Validation

03/02/09 University Institute of

Pharmaceutical Sciences, Panjab
Contents:

C. Definition.
D. FDA Guidelines.
E. Elements of Validation:
1. Installation Qualification.
2. Operational Qualification.
3. Performance Qualification.
D. Process Validation.
E. Types of Process Validation:
1. Prospective Validation.
2. Retrospective Validation.
3. Concurrent Validation.
4. Revalidation.
F. Total Approach to Process Validation.
G. Pilot Scale-up and Process Validation.
H. Process Validation: Order of Priority.
I. Process Design and Characterization.
J. Reference.

03/02/09 University Institute of

Pharmaceutical Sciences, Panjab
What is Validation?
•Documented evidence that the manufacturing process consistently produces
product that meets predetermined specifications
§Defines product quality

§Developed and validated based on a thorough understanding of the critical

process parameters
§Parameters are carefully controlled within the validated ranges to ensure a
consistent manufacturing process.
•Manufacturing process validation consists of successfully manufacturing at least three
full-scale batches in succession, which pass all in-process and product quality attributes

03/02/09 University Institute of

Pharmaceutical Sciences, Panjab
FDA Guidelines:
•The U.S. Food and Drug Administration (FDA) has proposed guidelines with
the following definition for process validation:

Process validation is establishing documented evidence which provides a

high degree of assurance that a specific process (such as the manufacture
of pharmaceutical dosage forms) will consistently produce a product meeting
its predetermined specifications and quality characteristics.

• According to the FDA’s Current Good Manufacturing Practices (CGMPs)

21CFR 211.110 a:
Control procedures shall be established to monitor output and to validate
performance of the manufacturing processes that may be responsible for
causing variability in the characteristics of in-process material and the drug
product. Such control procedures shall include, but are not limited to the
following, where appropriate:

1. Tablet or capsule weight variation

2. Disintegration time
3. Adequacy of mixing to assure uniformity and homogeneity
4. Dissolution time and rate
5. Clarity, completeness, or pH of solutions

03/02/09 University Institute of

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•Conventional quality control procedures for finished product testing encompass
three basic steps:

1. Establishment of specifications and performance characteristics.

2. Selection of appropriate methodology, equipment, and instrumentation to ensure
that testing of the product meets specifications.
3. Testing of the final product, using validated analytical and testing methods to
ensure that finished product meets specifications.

•With the emergence of the pharmaceutical process validation concept, the

following four additional steps have been added:

4. Qualification of the processing facility and its equipment.

5. Qualification and validation of the manufacturing process through appropriate
Means.
6. Auditing, monitoring, sampling, or challenging the key steps in the process for
conformance to in-process and final product specifications.
7. Revalidation when there is a significant change in either the product or its
manufacturing process.

03/02/09 University Institute of

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 ELEMENTS of VALIDATION

Equipment validation: Installation Qualification(IQ)

Operational Qualification(OQ)
Process validation: Performance Qualification(PQ)

03/02/09 University Institute of

Pharmaceutical Sciences, Panjab
Installation Qualification (IQ):
•This is the first step in validation.

•This protocol insures that the system/equipment and its components are
installed correctly and to the original manufacturer’s specifications.

•Calibration of major equipment, accessory equipment, and/or utilities should

be performed in this step as well.

03/02/09 University Institute of

Pharmaceutical Sciences, Panjab
Operational Qualification (OQ):
•This step proceeds after the IQ has been performed.

•In the OQ, tests are performed on the critical parameters of the
system/process. These are usually the independent and/or manipulated
variables associated with the system/equipment.

•All tests data and measurements must be documented in order to set a

baseline for the system/equipment.

03/02/09 University Institute of

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Performance Qualification (PQ):
•This is the third and final phase of validation.

•This phase tests the ability of the process to perform over long periods of time
within tolerance deemed acceptable.

•PQ is performed on the manufacturing process as a whole. Individual

components of the system are not tested individually.

03/02/09 University Institute of

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 PROCESS VALIDATION

FDA Guideline Definition…

“PROCESS VALIDATION” is establishing documented evidence which

provides a high degree of assurance that a specific process consistently
produce a product meeting it’s predetermined specifications and quality
attributes”

03/02/09 University Institute of

Pharmaceutical Sciences, Panjab
 PROCESS VALIDATION

03/02/09 University Institute of

Pharmaceutical Sciences, Panjab
 Types of Process Validation

1. Prospective validation
2. Retrospective validation
3. Concurrent validation
4. Revalidation

03/02/09 University Institute of

Pharmaceutical Sciences, Panjab
1. Prospective validation: is defined as the establishment of documented
evidence that a system does what it purports to do based on pre-planned
protocol. This validation is usually carried out prior to the introduction of new
drugs and their manufacturing process. This approach to validation is normally
undertaken whenever a new formula, process or facility must be validated before
routine pharmaceutical formulation commences.

03/02/09 University Institute of

Pharmaceutical Sciences, Panjab
2. Retrospective validation: is defined as the establishment of
documented evidence that a system does what it purports to do based on review
and analysis of historical data. This is achieved by the review of the historical
manufacturing testing data to prove that the process has always remained in
control.

03/02/09 University Institute of

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3. Concurrent validation: is similar to prospective, except the operating
firm will sell the product during the qualification runs, to the public at its market price.
This validation involves in process monitoring of critical processing steps and
product testing.

03/02/09 University Institute of

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4. Revalidation: It is the repetition of a validation process or a specific part of
it. This is carried out when there is any change or replacement in formulation,
equipment, plant or site location, batch size and in the case of sequential batches
that do not meet product and process specifications.

Conditions requiring revalidation study and documentation are listed as follows:

1. Change in a critical component (usually refers to raw materials).

2. Change or replacement in a critical piece of modular (capital) equipment.
3. Change in a facility and/or plant (usually location or site).
4. Significant (usually order of magnitude) increase or decrease in batch Size.
5. Sequential batches that fail to meet product and process specifications.

03/02/09 University Institute of

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03/02/09
Total Approach to Pharmaceutical Process Validation:

03/02/09 University Institute of

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Pilot Scale-up and Process Validation:
•The following operations are normally carried out by the development function prior
to the preparation of the first pilot-production batch. The development activities are
listed as follows:

1. Formulation design, selection, and optimization

2. Preparation of the first pilot-laboratory batch
3. Conduct initial accelerated stability testing
4. If the formulation is deemed stable, preparation of additional pilot laboratory
batches of the drug product for expanded nonclinical and/or clinical use.

•The pilot program is defined as the scale-up operations conducted subsequent to

the product and its process leaving the development laboratory and prior to its
acceptance by the full scale manufacturing unit.

•Thus, product and process scale-up should proceed in graduated steps with
elements of process validation (such as qualifications) incorporated at each stage of
the piloting program.

03/02/09 University Institute of

Pharmaceutical Sciences, Panjab
03/02/09 University Institute of
Pharmaceutical Sciences, Panjab
03/02/09 University Institute of
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Fig: Main piloting options.

Development
Pilot Plant Production
Laboratory

Pilot Batch Request

Development Production
Laboratory

Pilot Batch Completion

Request

03/02/09 University Institute of

Pharmaceutical Sciences, Panjab
03/02/09 University Institute of
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Process Validation: Order of Priority

A. Sterile Products and Their Processes

1. Large-volume parenterals (LVPs).
2. Small-volume parenterals (SVPs).
3. Ophthalmics, other sterile products, and medical devices.

B. Nonsterile Products and Their Processes

1. Low-dose/high-potency tablets and capsules/transdermal delivery systems
(TDDs).
2. Drugs with stability problems.
3. Other tablets and capsules.
4. Oral liquids, topicals, and diagnostic aids.

03/02/09 University Institute of

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Process Design and Characterization:
•Process capability is defined as the studies used to determine the critical process
parameters or operating variables that influence process output and the range of
numerical data for critical process parameters that result in acceptable process
output.

•If the capability of a process is properly delineated, the process should

consistently stay within the defined limits of its critical process parameters and
product characteristics.

•Process demonstration formerly called process qualification, represents the

actual studies or trials conducted to show that all systems, subsystems, or unit
operations of a manufacturing process perform as intended; that all critical
process parameters operate within their assigned control limits; and that such
studies and trials, which form the basis of process capability design and testing,
are verifiable and certifiable through appropriate documentation.

03/02/09 University Institute of

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03/02/09 University Institute of
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•Process characterization represents the methods used to determine the critical
unit operations or processing steps and their process variables, that usually affect
the quality and consistency of the product outcomes or product attributes.

•Process ranging represents studies that are used to identify critical process or test
parameters and their respective control limits, which normally affect the quality and
consistency of the product outcomes of their attributes.

03/02/09 University Institute of

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Validation is Always Part of the Picture

Phase II Commercial
Pre-IND Phase I Phase III
Manufacturing

Final process validation

Specification Development
Re-validation
Ongoing Validation
(DOE, IQ, OQ, PQ, PV)*

* DOE = Design of Experiment

• The extent of IQ, OQ, PQ, validation, IQ = Installation Qualification
etc. depends on complexity of product OQ = Operational
• 6 sigma target Qualification
PQ = Performance
Qualification
Reference:

3. Robert A. Nash; Alfred H. Wachter; “Pharmaceutical Process Validation”;

International Third Edition; pg. 17-40.

6. Guidance for Industry; Process Validation: General Principles and Practices

2008.

8. Rest from Internet.

03/02/09 University Institute of

Pharmaceutical Sciences, Panjab
Thank You