Validation of Pharmaceutical Processes, Equipments/Apparatus

Introduction
The development of a drug product is a lengthy process involving drug discovery, laboratory
testing, animal studies, clinical trials and regulatory registration. To further enhance the
effectiveness and safety of the drug product after approval, many regulatory agencies such as the
United States Food and Drug Administration (FDA) also require that the drug product be tested
for its identity, strength, quality, purity and stability before it can be released for use. For this
reason, pharmaceutical validation and process controls are important in spite of the problems that
may be encountered1. Process controls include raw materials inspection, in-process controls and
targets for final product. The purpose is to monitor the on-line and off-line performance of the
manufacturing process and then validate it. Even after the manufacturing process is validated,
current good manufacturing practice also requires that a well-written procedure for process
controls is established to monitor its performance. This paper provides an overview of
pharmaceutical validation and process controls in drug development. The validation concept can
be applied to new drugs, new dosage forms and generic drug development.

Essentials of Pharmaceutical Validation

Validation is an integral part of quality assurance; it involves the systematic study of systems,
facilities and processes aimed at determining whether they perform their intended functions
adequately and consistently as specified. A validated process is one which has been
demonstrated to provide a high degree of assurance that uniform batches will be produced that
meet the required specifications and has therefore been formally approved. Validation in itself
does not improve processes but confirms that the processes have been properly developed and
are under control. Adequate validation is beneficial to the manufacturer in many ways:  It
deepens the understanding of processes; decreases the risk of preventing problems and thus
assures the smooth running of the process.  It decreases the risk of defect costs.  It decreases
the risk of regulatory noncompliance.  A fully validated process may require less in-process
controls and end product testing.
Validation should thus be considered in the following situations:  Totally new process;  New
equipment;  Process and equipment which have been altered to suit changing priorities; and 
Process where the end-product test is poor and an unreliable indicator of product quality.

When any new manufacturing formula or method of preparation is adopted, steps should
be taken to demonstrate its suitability for routine processing. The defined process should be
shown to yield a product consistent with the required quality. In this phase, the extent to which
deviations from chosen parameters can influence product quality should also be evaluated. When
certain processes or products have been validated during the development stage, it is not always
necessary to revalidate the whole process or product if similar equipment is used or similar
products have been produced, provided that the final product conforms to the in-process controls
and final product specification. There should be a clear distinction between in-process control
and validation. In production, tests are performed each time on a batch to batch basis using
specifications and methods devised during the development phase. The objective is to monitor
the process continuously

Major Phases in Validation

The activities relating to validation studies may be classified into three:

Phase 1: This is the Pre-validation Qualification Phase which covers all activities relating to
product research and development, formulation pilot batch studies, scaleup studies, transfer of
technology to commercial scale batches, establishing stability conditions and storage, and
handling of in-process and finished dosage forms, equipment qualification, installation
qualification, master production document, operational qualification and process capacity.

Phase 2: This is the Process Validation Phase. It is designed to verify that all established limits
of the critical process parameter are valid and that satisfactory products can be produced even
under the worst conditions.
Phase 3: Known as the Validation Maintenance Phase, it requires frequent review of all process
related documents, including validation of audit reports, to assure that there have been no
changes, deviations, failures and modifications to the production process and that all standard
operating procedures (SOPs), including change control procedures, have been followed. At this
stage, the validation team comprising of individuals representing all major departments also
assures that there have been no changes/deviations that should have resulted in requalification
and revalidation5. A careful design and validation of systems and process controls can establish
a high degree of confidence that all lots or batches produced will meet their intended
specifications. It is assumed that throughout manufacturing and control, operations are conducted
in accordance with the principle of good manufacturing practice (GMP) both in general and in
specific reference to sterile product manufacture.

The validation steps recommended in GMP guidelines can be summarized as follows  As a pre-
requisite, all studies should be conducted in accordance with a detailed, pre-established protocol
or series of protocols, which in turn is subject to formal – change control procedures;  Both the
personnel conducting the studies and those running the process being studied should be
appropriately trained and qualified and be suitable and competent to perform the task assigned to
them;  All data generated during the course of studies should be formally reviewed and certified
as evaluated against pre-determined criteria;  Suitable testing facilities, equipment, instruments
and methodology should be available;  Suitable clean room facilities should be available in both
the ‗local‘ and background environment. There should be assurance that the clean room
environment as specified is secured through initial commissioning (qualification) and
subsequently through the implementation of a programme of re-testing – in-process equipment
should be properly installed, qualified and maintained;  When appropriate attention has been
paid to the above, the process, if aseptic, may be validated by means of ―process simulation”
studies;  The process should be revalidated at intervals; and  Comprehensive documentation
should be available to define support and record the overall validation process.

Protocols should specify the following in detail

 The objective and scope of study. There should already be a definition of purpose;  A clear
and precise definition of process equipment system or subsystem, which is to be the subject of
study with details of performance characteristics;  Installation and qualification requirement for
new equipment;  Any upgrading requirement for existing equipment with justification for the
change(s) and statement of qualification requirement;  Detailed stepwise statement of actions to
be taken in performing the study (or studies);  Assignment of responsibility for performing the
study;  Statement on all test methodology to be employed with a precise statement of the test
equipment and/or materials to be used;  Test equipment calibration requirements;  References
to any relevant standard operating procedures (SOP);  Requirement for the current format of the
report on the study;  Acceptance criteria against which the success (or otherwise) of the study is
to be evaluated; and  The personnel responsible for evaluating and certifying the acceptability
of each stage in the study and for the final evaluation and certification of the process as a whole,
as measured against the pre-defined criteria.

All personnel involved in conducting the studies should be properly trained and qualified
because they can, and often, have a crucial effect on the quality of the end product. All
information or data generated as a result of the study protocol should be evaluated by qualified
individuals against protocol criteria and judged as meeting or failing the requirements. Written
evidence supporting the evaluation and conclusion should be available. If such an evaluation
shows that protocol criteria have not been met, the study should be considered as having failed to
demonstrate acceptability and the reasons should be investigated and documented. Any failure to
follow the procedure as laid down in the protocol must be considered as potentially
compromising the validity of the study itself and requires critical evaluation of all the impact on
the study. The final certification of the validation study should specify the pre-determined
acceptance criteria against which success or failure was evaluated.

Validation of Analytical Assays and Test Methods

Method validation confirms that the analytical procedure employed for a specific test is suitable
for its intended use. The validation of an analytical method is the process by which it is
established by laboratory studies that the performance characteristics of the method meet the
requirement for the intended application. This implies that validity of a method can be
demonstrated only though laboratory studies.
Methods should be validated or revalidated:  before their introduction and routine use; 
whenever the conditions change for which the method has been validated, e.g., instrument with
different characteristics; and  wherever the method is changed and the change is outside the
original scope of the method. Strategy for Validation of Methods The validity of a specific
method should be demonstrated in laboratory experiments using samples or standards that are
similar to the unknown samples analyzed in the routine. The preparation and execution should
follow a validation protocol preferably written in a step-by-step instruction format as follows: 
Develop a validation protocol or operating procedure for the validation;  Define the application
purpose and scope of the method;  Define the performance parameters and acceptance criteria; 
Define validation experiments;  Verify relevant performance characteristics of the equipment; 
Select quality materials, e.g., standards and reagents;  Perform pre-validation experiments; 
Adjust method parameters and/or acceptance criteria, if necessary;  Perform full internal (and
external) validation experiments;  Develop SOPs for executing the method routinely;  Define
criteria for revalidation;  Define type and frequency of system suitability tests and/or analytical
quality control (AQC) checks for the routine; and  Document validation experiments and results
in the validation report.

Environmental Considerations: Cleaning and Clean Room Standards

Cleaning validation is documented proof that one can consistently and effectively clean a system
or equipment items. The procedure is necessary for the following reasons:  It is a customer
requirement – it ensures the safety and purity of the product;  It is a regulatory requirement in
active pharmaceutical product manufacture;  It also assures from an internal control and
compliance point of view the quality of the process. The FDA guide to inspections intended to
cover equipment cleaning (chemical residues only) expects firms to have written procedure
(SOPs) detailing the cleaning processes and also written general procedure on how cleaning
processes will be validated. FDA expects a final validation report which is approved by
management and which states whether or not the cleaning process is valid. The data should
support a conclusion that residues have been reduced to an ―acceptable level‖. Harder cited five
crucial elements: 1. A standard operating procedure (SOP) for cleaning with a checklist; 2. A
procedure for determining cleanliness (rinse or swab); 3. An assay for testing residual drug
levels; 4. Pre-set criteria for testing chemical and microbial limit to which to equipment must be
cleaned; and 5. Protocol for cleaning validation. Harder recommended that the procedure be
tested for, requiring it to be successful on three successive cleanings and there should be periodic
revalidation as well as revalidation after significant changes. Jenkins and Vanderwielen
presented an overview of cleaning validation covering strategy and determination of residue
limits, method of sampling and analysis noting that ―increased use of multipurpose equipment‖
has produced increased interest in cleaning validation. The cleaning protocol must be thorough
and must be checked. Training is essential. A validation program requires  criteria for
acceptance after cleaning,  appropriate methods of sampling,  a maximum limit set for
residues, and  test methods that must themselves be tested. Products to be tested may be put into
groups rather than testing all of them. The most important may not be the highest volume
product but those capable of causing the largest possible problems if contaminated or if they
contaminate the products (solubility of the drug is an important issue). Equipment may also be
tested in groups.

Process Validation
Process validation is the means of ensuring and providing documentary evidence that processes
(within their specified design parameters) are capable of repeatedly and reliably producing a
finished product of the required quality5. It would normally be expected that process validation
be completed prior to the release of the finished product for sale (prospective validation). Where
this is not possible, it may be necessary to validate processes during routine production
(concurrent validation). Processes, which have been in use for sometime without any significant
changes, may also be validated according to an approved protocol (retrospective validation).

Pre-requisites for Process Validation

Before process validation can be started, manufacturing equipment and control instruments as
well as the formulation must be qualified. The information on a pharmaceutical product should
be studied in detail and qualified at the development stage, i.e., before an application for
marketing authorization is submitted. This involves studies on the compatibility of active
ingredients and recipients, and of final drug product and packaging materials, stability studies,
etc. Other aspects of manufacture must be validated including critical services (water, air,
nitrogen, power supply, etc.) and supporting operations such as equipment cleaning and
sanitation of premises. Proper training and motivation of personnel are prerequisites to
successful validation.
The Pharmaceutical Process Equipment
The key idea of validation is to provide a high level of documented evidence that the equipment
and the process conform to a written standard. The level (or depth) is dictated by the complexity
of the system or equipment. The validation package must provide the necessary information and
test procedures required to provide that the system and process meet specified requirements.
Validation of pharmaceutical process equipment involves the following:

Installation Qualification: This ensures that all major processing and packaging equipment, and
ancillary systems are in conformity with installation specification, equipment manuals
schematics and engineering drawing. It verifies that the equipment has been installed in
accordance with manufacturers recommendation in a proper manner and placed in an
environment suitable for its intended purpose.

Operational Qualification: This is done to provide a high degree of assurance that the
equipment functions as intended. Operational qualification should be conducted in two stages: 
Component Operational Qualification, of which calibration can be considered a large part. 
System Operational Qualification,to determine if the entire system operates as an integrated
whole. 

These exercises assure, through appropriate performance lists and related documentation, that
equipment, ancillary systems and sub-systems have been commissioned correctly. The end
results are that all future operations will be reliable and within prescribed operational limits. At
various stages in a validation exercise there are needs for protocols, documentation, procedures,
specifications and acceptance criteria for test results. All these need to be reviewed, checked and
authorized. It would be expected that representatives from the professional disciplines, e.g.,
engineering, research and development, manufacturing, quality control and quality assurance are
actively involved in these undertakings with the final authorization given by a validation team or
the quality assurance representative.

Approaches to Validation Process

There are two basic approaches to the validation of the process itself (apart from the qualification
of equipment used in production, the calibration of control and measurement instruments, the
evaluation of environmental factors, etc). These are the experimental approach and the approach
based on the analysis of historical data. The experimental approach, which is applicable to both
prospective and concurrent validation, may involve  extensive product testing,  simulation
process trials,  challenge/worst case trials, and  control of process parameters (mostly
physical). One of the most practical forms of process validation, mainly for non-sterile products,
is the final testing of the product to the extent greater than that required in routine quality control.
It may involve extensive sampling, far beyond that called for in routine quality control and
specifications, and often for certain parameters only. Thus, for instance, several hundred tablets
per batch may be weighed to determine unit dose uniformity. The results are then treated
statistically to verify the normality of the distribution and to determine the standard deviation
from the average weight. Confidence limits for individual results and for batch homogeneity are
also estimated. Strong assurance is provided that samples taken at random will meet regulatory
requirements if the confidence limits are within compendial specifications. In the approach based
on analysis of historical data, no experiments are performed in retrospective validation, but
instead all available historical data concerning a number of batches are combined and jointly
analysed, if production is proceeding smoothly during the period preceding validation and the
data in process inspection and final testing of the product are combined and treated statistically.
The results including the outcome of process capability studies, trend analysis, etc., will indicate
whether the process is under control or not. Expert Evaluation This is an evaluation of the entire
study against the protocol requirements as outlined above. It should be prepared and the
conclusion drawn at each stage stated. The final conclusions should reflect whether the protocol
requirements were met. The evaluation should include an assessment of the planned calibration
and maintenance programmes for the equipment and instrumentation to maintain the validated
conditions. In addition, all process monitoring and control procedures required to routinely
ensure that the validated conditions are maintained should be reported. The evaluation should be
signed by authorized officers of the organization who were members of the team establishing the
protocol and who have appropriate expertise in the area assigned to them. Overall approval of the
study should be authorized by the head of the validation team and the head of the quality control
department. The Validation Report A written report should be available after completion of the
validation. If found acceptable, it should be approved and authorized (signed and dated). The
report should include at least the following:  Title and objective of study;  Reference to
protocol;  Details of material;  Equipment;  Programmes and cycles used;  Details of
procedures and test methods;  Results (compared with acceptance criteria); and 
Recommendations on the limit and criteria to be applied on future basis. Analytical Methods
Development and Validation :- Play important roles in the discovery, development, and
manufacture of pharmaceuticals. The official test methods that result from these processes are
used by quality control laboratories to ensure the identity, purity, potency, and performance of
drug products. In recent years, a great deal of effort has been devoted to the harmonization of
pharmaceutical regulatory requirements in the United States, Europe, and Japan. As part of this
initiative, the International Conference on Harmonization (ICH) has issued guidelines for
analytical method validation. The recent FDA methods validation draft guidance document as
well as USP both refer to ICH guidelines (2). Analytical guidance documents recently published
by the ICH are the following: ● stability testing (Q1) ● validation of analytical procedures (Q2)
● impurities in drug substances and products (Q3) ● specifications for new drug substances and
products (Q6). Additional regulatory guidance can be found on the FDA Web site
www.fda.gov/cder/guidance and on the ICH Web site www.ich.org. These sites ensure access to
current methods development and validation guidelines. The methods validation documentation
requirements for IND and NDA submissions are outlined in the chemistry, manufacturing and
controls (CMC) guidance document (2). The current trend continues to be in the direction of
phase-dependent methods development and validation. Nonvalidated screening methods are used
to monitor the synthesis of active ingredients or to confirm their identity during discovery and
preclinical research. Analytical methods are progressively optimized and a preliminary
validation package is furnished as part of the IND application before Phase I safety trials are
initiated. All analytical methods should be fully optimized and validation completed before the
NDA is submitted at the end of Phase III studies. Method validation is a continuous process. The
goal is to ensure confidence in the analytical data throughout product development. The method
development and validation processes The steps of methods development and method validation
depend upon the type of method being developed However, the following steps are common to
most types of projects: ● method development plan definition ● background information
gathering ● laboratory method development ● generation of test procedure ● methods validation
protocol definition ● laboratory methods validation ● validated test method generation ●
validation report. A well-developed method should be easy to validate. A method should be
developed with the goal to rapidly test preclinical samples, formulation prototypes, and
commercial samples. As the methods development and validation processes advance, the
information gathered is captured in the design and subsequent improvement of the method.
Ideally, the validation protocol should be written only following a thorough understanding of the
method‘s capabilities and intended use. The validation protocol will list the acceptance criteria
that the method can meet. Any failure to meet the criteria will require that a formal investigation
be conducted. The required validation parameters, also termed analytical performance
characteristics, depend upon the type of analytical method. Pharmaceutical analytical methods
are categorized into five general types (3): ● identification tests ● potency assays ● impurity
tests: quantitative ● impurity tests: limit ● specific tests. The first four tests are universal tests,
but the specific tests such as particle-size analysis and X ray diffraction are used to control
specific properties of the active pharmaceutical ingredient (API) or the drug product. Validation
requirements depend upon the type of test method, including ● specificity: ability to measure
desired analyte in a complex mixture ● accuracy: agreement between measured and real value ●
linearity: proportionality of measured value to concentration ● precision: agreement between a
series of measurements ● range: concentration interval where method is precise, accurate, and
linear ● detection limit: lowest amount of analyte that can be detected ● quantitation limit:
lowest amount of analyte that can be measured ● robustness: reproducibility under normal but
variable laboratory conditions. Only specificity is needed for an identification test. However, the
full range of specificity, accuracy, linearity, range, limit of detection (LOD), limit of quantitation
(LOQ), precision, and robustness testing is needed for more-complex methods such as
quantitative impurity methods. The validated test method is included in the validation report that
summarizes the results of the validation studies. Both the validation report and test method are
submitted as parts of the NDA or ANDA. Advances in technology and equipment Recent
progress in methods development has been largely a result of improvements in analytical
instrumentation. This is especially true for chromatographs and detectors. Isocratic and gradient
reverse-phase HPLC have evolved as the primary techniques for the analysis of nonvolatile APIs
and impurities. The HPLC detector of choice for many types of methods development is the
photodiode array (PDA) detector because it can be used for both quantitative and qualitative
analysis. The use of a PDA detector to determine peak purity of the active ingredient in stressed
samples greatly facilitates the development of stability-indicating assays. The emphasis on the
identification of trace impurities and degradants has led to the increased use of hyphenated
techniques such as liquid chromatography–mass spectrometry (LC–MS) and liquid
chromatography–nuclear magnetic resonance spectroscopy (LC–NMR). This trend will continue
with the need to better define degradation pathways. The ultraviolet (UV) absorbance detector
remains the most common HPLC detector for potency and impurity analysis. Once specificity
has been demonstrated, the PDA detector is replaced with a variable wavelength detector and the
HPLC effluent is monitored at fixed wavelengths. Stability-indicating and impurity methods
often are required to measure analytes within a wide concentration range. For example, process
impurities and/or degradation products may be present at levels of 0.1%, and the main active
ingredient typically is present at the nominal concentration (100%). This amount is well within
the linear range of a fixed wavelength detector but not within the linear range for LC–MS
detectors. Recent FDA and ICH guidance about chiral drug products and impurities has posed
new challenges for methods development scientists (3). However, recent advances in the use of
chiral HPLC columns has greatly facilitated progress in this area. The advances are primarily a
result of the introduction of chiral stationary phases (CSPs) prepared by reacting amylose or
cellulose derivatives with silica. The new CSPs allow trace levels of enantiomeric impurities to
be measured. Gas chromatography remains the method of choice for the analysis of volatile
compounds. Gas chromatography with mass spectrometry detection (GC–MS) is increasingly
being used to identify impurities and to determine active ingredient peak purity in stressed
samples. Advances in laboratory robotics and automation also are beginning to be applied to
methods development and validation. Development teams are using laboratory robotics to
develop automated methods for high-volume tests. An in-depth review of all the recent advances
in analytical instrumentation is beyond the scope of this article. However, several methods
should be noted. Advances in the use of nondestructive infrared (IR) and near-infrared
spectroscopy (near IR) and NMR techniques are particularly promising for methods development
scientists. Issues and challenges For a methods development and validation program to be
successful, a holistic approach is recommended. A common challenge encountered during
methods development and validation is that methods are typically developed by the R&D
department, whereas validation is typically the responsibility of a validation group. It‘s important
that the R&D and validation groups work as one team. Various groups also may be responsible
for ensuring the suitability of the methods to support early clinical phases and commercial
manufacturing. The transfer of analytical methods from one group to another then becomes an
important step for ensuring that the proper validation is in place to justify its intended use.
Because the method will be run by several groups during its progression from development to
validation, the method must be robust. This means the method should provide reliable data, both
on a wide range of equipment and in the hands of several chemists. A common weakness in
development and validation of methods is that the methods are not robust enough. If robustness
is not built into methods early in development, then the result most likely will be loss of
efficiency during routine QC testing and a lengthy and complicated validation process as well.
Another challenge encountered early in the development of methods intended to support stability
studies is ensuring that the method is stability indicating. This process is typically achieved by
conducting forced-degradation studies. The design and execution of these studies requires
thorough knowledge of the product being tested as well as a good understanding of the analysis
technique. As mentioned previously, new regulatory guidelines are being published governing
the expectations of regulatory agencies throughout the world for methods development and
validation. Another challenge is that many pharmaceutical companies must upgrade methods to
meet current regulatory standards. From a simple method improvement to a complete
redevelopment and subsequent cross-over to an older method, the upgrade of analytical methods
can be a daunting task. For this reason, one must be alert to current trends in regulatory
guidelines and to adopt a proactive approach to changes that may affect development and
validation programs. Finally, one of the key requirements for methods validation (which is also
one of the key challenges), is that only wellcharacterized reference materials with well
documented purities should be used during method validation activities. The challenge stems
from the fact that, in some cases, the tools used to characterize reference standard materials are
being developed and validated at the same time as the reference standard itself. Conclusion The
efficient development and validation of analytical methods are a critical elements in the
development of pharmaceuticals. Success in these areas can be attributed to several important
factors, which in turn will contribute to regulatory compliance. Experience is one of these
factors––both the experience level of the individual scientists and the collective experience level
of the development and validation department. A strong mentoring and training program is
another important factor for ensuring successful methods development and validation.