Process Validation (PV) &

Verification of Drug Product

 Post author:Janki Singh
 Post published:21/11/2020
Standard Operating Procedure (SOP), Guideline and Protocol for Process
Validation and Verification for Drug Product (Tablet, Capsule etc.)

Process Validation (PV) Procedure

1.0 Objective :

o To lay down the procedure for Process Validation of pharmaceuticals
products.

o Process validation provides documented evidence that a process is
capable of reliably and repeatedly render a product of the required
quality.
2.0 Scope :

o This SOP is applicable for process validation and process verification of
Pharmaceuticals Products.
3.0 Responsibility :

Chemist QA :  To prepare & review the process validation

and above protocol & validation report.
 To draw samples as per validation protocol, and
submit to Quality Control for analysis.

Officer QC and :  To analysis validation samples with the

above validated method & submit the results to Head
Quality control.

Head :  To review the process validation protocol &

QC/Designee report.
 To update the laboratory for validation sample
analysis & planning for analysis, interpretation
the data of analysis or contract validation
testing.

Chemist :  To execute process as per routine production

Production and batches and as guided by validation protocol.
above

Engineering :  To provide the supporting utility systems.

Production :  To review the process validation protocol &
Head/Designee report.
 To Plan & supervise manufacturing/validation
activity.

Head :  Approval of process validation protocol and

QA/Designee report.

4.0 Procedure – Process Validation & Verification :


o General Procedure for Process Validation

o Process validation shall be carried out for the drug products, which are
being manufactured for the first time.

o Homogeneity within a batch and consistency between batches are
goals of process validation activities.

o Process Validation shall consist of the manufacture of the product on
the equipment specified for the purpose.

o Process validation shall include in-process control procedures to assure
final product quality.

o Each step of a manufacturing process is controlled to assure that the
finished product meets all quality attributes including specifications.

o The number of batches manufactured and the number of samples taken
should be based on quality risk management principles, allow the
normal range of variation and trends to be established and provide
sufficient data for evaluation.

o An initial validation exercise with minimum three batches may need to
be supplemented with further data obtained from subsequent batches
as part of an on-going process verification exercise.

o Prerequisites for Process Validation:

o Validation shall be performed for new manufacturing processes,
equipment and when major changes have been made or implemented
to premises, systems, equipment, materials and /or processes.

o Ensure that all relevant SOP’s are in place and training is completed on
equipment operations, manufacturing instructions and sampling
strategy are in place.

o Also that the operators and supervisory persons who will be running the
validation batches have the understanding of the process.

o The process validation requires that method validation, calibrated
instruments and qualified production support systems shall be
 established with proper documentation prior to execution of process
validation studies.

o Furthermore, the process shall be fully developed, optimized and
documented.

o Process validation shall focus on process performance at the set-point
of each operating parameter range.

o When any new manufacturing formula or method of preparation is
adopted, validation shall be done to demonstrate its suitability for
routine processing.

o Validation can be prospective, concurrent or revalidation depending on
when validation is performed but the type of validation shall be
recorded in the respective validation protocol.

o In case of prospective or concurrent validation studies, the protocol
shall specify a sufficient number of replicate process runs to
demonstrate reproducibility and provide an accurate measure of
variability among successive runs.

o The test conditions for the validation runs shall encompass upper and
lower processing limits and circumstances, including those within
standard operating procedures, which pose the greatest chance of
process or product failure compared to ideal conditions.


o In case of prospective and concurrent validation,


o The process validation protocol shall be written in a standard format
that would enable the user to demonstrate that a process step, process
condition, test requirement, or other relevant parameter or item that
must be controlled within predetermined criteria to ensure that the
product meet it specifications.

o The process validation protocol shall be prepared by the Quality
Assurance department.

o The protocol shall be submitted for initial document approval prior to
beginning of the execution in case of contract manufactured product.
 Process validation involves a series of activities taking
place over the lifecycle of the product and process as
mentioned below:
o Stage 1: Process Design Development :

o The commercial Manufacturing process is defined during this stage
based on knowledge gained through development and scale-up
 activities that can consistently deliver a product that meets its quality
attributes.

o A successful validation program depends upon information and
knowledge from product and process development.

o It enables us to

o
 Understand the sources of variation.

o
 Detect the presence and degree of variation.

o
 Understand the impact of variation on the process and ultimately on
product attributes.

o
 Control the variation in a manner commensurate with the risk it
represents to the process and product.

o Stage II: Process Qualification/ Validation :

o During this stage, the process design is evaluated to determine if the
process is capable of reproducible commercial manufacturing.

o This stage has two elements:

o
 Proper design of manufacturing facility

o
 Equipment must be of appropriate design, adequate size and
suitably located

o
 Automated, mechanical and electronic equipment must be
calibrated, inspected or checked.

o
 Utility systems and equipment are built and installed in compliance
with the design specification and qualified (e.g. built as designed
with proper materials, capacity, and functions, and properly
connected and calibrated).

o
 Utility systems and equipment operate in accordance with the
process requirements in all anticipated operating ranges.

o Process Performance Qualification:

o
 Higher level of sampling

o
 Additional testing

o
 Greater scrutiny of process performance

o Stage III: Continued Process Verification:

o An alternative approach to process validation in which manufacturing
process performance is continuously monitored and evaluated.

o Establishing a Monitoring Program:

o A Program of Continued Process Verification (CPV) provides a means to
ensure that processes remain in a state of control following the
successful process qualification stage.

o The information and data collected in stages 1 and 2, set the stage for
an effective control strategy in routine manufacturing and a meaningful
CPV program.

o The understanding of functional relationships between process inputs
and corresponding outputs established in earlier stages in fundamental
to the success of the CPV program.

o Continued monitoring of process variables enables adjustments to
inputs covered in the scope of a CPV plan.

o It compensates for process variability, to ensuring that outputs remain
consistent.

o Since all sources of potential variability may not be anticipated and
defined in stage 1 and 2, unanticipated events or trends identified from
continued process monitoring may indicate process control issues and /
or highlight opportunities for process improvement.

o Science and risk-based tools help to achieve high levels of process
understanding during the development phase, and subsequent
knowledge management across the product life stage and facilities
implementing continuous monitoring.

o Documenting the Continuous Process Verification
Program:

o A product-specific Continuous Process Verification (CPV) plan should
include the following elements:

 o
 Roles and responsibilities of various functional groups.

o
 Sampling and testing strategy.

o
 Data analysis methods (e.g., statistical process control methods).

o
 Acceptance criteria (where appropriate).

o
 Strategy for handling Out of Trend and out of specification

o Continuous Process Verification data review:

o Continuous process verification is required during product life cycle
either

o
 Introduction of new commercial product e. Stage IIIA

o
 Continued process verification for exiting product e. Stage IIIB

o The goal of this stage is continual assurance that the process remain in
state of control (i.e. Validation stage) during the commercial
manufacturing.

o A system(s) for detecting unplanned departure s from the process as
designed is essential to accomplish this goal.

o Evaluation of Post-PPQ batches of new commercial
products i.e. Stage IIIA

o Batches manufactured during PPQ study shall be evaluated to get
assurance of the process/product robustness and to identify the drifts,
Refer the CPV program for new product, if there is not significant
variability observed during PPQ study, New product shall be directly
considered as routine batch and shifted in Stage IIIB and monitoring
shall be done.

o If there was variability in any of the process parameter or Quality
attributes as concluded in the process validation report then this stage
III A is applicable to products

o If new products are developed according to QbD principles, the CQA,
CPP, CMA and control strategy identified during development (Stage I,
process design) are based on process understanding and quality risk
management provided by the R&D for CPV monitoring.

o Strategy of all site shift products introduced at site first time shall be
decided based on the conclusion made in the Stage-II i.e. in the process
validation report of respective product.

o Protocol shall be designed accordingly.

o The number of batches requirement will be evaluated based on the
outcome PPQ study that should identified in respective report based on
the respective parameter variability and accordingly the sampling plan
can be decided based on the statistical analysis.

o Based on the assessment/trend impact on the validated state shall be
evaluated and accordingly improvement plan shall be finalized if
required.

o Post monitoring, if process considered in state of control the routine
batch release shall be proceeds with defined sampling plan and
acceptance criteria.

o Preparation of continuous verification protocol

o All new products become part of the CPV program stage-IIIA after their
stage-II validation.

o The CPV protocol should be prepared as per product name, details and
the protocol shall define the concept, the criteria and the scope of
trending and reporting for identified parameters as concluded in the
Stage-II.

o The protocol should be revised whenever one or more changes in
process are made to establish new CPV limits if required.

o Selection of CQAs, CPPs and CMAs for monitoring:

o For new development product the specific CQAs, CPPs and CMAs are
given by R&D Department based on risk assessment in product
development report (PDR) and experience from Process validation.

o For all site shift product the critical process parameters and critical
quality attributes included in the enhanced sampling and testing in
Stage 2 should be considered initially for continued monitoring in Stage
3 based on the variability.

o With the appropriate risk-based analysis and documented justification
(scientifically and statistically justified), certain Stage 2 parameters
may be eliminated or the level of sampling testing could be reduced in
the Stage III plan.

o Number of batches for defining CPV limit :

o Data from a minimum of 30 batches after PPQ will be required, but
number of batches can be reduce or increase based on the variability in
the process parameter or results and with scientific rationale.

o Evaluation and establishment of CPV limit

o When evaluating the performance of a process, it is often useful to set
limits to provide an indication about when the variability of a parameter
or attribute may be changing, and therefore, needs further attention.

o QA personnel shall enter the values of CPPs from executed BMR and QC
personnel shall enter the values of CMAs and CQAs in worksheet form
in analytical reports as required.

o The data should be statistically trended and reviewed by trained
personnel (with adequate training in statistical process control
techniques).

o While collecting the data of a minimum of 30 batches or as defined, if
any change is made in manufacturing process through change
management and such a change has an impact on critical attributes,
then the process of data collection has to be restarted after the change
is made effective and with proper justification, in order to establish CPV
limits.

o The new set of data must cover a minimum of 30 batches.

o Where special causes for variations are identified, these values should
be removed from calculations for the establishment of CPV limits.

o The real-time control (±3 sigma) shall be considered as limit before
releasing of any batch.

o This control evaluation shall be started after production of 30 batches
in order to collect sufficient data.

o Any outlying data shall be investigated.

o While it is possible that past data may fall as an outlier, this must be
investigated and documented.

o Report for freezing the CPV limit

o This should define the CPV limit of each attribute being monitored as
identified.

o This should evaluate the process capability index of each attribute as
identified.

o This report might suggest ways to improve and/or optimize the process
by altering some aspect of the process or product, such as the
 operating conditions (ranges and set-points), process controls,
component, or in-process material characteristics.

o When the root cause(s) has been determined for results which are out
of CPV limits, then, for purposes of improvement of process, QA
personnel together with subject matter expert/s shall take necessary
corrective and/or preventive action(s) for such improvement.

o The report should assess the action plan for improvement of process,
i.e. to check if the change(s) in process design require:

o
 Re-development of process.

o
 Re-process validation (verify control strategy).

o
 Reestablish process and sampling plan.

o Existing/legacy products developed traditionally may not have critical
attributes or parameters defined in their submissions shall also be
considered for process verification as per above procedure.

o If drug product/substance, not having defined CQAs, CPPs, and CMAs
with PDR and PPQ reports, is adjudged to have a level of risk, the risk
assessment shall be performed by a cross-functional team in order to
identify CQAs, CPPs, and CMAs for monitoring in CPV.

o The assessment will be based on TT, engineering batch report, PPQ
report, OOS, OOT, CC, audit outcome and deviations, product
performance on stability, outcome of management review, based on
APQR, and current process understanding.

o Continued Process Verification for existing routine
product i.e. Stage IIIB:

o The routine batch monitoring and release shall be done as follows (But
Not Limited to)

o Product Quality Review (PQR):

o PQR is an organized and comprehensive evaluation of all production,
analytical and quality assurance data associated with drug products,
done annually to identify needs for any corrective / preventive actions
that would lead to product improvements and also ensure that the
process remains in control.

o Maintaining the quality of incoming materials and components by
means of a comprehensive testing program for same data of key
incoming materials / components used for a product shall also be
 evaluated / trended to check for need for any corrective / preventive
actions either as a part of the PQR process, or through a separate
program.

o Timely assessment of Deviations, Changes, Out-of-Specification
Results, Product Quality complaints by carrying out Investigations, Root
cause Analysis and initiating CAPAs for same as well as trending of
them periodically.
o Ongoing programs to collect and analyze product and process data that
related to product quality with the help of trends, etc. i.e. In process
and Finished product testing controls and OOT monitoring.

o Maintenance of facility, Utilities and Equipment:

o Maintenance of a facility, Utilities and Equipment is an important aspect
of ensuring that a process remains in a “State Of Control”.

o Once established qualification status shall be maintained through
exhaustive preventive maintenance program, periodic Performance
verification of equipment / utilities, routine monitoring program of
facilities, Requalification program for utility.

o For all ongoing products continuous process verification shall be
consider as PQR

o Detail APQR Procedure to be followed as per respective SOP .
 Continuous process verification tools

o Continued Process Verification can be done using many tools and
methodologies as mentioned PQR SOP

o Some of them are listed below:

o
 Graphical charts; for example, Control charts. Line charts can also
be used as tools to determine whether a manufacturing process is in
a state of statistical control.

o Statistical tools as explained below:

o
 Calculation of control limits

o The UCL and LCL shall be calculated as below:

o
 UCL (Upper Control Limit) = Average + 3σ

o
 LCL (Lower Control Limit) = Average – 3σ

 o
 Where Average stands for mean and σ stands for standard
deviation.

o
 For CPP and CQA with a single-side specification, the UCL and LCL
shall be considered as below:

o
 Products having Upper Specification Limit, only UCL shall be
considered

o
 Products having Lower Specification Limit, only LCL shall be
considered

o If the calculated UCL and LCL are different from the specification limits,
then specification limits shall be consider as UCL and LCL.

o Statistical process control indices which should be used are Cp (Process
Capability), Cpk (Process Capability Index), Pp (Process Performance)
and Ppk (Process Performance Index).

o Cp is a capability tracking mechanism, which compares the width of a
product with variation with the process. This metric uses estimated
standard deviation.
 Formula for two-sided specification:
Cp = (Allowable Range) / 6 X SD i.e. (UQL-LQL) / 6 X SD

o Cpk uses estimated standard deviation to determine how well a system
can meet the specification limits.

o It also takes the target value into account.

o Cpk shall be calculated for both side i.e. on UQL and LQL and minimum
of both shall be considered as Cpk.
 Formula for one-sided specification:
CpK (min), Lower = Estimated Mean – LQL / 3 X SD
CpK (max), Upper = UQL-Estimated Mean / 3 X SD
Where,

o Cpk: evaluate the centering of the process (minimum of C pK (min) and CpK (max))

o SD: Denotes standard deviation.

o UQL: Denotes Upper Quality level

o LQL: Denotes Lower Quality level

o Acceptance criteria for Cp and Cpk:

 o Cpk ‹ 1.0, then process is not capable.

o Cpk =1.0-1.33, Process is barely capable and in state of control with
alert.

o If Cpk ≥1.33 Process is capable and in state of control.

o Same criteria are applicable for Cp.

o Pp shows process performance. It indicates well a system performs
when it comes to upper and lower specification limits.

o However, it does not focus on the average and instead concentrates on
the spread, formula for Pp is similar as Cp.

o Ppk uses actual standard deviation to determine process variation.

o The capability rate for Ppk is calculated using the formula below as per
Cpk.
 Types of Process Validation:

o Prospective process validation:

o This shall be performed before an entirely new product is introduced by
the company or when there is a change in the manufacturing process
which may affect the product’s characteristics, such as uniformity and
Identity etc.

o During product development the production process may be broken
down into individual steps.

o Each step can be evaluated on the basis of experience or theoretical
considerations to determine the critical factors/parameters that may
affect the quality of the finished product.

o A series of experiments may be devised to determine the criticality of
these factors.

o Representatives from production, QC/QA, and engineering development
will normally be involved in this process.

o These experiments may incorporate a challenge element to determine
the robustness of the process.

o Each experiment should be planned in an authorized and documented
protocol.

o The criticality of these factors should be determined through a “worst-
case” challenge where possible.

o Master Batch Documentation can be prepared/finalize only after the
critical parameters of the process have been identified and machine
settings, component specifications and environmental conditions have
been determined.

o The batches/runs under validation should be documented
comprehensively.

o The following items should be included in the validation
report:


o
 A description of the process – Batch/Packaging Document, including
details of critical steps.

o
 A detailed summary of the results obtained from in-process and final
testing, including data from failed tests.

o
 When raw data are not included reference should be made to the
sources used and where it can be found.

o
 Any work done in addition to that specified in the protocol or any
deviations from the protocol should be formally noted along with an
explanation.

o
 A review and comparison of the results with those expected.

o
 Formal acceptance/rejection of the work by the team/persons
designated as being responsible for the validation, after completion
of any corrective action or repeated work.

o Concurrent Process Validation:

o If concurrent validation approach shall be adopted, there should be
sufficient data to support a conclusion that any given batch of product
is uniform and meets the defined acceptance criteria.

o The results and conclusion should be formally documented and
available to the Qualified Person prior to certification of the batch.

o
 It is important in concurrent process validation, however, that the
premises and equipment to be used have been previously qualified
and that the decision to carry out concurrent validation is made by
authorized personnel.

o
 Documentation requirements are the same as specified for
Prospective Validation and the testing to be carried out in-process
and on the finished product will be as specified in approved
protocols.

o
 The completed protocols and reports for the batch to be released
should be reviewed and approved before product is released for sale
or supply.

o
 This shall be carried out during routine production of products
intended for sale.

o Prospective & Concurrent Validation:

o
 The number of batches (minimum of 3) should be based on the
variability of the process, the complexity of the process product and
experience.

o
 Validation studies shall be carried out on minimum 3 consecutive
batches of the product manufactured by the same manufacturing
process, under identical conditions and set or equivalent of
equipment controlling the critical process parameters on the basis of
Process validation Protocol and tested for compliance to the pre-
determined specification which also includes in-process sampling
and testing,

o
 Process validation protocol specific the manufacturing conditions,
control, testing and expected outcomes.

o
 A process validation protocol should be prepared which defines the
critical process parameters (CPP), critical quality attributes (CQA)
and the associated acceptance criteria which should be based on
development data or documented process knowledge Process
validation protocol shall include, but are not limited to the following

o

 A short description of the process and a reference to the
respective Master Batch Record;

o

 Functions and responsibilities;
 
o

 Summary of the CQAs to be investigated;

o

 CPPs Summary and their associated limits;

o

 Summary of other (non-critical) attributes and parameters which
will be investigated or monitored during the validation activity,
and the reasons for their inclusion;

o

 List of the equipment/facilities to be used (including
measuring/monitoring/recording equipment) together with the
calibration/qualification status;

o

 List of analytical methods and method validation, as appropriate.

o

 Proposed in-process controls with acceptance criteria and the
reason(s) why each in-process control is selected;

o

 Additional testing to be carried out with acceptance criteria;

o

 Sampling plan and the rationale behind it;

o

 Methods for recording and evaluating results;

o

 Process for release and certification of batches (if applicable).
 Process evaluation and selection:

o Select and mention the processing steps needed for the initial scale-up
in protocol are as follow but not limited to.
S Oral liquid Tablet Capsule
r
.
N
o

1 Physicoche Dry Mixing : Blending :

. mical param  Mixing time  Flow properties
eters  Uniformity of  Moisture content/LOD
 Appearance Content (If  Uniformity of Blend (If
 pH applicable) applicable)
 Weight per  Speed of
ml impeller

2 Mixing: Granulation: Filling of Capsules

.  Determine  Binder  Powder flow from hopper
and temperature  Height of Powder in Hopper
evaluate  Speed of  Speed of Filling Machine
specificatio impeller  All physical characteristics
n  Speed of i.e. Average Fill Weight,
 Mixed chopper Uniformity of Fill weight,
ingredients  Ampere load Disintegration / Dissolution,
Appearance  Time for locking of capsules etc
 In-process addition of
testing binder
 Assay of  Moisture
the active content/LOD
ingredient

3 Filling and Drying Packing:

. sealing  Optimal LOD  Forming Temperature
 Uniformity of the dried  Sealing Temperature
of volume granulation  Machine Speed
 Sealing of  Air Flow, Inlet  Sealing i.e. Leak Test
the bottle Temperature,  Coding Details
 Presence of and Outlet
foreign Temperature
particles. & Load to be
 Homogenei dried.
ty,  Racking time
wherever and intervals
required  Drying time

4 —– Blending —–
.  Mixing Time
 RPM of
blender (If
applicable)
 Flow
properties
  LOD
 Uniformity of
blend (If
applicable)

5 —– Tablet (core) —–
. compression
 In-process
checks at
variable
machine
speed &
Compaction
force
(Hardness)
 Height of
powder in
hopper

6 —– Coated tablets —–
.  Wight gain,
Inlet
temperature,
Bed
Temperature,
Pan Speed,
Peristaltic
pump, Spray
rate & cycle,
Solution
stirring,
Atomizing Air
pressure.
 Pan negative
pressure,
Distance
between Gun
& bed.

7 —– Packing: —–
.  Forming
temperature
 Sealing
Temperature
 Machine
Speed
 Sealing i.e.
Leak Test
 Batch Coding
Details
 (embossing
and printing )

o The drug having dose proportional formula shall be validated once up
to common stage and all subsequent stage shall be validated
separately.

o Individual quantifiable acceptance criteria will be pre-defined and
specified for all process critical parameters in the individual protocols.
 Revalidation Criteria:

o Once a process has been validated, it is considered to be in a state of
control.

o As long as all conditions and control parameters remain unchanged, the
process continues in its validated state.

o Consideration for the need revalidation, whenever there is change in,
Revalidation shall be considered under following considerations and it
should be initiate through change control procedure.

o Revalidation shall be carried out for following cases:

o
 Change in formula

o
 Change in Manufacturing (Procedure and/or process)

o
 Raw materials change (physical properties such as density,
viscosity, particle size etc.)

o
 Change of API source.

o
 Batch size change.

o
 Change in or modification of critical equipment.

o
 Change in facility and installations, which influence the process.

o
 Manufacturing area or site change.

o
 Transfer of processes to another site or unit.
 
o
 As per the recommendations In Change Control form, Investigation
reports or complaint evaluation and on appearance of negative
quality trends, if required.

o
 On the basis of annual product review, self inspection, trend analysis
or non conformance.

o The revalidation study shall be carried out as per the protocol prepared
for individual activity.

o The revalidation protocol and report shall prepared as per procedure
described for prospective and concurrent validation
 Risk Assessment:

o This includes rationale for critical process parameters and critical in
process parameters including the worst case scenario consideration or
challenge study to be performed for the selection of critical process
parameters as per SOP for Quality Risk Assessment.

o Rationale for Critical Process Parameters: This shall indicate the
rationale for the selection of critical process parameters.

o Critical in process controls: This shall define the rationale for the
selection of critical in process parameters used in the process
validation study.

o Worst case scenario or challenge study: This shall include the
challenges during the process validation considering the probable
failures or worst case parameters without affecting the quality
attributes.
 Sampling Plan and Acceptance Criteria:

o The validation team shall schedule the validation program & inform the
respective departments about the program.

o The validation team shall consist of staff members from Production,
Quality Control, Engineering and Quality Assurance.

o Validation activity shall be performed by validation team.

o The responsibility of each department shall be mentioned in the
respective validation protocol.

o Process parameters that could affect the critical quality attributes of
the product shall be identified.

 o Key parameters shall be frozen in Process validation protocol and
associated batch records before undertaking process validation
exercise.

o Range for each critical process parameters expected to be used during
routine manufacturing and process control shall be determined.

o All the equipment/instrument to be used shall be checked for the
qualification & calibration status. Qualification & calibration status shall
be mentioned in report.

o The validation program shall only be started after the confirmation of
the equipment and instrument status.

o During the process validation extensive sampling and testing shall be
performed on the product at various stages and shall be documented
comprehensively.

o The sampling plan, including sampling points, number of samples, and
the frequency of sampling for each unit operation and attribute is
defined in respective protocol.

o The number of samples taken during validation shall be adequate to
provide sufficient statistical confidence of quality both within a batch
and between batches.

o The extent of sampling, tests and acceptance must take into
consideration the level of risk.

o Sampling Plan and Acceptance Criteria shall be as per
below table:

Stage Sampling Plan

For Tablet

Dry Mix ( If  Sample from at least five different

applicable) locations in triplicate evenly
distributed throughout the mixer
(e.g. RMG)
 Sample Size 1X – 3X (Where X:
Avg. Wt. of single dose unit)
 Send one set for analysis to QC
and two set shall be reserved with
QA (for investigation of OOS/OOT if
required.)
 Sample shall be destroyed after
completion of report.

Drying  One sample shall be analyzed after

 each drying or as defined in
protocol.

 At least 1 samples from different

locations after final drying process
as per sample plan.

Pre-blend or Final  Sample from at least ten different

Blend / Mix locations in triplicate evenly
distributed throughout the
blending (e.g. Bin Blender).
 Sample Size 1X – 3X (Where X:
Avg. Wt. of single dose unit)
 Send one set for analysis to QC
and two set shall be reserved with
QA (for investigation of OOS/OOT if
required.)
 Sample shall be destroyed after
completion of report.

 Composite sample for QC analysis

as per protocol

Compression  Speed challenge, Hopper Level

Study and Hardness (Compaction)
challenge as per protocol.
 Sample quantity shall be sufficient
for complete testing of in-process
parameter.

 Composite sample for QC analysis

as per protocol

Coating  Composite sample for QC analysis

as per protocol

Primary  Speed challenge and temperature

packaging challenge shall be performed as
per protocol.

Finished Product  Sampling shall be done throughout

packing process as per protocol.

For Liquid

Before Filtration or  Samples from Upper Layer,

Sieving Middle Layer, Lower layer &
Mixed sample. (E.g.
Manufacturing Tank). Sample
 Size: 100- 200ml
 As per process validation
protocol (if applicable)

After Filtration or  Composite sample from (e.g.

Sieving Storage Tank)
 Sample Size: 100- 200ml as
per process validation
protocol (if applicable)

Filling, Sealing &  Sampling as per process

Labeling validation protocol

Finished product  Sampling as per process

validation protocol

For Capsule

Pre-blend or Final Blend / Mix  Sample from at least

ten different locations
in duplicate evenly
distributed throughout
the blending (e.g. Bin
Blender).
 Sample Size 1X – 3X
(Where X: Avg. Wt. of
single dosage unit)
 Send one set for
analysis to QC and one
set shall be reserved
with QA (for
investigation of
OOS/OOT if required.)
 Sample shall be
destroyed after
completion of report.

 Composite sample

Filling & Polishing  Speed challenge and

Hopper Fill Study shall
be carried out as per
process validation
protocol

Primary packaging  Speed challenge and

temperature challenge
shall be performed as
per protocol.
Finished Product  Sampling shall be done
throughout packing
process as per
protocol.

o Procedure for Sampling and Analysis:
o Sampling shall be done by trained QA person as per the sampling plan
described in validation protocol.

o QA shall send the sample with intimation as per Annexure-V to QC
department for analysis as per protocol.

o QC Personnel shall receive the sample with intimation.

o After complete analysis QC department shall provide the complete
report with raw data to QA.

o Validation data for all the critical parameters shall be collected &
evaluated against predetermined set of limits.

o A report of the validation shall be prepared by QA in computerized
format but not limited to defined contents in annexure.

o Contents shall be changed as per requirement.

o Summary report detailing the critical validated product/machine
parameter that is to be followed in routine production in future shall be
prepared & conclusion drawn from it shall be mentioned in the report.

o Recommendation of process validation report shall be
shared with user department.


o Any exceptional conditions encountered during Process Validation shall
be investigated and the appropriate course of action (justification,
correction, or re-qualification studies) determined.

o Any deviations or exceptions to approved protocols shall be noted,
investigated and resolved and if required CAPA shall be initiated and
shall be executed and closed.

o On completion of validation batches study, the respective documents
shall be revised to incorporate the changes in operational parameters if
recommended In the Process Validation report through change control
procedure.

o If a change is proposed in any of the procedures, processes, or
equipment, which may impact the quality then that, shall be done by
following change control procedures.

 o All changes must be formally requested, documented and accepted by
the Validation Team and Quality Assurance department.

o The proposed changes shall be scientifically assessed and based on
assessment need of re-validation or revision of document shall be
determined.

o After the confirmation that the process design is capable of
reproducible commercial manufacture, continuous process verification
of the process is carried out as per recommendation of process
validation report (If applicable).
 Release of Process Validation Batch:

o Validation batches shall be released after reviewing the Batch
Manufacturing & Batch Packing Record.

o Analysis results shall be reviewed and should be complying with the
specification.

o Interim report shall be prepared if three consecutive batches are not
manufactured.

o However, such batches shall remain under monitoring until accelerated
stability studies are completed.
 Stability studies:

o Stability samples from the process validation batches shall be drawn
and kept for stability study as described in the stability protocol.
 Storage of Documents:

o Process Validation protocol and validation reports along With attached
documents shall be filed and stored In Quality Assurance Department.

o Process Validation Planner shall be prepared as per Annexure No. VI
and updated annually.

o Ongoing Process validation/ verification detail shall be updated in
Annexure No. VII
5.0 Reference (S)

o Validation Master Plan

o Working Document QAS/03.055/REV.2

o Validation Guidelines for Pharmaceutical Dosage Forms (GUI-029)

o Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal
Products for Human and
o Veterinary Use, Annex 15: Qualification and Validation

 o Validation Master Plan Installation and Operational Qualification Non-
Sterile Process Validation Cleaning Validation (PI 006-3).

o WHO Technical Report Series, No. 937, Annex-4, Appendix-7
6.0 Annexure (S)
Annexure I : Flow diagram for process validation

Annexure II : Process Validation Protocol Number Issuance

log
 Sr. Date Product Name Batch size Protocol No. an
No. effective date

Checked by Report No. & Issued by Checked by

Effective date

Annexure III : Template for Process validation Protocol

Sr. Subject
No.

1. Table of Contents

2. Protocol Approval

3. Objective

4. Scope

5. Responsibilities

6. Validation Criteria

7. References

8. Product Profile

9. Description of Equipments to be used

10. Weightment sheet of Materials

11. Process Flow Chart

12. Sampling Plan

13. Methodology of Sampling

14. Abbreviation

15. Schematic diagram of equipment

16. Deviation/OOS (if any)

17. Enclosures

18. Revision History

Annexure IV : Template for Process validation Reports

Sr. No. Subject

1. Table of Contents

2. Approval

3. Objective

4. Scope

5. Responsibility of Validation Team

6. Batch Details

7. Training of Validation Team

8. Description of Equipments used

9. Summary of critical process parameters

10. Packing Details

11. Results of Finished Product

12. Yield

13. Deviation Report (If any)

14. Summary Report

15. Conclusion

16. Recommendation if any

Annexure V : Sample intimation Slip

Product Batch No. Batch Size

Mfg. Date Exp. Date Date

Stage

Sample for analysis for :-

Test √ (done) & x No. of Samples Sample collected

(not done) by QA
 Description

Physical Parameters

Uniformity of Content

Dissolution

Disintegration

Water / LOD

pH

Wt. per ml

Assay

Microbial test

Additional Test

Report Received By (QA)

Annexure VI : Process Validation Planner

Process Validation Planner …..
Document No.: ……..
Section: Dosage Form:
Effective Date:

Sr. Product Composition Reason Marke Batch Batc

No. Name for t No. h
validatio size
n

1.

2.
Sr. Product Composition Reason Marke Batch Batc
No. Name for t No. h
validatio size
n

3.

Particulars Prepared By Reviewed By Appro

Sign.

Date

Annexure VII : Ongoing Process Validation/ Verification

Detail

Sr. No. Product Name Composition Reason for Market

validation

1.

2.

3.

Sr. No. Batch size Validation Updated by Checked by

Status (sign./Date) (sign./Date)

1.

2.

3.

Particulars Verified By(Sign./ date) Approved By

Sign.

Date

*********************************************END