Validation Overview

VALIDATION
❑ The concept of validation was first proposed by two FDA officials, Ted Byers and Bud
Loftus, in the mid 1970’s in order to improve the quality of pharmaceuticals.

❑ It was proposed in direct response to several problems in the sterility of large volume
parenteral market.

❑ The first validation activities were focused on the processes involved in making these
products, but quickly spread to associated process of pharmaceutical.

❑ 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.

❑ Validation involves a combination of planning, developing requirements & specifications,

and verifying requirements.
 VALIDATION
❑ The International Council for Harmonization of Technical Requirements for
Pharmaceuticals for Human Use (ICH) describes validation as a program that establishes
and documents that a specific process, method, or system will consistently produce a
result meeting pre-determined acceptance criteria.

❑ According to WHO definition, validation is the documented act of proving that any
procedure, process, equipment, material, activity or system actually leads to expected
result.

❑ Validation covers several areas in pharmaceutical manufacturing including:

✓ Process Validation
✓ Cleaning Validation
✓ Analytical Method Validation
✓ Computerized System Validation
 VALIDATION AREAS
❑ Process Validation is the documented evidence that a process when operated within
established parameters, can perform effectively and reproducibly to yield an intermediate
or Active Pharmaceutical Ingredient (‘API’) meeting predetermined specifications and
quality attributes [ICH Q7].

❑ To rephrase it, process validation is proving that a process works correctly within defined
criteria. Thus, process validation establishes the quality attributes and process parameters
for pharmaceutical drug manufacturing to ensure specific outcomes. These outcomes are
product quality and consistency.

❑ Additionally, process validation relies very heavily on the qualification of equipment.

Because equipment functionality must be confirmed before a process can be validated.
For example, qualifying the installation, operation, and performance of a 50-liter
fermenter before validating the fermentation process would be a critical first step.
 VALIDATION AREAS
❑ In a similar fashion to process validation, Cleaning Validation is the collection,
evaluation, and reporting of data associated with cleaning procedures that meet
predetermined specifications within established operating parameters to avoid
contamination or carryover of materials in drug manufacturing. In other words, cleaning
validation focuses on proving a cleaning procedure can repeatedly remove a previous
product or cleaning agents from equipment used in production.

❑ Analytical Method Validation is the collection, evaluation, and reporting of data

associated with analytical method execution that provides documented evidence that the
method is suitable for its intended analysis. Analytical method validation focuses on the
capabilities of a test method. Test method capabilities like specificity, linearity, range,
accuracy, precision, limits on detection and quantitation, robustness, and system
suitability. While process validation supports the establishment of production processes
for a drug, analytical method validation supports quality control testing.
 VALIDATION AREAS
❑ Computerized System Validation is the collection, evaluation, and reporting of
documented evidence that the process(es) or operation integrated with a computer system
performs as intended, effectively, and compliantly with applicable regulations.
Computerized system validation also relies on qualification. Mainly, qualification of the
computer system and equipment to support validation of the whole computerized system
used by a pharmaceutical manufacturer.

❑ Qualification is sometimes referred to as equipment validation in the pharmaceutical

industry. However, confirming equipment functionality is more appropriately referred to
as qualification rather than validation in the pharmaceutical industry. Qualification
directly addresses equipment meanwhile validation addresses processes and/or workflows
in the pharmaceutical industry.
 VALIDATION AREAS
❑ Qualification is proving that equipment is properly installed, working correctly, and
achieving expected results. Therefore, qualification confirms and documents the design,
installation, operation, and performance of facilities, systems, laboratory instruments, and
equipment perform as intended.

❑ Qualification occurs prior to process validation. Because the equipment, laboratory

instruments, and systems must work correctly before confirming a process performs
effectively and reproducibly.

❑ Performing qualification occurs in a stepwise manner for design, installation, operation,

and performance. Each step is commonly referred to as Design Qualification (DQ),
Installation Qualification (IQ), Operational Qualification (OQ), and Performance
Qualification (PQ).
VALIDATION VS CALIBRATION
 VALIDATION RELATED TERMS
❑ Validation Protocol: A written plan stating how validation will be conducted, including
test parameters, product characteristics, production equipment, and decision points on
what constitutes acceptable test results.

❑ Change Control: A written procedure that describes the action to be taken if a change is
proposed to facilities, materials, equipment, and/or processes used in the fabrication,
packaging, and testing of drugs that may affect the operation of the quality or support
system.

❑ Validation Master Plan: An approved written plan of objectives and actions stating how
and when a company will achieve compliance with the GMP requirements regarding
validation.

❑ Critical Process Parameter: A parameter which if not controlled will contribute to the
variability of the end product.
 VALIDATION RELATED TERMS
❑ Worst case: The highest and /or lowest value of a given parameter actually evaluated in
the validation exercise.

❑ Validation Team: A multi-disciplinary team of personnel primarily responsible for

conducting and/or supervising validation studies. Such studies may be conducted by
person(s) qualified by training and experience in a relevant discipline.
RESPONSIBILITIES OF VALIDATION TEAM
 WHY VALIDATION IS REQUIRED?
The most important reasons for validation include the followings:

❑ Assurance of Quality: Quality variations among units within a batch, or among different
batches, are seldom detected by testing of finished product samples. Validation challenges
the adequacy and reliability of a system or process to meet pre-determined criteria. A
successful validation, therefore, provides a high degree of confidence that the same level
of quality is consistently built into each unit of the finished product, from batch to batch.

❑ Process Optimization: The optimization of a process for maximum efficiency, while

maintaining quality standards, is a consequence of validation. Literal meaning of word to
optimize is “To make as effective, perfect or useful as possible”. The optimization of the
facility, equipment, systems, and processes results in a product that meets quality
requirements at the lowest cost.
 WHY VALIDATION IS REQUIRED?
❑ Cost Reduction: The consistency and reliability of a validated process to produce a
quality product provide indirect cost savings resulting from a decrease or elimination of
product rejections, reworks and retesting. Final release of the product batch would be
expedited and free of delays and complications caused by lengthy investigations of
process or analytical variances. In addition, product quality complaints and potential
product recalls would be minimized.

❑ Compliance: Validation is considered to be an integral part of GMPs. Worldwide

compliance with validation requirements is necessary for obtaining approval to
manufacture and to introduce new products.

❑ Safety: Validation can also result in increased operation safety. e.g.: gauges used on
equipment that designed to operate at certain temperature and pressures must be reliable
i.e. they must be calibrated.
 VALIDATION GUIDELINES?
The validation steps recommended in GMP guidelines can be summarized as follows:

1. 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.

2. 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.

3. All data generated during the course of studies should be formally reviewed and certified
as evaluated against pre-determined criteria.

4. Suitable testing facilities, equipments, instruments and methodology should be available.

 VALIDATION GUIDELINES?
Cont…….

5. Suitable clean room facilities should be available in both the ‘local’ and background
environment.

6. In-process equipment should be properly installed, qualified and maintained.

7. When appropriate attention has been paid to the above, the process, if aseptic, may be
validated by means of “process simulation” studies.

8. The process should be revalidated at intervals.

9. Comprehensive documentation should be available to define support and record the

overall validation process.
 PHARMACEUTICAL PROCESS VALIDATION
❑ Pharmaceutical process validation is the most important and recognized parameters of
cGMP. Assurance of product quality is derived from careful and systemic attention to a
number of important factors, including: selection of quality process through in-process
and end-product testing.

❑ US FDA Definition: “Process validation is establishing documented evidence which

provides a high degree of assurance that a specified process will consistently produce a
product meeting its pre-determined specifications and quality characteristics.”

❑ ICH Definition: “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 quality.”

❑ Three (03) consecutive lots must be produced and all facility, EQ, support systems,
product specification, and process being validated must pass at all steps.
 PHARMACEUTICAL PROCESS VALIDATION
The following is a list of examples of processes which:

A. should be validated
B. may be satisfactorily covered by verification and
C. processes which may be verifiable, but for business purposes, validation can be
chosen.

A. Processes which should be validated

✓ Sterilization processes

✓ Clean room ambient conditions

✓ Aseptic filling processes

✓ Sterile packaging sealing processes

✓ Lyophilization process

✓ Heat treating processes

 PHARMACEUTICAL PROCESS VALIDATION
B. Processes which may be satisfactorily covered by verification

✓ Manual cutting processes

✓ Testing for color, turbidity, total pH for solutions

✓ Visual inspection of printed circuit boards

✓ Manufacturing and testing of wiring harnesses

C. Processes which may be verifiable, but for business purposes, validation can be
chosen

✓ Certain cleaning processes

✓ Certain human assembly processes

✓ Numerical control cutting processes

✓ Certain filling processes

 PHARMACEUTICAL PROCESS VALIDATION
❑ Process validation may be required in following cases:

New product or existing products as per SUPAC changes. Change in site of

manufacturing. Change in batch size. Change in equipment. Change in process
existing products. Change in composition or components. Change in the critical
control parameters. Change in vendor of API or critical excipient. Change in
specification on input material. Abnormal trends in quality parameters of product
through review during Annual Product Review (APR). Trend of Out of Specification
(OOS) or Out of Trend (OOT) in consecutive batches.
 STAGES OF PROCESS VALIDATION
❑ Process validation involves a series of activities taking place over the lifecycle of the
product and process. The activities relating to validation studies may be classified into
three stages:

❑ Stage 1 – Process Design: The manufacturing process is defined during this stage based
on knowledge gained through development and scale-up activities, and the outcome is the
design of a process suitable for routine manufacturing that will consistently deliver
product that meets its critical quality attributes. It 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, storage and
handling of in-process and finished dosage forms, equipment qualification, installation
qualification, master production documents, operational qualification, process capability.
Also, this is the stage in which the establishment of a strategy for process control is
taking place using accumulated knowledge and understanding of the process.
 STAGES OF PROCESS VALIDATION
❑ Stage 2 – Process Qualification: During this stage, the process design is evaluated to
determine if the process is capable of reproducible commercial manufacturing. It
confirms that all established limits of the Critical Process Parameters are valid and that
satisfactory products can be produced even under “worst case” conditions. GMP
compliant procedures must be followed in this stage and successful completion of this
stage is necessary before commercial distribution of a product.

❑ Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine

production that the process remains in a state of control. The validation maintenance
stage requires frequent review of all process related documents, including validation audit
reports to assure that there have been no changes, deviations, failures, modifications to
the production process, and that all SOPs have been followed, including change control
procedures.
 PROCESS VALIDATION TYPES
Depending on when it is performed in relation to production, validation can be prospective,
concurrent and retrospective.

1. Prospective validation: It is defined as the established documented evidence that a

system does what it purports to do based on a preplanned protocol. This validation
usually carried out prior to distribution either of a new product or a product made under a
revised manufacturing process. Performed on at least three successive production-sizes
(consecutive batches). In prospective validation, the validation protocol is executed
before the process is put into commercial use. During the product development phase, the
production process should be categorized into individual steps. Each step should be
evaluated on the basis of experience or theoretical considerations to determine the critical
parameters that may affect the quality of the finished product.
 PROCESS VALIDATION TYPES
2. Concurrent validation: It is similar to prospective, except the operating firm will sell
the product during the qualification runs, to the public at its market price, and also similar
to retrospective validation. This validation involves in-process monitoring of critical
processing steps and product testing. This helps to generate and documented evidence to
show that the production process is in a state of control.

3. Retrospective validation: It is defined as the established documented evidence that a

system does what it purports to do on the review and analysis of historical information.
This is achieved by the review of the historical manufacturing testing data to prove that
the process has always remained in control. For retrospective validation, generally data
from ten to thirty consecutive batches should be examined to access process consistency,
but fewer batches may be examined if justified.
 REVALIDATION
❑ Re-validation provides the evidence that changes in a process and/or the process
environment that are introduced do not adversely affect process characteristics and
product quality. Documentation requirements will be the same as for the initial validation
of the process.

❑ Facilities, systems, equipment and processes, including cleaning, should be periodically

evaluated to confirm that they remain valid. Where no significant changes have been
made to the validated status, a review with evidence that facilities, systems, equipment
and processes meet the prescribed requirements fulfils the need for revalidation.

❑ Revalidation becomes necessary in certain situations. Some of the changes that require
validation are as follows:

✓ Changes in raw materials (physical properties such as density, viscosity, particle size
distribution and moisture etc that may affect the process or product).
 REVALIDATION
✓ Changes in the source of active raw material manufacturer.

✓ Changes in packaging material (primary container/closure system)

✓ Changes in the process (e.g., mixing time, drying temperatures and batch size)

✓ Changes in the equipment (e.g., addition of automatic detection system). Changes of

equipment which involve the replacement of equipment on a “like for like” basis would
not normally require revalidation except that this new equipment must be qualified.

✓ Changes in the plant/facility.

A decision not to perform revalidation studies must be fully justified and documented.
 QUALIFICATION
The validation of a process requires the qualification of each of the important elements of the
process. Qualification may be of the following types:

Design Qualification (DQ): The first element of validation of new facilities, systems or
equipment could be design qualification. The compliance of the design with GMP should be
demonstrated and documented.

Installation Qualification (IQ): IQ is a method of establishing with confidence that all

major processing, packaging equipment and ancillary systems are in conformance with
installation specifications, equipment manuals, schematics and engineering drawings. This
stage of validation includes examination of equipment design, determination of calibration,
maintenance and adjustment requirements. Installation qualification should be performed on
new or modified facilities, systems and equipment.
 QUALIFICATION
Operational Qualification (OQ): The conduct of an Operational qualification (OQ) should
follow an authorised protocol. The critical operating parameters for the equipment and
systems should be identified at the O.Q stage. The plans for the O.Q should identify the
studies to be undertaken on the critical variables, the sequence of those studies and the
measuring equipment to be used and the acceptance criteria to be met. Studies on the critical
variables should include a condition or a set of conditions encompassing upper and lower
processing and operating limits referred to as “worstcase” conditions. The completion of a
successful OQ should allow the finalization of operating procedures and operator instructions
documentation for the equipment. This information should be used as the basis for training of
operators in the requirements for satisfactory operation of the equipment.
 QUALIFICATION
Performance Qualification (PQ): PQ should follow successful completion of installation
qualification and operational qualification. PQ is establishing by objective evidence that the
process, under anticipated conditions, consistently produces a product which meets all
predetermined requirements.

Re-Qualification: Modification to, or relocation of equipment should follow satisfactory

review and authorization of the documented change proposal through the change control
procedure. This formal review should include consideration of re-qualification of the
equipment. Minor changes or changes having no direct impact on final or in-process product
quality should be handled through the documentation system of the preventive maintenance
program.
 VALIDATION PROTOCOL
❑ Validation protocol is a written plan stating how validation will be conducted, including
test parameters, product characteristics, production and packaging equipment, and
decision points on what constitutes acceptable test results.

❑ This document should give details of critical steps of the manufacturing process that
should be measured, the allowable range of variability and the manner in which the
system will be tested.

❑ The validation protocol should be numbered, signed and dated, and should contain as a
minimum the following information:

✓ Objectives, scope of coverage of the validation study

✓ Validation team membership, their qualifications and responsibilities

VALIDATION PROTOCOL
✓ Type of validation: prospective, concurrent, retrospective, re-validation

✓ Number and selection of batches to be on the validation study

✓ A list of all equipment to be used; their normal and worst-case operating parameters

✓ Outcome of IQ, OQ for critical equipment

✓ Requirements for calibration of all measuring devices

✓ Critical process parameters and their respective tolerances

✓ Description of the processing steps: copy of the master documents for the product

✓ Sampling points, stages of sampling, methods of sampling, sampling plans

✓ Statistical tools to be used in the analysis of data

VALIDATION PROTOCOL
✓ Training requirements for the processing operators

✓ Validated test methods to be used in in-process testing and for the finished product

✓ Specifications for raw and packaging materials and test methods

✓ Forms and charts to be used for documenting results

✓ Format for presentation of results, documenting conclusions and for approval of

study results.
 VALIDATION MASTER PLAN
❑ A validation master plan is a document that summarizes the company's overall
philosophy, intentions and approaches to be used for establishing performance adequacy.
The validation master plan should be agreed upon by management.

❑ The validation master plan should provide an overview of the entire validation operation,
its organizational structure, its content and planning.

❑ All validation activities relating to critical technical operations, relevant to product and
process controls within a firm should be included in the validation master plan. It should
comprise all prospective, concurrent and retrospective validations as well as re-
validation.

❑ The validation master plan should be a summary document and should therefore be brief,
concise and clear.
 VALIDATION MASTER PLAN
❑ The format and content should include:

✓ Introduction: validation policy, scope, location and schedule

✓ Organizational structure, personnel responsibilities

✓ Plant/ process /product description: rational for inclusions or exclusions and extent of
validation

✓ Specific process considerations that are critical and those requiring extra attention

✓ List of products/ processes/ systems to be validated, summarised in a matrix format,

validation approach

✓ Re-validation activities, actual status and future planning

✓ Key acceptance criteria

 VALIDATION MASTER PLAN
✓ Documentation format

✓ Reference to the required SOP's

✓ Time plans of each validation project and sub-project.

VALIDATION REPORT
❑ Validation report summarizes all validation results, gives recommendations for fixing
errors and/or improving the overall quality of the speech corpus and gives an executive
summary. It should be approved and authorized (signed and dated).

❑ The report should include at least the followings:

✓ Aim and purpose of study

✓ Reference to protocol
VALIDATION REPORT
✓ Details of material

✓ Equipment

✓ Program and cycles used

✓ Details of procedures and test methods

✓ Critical process steps studied

✓ Acceptance criteria evaluation

✓ Results (compared with acceptance criteria)

✓ Recommendations on the limit and criteria to be applied in future and

✓ Attachments (e.g. batch records)