An Overview of Pharmaceutical Validation and Process Controls in Drug Development

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 performance2.
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 control3. Adequate validation
is beneficial to the manufacturer in many
ways3:
· 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 endproduct
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
continuously4.

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,
scale-up 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 follows5:
· 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
detail6:
· 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 endproduct.
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 evaluated5.
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 studies7. Methods
should be validated or revalidated8, 9:
· 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
follows10:
· 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 reasons11, 12:
· It is a customer requirement – it
ensures the safety and purity of the
product;
· It is a regulatory requirement in active
pharmaceutical product manufacture;
and
· It also assures from an internal control
and compliance point of view the
quality of the process.
The FDA guide to inspections13 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”14. Harder14 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.
Harder14 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 Vanderwielen15 presented an
overview of cleaning validation covering
strategy and determination of residue limits,
method of sampling and analysis noting that
“increased use of multi-purpose 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 them16. 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 some
time without any significant changes, may
also be validated according to an approved
protocol (retrospective validation)10-17.
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 validation18-20.
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
requirements21. Validation of pharmaceutical
process equipment involves the following10:
· 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.
· Process Performance Qualification:
This verifies that the
system is repeatable and is
consistently producing a quality
product14.
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 representative22.

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 involve23
· 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
specifications24.
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 department21.
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 following4:
· 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.

Conclusion
It is necessary, before approval of a new
drug, that an accurate and reliable
assessment for its effectiveness and safety
for the intended indication and target patient
population is demonstrated. Pharmaceutical
validation which includes assay validation,
cleaning validation, equipment validation as
well as the overall process validation is
crucial in stability analysis, animal studies
and early phases of clinical development
such as bioavailability/bioequivalence
studies. After the drug is approved,
pharmaceutical validation and process
control are necessary to ensure that the drug
product will meet/set pharmaceutical
standards for identity, strength, quality,
purity, stability, evaluation safety and
efficacy.
In general, pharmaceutical validation and
process control provide a certain assurance
of batch uniformity and integrity of the
product manufactured.
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