and carrying out planned changes (Change control).
22. Control of changes to validated processes or systems
As soon as a process or system is validated, i.e. the corresponding validation
documentation has been approved by quality assurance, changes can be made to the
process or system but only in accordance with the SOP 400-600-03 Reporting, evaluating
and carrying out planned changes (Change control).
A product file is saved containing the following current results (with reference to original
documents) for each product where process validation is complete:

changes to the formulation, process, facilities, software, specifications of raw

materials, raw materials or product, packaging, etc.
results of all regular and exceptional approvals
results of stability testing

complaints and recalls

OOS situations
revalidation or requalification activities

This product file is evaluated yearly (at the latest during the month of the validation
approval) in accordance with the SOP 100-500-02 Annual Product Review, APR to
check whether the process can still be considered validated.
23. Distribution list
See appendix 3 for the current distribution list for this VMP.
24. Change history

First issued: 03.07.1998

Existing version: 01.05.2003. Complete revision of validation concept, modified
to suit the new company structure, contract manufacturers are included in the
VMP.

7.F.3 Example for a validation matrix

Pharmaceutical
company

Validation matrix

P. x of xx

VMP-0815-4713

Appendix 1 to Validation master plan

VMP-0815-4711 for Ixberg site

valid from
01.05.2003

All process validation projects to be carried out as part of VMP-0815-4711 are listed with
time and capacity estimates and priorities in tables in this appendix (validation matrix).
Matrixing, bracketing and prioritization are based on individual risk analyses (RA-08159912 to RA-0815-9922).
compiled

(Date/signature Validation manager)

checked

(Date/signature Head of Production)

approved

(Date/signature QA management)

authorized

(Date/signature Managing director)

Name

Figure 7.F-5 Validation matrix - Appendix 1

Process
Product Qualification
product
validation
no.
complete
group
priority

Time
frame

Capacity
Staff
days

Powder and
effervescent
granules

31XXX

bPowder

315258

yes

12

Dec. 03 20
- Jan. 04

cPowder

315269

yes

13

Dec. 03 30
- Jan. 04

dGranulates

315300

yes

Group A Aug. Sep. 03

40

dGranulate forte 315325

yes

Group A Aug. Sep. 03

see above

tablets - directly
compressed

95XXX

r tablets

957834

yes

s tablets

957869

yes

s-Retard tablets

957641

no

t-tablets

957693

yes

Group B

see
above

see above

t-tablets forte

957695

yes

Group B

see
above

see above

u-tablets

959695

yes

Oct. 30
Nov. 03

tablets
- from wet/dry
granulates

94XXX

v tablets

947834

yes

10

Nov. - 15
Dec. 03

vRetard tablets

947847

yes

11

Nov. - 10
Dec. 03

w tablets

947941

yes

Group C

Sep. Oct. 03

30

w tablets forte

947943

yes

Group C

see
above

see above

Film coated
tablets

97XXX

xTabs

978634

yes

12

Jan. Feb. 04

25

Oct. 25
Nov. 03
Group B

May 50
Aug. 03
Oct. 15
Nov. 03

yRetard tablets

978347

yes

13

Jan. 50
Mar. 04

zLong tablets

978941

yes

14

Jan. Feb. 04

Sugar coated
tablets

99XXX

mSugar coated
tablets

998783

yes

15

Feb. 20
Mar. 04

nSugar coated
tablets

997834

yes

16

Feb. 25
Mar. 04

Capsules

56XXX

eCapsules

569834

yes

17

Apr. 40
May 04

fCaps long

569878

yes

18

Apr. 20
May 04

gCapsules

569883

yes

Group D Sep. Oct. 03

30

gCapsules forte

569884

yes

Group D see
above

see above

Pellets

66XXX

oPellets

667841

yes

Group E

May July 03

40

pPellets

667834

yes

Group E

see
above

see above

pPellets retard

667342

yes

Group E

see
above

see above

qPellets forte

667830

yes

Group E

see
above

see above

qPellets retard

669878

yes

June July 03

20

qPellets long

669734

no

June July 03

30

957834

yes

19

Group F

May 04 15

957869

yes

19

Group F

May 04 see above

957641

no

20

Group G June 04 20

957693

no

20

Group G June 04 see above

957834

no

20

Group G June 04 see above

957869

no

20

Group G June 04 see above

30

Primary packaging: blister

957641

no

20

Group G June 04 see above

957693

no

21

Group H July 04

15

957695

no

21

Group H July 04

see above

959695

no

21

Group H July 04

see above

947834

yes

19

Group F

May 04 see above

947847

yes

19

Group F

May 04 see above

947941

yes

22

Group I

Sep. 04

25

947943

yes

22

Group I

Sep. 04

see above

978634

yes

22

Group I

Sep. 04

see above

978347

yes

22

Group I

Sep. 04

see above

978941

yes

22

Group I

Sep. 04

see above

998783

yes

23

Group K Oct. 04

15

997834

yes

23

Group K Oct. 04

see above

569834

yes

22

Group I

Sep. 04

see above

569878

yes

22

Group I

Sep. 04

see above

569883

yes

23

Group K Oct. 04

see above

569884

yes

23

Group K Oct. 04

see above

315258

yes

24

Group L

Sep. 04

20

315269

yes

24

Group L

Sep. 04

see above

315300

yes

24

Group L

Sep. 04

see above

315325

yes

24

Group L

Sep. 04

see above

669734

no

25

Oct. 04

10

957834

yes

26

Group M May 30
June 04

957869

yes

26

Group M May see above

June 04

957641

no

27

July 04

957693

yes

26

Group M May see above

June 04

957834

yes

26

Group M May see above

June 04

957869

yes

28

Group O July 04

15

957641

yes

28

Group O July 04

see above

957693

yes

28

Group O July 04

see above

Filling of sachets

Final packaging

10

957695

yes

26

Group M May see above

June 04

959695

yes

26

Group M May see above

June 04

947834

no

29

Sep. 04

10

947847

yes

30

Sep. 04

15

947941

yes

26

Group M May see above

June 04

947943

yes

26

Group M May see above

June 04

978634

yes

26

Group M May see above

June 04

978347

yes

26

Group M May see above

June 04

978941

yes

28

Group O July 04

see above

998783

yes

28

Group O July 04

see above

997834

no

31

Sep. 04

569834

yes

32

Group P

Oct. 20
Nov. 04

569878

yes

32

Group P

Oct. see above

Nov. 04

569883

yes

32

Group P

Oct. see above

Nov. 04

569884

yes

32

Group P

Oct. see above

Nov. 04

315258

yes

32

Group P

Oct. see above

Nov. 04

315269

no

33

Dec. 04 15

315300

no

34

Dec. 04 10

315325

yes

32

Group P

Oct. see above

Nov. 04

669734

yes

32

Group P

Oct. see above

Nov. 04

Total

15

875

7.F.4 Example for a test plan

Pharmaceutical company

Test plan for

process validations

P. x of xx

VMP-0815-4715

Enclosure 2 for the validation master

plan for solid dosage forms for the
Ixberg site

valid from
01.05.2003

Validation project: example - tablets 0.5 mg

Processing step #: # 04 - Blending
Sampling:

1. For blending uniformity:

The blending process is interrupted at the specified times. The blending container is
opened carefully. Using a stainless steel lance (sample volume 1 ml, int. no. 3434) three
samples are taken from the upper edge area of the blending container, three samples from
the center area and three samples from the lower edge area of the blending container. The
samples are emptied into prepared, numbered and dated small glass bottles (int. no.
5634).
2. For angle of repose
After taking the CU sample, use a stainless steel scoop (volume 200 ml, int. no. 3478) to
take three samples of approximately 200 g each from the upper area of the blending
container. The samples are emptied into and sealed immediately in prepared, numbered
and dated small wide-necked bottles (int. no. 1537). Ensure that these samples are not
agitated during transport to the control laboratory; note also cf. SOP 300-240-02
Sampling instructions and plans.
compiled

(Date/signature Validation manager)

checked

(Date/signature Head of Production)

approved

(Date/signature QA management)

Batch

#03 06 135

# 03 06 136

#03 06 137

Batch size

500,000 pc

650,000 pc

500,000 pc

Equipment/machine

Fantasy blender I

Fantasy blender I

Fantasy
blender II

Machine parameters

Speed of rotation

200 UpM

250 UpM

150 UpM

Blending time

10, 15, 20 mins

10, 15, 20 mins

10, 15, 20, 25

min

yes

yes

yes

Test parameters

Uniformity
of mixture

Angle of repose

yes

yes

yes

Sample number

Content Uniformity 3 * 9 samples:

(CU)
(# 1 - 27)

3 * 9 samples
(# 37 - 53)

4 * 9 samples
(# 63 - 89)

Angle of repose

3 * 3 samples
(# 54 - 62)

4 * 3 samples
(# 90 - 99)

3 * 3 samples
(# 28 - 36)

Figure 7.F-6 Validation matrix - Enclosure 2 test plan

Acceptance criterion
Content Uniformity
Angle of repose alpha
Mean value
x = 98 - 102 % labelclaim < 30
Single values

no value < 95 % or > 105 % no value > 40

Standard deviation

srel < 1.5 %

srel < 2.5 %

Summary
The validation master plan (VMP) is a document required in the PIC/S guideline PI 006
and in appendix 15 of the EU GMP Guideline, which serves to structure and control the
validation work. A VMP or equivalent documents are also expected in the USA. The
general procedure for validation projects, responsibilities and company-specific
terminology is defined in the validation master plan. The VMP can be structured in
different ways according to the application area. A VMP can, for example, cover the
corporate validation strategy of a global group, or concern only a single drug product.
The VMP is used for internal and external communication.

7.G Risk analysis

Here you will find answers to the following questions:

Which tools may be used in order to define the adequate scope and extent of
validation?
How may a risk analysis be performed?

7.G.1 Finding out the adequate extent of validation

The scope of the validation activities required depends on the type of manufacturing
operation and the use of the product. It is easy to appreciate that a complex
manufacturing process which requires technically sophisticated equipment, specially
trained staff and permanent process monitoring and which concerns a product with a
narrow therapeutic range for parenteral use must be validated more thoroughly than a
skin antiseptic solution for use on intact skin. It is expected by authorities, that a
systematic, documented approach is done for each validation project in order to
determine how much validation work is necessary in the individual case. Nowadays risk
analysis is the favorite tool to evaluate scope and extend of validation activities.

7.G.2 Carrying out risk analysis

Risk analysis should be carried out at the very beginning of each validation project to
assess the individual product risk and the process risk. The "risk" is generally understood
to be increased as probability of occurrence of product failures increases. It is also
increased, as significance of product failures increases, but it is decreased if there are
means to discover the product defects. (See chapter 19.B Risk analysis.)
Figure 7.G-1 Fundamental questions for risk analysis
Fundamental questions for risk analysis
Product risk: Does the product itself present certain risks, e.g. due to its administration
route (e.g. parenteral), its narrow therapeutic range or physicochemical properties (e.g.
sensitivity to light)?
Process risk: Is the process complex? Does it consist of many individual steps? Does it
have to be precisely monitored? Does it require specially trained members of staff? How
much experience is there with the facilities/equipment used?
Quality assurance activities: Are there opportunities to detect any errors that may have
occurred?
For the purposes of risk analysis, the entire production process is divided into individual
processing steps and each processing step is assessed with regard to possible failures

which might occur. Each failure is then assigned with a probability and a significance of
occurrence, as well as the ability to detect a failure in case the error really had occurred.
There are various ways of grading these three factors, i.e. allocating numbers and
calculating the risk of each processing step. The aide mmoire Inspection of qualification
and validation in pharmaceutical manufacture and quality control gives FMEA, fault tree
analysis, fishbone analysis and the HACCP concept. Whichever technique is used, it is
important that the result of the risk analysis identifies the "critical" and "non-critical"
processing steps and that the process of decision is transparent and documented.
The risk analysis can be drawn up as a separate document or, for smaller validation
projects, it may also be part of the validation protocol. Risk analysis can also be used in
validation master plans, in order to give weightings to sub-projects.
Summary
Risk analysis is a versatile tool for assessing and weighting possible or actual events. It is
used, for example, in the planning stages of a validation to determine and justify which
processing steps are to be considered as "critical". Risk analysis is also useful when
allocating priorities in complex validation projects.
Notice

Copyright:
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GMP Publishing
Himmelreichstrasse 5
D-79650 Schopfheim (near Basel)
Tel +49 (0)7622 666 86-70
Fax +49 (0)7622 666 86-77
eMail [email protected]
info http://www.gmp-publishing.com

7.H Validation protocol and report

Here you will find answers to the following questions:

Which information and requirements are included in a validation protocol?

What is the content of a validation report?
Who has to authorize validation protocols and reports?
What must be taken into consideration when drawing up a sampling plan?
What is the procedure if modifications have to be made to the validation protocol
during validation?
What is the procedure if analysis reveals that there are deviations from the
requirements in the validation protocol?
How is a validation batch defined when production is continuous?
What is the procedure if for an important raw material there is only one single
batch available on the market?
For how long and where must validation documents be archived?

The general principle of the GMP-compliant documentation (e.g. for manufacture,

cleaning, analysis, qualification, maintenance, etc.) is that a plan or protocol containing
all the work stages to be carried out and the exact acceptance criteria is first drawn up and
then authorized by the responsible person. While the work is being carried out, the actual
data is recorded and entered in a record. The actual data is then compared with the
requirements, conclusions are drawn and this is all authorized by the responsible person.
This may either take place as part of the record or as a separate outline report. It is
important to note, for the USA, all validation plans, protocols, etc. must be reviewed and
approved by the quality unit of the firm.
The documentation for validation projects is also structured accordingly. Requirements
for the format and structure of the validation protocol and report should be set out in the
validation master plan.

7.H.1 Elements of the validation protocol

Unless it is already governed by the VMP, a validation protocol must take the aspects
listed in figure 7.H-1 into consideration (see also PIC/S PI 006 and Annex 1 of the
EMEA Note for Guidance on Process Validation).
Figure 7.H-1 Content of a validation protocol
Content of a validation protocol

Specifications of the product to be validated

Batch numbers of the validation batches
Detailed sequence of operation with in-process controls
Reference to authorized master production records

Quality attributes (e.g. content, yield, physical characteristics)

Quality of raw materials used
List of the facilities and equipment used and any alternatives
Risk analysis (if not documented in a separate document)
Definition of the critical/quality-relevant processing steps and process parameters
(e.g. temperature, pressure, time, pH, stirring speed, etc.)
Specification of the setting parameters and acceptance thresholds for the
equipment and machines
Compilation of the test plans
Establishment of the acceptance criteria
Sampling plans
Analytical methods with cross reference to the method validation
Statistical techniques for trial interpretation
Any process capability investigations
Schedule
Procedure in the event of changes to the validation protocol
Authorization of the validation protocol
Departments involved in the validation/responsible members of staff
Reference documents, e.g. validation master plan, SOPs, development reports,
reports on pilot batches, IQ/OQ/PQ reports
Qualification status of the equipment used, including calibration

Determination of the validation batches

The production and/or packaging batches which are intended to be included in the
process validation must be listed in the validation protocol.
At least 3 consecutive batches must be produced for the prospective and the concurrent
validations. The size of these batches must correspond to the recent commercial scale. If
flexibility in batch size is desired for routine production, these different batch sizes
should be covered in the validation (cf.. EMEA Note for Guidance on Process Validation,
Paragraph 5), for example, at least one batch should be manufactured in both the smallest
and the largest intended batch sizes. If the batch size of the validation batches differs
greatly from the intended production scale (e.g. by more than a factor of 10), for
example, because the active pharmaceutical ingredient is very expensive, this deviation
must be justified in the validation protocol and the possible effect of the difference on the
validity of the validation must be discussed. If production is later in the routine, the new
batch size must be concurrently (if acceptable to local authorities) or prospectively
revalidated (see chapter 7.D.2 Incidences requiring revalidation).
In this context, the concept of a "batch" occasionally causes difficulties, especially when
there is continuous production or production in lots (with intermediate cleaning only).
For the purpose of process validation it should be tried to stick as close as possible to the
official definition ("a defined quantity of starting material, packaging material or product
processed in one process or series of processes so that it could be expected to be

homogeneous" - EU GMP Guideline) or to written, internal definitions (e.g. batch = lot)

of the company.
If the concept of a production batch is to be defined differently than usual for validation
purposes only (e.g. between two intermediate cleaning procedures), this variation must be
well justified (in writing, in the validation protocol or even in the VMP).
Detailed sequence of operation with in-process controls

The basis of this is an approved master production record (reference to which must be
given) with required setting parameters and acceptance limits for the equipment and
machines. If the batch size of the validation batches differs from the routine production
batch size by more than a factor of 10 , this deviation must be justified in the validation
protocol and the possible effect of the difference on the validity of the validation must be
discussed. If production is later in the routine, the new batch size must be concurrently (if
acceptable to local authorities) or prospectively revalidated.
If several dosages of a preparation are to be validated together using the bracketing,
matrixing or family grouping concept, the rationale and the exact procedure must be
detailed in the validation protocol. (See chapter 7.F Validation master plan.)
Quality attributes

These include content, yield and physical characteristics of the product, for example.
However, this involves more than simply fulfilling the final product specifications - these
are checked by the batch release in any event (EMEA Note for Guidance on Process
Validation, Paragraph 1). The point of validation is to make certain that the process is
reproducible, in addition to fulfilling the specifications. The question is therefore: "how
can I tell that my process is running well?" or even: "what conditions must be fulfilled for
my product to be good?"
Examples of such quality attributes - in addition to fulfilling the final product
specifications - are:

Fulfillment of special requirements for the yield

Specifications of intermediate products
Critical control points (CCPs)
Process or product parameters that are not included in the final product
specification
Sampling procedure suitability
Suitability of in-process controls
Process capability investigations

Quality of the raw materials used

The quality of the starting materials which are used in the process validation has a direct
influence on the result of the validation. Therefore, the raw materials must be specified

and the qualified suppliers must be listed in the validation protocol, unless the
specifications and suppliers are determined by internal product numbers. If the validation
is carried out by third parties, it is important to decipher internal product codes in the
validation protocol so that the raw material quality required is clearly comprehensible to
the contractual partner.
In order to cover possible differences in quality between the various approved suppliers
or even differences between batches from the same supplier in the process validation, the
production of validation batches should be planned such that different batches of raw
materials are used. This is particularly important for the active pharmaceutical ingredient,
but also for quality relevant excipients, for example excipients that affects the dissolution,
or for (synthetically modified) natural products. When validating packaging processes, it
is important to purposely use different batches of packaging materials.
Occasionally, it is difficult to obtain different batches of excipients or packaging
materials from the manufacturer for the purposes of validation - especially when these are
new types of packaging or excipients and only one batch is available from just one
manufacturer. The supplier is then often confronted with the requirement for three
different batches to be supplied. In these cases, thorough consultation between the
supplier and pharmaceutical manufacturer is necessary and in both parties' interests. The
question arises of how much more knowledge and explanatory power the process
validation would provide in regard to this point if the three required batches of starting
materials are generated from a single production lot with more or less arbitrary
subdivision, e.g. by briefly switching off the equipment and starting it up again, or by
using different packaging processes. In this case, the "three batches" of starting material
are indeed largely identical. The amount of work required for the process validation
remains the same however - without the desired gain in knowledge.
In this case, it makes more sense to complete the validation using the single batch of
starting material in the first place (to be justified in the validation protocol). Then, as
soon as new starting material batches are actually available (good communication
between the manufacturer and pharmaceutical customer is required), the effect of these
new batches can be investigated in an concurrent validation (only for this aspect complete revalidation may not necessarily be required).
List of the facilities and equipment used, including measuring and recording instruments and any
alternatives

The result of a process validation is only ever valid for the facilities and machines used
when the validation was carried out. A transfer to similar or other equipment should be
proven, where necessary, with revalidation. It is therefore important that the equipment
be precisely defined in the validation protocol. Its calibration status must also be noted. If
alternatives are permitted for certain processing steps, e.g. different types of blenders, this
must be explained in the validation protocol. In this case, the validation must be planned
in such a way that suitable data is collected for all specified types of blenders. More than
three validation batches may be required.

Risk analysis

As part of the risk analysis, the effect of any deviations on the quality of the final product
is evaluated for each processing step. The risk analysis may be drawn up as a separate
document and referred to in the validation protocol (see chapter 7.G Risk analysis).
Definition of the critical processing steps and process parameters

As a result of risk analysis, the processing steps are divided into non-critical and critical.
Critical processing steps require validation. The relevant samplings and tests, the results
of which justify the process parameters provided in the manufacturing instructions, must
therefore be established in the validation protocol.
Occasionally, it is revealed that process parameters, which were classified as "critical" in
the risk analysis cannot be technically implemented such as for example, uncontrolled
humidity in an air supply to a dryer.
If this is the case, the range (e.g. limits for humidity) within which the process (from
experience) is reliable and reproducible must be determined and this must be documented
in the process validation.
If at a later stage the parameters move outside this validated range (e.g. dryer air supply
too moist) and it is not possible to influence this in any way, the process must not be
carried out on this day because it is not running under validated conditions.
If the process goes ahead in spite of this, this deviation must be thoroughly investigated
and a thorough risk analysis carried out: how great is the risk caused to the product
because it was manufactured with a non-validated step in the process? Such a deviation
may warrant discussions with local regulatory authorities.
However, it may also mean that certain parameters may have to be modified, e.g. the
dryer air supply must be attached to a cold trap.
Compilation of test plans

Detailed descriptios of the investigations that are carried out for validation purposes in
addition to the normal in-process controls specified in the manufacturing instructions.
These tests may include:

More frequent monitoring of process parameters

More frequent in-process controls
Additional examinations, e.g. content uniformity or particle size distribution
Tests after intentionally built in events, e.g. longer holding times,
reduced/increased production speeds.
Function controls (e.g. for automatic detection systems)

The test method must be detailed for every individual test. When establishing a test plan,
it is important to make sure that enough data is collected so that any subsequent statistical
interpretation is meaningful.
Determination of the acceptance criteria

It is important to determine and establish the results that are expected and the range of
variation which is acceptable, or conversely, establish the outer limits for the acceptance
criteria, which if exceeded would indicate that the process is not running in a controlled
manner.
Sampling plan

Almost every test begins with the taking of a sample. Unsuitable sampling can hardly
result in a meaningful test result. Therefore, it is important that each sample that is to be
taken as part of the validation project is described in detail in a sampling plan, which is
part of the validation protocol. Sampling is often paid little attention during the planning
stages, but inadequate sampling is quickly blamed when unexpected results are obtained.
Besides, it is important to plan for samples for validation purposes in addition to the
regular in-process control samples specified in the manufacturing instructions, e.g.
regularly during a manufacturing operation or from various points in a container. This is
especially important for critical production stages.
The following must be described in detail in the sampling plan:

Place (where? top - middle - bottom)

Time (when? time, frequency or start - middle - end)
Type (how? using which instrument?)
Quantity (how many g, ml or pieces per sample?)
Number of samples (how many samples at each time?)
Use (for content uniformity, determination of physical properties, residual
moisture, etc.)
Packaging and storage (in the case samples are not tested immediately at the
sampling side, but transferred to a laboratory)
Labeling (traceability of sample series)

An intended use must be known for all samples. Samples must not be taken "just in case".
In contrast, the testing schedule can allow for specific testing (e.g. uniformity of content),
e.g. 40 samples to be taken according to the plan, only 20 of which are to be tested
initially and the other samples only to be analyzed in a predetermined case (e.g. standard
deviation exceeds xyz).
It is also important that the members of staff who carry out the sampling are specially
trained ans documented.
Examples for sampling can be found in figure 7.H-2 and figure 7.H-3.

It is useful to keep all samples taken during validation runs until the validation is
completed (i.e. authorized). Of course, this excludes those cases in which the samples are
not stable for this length of time, for example because they separate, are affected by
oxidation or deteriorate in other ways. Regardless of the length of time that the samples
are stored, the maximum length of time that the prepared analytical samples are stored
must naturally have been established in the corresponding method of analysis and
verified in the analytical method validation.
Reference documents

For example: validation master plan, SOPs, development reports, reports on pilot batches,
IQ/OQ/PQ reports.
Figure 7.H-2 Example for sampling (1)
Sampling from a blending container for content uniformity determination
1st sample: top left of container
2nd sample: top center of container
3rd sample: top right of container
4th sample: center left of container
5th sample: center of container
6th sample: center right of container
7th sample: bottom left of container
8th sample: bottom center of container
9th sample: bottom right of container
10th sample: above the opening in the base of the container
Time: directly before granulation, with a probe, 0.5 g per sample in labeled (numbered)
glass containers (item no. XYZ 1234.56),
Figure 7.H-3 3 example for sampling (2)
Sampling during tabletting for content uniformity determination.
1st sample: start of tabletting
2nd sample: middle of tabletting

3rd sample: end of tabletting

Sample taken from the discharge with tweezers, 20 pieces in each labeled (numbered)
wide-necked bottle (item no. ABC 1234.98),
or
1st sample: after 30 minutes
2nd sample: after 60 minutes
3rd sample: after 90 minutes
etc.
Sample is taken automatically, "Sampling 3" program, 40 tablets per sample in labeled
(numbered) plastic bags (item no. RST 9876.77),
or
1st and 2nd sample: after 100,000 tablets
3rd - 10th sample: after 200,000 tablets
11th and 12th sample: after 300,000 tablets
etc.
Sample taken from the discharge with tweezers, 20 pieces in each labeled (numbered)
wide-necked bottle (item no. ABC 1234.98),
Departments involved in the validation and responsible members of staff
Qualification status of the facilities and equipment used

A prerequisite for carrying out validation is that the qualification of the facilities,
machines, utilities devices and computer programs is complete (see chapter 7.E.4
Prerequisites for carrying out a validation project). The actual status of these activities
must be documented in the validation protocol.
Validation of analytical methods

Valid analytical methods must be available for the testing defined in the validation
protocol. The validation status of the analytical methods must be documented in the
validation protocol.

Schedule

Manufacturing a validation batch takes considerably more time than routine production.
It is important to take this aspect into consideration when scheduling production and to
draw up a detailed schedule to prevent misunderstandings. The three validation batches
must be scheduled for manufacture on different days, with different staff or during
different shifts, if possible, to make this as realistic as possible.
Techniques for interpretation of the test results

If the validation master plan does not detail this sufficiently, the validation protocol
should prospectively establish which statistical tools may be used to interpret the trial.
This will prevent any critics from subsequently implying that the result of the validation
was influenced by a choice of questionable statistical techniques.
The PIC/S document PI 006 also names process capability investigation as a tool to be
used in the framework of process validation..
Figure 7.H-4 Cover sheet of a validation protocol for a process validation.
Validation protocol
Product:
Material number:
Batch designation: from to
Version:
Compiled on:
Author:
Rationale for the validation:
Type of validation: prospective/concurrent/retrospective
Start of validation:
End of validation:
Authorization of the validation protocol
Head of Production: date/signature
Head of Quality Control: date/signature
Quality assurance: date/signature

Development: date/signature
Client authorization: date/signature
Procedure in the event of changes to the validation protocol

Unless it is detailed in the validation master plan, this procedure must be established in
case it is realized during production that changes are required to the validation protocol.
Changes must be documented, justified and authorized by the responsible person in the
form of an appendix to the validation protocol. It is particularly important that all staff
involved is informed of the changes.
Authorization of the validation protocol

To prevent misunderstandings, all departments involved must check the validation

protocol before it is authorized by the responsible person(s) named in the Validation
Master Plan, e.g. Head of Production, Head of Quality Assurance and/or Qualified Person
(figure 7.H-4).

7.H.2 Content of a validation report

The validation data results and experiences are summarized, analyzed, and evaluated in
the validation report. Problems and deviations during production and testing are also
addressed in the validation report. For validation batches that are produced at large
intervals from each other and for the concurrent validation, an individual report is drawn
up for each validation batch.
Figure 7.H-5 Content of a validation report
Content of a validation report

Batch production records with the actual settings of the facilities and machines
and the actual process parameters
Results of the in-process controls, the final product quality controls and the
additional validation experiments, including the results of unsuccessful trials
Raw data from the analytical investigations or reference to corresponding
documents
Deviations from the validation protocol, additional investigations (with rationale),
special observations
Assessment of the results in comparison to the requirements
Determination of follow-up measures, e.g. further validation measures, additional
in-process controls or tighter process parameters in the manufacturing instruction
Authorization of the validation report (following implementation of the
recommendations)

A validation report contains the following details:

A summary which also specifies the findings of the validation. Has the process
been found validated?
Batch production records with the actual settings of the facilities and
machines and the actual process parameters (hand-written entries in the batch
production records or machine printouts). The raw data is checked for
completeness and plausibility and evaluated using the techniques specified in the
validation protocol, if necessary, before it is compared with the requirements in
the validation protocol.
Results of the in-process controls, the final product quality controls and the
additional validation experiments, including the results of unsuccessful trials.
These results are also checked for completeness and plausibility and interpreted
using the techniques specified in the validation protocol, if necessary, before it is
compared with the requirements in the validation protocol.
Raw data from the analytical investigations or reference to corresponding
documents: If the raw data from the analytical investigations is not included in
(or appended to) the validation report, the document must state where this raw
data can be found.
Deviations from the validation protocol, additional investigations (with
rationale), special observations: When the production and test protocol are
interpreted, deviations from the requirements in the validation protocol must be
justified and explained. The effect on the validation result must be discussed.
Assessment of the results in comparison to the requirements: Once the data
and information has been interpreted, it is compared with the requirements in the
validation protocol and the results are assessed. There should be a discussion and
justification of how the result of the validation can be transferred to the routine
conditions.
Determination of follow-up measures: The results of the validation may
indicate the need to modify the manufacturing instruction for the routine process
so that, for example, additional control measures (IPC) are defined or tighter
requirements for machine settings or narrower limits for the process parameters
are set. However, the investigations often show that the observed process cannot
yet be designated as validated. Then, further validation measures must be
completed, e.g. more precise investigations of individual processing steps. In the
worst cases, the process even has to be optimized before the validation study is
repeated. Such follow-up measures must be suggested in the validation report.
Authorization of the validation report: If the results of the validation batches
prove that the investigated process is reproducible and results in a product with
the specified quality, the validation report must be authorized by the responsible
person(s) named in the Validation Master Plan, e.g. Head of Production, Head of
Quality Assurance and/or Qualified Person.

7.H.2.1 How to deal with deviations from the requirements in the validation
protocol
In practice, problems often occur when validation batches are being produced and the
requirements cannot be fulfilled. These problems and deviations must be documented in

the validation report, together with the measures implemented to trace and rectify the
problems/deviations.
Possible causes may be:

A process that has been inadequately developed/not optimized (this includes

correlations that are not known, for example between granulation time and
homogeneity, particle size distribution or bulk weight, or between particle size
distribution and homogeneity or disintegration time)
Insufficient data material on which the machine settings and process parameters
were specified
Unqualified facilities or non-calibrated measuring points

Unexpectedly large variability in the process parameters is often observed during

production and this may lead to thinking about extension of the specified limits.
However, this sort of extension must be very well justified and the data must prove that it
has no effect on the quality of the final product. This can result in a crisis in the line of
argumentation, especially if the validation protocol had stated that the corresponding
process parameter was "critical", and that a small modification would therefore have a
great effect on the product quality. Such deviations may well require a completely new
validation to be performed on the modified process.
Deviations from the validation plan which call the validation study into question require
follow-up measures (see chapter 7.H.2 Content of a validation report).
7.H.2.2 Archiving of the validation documents
The documentation drawn up as part of the process validation (plans, raw data, reports)
should be available at the manufacturing site (for packaging validation, at the packaging
site) so that it is accessible for any inspections by authorities (cf. EMEA Note for
Guidance on Process Validation, Paragraph 4). The length of time that the validation
documentation is to be archived depends on how long the corresponding product is in
circulation. The validation documents must be kept for at least as long as the batch
documentation for the last ever batch produced. In Europe, this is at least 1 year after the
expiration date or 5 years after batch certification by the Qualified Person, whichever is
the longer period, in accordance with directive 2001/ 94/ EC. If clinical studies are still
being carried out with the product at that time, the documentation must be archived for at
least 5 years after the completion or formal discontinuation of the last clinical trial in
which the batch was used. Retention periods for all validation reports, documents, and
records should always comply with local regulatory requirements for the country where
the product will be distributed, whether it is the EU, the USA, or any other country.
Summary
The validation protocol defines the detailed procedure for a validation study. The
schedule, responsibilities and assessment techniques are defined in addition to the precise

description of the sequence of operation, IPC, quality attributes, apparatus, raw materials,
analytical methods, test plan, sampling and acceptance criteria.
The data collected while the validation batches are produced is assessed in the validation
report and compared with the requirements. If the acceptance criteria are fulfilled, the
validation report can be authorized and the process can be declared validated.
Notice

Copyright:
Maas & Peither AG
GMP Publishing
Himmelreichstrasse 5
D-79650 Schopfheim (near Basel)
Tel +49 (0)7622 666 86-70
Fax +49 (0)7622 666 86-77
eMail [email protected]
info http://www.gmp-publishing.com

7.I Quality by Design

It is a known fact that quality cannot be tested into a product, but must be created with a
suitable product design. Likewise, the safety and reproducibility of processes cannot be
achieved through validation. Validation can only prove whether a process is suitable or
not. The suitability itself results from the careful development and optimization of the
process. These should achieve a degree of understanding of processes which will allow
them to be predictably formulated. The use of process-analytical technologies and the
establishment of a design space, among other things, are useful for this. The following
chapter illustrates the significance of these principles for process validation.

7.I.1 Process development

Process validation is designed to prove the suitability of processes. Suitability must be
ensured by the design of the process. The development of a suitable process design is
part of the pharmaceutical development and must be described in the application file for
marketing authorization of a new drug product.
The principle that quality cannot be tested into a product, but that it results from a
suitable design has been applied in the European approval system for a long time now. In
November 2005, the ICH (International Conference on Harmonization) launched the ICH
M4 document, which describes a standardized format for application files for marketing
authorization. But even before this, applicants were required to describe the
pharmaceutical development of the drug product in the application file. Today, in Section
3.2.P.2 of the CTD, details are to be given about the pharmaceutical development,
especially the selection and optimization of the manufacturing process, and its critical
aspects are to be presented. Since ICH guidances are a harmonization effort jointly
developed and negotiated by the EU, Japan, and the USA, the ICH guidances are
common expectations for all three regions of the world and should be used appropriately
Among other things, the development phase of a drug product serves to determine the
optimum design of the manufacturing process and to verify which control and checking
equipment is required to ensure the process runs smoothly. Experience from the
development phase should make it possible to determine the critical parameters of the
process. There are various methods for doing this which can also be applied in the
subsequent process validation phase, so that it is acceptable to refer back to the results.
The fishbone and Pareto analyses should be mentioned as examples here (see figure 7.I1).
Figure 7.I-1 Fishbone diagram and Pareto analysis as
methods of process development

to enlarge, click here!

The fishbone diagram (cause-and-effect diagram) can be used to analyze a defined
effect (e.g. fault) for its causes. The effect is entered as the "fish head"; the individual
"fishbones" are the main influencing variables, which can be further differentiated into
secondary influencing variables. Possible solutions to the most likely disturbance variable
are sought and implemented (see also chapter 10.D Methodologies to be Used to
Facilitate Risk Management).
Pareto analysis is a way of setting priorities in complex situations which result from a
large number of problems and causes of failure. The greatest, most significant or most
expensive problem is logically approached first. The Pareto analysis shows the
influencing factors relevant to a situation in order of their size and significance. It often
turns out that many of the known problems are insignificant, but that small problems are
still important.
During the improvement phase, the batch consistency is documented, following the
enlargement of the laboratory scale to approximately 1/10 of the subsequent commercial
scale. The efficiency of the process is technically and economically optimized (see
chapter 16.B.7 Process optimization: Basic principles for process validation).
The information obtained as part of the pharmaceutical development forms the basis for
subsequent risk management of the product quality (see chapter 10 Considerations on
Risk Management). The development of a manufacturing procedure and its ongoing
development by means of a continuous improvement process throughout the entire
product life cycle are the foundations upon which a deeper understanding of the process
can be built.

Whereas the examination of the critical factors of a manufacturing process requires a

certain minimum understanding of the process, other approaches, such as multivariate
data analysis (MVDA, see chapter 7.I.4 Multivariate Data Analysis (MVDA)), statistical
design of experiments (DoE, see chapter 7.I.3 Statistical Design of Experiments (DoE))
together with process analytical technologies (PAT, see chapter 7.J Process Analytical
Technology (PAT)) go even further. It is generally recognized that these tools can be
used to better explain the relationship between the variabilities of a process or starting
material and the quality of the final product. They are used to create a basis for optimum
process checking and process control which ensures that the final product automatically
has the required quality.

7.I.2 Design space

The design space concept (for a definition, see figure 7.I-2) is a modern approach for
increasing the flexibility of the production process. Classical manufacturing processes are
routinely characterized by process parameters (e.g. temperature, time, pressure, stirring
speed) for which acceptance criteria with upper and lower limits for production are
defined. The process must be controlled within these limits so that a product is obtained
which conforms to specifications. These limits are usually derived from the proven
acceptable ranges (PAR) during development, i.e. the limits above and below which the
product is likely to be defective. The process is defined in this way and implemented
within these fixed limits. Such rigid processes are only able to adapt to variable
requirements, e.g. due to various starting material qualities or environmental conditions.
Figure 7.I-2 Definition of the design space
Design space according to ICH Q8
The multidimensional combination and interaction of input variables (e.g., material
attributes) and process parameters that have been demonstrated to provide assurance of
quality. Working within the design space is not considered as a change. Movement out of
the design space is considered to be a change and would normally initiate a regulatory
post approval change process. Design space is proposed by the applicant and is subject to
regulatory assessment and approval.
Figure 7.I-3 Statements from the EMEA about design space
Statements from the EMEA about design space
Question
When PAT is implemented will
the manufacturer be allowed to
make changes to the process
without need for regulatory
"approval"?

Answer
It is anticipated that the introduction of PAT-based
systems will change the way knowledge is presented
in the dossier demonstrating greater understanding of
the variables that affect product quality attributes, as
well as the methods to monitor and control them.
One of the expected outcomes is that a "Design
Space" within the boundaries of the knowledge
described in the development part of the dossier will
be established and the process control strategy will

fall within this space. We envisage that

manufacturers will be able to introduce adjustments
without the need for a variation submission provided
the manufacturer operates within the "Design Space"
defined in the original submission or subsequent
variation.
Is it possible for a product to have
two specifications - one for realtime release based on on-line
measurements and another for
end-of-life testing?

In current EU legislation, a medicinal product must

have two specifications: release and end of shelf life
that take into account relevant monographs of the Ph.
Eur. How the manufacturer ensures compliance with
the release specifications is open but has to be
described in the submission. In the case of PATbased submissions we foresee a third "specification"
based on process measurements and controls that the
manufacturer will base release decisions upon. A key
issue that has to be addressed in the submission is the
relationship between these parameters and the release
specifications. Nevertheless when tested after release
using conventional methods, the product must
comply with the end of shelf life specifications.

Will it be possible to widen the

limits for an "approved product
and process specification" if, postapproval, such changes are found
to have no significant effect on
product quality?

It is important to distinguish between process

specifications and finished product specifications. In
principle, as elaborated in the answer to Question 1,
it should be possible to introduce adjustments
provided they fall within the "design space" already
defined in the dossier without the need for further
variation application. On the other hand, changes to
the finished product specification will be subject to
the variations regulations.

Often, the process parameters themselves interact with each other. For example, to dry a
product, either a high temperature and a short drying time or a lower temperature and a
relatively longer drying time can be worked with. If you also work with a variable air
volume flow to support the drying process, the aforementioned parameters can be
adapted accordingly, i.e. the positions of the upper and lower limits are moved depending
on the parameters with which they interact. Based on this knowledge of the multifactorial
dependencies, multidimensional spaces which characterize a multifactorial parameter
range in which a specification-compliant product is contained can be graphically and
mathematically represented (design space). The advantage of the design space concept is
obvious: variable characteristics of a starting material (e.g. humidity, particle size,
surface) can be balanced within the design space by simultaneously varying several
parameters so that the quality of the end product remains constant. Process analytical
technologies (see chapter 7.I.4 Multivariate Data Analysis (MVDA)) are useful for
measuring and controlling these parameters.

The design space must also be checked for suitability, in the same way as the classical
acceptance criteria during the validation. However, further tools are used to verify a
design space, e.g. statistical design of experiments (see chapter 7.I.3 Statistical Design of
Experiments (DoE)) and multivariate data analysis (see chapter 7.I.4 Multivariate Data
Analysis (MVDA)).
Data from the research and development phase and experience from production should
enable a deeper understanding of the process. Investigations of a wider range of
materials, sequences of operations and process parameters are required for this in order to
build up the required knowledge. These findings may result from experiments from
statistical designs of experiments, data from PAT applications or existing production
experience. A value space for a special manufacturing process is defined based on the
necessary process parameters and within the limits of which the process runs stably. If
the correct limits are selected, the number of change notifications required can thus be
reduced. The selection of the correct process parameters is therefore an indispensable
requirement. Process analysis thus has a particular significance in the implementation of
the design space concept. PAT tools are often used for this (see chapter 7.I.4 Multivariate
Data Analysis (MVDA)), but it is not necessarily always the case.
Design space descriptions generally contain a particularly large number of variables
with the interesting information hidden in combinations of variables. It is therefore nearly
impossible to discover the most important information and correlations in the data
visually or using traditional methods. Even if only two settings are to be investigated for
eight factors in a process (known as screening), it would require 28 = 256 trials. For three
settings per factor, the requirement would be 38 = 6561 experiments. From this, it is
obvious that a pure trial and error approach only has a very low chance of achieving
anywhere near the ideal development conditions.
Figure 7.I-4 Determining the design space

to enlarge, click here!

In order for a design space to be determined, considerable amounts of information must
first be gathered using practical measurements and theoretical model calculations. This
data also covers parameter ranges which yield specification-compliant and non-

specification-compliant products. This range is known as the knowledge space (see

figure 7.I-4).
Within the knowledge space, a range is determined within which a specificationcompliant product is obtained. This range is called the design space. In routine
production, the process is controlled in a way that it runs within the design space. For
this, a smaller range, the control space, is generally established.
The fact that a process can be run within the defined design space and thus deliver a
specification compliant product is typically verified with a defined collection of batch
specific product and process information, the process signature (see figure 7.I-5).
Figure 7.I-5 Example of an acoustic process signature

to enlarge, click here!

The process signature is obtained from process analytical at-line, on-line or in-line
measurements (see figure 7.J-1). The variety of dimensions in a design space is typically
dependent on each other. There are relationships - so-called correlations - between
categories in different dimensions. They describe how design alternatives fit with each
other, i.e. they indicate advantageous or disadvantageous combinations of design
decisions.

7.I.3 Statistical Design of Experiments (DoE)

In order that the design space concept can be effectively implemented, various tools are
required that support both the creation and the manipulation of design-space descriptions.
Design-space descriptions are therefore usually based on software-assisted statistical
design of experiments.
Pharmaceutical processes are often dependent on a relatively large number of variables
(e.g. temperature, time, humidity, pressure, particle size). It is practically impossible to
test every combination of variables during process development in order to determine the
relevant correlations between the individual variables.

Even where there is enormous time pressure for developing new formulations, DoE (see
figure 7.I-6) can release enormous potential. It uses a minimal number of experiments to
provide an empirical process model for the interrelationship between the control and
disturbance variables in the process and the resulting product and process characteristics.
An appropriate system analysis of the process parameters, their adjustment ranges and the
selection and measurability of the target variables must be carried out.
Figure 7.I-6 Methods of statistical design of experiments (DoE)
to enlarge,
click here!

In contrast to conventional process development using the variation of parameters for

each experiment, DoE advocates virtually maximizing the "experiment space" and hence
varying several factors at the same time.
As part of the DoE, experiment designs are created which take account of the following:

Number of factors to be investigated (at least two)

Type of factors to be investigated:
o qualitative features: nominal (e.g.: yes/no or good/bad) or ordinal
(sequential relationship, e.g.: grouping, >, =, <)
o quantitative features: continual (infinite value range, e.g. temperature
measurement values or diameter of a tablet) or discrete (integer observed
values, e.g. manufactured packages/hour or deviations/batch)
Inclusion of existing information
Determination of the desired accuracy and reliability of the evidence

Conventional designs in DoE (see figure 7.I-6) are

Full factorial designs

Fractional factorial designs
Central composite designs
Box-Behnken designs
D-optimal design
Taguchi designs

Mixed designs

In particular, fractional factorial designs (so-called screening designs) provide the

possibility of significantly reducing the number of experiments. Results from screening
designs can also be transferred to a subsequent series of experiments with less
investigated factors, known as response surface designs. Response surface designs are
used to determine and then optimize non-linear interrelationships.

7.I.4 Multivariate Data Analysis (MVDA)

Large data records with several variables can be reliably interpreted with multivariate
data analysis (MVDA). In the MVDA, the probabilistic criteria of univariate statistics are
joined by added algebraic criteria for reducing the dimensionality of the feature or sample
space and by geometric criteria for suitable graphical representations. It should be noted
that the problems of estimating parameters and inferring the whole from the random
sample that are prominent in univariate statistics are generally secondary concerns in
multivariate statistics and data analysis. In this respect, multivariate statistics and data
analysis can only be considered as a generalization of univariate statistics and data
analysis.
Multivariate data is organized in a matrix, i.e. as a data table, that has as many rows as
the number of objects/samples being investigated and as many columns as the
features/variables being measured.
The following methods, among others, are employed for this:

Principle of principal components analysis (PCA)

Multivariate regression methods
o Multi-linear regression (MLR)
o Partial least squares regression (PLS-R)
o Principal component regression (PCR)
Creation of multivariate calibration models for predicting unknown data

Summary

Quality must be generated by a suitable process design; this is an important

prerequisite for valid processes.
A suitable process design must be created in the development phase.
The design space concept allows processes to be designed flexibly so that they
can adapt to various starting material qualities and process conditions.
DoE allows the relationship between control and disturbance variable and the
resulting product and process characteristics to be recognized with a minimum
number of experiments.
Large data records can be reliably interpreted with MVDA.

Notice

Copyright:
Maas & Peither AG
GMP Publishing
Himmelreichstrasse 5
D-79650 Schopfheim (near Basel)
Tel +49 (0)7622 666 86-70
Fax +49 (0)7622 666 86-77
eMail [email protected]
info http://www.gmp-publishing.com

7.J Process Analytical Technology (PAT)

"Process Analytical Technologies (PAT) is a system for designing, analyzing, and
controlling manufacturing through timely measurements of critical quality and
performance attributes of raw and in-process materials and processes with the goal of
ensuring final product quality." (Definition from the FDA and EMEA)

7.J.1 Process-analytical measurements

Process analytical measurements are characterized by the fact that they are taken close to
the process, i.e. at-line, on-line or in-line (see figure 7.J-1).
Figure 7.J-1 Options for process analytical measurements
to
enlar
ge,
click
here!

Figure 7.J-2 shows the difference in the process control between the use of PAT and
conventional analysis of intermediate and finished products.
Figure 7.J-2 Approaches to conventional and PAT controlled processes
to enlarge, click
here!

PAT should not, however, be considered as an exclusively analytical instrument. It is not

only the application of modern analysis technologies, such as NIR/Raman spectroscopy
or acoustic measurements. PAT should also not be taken to mean that product-related
investigations are simply replaced with at-line, on-line or in-line investigations (see
figure 7.J-1). In fact, a clear understanding of the analytical technologies used and their
strengths and limitations is an essential requirement for the application of PAT. For this,
it is often necessary to employ a number of suitable, coordinated tools (see figure 7.J-3).

Figure 7.J-3 PAT tools

to enlarge, click here!

For example, the analytical determination of the residual moisture in a granulate is
measured using suitable in-process controls (on-line or in-line), and the results are then
chemometrically evaluated. The critical factors of the drying process are then determined
on the basis of a statistical design of experiments (DoE), and options to improve the
control/regulation of the process are thus established.
The user must therefore have a good understanding of the process that is to be checked or
controlled using PAT. This requires himor her to know and be able to explain the causes
of critical variabilities and counter regulate them with suitable process control. Finally,
the PAT user must be able to predict the quality of the finished product given certain
material specifications, process parameters and other manufacturing and environmental
conditions. The application of PAT therefore requires a necessarily profound
understanding of the process.
Nowadays, there are a large number of new analytical and chemometric options for
improving pharmaceutical development, manufacture and quality control with which
innovative approaches to product and process development and process analysis and
control can be implemented. Systems supported by fiber optics in particular, such as FTNIR and Raman technology, provide the possibility of direct in-process control without
the samples having to be extracted or complex wet-chemical investigations having to be
carried out.

7.J.2 Evaluation of the data

The considerable volumes of data that are generated when PAT is employed represent a
challenge. They can essentially only be processed with powerful computer-assisted
systems. The amount of data requires an appropriate evaluation using suitable
chemometric tools (for an example, see figure 7.J-4).
Figure 7.J-4 Chemometric tools in NIR spectroscopy
Chemometric tools in NIR spectroscopy

Data preprocessing procedures (comparison of mismatching between spectra,

highlighting of structural features), e.g. using multiplicative scatter correction
(MSC), standard normal variates (SNV), smoothing algorithms (polynomial
fitting after Savitzky-Golay or Taylor)
Data compression by means of principal components analysis (PCA)
Multivariate classification/qualitative analysis, e.g. using cluster analysis
Multivariate regression/quantitative analysis, e.g. using principal component
regression (PCR), partial least squares regression (PLSR)

From an implementation point of view, it should be noted that the calibration models
(spectrum libraries) used for comparison or standardization purposes cannot generally be
transferred from one measuring system to another, i.e. they are only valid for one factory
and possibly only for one facility. The quality of the calibration model is also heavily
dependent on the accuracy of the reference data, the selection of the calibration set, the
individual instrument configuration (measurement mode) and the multivariate spectrum
analysis (data preprocessing, regression algorithm). This limits much PAT usage to the
field of large batch manufacturing in which the considerable effort associated with the
creation of the calibration model is economically calculated.

7.J.3 Possible applications

In the pharmaceutical industry, there is a range of possible applications for PAT. A small
selection is shown in figure 7.J-5.
Figure 7.J-5 Possible applications for PAT
Possible applications for PAT
Determination of moisture
o Lyophilized powders
o Granulates
o Tablets

Determination of content
o Parenteral
o Powdered mixtures
o Tablets

Determination of identity
o Starting materials
o Packaging materials
o Finished products

PAT follows the quality by design (QbD) principle, which is described in detail in the
ICH Q8 document Pharmaceutical Development (see chapter E.7 ICH Q8:
Pharmaceutical Development). QbD and PAT is being actively developed and pursued by
the EU and USA regulators. It can be fully expected that the pharmaceutical industry will
continue to see further evolution of these concepts into the future as an opportunity to
improve products while improving efficiency and costs.

Figure 7.J-6 Basic principles of PAT and QbD

The basic principles of PAT and QbD
Detailed understanding of the process and the parameters to be controlled
Recording of the critical process parameters that cause process fluctuations and
variations in quality
Development of a checking and control system for ensuring process
reproducibility and product quality

It is an important objective to ensure that all possible types of variation that can influence
a process are recognized, understood and handled by means of suitable process checking
and control. This focuses on the critical product and process parameters, for which reason
the ICH Q9 document Quality Risk Management should also be taken into consideration
in this context (see chapter E.9 ICH Q9: Quality Risk Management). These principles can
naturally also be transferred to the manufacture of APIs.
Figure 7.J-7 Comparison between conventional processes and
PAT-controlled processes
to
enlarge,
click
here!

The consistent application of PAT can cause a paradigm shift in conventional

pharmaceutical manufacturing:
Without PAT: in conventional manufacturing processes, the critical process parameters
are fixed as far as possible by the marketing authorization. As a result, the manufacturing
instructions derived from the authorization are relatively strict and allow only minimal
deviations during the process cycle. Normally, pharmaceutical manufacture is carried out
using batch production and laboratory tests for quality analysis are performed on selected
samples (see figure 7.J-7). Changes to process parameters require the regulatory
authorities to be advised of the amendment. This makes it more difficult to achieve

ongoing knowledge acquisition and improvements. Because the conventional process is

primarily monitored using the quality of intermediate and final products, preventative
control for quality assurance is not usually (comprehensively) possible. If there is a strict
process design, changes to the starting material properties inevitably result in - usually
undesirable - changes to the properties of the final product. This can be traced back to the
lack of knowledge about the internal sequence of operations and material-oriented
adaptations to the process parameters are not possible.
With PAT: the application of PAT allows a process to be measured and controlled in
real time. Variations in starting materials and intermediates can be ideally overcome by
adapting the relevant process parameters so that the quality of the final product remains
the same. This means that processes can be configured in a flexible way. Granulate
drying or powder mixing is not strictly ended after the specified time, but rather
continues until the specified product properties or process features that are monitored and
controlled with PAT have been achieved.

7.J.4 Implementations of PAT

For the implementation of PAT, relationships or dependencies between parameters must
be covered by multivariate data analyses (MVDA) based on solid data (e.g. batch
documentation, data from the Laboratory Information Management System (LIMS)). If
historical data is not available (or not in sufficient quantities), it must be compiled on the
basis of a statistical design of experiments (DoE). A procedure of this kind requires a
multidisciplinary approach: representatives from different disciplines (e.g.
chemometry/statistics, instrumental analysis, system technology, informatics) must work
closely with each other. The sequence of operations and the product must be subjected to
a careful risk analysis. The decision must be made as to which analytical system should
be used and at which processing step in order to achieve meaningful monitoring. Finally,
variabilities in the process should not be simulated by excessive fluctuations in the
measuring system itself. For this, it will be essential to recognize all types of critical
process variations and to reduce them far enough that a stable and reproducible process is
achieved. The results can then be used to determine the critical PAT parameters. It is
advisable to use quality control cards for the continuous monitoring.
PAT allows a number of questions to be more easily answered for the field of
pharmaceutical development, such as:

What influences the release of the medical substance?

How do differences in the quality of APIs and excipients affect the final product
quality and how does the process react to the variabilities?
Which process parameters are important for final product quality?

7.J.5 Advantages of PAT implementation

The implementation of PAT in new manufacturing procedures or in existing

manufacturing operations can bring about advantages with regard to cost and the
competition.
The benefits of PAT implementation are:

greater flexibility in process design, also from a regulatory point of view;

"a reduction in costs due to the prevention/reduction of errors, an improvement in
processing times and yield;
a reduction or elimination of end-product testing with an impact on release,
meaning that the product can be released immediately at the end of the process on
the basis of PAT data (real-time release);
simplification of the initial and ongoing process validation (replacement of the
three validation batches with continuous validation); and
Simplified implementation of changes to starting materials.

7.J.6 PAT in the USA and Europe

The procedure for implementing PAT brought about a need for further harmonization,
which still exists today, on the part of both industry and the authorities. This is
particularly the case concerning the documentary evidence required in the authorization
process and in practice, and concerning the correlation between process measurement
data and approval decisions. On the part of industry, there is sometimes the fear that the
introduction of modern technologies would raise the standard of the authorization
procedure and the expectations of the regulatory authorities. In the past, this has caused
industry to hold back from submitting new PAT applications, which is not a desirable
outcome from the point of view of health protection and the necessity for the continual
improvement of products and processes. Recognizing the need to counteract this general
reticence towards innovation, the FDA started a new initiative called Pharmaceutical
CGMPs for the 21st Century: A Risk-Based Approach in August 2002. The FDA made
PAT one of the central points of their GMP Initiative for the 21st Century and, in 2002, it
founded an internal PAT working group to focus on this. In 2004, the FDA brought out
its Guidance for Industry PAT - A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance, in which it sets out its ideas for the
application of process-analytical technologies in the pharmaceutical industry (see chapter
D.11 Guidance for Industry PAT - A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance).
At the European level, a PAT working group composed of assessors from the regulatory
authorities and GMP inspectors was established by the EMEA in 2003.
The objectives of the working group include the following:

To determine the need to adapt the rules for the use of PAT technologies and, if
necessary, to develop additional guidelines for the authorization process and for
inspections.

To define approval procedures in connection with the application of PAT

To coordinate the sampling and investigation procedures of the official
investigation centers (OMCLs) in connection with PAT
To develop procedures for analysis during the authorization process and
inspections using models of application files for marketing authorization for PAT
applications
To ensure a regular exchange of experiences with EDQM and FDA

At the EU level, there is already an array of relevant rules for PAT, which must be
observed during implementation and application:

Development of Pharmaceutics (CPMP/QWP/054/98)

Note for Guidance on Parametric Release (CPMP/QWP/3015/99)
Annex 17 to the EU-GMP Guideline (see chapter C.6.17 Annex 17 Final version Parametric Release)
Note for Guidance on Near infrared spectroscopy (CPMP/QWP/3309/01)

The EMEA PAT working group has also published a Reflection Paper, which contains
information about the necessary chemical, pharmaceutical and biological data in the
application file for marketing authorization (Common Technical Document, CTD) for
PAT applications. The EMEA homepage also contains a Questions and Answers section
in which general interest questions about PAT applications are answered.
Industry also established PAT working groups at an early stage, e.g. the European
working group of the EFPIA (European Federation of Pharmaceutical Industries and
Associations) and the PAT working groups of the ISPE (International Society for
Pharmaceutical Engineering) and the ASTM (American Society for Testing and
Materials).
Summary

Notice

PAT is a system for control and regulation in manufacturing.

PAT is used for real-time measurement of critical process or product attributes.
PAT enables flexible process design in accordance with the properties of the
starting materials and intermediate products.
PAT allows processes to be run more efficiently and with fewer errors.
Consistent use of PAT makes real-time release possible.
"PAT is being strongly supported in concept by both the EU and the USA
regulators

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