An Overview of Pharmaceutical Validation
An Overview of Pharmaceutical Validation
An Overview of Pharmaceutical Validation
ISSN: 22312781
ABSTRACT
Quality is the primordial intention to any industry and its products manufactured. Multiple
views on obtaining such quality are the current interest in the pharmaceutical industry.
Acquainted with a practice that puts us in common and routine convention ensured to
deliver a quality that sounds globally in terms of a spoken quality is on the dais of
pharmaceutical arena. Validation is the mean of catering enormous benefits to even more
than the acceptable quality level which in the global standard scale. Lending importance to
validation is increasingly profound in recent years. Validation is the art of designing and
practicing the designed steps alongside with the documentation. Validation and quality
assurance will go hand in hand, ensuring the through quality for the products. Hence, an
emphasis made on to review that gives a detailed, overview of validation concept of
designing, organizing and conducting validation trials. Additionally a view of validation
against the quality assurance, drug development and manufacturing process has been
discussed.
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10. Fewer complaints about process- deficiencies. Any changes to the plan as
related failures. defined in the protocol should be documented
11. Reduced testing in process and in with appropriate justification.
finished goods. After completion of a satisfactory
12. More rapid and reliable start-up of qualification, a format release for the next step
new equipments in qualification and validation should be made
13. Easier scale-up form development as a written authorization.
work.
14. Easier maintenance of equipment. Validation set up
15. Improved employee awareness of To establish the desired attributes. These
processes. attributes include physical as well as chemical
16. More rapid automation. characteristics. In the case of parenterals, these
17. Government regulation (Compliance desirable attributes should include stability,
with validation requirements is absence of pyrogens, and freedom from visible
necessary for obtaining approval to particles.
manufacture and to introduce new Acceptance specifications for the product
products) should be established inorder to attain
uniformity and consistently the desired
Planning for Validation product attributes, and the specifications
All validation activities should be planned. should be derived from testing and challenge
The key elements of a validation programme of the system on sound statistical basis during
should be clearly defined and documented in the initial development and production phases
a validation master plan (VMP) or equivalent and continuing through subsequent routine
documents. production.
The VMP should be a summary The process and equipment should be selected
document, which is brief, concise and to achieve the product specification. For
clear. example; design engineers; production and
The VMP should contain data on at quality assurance people may all be involved.
least the following: The process should be defined with a great
1. Validation policy. deal of specificity and each step of the process
2. Organisational structure of validation should be challenged to determine its
activities. adequacy. These aspects are important inorder
3. Summary of facilities, systems, to assure products of uniform quality, purity
equipment and processes to be and performance.
validated.
4. Documentation format: The format to TYPES/METHODS OF VALIDATION
be used for protocols and reports. Prospective validation
5. Planning and scheduling. It is defined as the established documented
6. Change control. evidence that a system does what it purports
7. Reference to existing document. to do based on a pre-planned protocol. This
8. Incase of large projects, it may be validation usually carried out prior to
necessary to create separate validation distribution either of a new product or a
master plans. product made under a revised manufacturing
process. Performed on at least three successive
Documentation production-size (Consecutive batches).
A written protocol should be established that In Prospective Validation, the validation
specifies how qualification and validation will protocol is executed before the process is put
be conducted. The protocol should be into commercial use. During the product
reviewed and approved. The protocol should development phase, the production process
specify critical steps and acceptance criteria. should be categorized into individual steps.
A report that cross-references the qualification Each step should be evaluated on the basis of
and/or validation protocol should be experience or theoretical considerations to
prepared, summarizing the results obtained, determine the critical parameters that may
commenting on any deviations observed, and affect the quality of the finished product. A
drawing the necessary conclusions, including series of experiment should be designed to
recommending changes necessary to correct determine the criticality of these factors. Each
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Validation Team
(Those responsible from Quality control, production and engineering)
Fig. 1
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Fig. 2
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The completion of satisfactory I.Q and O.Q Evidence should be available to support and
exercises should permit a formal “release” of verify the operating parameters and limits for
the equipment for the next stage in the process the critical variables of the operating
validation exercise as long as calibration, equipment. Additionally, the calibration,
cleaning, preventive maintenance and cleaning, preventive maintenance, operating
operator training requirements have been procedures and operator training procedures
finalized and documented. and records should be documented.
Operation qualification (OQ) should follow
Installation qualification. Regulations of Validation
The three basic and most important reasons
OQ should include, but not be limited to the for validation are quality assurance,
following: economics and compliance.
Tests that have been developed from
knowledge of processes, systems and 1. Quality assurance
equipment. Product quality cannot be assumed for a
Tests to include a condition or a set of process by routine quality control testing
conditions encompassing upper and because of the limitation of statistical sampling
lower operating limits, sometimes and the limited sensitivity if the finished
referred to as “worst case” conditions. product testing. Quality variations among
The completion of a successful units within a batch, or among different
Operational qualification should allow batches, are seldom detected by testing of
the finalization of calibration, finished product samples. Validation
operating and cleaning procedures, challenges the adequacy and reliability of a
operator training and preventive system or process to meet pre-determined
maintenance requirements. It should criteria. A successful validation, therefore,
permit a formal “release” of the provides a high degree of confidence that the
facilities, systems and equipment. same level of quality is consistently built into
Equipment operational procedures each unit of the finished product, from batch
established and challenged. to batch. The Pharmaceutical Manufacturers
Equipment control functions. Association (PMA) and the FDA have
Calibration requirements & schedules recognized the product quality assurance
established. concept of validation.
Maintenance requirements &
established schedules. 2. Economics
The direct economics benefit of validation is a
Performance qualification reduction in the cost associated with process
Performance qualification (PQ) should follow monitoring, sampling and testing. The
successful completion of Installation consistency and reliability of a validated
qualification and Operational qualification. process to produce a quality product provide
PQ should include, but not be limited indirect cost savings resulting from a decrease
to the following: or elimination of product rejections, reworks
Tests, using production materials, and retesting. Final release of the product
qualified substitutes or simulated batch would be expedited and free of delays
product, that have been developed and complications caused by lengthy
from knowledge of the process and investigations of process or analytical
the facilities, systems or equipment. variances. In addition, product quality
Tests to include a condition or set of complaints and potential product recalls
conditions encompassing upper and would be minimized.
lower operating limits.
Although PQ is described as a separate 3. Compliance
activity, it may in some cases be appropriate to Specific current Good Manufacturing Practices
(cGMP) references to variation are found in
perform it in conjunction with OQ.
following sections of 21CFR211
Qualification of established (in-use) facilities,
systems and equipment 211.884(d) Variation of suppliers test result
for components when these
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results are accepted in lieu of in-house testing program for production equipment and
after receipt. facilities/process systems.
211.110(a) Validation of manufacturing To develop validated analytical
process to ensure batch uniformity and methods to allow:
integrity of drug products. The stability program to be carried
211.165(e) Validation of analytical out.
methodologies. The testing of raw materials and
The requirement of validation is also implied finished product
in 211.100(a). This section of GMP requires The development of release
that written procedures and process controls specifications for the raw materials
be established to ensure that the drug and finished product.
products have to “identify strength, quality The testing of processed material at
and purity are represented to possess”. certain specified stages.
The FDA’s draft Mid Atlantic Pharmaceutical Quality assurance is the effort taken to ensure
Inspection Guidance Program for Prescription compliance with government regulations for
Drug Plants, issued in January 1990,emphasis the systems, facilities, and personnel involved
the importance of validation in the with manufacturing products. QA audits will
manufacturing process. be quite varied in scope to achieve this
assurance. These responsibilities include batch
Process validation and quality assurance record reviews, critiques of product design,
The relationship of quality assurance and process validation activity, and, possibly,
process validation goes well beyond the audits of other departments’ operations.
responsibility of any quality assurance (QA)
function. Nevertheless, it is a fair to say that A typical Validation Blueprint of Equipment
process validation is a QA tool, because it validation
establishes a quality standard for the specific Introduction
process. 1. Installation qualification
Quality assurance in pharmaceutical Facilities
companies embodies the effort to assure that Utilities
products have the strength, purity, safety and Equipment
efficacy represented in the company’s new 2. Operation qualification
drug application (NDA) filings. Testing Protocols for Utilities and
Although quality assurance is usually Equipment
designated as a departmental function, it must 3. Validation
also be an integral part of an organization’s Testing protocols for products and
activities. When process validation becomes a Cleaning systems
general objective of the technical and 4. Documentation
operational groups within an organization, it 5. Validation of the QA testing
becomes the driving force for quality laboratory
standards in development work, engineering 6. SOPs
activities, quality assurance, and production. 7. Training of personnel
The quality assurance associated with the 8. Organization charts
pharmaceutical development effort includes 9. Schedule of events
the following general functions:
1. To ensure that a valid formulation is When an organization follows the precepts of
designated. total quality management (TQM), the concept
2. To qualify the process that will be of continuous improvement would routinely
scaled up to production-size batches. be used.
3. To assist the design of the validation When process validation is used as a quality
protocol. assurance tool instead of a final examination,
4. To manufacture the bio batches for the an organization’s operations will improve or
clinical program, which will become stay at the highest quality level possible. The
the object of the FDA’s preapproval effort will be properly documented, and the
clearance. overall attitudes of all the affected personnel
To work with production and engineering to will be positive. Finally, a more logical
develop and carry out the qualification
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the process should provide adequate proof of The role of pilot scale batches is to provide
the feasibility of the process at the production data predictive of the production scale
scale thereby ensuring the consistent quality of product. It may be necessary to further
the product in line with the approved develop and optimise the manufacturing
specification. process using pilot scale batches. The pilot
scale batch therefore provides the link
Relationship between Process Validation between process development and industrial
and Specification of the Finished Product production of the product.
The ICH guideline Q6A specification for new The purpose of the pilot batch is to challenge
drug substances and products permits skip lot the method proposed for routine production,
testing, i.e., replacement of routine verification i.e. to analyse and evaluate:
of certain tests on a batch by batch basis. The difficulties and the critical points
In addition, data generated through process of the manufacturing process.
evaluation or validation can be used to justify The apparatus and methods most
why certain test need not be conducted appropriate to large scale production.
routinely on the finished product at release. To summarize, the production of pilot
batches should provide a high level of
Data submission assurance that the product and
Validation data should be generated for all process will be feasible on an
products to demonstrate the adequacy of the industrial scale.
manufacturing process. It is recognized that, at
the time of submission, process validation Production Scale Batches
data may not always be available. These batches are of the size, which will be
Nevertheless it is essential that valid produced during the routine marketing of the
manufacturing processes are always utilized. product. Data on the production scale may not
Validation data should be held at always available prior to granting marketing
manufacturing location and made available authorization.
for verification by concerned authorities. Where production scale data are not available
or presented at the time of submission, the
Laboratory scale batches two-stage approach outlined below should be
These are produced at the research and early followed.
development laboratory stage: they may be of First a thorough evaluation and
very small size (e.g. one tenth of intended characterization of the critical process
production batch). These batches may find parameters at laboratory or pilot scale,
many uses, for example to support followed by a formal validation programme
formulation and packaging development, on production scale batches for which the
clinical and/or pre-clinical studies. “validation scheme” has been described.
The data derived from these batches assist in
the evaluation and definition of critical Data requirements
product performance characteristics and Since it is not generally considered useful to
thereby enables the choice of appropriate conduct full validation studies on the pilot
manufacturing process. scale batches, the validation scheme outlined
should be completed for each product for
Pilot Batches subsequent verification at the production
These may be used in the process scale.
development or optimisation stage may be
used to support formal stability studies and CONCLUSION
also support pre-clinical and clinical Validation has been proven assurance for the
evaluation. Pilot Batch size should correspond process efficiency and sturdiness and it is the
to at least 10% of the production scale batch, full fledged quality attributing tool for the
i.e.such that the multiplication factor for the pharmaceutical industries. Validation is the
scale-up does not exceed 10.For oral dosage commonest word in the areas of drug
forms this size should generally be 10% of the development, manufacturing and specification
production scale or 100,000 units whichever is of finished products. It also renders reduction
the greater. in the cost linked with process monitoring,
sampling and testing. Apart from all the
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