a reveiw on pharmaceutical validation

Contents

Glossary: ....................................................................................................................................................... 5

1. Introduction to validation .................................................................................................................. 9

1.1 Definition ............................................................................................................................................ 9

1.2 History of validation ......................................................................................................................... 10

1.2.1 Equipment Qualification and Process Qualification: ................................................................. 11

1.3 Why validation? ................................................................................................................................ 13

1.4 What has to be validated? ................................................................................................................. 14

1.5 Scopes of Validation ......................................................................................................................... 15

1.6 Pre-Requisites for Successful Validation .......................................................................................... 17

1.7 Approaches of Validation ................................................................................................................. 18

1.8 Phases in Validation .......................................................................................................................... 18

1.9 Validation Decision Tree: ................................................................................................................. 20

2. Organizing for Validation ................................................................................................................ 22

2.1 Staffing issues ................................................................................................................................... 22

2.2 Department interactions .................................................................................................................... 22

2.3 Master planning or planning for Validation ...................................................................................... 24

2.4 Benefits of Master Planning .............................................................................................................. 24

2.5 Validation Process ............................................................................................................................ 25

2.6 Validation Plan .................................................................................................................................. 25

2.7 Typical validation master plan structure ........................................................................................... 26

2.8 Validation Protocol ........................................................................................................................... 27

2.9 Validation set up ............................................................................................................................... 29

2.10 Relationship between validation and qualification ......................................................................... 29

2.10.1 Design Qualification (DQ) ....................................................................................................... 30

2.10.2 Installation Qualification (IQ) .................................................................................................. 32

2.10.3 Operational Qualification (OQ) ............................................................................................... 33

2.10.4 Performance Qualification (PQ) .............................................................................................. 34

2.10.5 Component Qualification (CQ) ................................................................................................ 35

2.10.6 Requalification ......................................................................................................................... 35

2.10.7 Revalidation ............................................................................................................................. 35

2.10.8 Revalidation after change ......................................................................................................... 36

A REVIEW ON PHARMACEUTICAL VALIDATION

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2.10.9 Change Control ........................................................................................................................ 36

2.11 Documentation ................................................................................................................................ 37

3. Areas of Validation ........................................................................................................................... 43

3.1 Process Validation ............................................................................................................................ 44

3.1.1 Pilot Scale-Up and Process Validation ...................................................................................... 45

3.1.2 Priority Order in Process Validation .......................................................................................... 46

3.1.3 Stages of Process Validation ...................................................................................................... 47

3.1.4 Types of process validation ........................................................................................................ 52

3.1.5 Process Validation Decision ...................................................................................................... 59

3.1.6 Sterilization Validation .............................................................................................................. 62

3.2 Analytical method validation ............................................................................................................ 66

3.2.1 Why analytical methods need to be validated? .......................................................................... 67

3.2.2 Types of analytical procedures to be validated .......................................................................... 67

3.2.3 Advantages of analytical method validation .............................................................................. 67

3.2.3 Strategy for validation of methods ............................................................................................. 68

3.2.4 Analytical procedure .................................................................................................................. 68

3.2.5 Validation Parameters ................................................................................................................ 69

3.2.6 Data Elements Required for Validation ..................................................................................... 76

3.3 Facilities Validation .......................................................................................................................... 77

3.3.1 The Engineering Design Process for a Facility .......................................................................... 77

3.3.2 Conceptual Design: .................................................................................................................... 77

3.3.3 Purposes: .................................................................................................................................... 78

3.3.4 Qualification Activities .............................................................................................................. 79

3.3.5 Qualification Cost ...................................................................................................................... 79

3.3.6 Design Development: ................................................................................................................. 79

3.3.7 Facility Qualification Plan ......................................................................................................... 80

3.3.8 Qualification .............................................................................................................................. 81

3.4 Computer System Validation ............................................................................................................ 86

3.4.1 History of computer system validation in brief .......................................................................... 86

3.4.2 Importance of CSV .................................................................................................................... 87

3.4.3 Typical Computer System Validation ........................................................................................ 87

3.4.4 Advantages of CSV .................................................................................................................... 89

3.4.5 Software validation .................................................................................................................... 90


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3.4.6 Software Life Cycle ................................................................................................................... 90

3.4.7 Construction or coding ............................................................................................................... 94

3.4.8 Testing by the Software Developer ............................................................................................ 94

3.4.9 User Site Testing ........................................................................................................................ 95

3.5 Equipment Validation ....................................................................................................................... 96

3.5.1 Reason of Equipment Validation ............................................................................................... 96

3.5.2 Content of Equipment Validation .............................................................................................. 96

3.5.3 Balances and Measuring Equipment .......................................................................................... 97

3.5.4 Production equipment ................................................................................................................ 97

3.5.5 Control laboratory equipment .................................................................................................... 97

3.5.6 Washing, cleaning and drying equipment .................................................................................. 98

3.5.7 Equipment Validation Process ................................................................................................... 98

3.5.8 HPLC method calibration ........................................................................................................ 100

3.5.9 HVAC Validation .................................................................................................................... 107

3.6 Cold Chain Validation .................................................................................................................... 117

3.6.1 Uses .......................................................................................................................................... 117

3.6.2 Strategy .................................................................................................................................... 118

3.6.3 Evaluation and Reporting......................................................................................................... 119

3.6.4 Ongoing Monitoring ................................................................................................................ 119

3.7 Source Validation: .......................................................................................................................... 120

3.7.1 Methods of vendor validation .................................................................................................. 120

3.7.2 Corrective and Preventive action ............................................................................................. 123

3.7.3 Importance of Source Validation ............................................................................................. 124

3.8 Personnel Validation ....................................................................................................................... 127

3.8.1 GMP Requirement ................................................................................................................... 127

3.8.2 Responsibilities ........................................................................................................................ 127

3.8.3 Training for personnel .............................................................................................................. 129

3.9 Packaging Validation: ..................................................................................................................... 130

3.9.1 Packaging Materials ................................................................................................................. 131

3.9.2 Packaging Equipment .............................................................................................................. 131

3.9.3 Assess the GMP Risk ............................................................................................................... 132

3.9.4 Line Layout .............................................................................................................................. 132

3.9.5 Operating Procedure and Training ........................................................................................... 132


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3.9.6 Conduct of Packaging Validation ............................................................................................ 133

3.9.7 Performance qualification examples ........................................................................................ 135

3.9.8 Tests that can be performed for packaging validation ............................................................. 136

3.10 Cleaning Validation ...................................................................................................................... 139

3.10.1 Necessity ................................................................................................................................ 140

3.10.2 Advantages ............................................................................................................................. 140

3.10.3 Contamination ........................................................................................................................ 140

3.10.4 Cross Contamination .............................................................................................................. 140

3.10.5 Mechanism of Contamination ................................................................................................ 141

3.10.6 Cleaning Agent selection ....................................................................................................... 141

3.10.7 Sampling Techniques ............................................................................................................. 142

3.10.8 Sampling Methods ................................................................................................................. 143

3.10.9 Level of Cleaning ................................................................................................................... 145

3.10.10 Cleaning Validation procedure ............................................................................................ 146

3.10.11 Strategy on Cleaning Validation Studies ............................................................................. 146

3.10.12 Analyzing cleaning validation samples ................................................................................ 148

3.10.13 Data analysis for estimating possible contamination ........................................................... 149

4. Future Aspects of Validation ............................................................................................................. 150

4.1. Latest Technology .......................................................................................................................... 150

4.2 Automated Inspection/Identification ............................................................................................... 150

4.3 Process Automation ........................................................................................................................ 150

4.4 Robotics .......................................................................................................................................... 151

4.5 Isolation........................................................................................................................................... 151

5. Conclusion ....................................................................................................................................... 153

6. References ........................................................................................................................................ 154


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Glossary:

1. Calibration The set of operations that establish, under specified conditions, the

relationship between values indicated by an instrument or system for measuring (for e.g.

weight, temperature, pH), recording and controlling, or the values represented by a material

measure, and the corresponding known values of a reference standard. Limits for acceptance

of the results of measuring should be established.

2. Computer validation - Documented evidence which provides a high degree of assurance

that a computerized system analyses, controls and records data correctly and that data

processing complies with predetermined specifications.

3. Commissioning The setting up, adjustment and testing of equipment or a system to ensure

that it meets all the requirements, as specified in the user requirement specification, and

capacities as specified by the designer or developer. Commissioning is carried out before

qualification and validation.

4. Concurrent validation Validation carried out during routine production of products

intended for sale.

5. Cleaning validation Documented evidence to establish that cleaning procedures are

removing residues to predetermined levels of acceptability, taking into consideration factors

such as batch size, dosing, toxicology, and equipment size.

6. Design qualification (DQ) Documented evidence that the premises, supporting systems,

utilities, equipment and processes have been designed in accordance with the requirements of

GMP.

7. Good engineering practices (GEP) Established engineering methods and standards that

are applied throughout the project life-cycle to deliver appropriate, cost-effective solutions.

8. Installation qualification (IQ) The performance of tests to ensure that the installations

(such as machines, measuring devices, utilities and manufacturing areas) used in a

manufacturing process are appropriately selected and correctly installed and operate in

accordance with established specifications.

9. Operational qualification (OQ) Documented verification that the system or subsystem

performs as intended over all anticipated operating ranges.

10. Performance qualification (PQ) Documented verification that the equipment or system

operates consistently and gives reproducibility with defined specifications and parameters for


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prolonged periods. (In the context of systems, the term process validation may also be

used.)

11. Process validation Documented evidence which provides a high degree of assurance that a

specific process will consistently result in a product that meets its predetermined

specifications and quality characteristics.

12. Prospective validation Validation carried out during the development stage on the basis of

a risk analysis of the production process, which is broken down into individual steps; these

are then evaluated on the basis of past experience to determine whether they may lead to

critical situations.

13. Qualification Action of proving and documenting that any premises, systems and

equipment are properly installed, and/or work correctly and lead to the expected result.

Qualification is often a part (the initial stage) of validation, but the individual qualification

steps alone do not constitute process validation.

14. Retrospective validation Involves the evaluation of past experience of production on the

condition that composition, procedures, and equipment remain unchanged.

15. Revalidation Repeated validation of an approved process (or a part thereof) to ensure

continued compliance with established requirements.

16. Standard Operating Procedure (SOP) An authorized written procedure giving

instructions for performing operations not necessarily specific to a given product or material

but of a more general nature (e.g. equipment operation, maintenance and cleaning;

validation; cleaning of premises and environmental control, sampling and inspection).

Certain SOPs may be used to supplement product-specific master batch production

documentation.

17. Validation Action of proving and documenting that any process, procedure or method

actually and consistently leads to the expected results. The aim of validation is not to correct

or detect deviations in the packed product but to prevent deviations in the final packed

products as far as is practicable and economic.

18. Validation protocol (or plan) (VP) A document describing the activities to be performed

in a validation, including the acceptance criteria for the approval of a manufacturing process

or a part thereof for routine use.


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19. Validation report (VR) A document in which the records, results and evaluation of a

completed validation programme are assembled and summarized. It may also contain

proposals for the improvement of processes and/or equipment.

20. Validation master plan (VMP) - The VMP is a high-level document that establishes an

umbrella validation plan for the entire project and summarizes the manufacturers overall

philosophy and approach, to be used for establishing performance adequacy. It provides

information on the manufacturers validation work programme and defines details of and

timescales for the validation work to be performed, including a statement of the

responsibilities of those implementing the plan.

21. Verification The application of methods, procedures, tests and other evaluations, in

addition to monitoring, to determine compliance with the GMP principles.

22. Worst case A condition or set of conditions encompassing the upper and lower processing

limits for operating parameters and circumstances, within SOPs, which pose the greatest

chance of product or process failure when compared to ideal conditions. Such conditions do

not necessarily include product or process failure.

23. URS User Requirements Specification (URS) provides a clear and precise definition of

what the user wants the system to do. It defines the functions to be carried out, the data on

which the system will operate and the operating environment. The URS define also any non-

functional requirements, constraints such as time and costs and what deliverables are to be

supplied. The emphasis should be on the required functions and not the method of

implementing those functions.

24. Acceptance Criteria The criteria a product must meet to successfully complete a test

phase or to achieve delivery requirements.

25. Change Control A formal system of reviewing and documenting proposed or actual

change that might affect the validated status of a system, equipment or process followed by

action to ensure ongoing validated state.

26. Requirement It can be any need or expectation for a system. It reflects the stated or

implied needs of the customer, and may be market-based, contractual, or statutory, as well as

an organizations internal needs.

27. Specification It is a document that states requirements.


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28. Quality Assurance It can be defined as the totality of the arrangements made with the

object of ensuring that pharmaceutical products are of the quality required for their intended

use. In addition, it ensures that arrangements made for the manufacture, supply and use of the

correct starting and packaging materials.

29. Quality Control It is the part of GMP concerned with sampling, specifications and testing,

and with the organization, documentation and release procedures which ensures that the

necessary and relevant tests are actually carried out and that materials are not released for

used, nor products released for sale or supply, until their quality has been judged to be

satisfactory. It is not confined to laboratory operations but must be involved in all decisions

concerning the quality of the product.


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1. Introduction to validation

1.1 Definition

Validation is not a one-time event but on-going process covering all phases of a product or

process. Literally, validation in pharmaceuticals means to be valid or justifiable. Simply saying,

validation means action of proving effectiveness. According to FDA 1987 validation is

establishing documented evidence which provides a high degree of assurance that a specific

process will consistently produce a product meeting its predetermined specifications and quality

attributes.1 According to European Commission- 1991, validation is an act of proving in

accordance of GMPs that any process actually leads to expected results. According to European

Commission-2000, validation is documented evidence that the process, operated within

established parameters, can perform effectively and reproducibly to produce a medicinal product

meeting its predetermined specifications and quality attributes.

Validation is the evaluating of processes, products or analytical methods to ensure compliance

with product or method requirements. Prerequisites to fulfill these requirements for analytical

laboratories are properly functioning and well documented instruments (hardware and firmware),

computer hardware and software and validated analytical methods.2

Validation is an essential part of good manufacturing practices (GMP). It is, therefore, an

element of the quality assurance programme associated with a particular product or process. The

basic principles of quality assurance have as their goal the production of products that are fit for

their intended use. These principles are as follows:

Quality, safety and efficacy must be designed and built into the product.

Quality cannot be inspected or tested into the product.

Each critical step of the manufacturing process must be validated. Other steps in the process

must be under control to maximize the probability that the finished product consistently and

predictably meets all quality and design specifications.

Validation of processes and systems is fundamental to achieving these goals. It is by design and

validation that a manufacturer can establish confidence that the manufactured products will

consistently meet their product specifications.

Documentation associated with validation includes:

Standard operating procedures (SOPs)


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Specifications

Validation master plan (VMP)

Qualification protocols and reports

Validation protocols and reports.

The implementation of validation work requires considerable resources such as:

Time: Generally validation work is subject to rigorous time schedules.

Financial: Validation often requires the time of specialized personnel and expensive

technology.

Human: Validation requires the collaboration of experts from various disciplines (e.g. a

multidisciplinary team, comprising quality assurance, engineering, manufacturing and other

disciplines, depending on the product and process to be validated).3

Chapman purported Validation means nothing else than well-organized, well-documented

common sense.4

1.2 History of validation:

Validation is a subject that has grown in importance within the global healthcare industry over

the past 25 years. Its origin can be traced to terminal sterilization process failures in the early

1970s. Individuals in the US point to the LVP sterilization problems of Abbott and Baxter, while

those in the U.K. cite the Davenport incident.5 Each incident was a result of a non-obvious fault

coupled with the inherent limitations of the end-product sterility test. As a consequence of these

events, non-sterile materials were released to the market, deaths occurred, and regulatory

investigations were launched. The outcome of this was the introduction by the regulators of the

concept of Validation.

The initial reaction to this regulatory initiative was one of puzzlement, only a limited number of

firms had encountered difficulties, and all of the problems were seemingly associated with the

sterilization of LVP containers. It took several years for firms across the industry to understand

that the concerns related to process effectiveness were not limited to LVP solutions, and even

longer to recognize that those concerns were not restricted to sterile products. From its earliest

days, validation was identified as a new regulatory requirement to be added to the list of things

that firms must do, with little consideration of its real implications. The first efforts reflected


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what can be termed the scientific method of observation of an activity, hypothesis/predition of

cause/effect relationship, and experimentation followed by new observations in the form of the

experimental report. In the pharmaceutical validation model this has evolved into the validation

protocol (hypothesis and prediction), field execution (experimentation), and summary report

preparation (documented observations).6

By 1980, it was evident to all that validation was here to stay, so pharmaceutical firms began to

organize their activities more formally. Ad hoc teams and task forces that had started the efforts

were replaced by permanent Validation Departments whose responsibilities and scope varied

with the organization but whose purpose was to provide the necessary validation for a firms

products and processes. The individuals in these departments were the first to grapple with

validation as their primary responsibility, and their methods, concepts, and practices have served

to define validation ever since as establishing documented evidence which provides a high

degree of assurance that a specific process will consistently produce a product meeting its pre-

determined specifications and quality attributes.7

The first efforts at validation were rather crude and limited in their understanding of the full

implications but slowly made significant strides. For e.g. the first sterilization validations were

performed without prior qualification of the equipment. Once validation had been established as

discipline, methods for its execution became substantially more formalized and rigorous.

Perhaps, most important was stride was separation of activities into two major categories.

1.2.1 Equipment Qualification and Process Qualification:

It was apparent by then that validation had to be more closely integrated into the mainstream of

cGMP operations in order to maximize its effectiveness in larger organizations. A number of

areas can be identified as pre-requisites for process or system validation. The origins of these

elements can be identified in the cGMP requirements for drugs and devices (Table 1).8

With this understanding, the industry began to recognize that validation offered advantages to the

firm and implemented validation objectives that were non-regulatory and geared for the

optimization of processes and systems. The attention being placed on validation at this time led

to important changes in how firms approached its implementation and should be integrated with

other GMP.


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Table 1:- Pre-Requisites for Validation

1 Process Development [21 CFR 820.30Design Control]. The activities performed to

define the process, product or system to be evaluated.

2 Process Documentation [21 CFR 211 Subparts F - Production and Process controls and J-

Records and Reports]. The documentation (batch records, procedures, test methods,

sampling plans) and processes (software) that define the operation of the equipment to

attain the desired result.

3 Equipment Qualification [21CFR 211 Subparts C Buildings and Facilities and D-

Equipment]. The specifications, drawing, checklists and other data that support the

physical equipment (hardware) utilized for the process.

4 Calibration [21 CFR 211 Subparts D Equipment]. The methods and controls that

establish the accuracy of data.

5 Analytical Methods [21CFR 211 Subparts I Laboratory Controls]. The means to

evaluate the outcome of the process on the materials.

6 Cleaning [21 CFR 211.67Equipment Cleaning and Maintenance]. A specialized process,

the intent of which is to remove the traces of the prior product from the equipment.

7 Change Control [21 CFR 211. 100(b) Equipment Cleaning and Maintenance]. A

formalized process control scheme that evaluates changes to documentation, materials,

and equipment.

The pharmaceutical industry participated in the introduction of computers into the manufacturing

environment during the 1980s. This led to FDA concerns relative to the validation of

computerized system used within the industry. The pharmaceutical industrys response to the

FDAs new concerns regarding validation of computerized systems was somewhat different than

what had occurred previously. The Pharmaceutical Manufacturers Association established an

interdisciplinary group called the Computer Systems Validation Committee (CSVC) in late 1983

to address how the industry would address the FDAs concerns. Through the creation of the


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CSVC, the industry began to assume a position of leadership regarding validation. Through the

auspices of the CSVC, an industry approach to the validation of computerized systems in the

GMP environment was established.9 Central to the industry position, was the adoption of the

life cycle concept as an appropriate model for managing the activities needed for the

successful validation of computerized systems (Figure 1). The life cycle approach focuses on

managing a project from cradle to grave. When employing the life cycle approach, the design,

implementation, and operation of system (or project) are recognized as interdependent parts of

the whole. Operation and maintenance concerns are addressed during the design of the system

and confirmed in the implementation phase to ensure their acceptability. The adoption of the life

cycle methodology afforded such a degree of control over the complex tasks associated with the

validation of computerized systems that it came into nearly universal application within a very

short period.

Figure 1

1.3 Why validation?

First and foremost, among the reasons for validation is that it is a regulatory requirement for

virtually every process in the global healthcare industry for pharmaceuticals, biologics, and

medical devices. Regulatory agencies across the world expect firms to validate their processes.

The continuing trend toward harmonization of requirements will eventually result in a common

level of expectation for validations worldwide.

Number of tangible and intangible benefits of validation was realized (Table 2)10

. In the

intervening years, there has been repeated affirmation of those expectations at other firms, large


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and small. Regrettably, there has been little quantification of these benefits. The predominance of

compliance-based validation initiatives generally restricts objective discussion of cost

implications for any initiative. But once a process/product is properly validated, it seem that

reduced sample size and intervals could be easily justified, and thus provide a measurable return

on the validation effort. Aside from utility systems, it is hardly ever realized and represents one

of the major failings relative to the implementation of validation in pharmaceutical industry.

Table 1: Benefits of Validation

Increased throughput

Reduction in rejections and reworks

Reduction in utility costs

Avoidance of capital expenditures

Fewer complaints about process related failures

Reduced testing in process and finished goods

More rapid and accurate investigations into process deviations

More rapid and reliable startup of new equipment

Easier scale-up from development work

Easier maintenance of the equipment

Improved employee awareness of processes

More rapid automation

Validation and validation-like activities are found in a number of industries, regulated and

unregulated. Banking, aviation, software, microelectronics, nuclear power, among others all

incorporate practices closely resembling validation of health care product production. The health

care industries fixation on compliance has perhaps blinded us the real value of validation

practices.

1.4 What has to be validated?

Validation efforts in the analytical laboratory should be broken down into separate components

addressing the equipment (both the instrument and the computer controlling it) and the analytical

methods run on that equipment. After these have been verified separately they should be checked

together to confirm expected performance limits (so-called system suitability testing), and finally


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the sample analysis data collected on such a system should be authenticated with suitable

validation checkouts. Other activities include checking reference standards and qualification of

people.

1) Equipment: All (computerized) equipment that is used to create, modify, maintain, archive,

retrieve, or distribute critical data for cGMP/GCP/GLP purposes should be validated.

Validation of hardware includes testing the instrument according to the documented

specifications. Even though this may include word processing systems to create and maintain

SOPs, it covers analytic systems only. If instruments consist of several modules, a modular

HPLC system for example, the entire system should be validated. Validation of computer

systems must include the qualification of hardware and software.

2) Analysis method: Validation covers testing of significant method characteristics, for e.g

sensitivity and reproducibility.

3) Analytical system: The system combines instrument, computer and analytical method. This

validation usually referred to as system suitability testing, tests the system for documented

performance specifications for the specific analysis method.

4) Data: When analyzing samples the data must be validated. The validation process includes

documentation and checks for data plausibility, consistency, integrity, and traceability. A

complete audit trail must be in place, which allows tracing back the final result to the raw

data for integrity.

5) Personnel: People should be qualified for their jobs. This includes education, training and/or

experience.

6) Reference standards: Reference standard should be checked for purity, identity,

concentrations and stability.11

1.5 Scopes of Validation

There should be an appropriate and sufficient system including organizational structure and

documentation infrastructure, sufficient personnel and financial resources to perform

validation tasks in a timely manner. Management and persons responsible for quality

assurance should be involved.


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Personnel with appropriate qualifications and experience should be responsible for

performing validation. They should represent different departments depending on the

validation work to be performed.

There should be proper preparation and planning before validation is performed. There

should be a specific programme for validation activities.

Validation should be performed in a structured way according to the documented procedures

and protocols.

Validation should be performed for:

For new premises, equipment, utilities and systems, and processes and procedures.

At periodic intervals, and

When major changes have been made.

(Periodic revalidation or periodic requalification may be substituted, where appropriate, with

periodic evaluation of data and information to establish whether requalification or revalidation is

required).

Validation should be performed in accordance with written protocols. A written report on the

outcome of the validation should be produced.

Validation should be done over a period of time, e.g. at least three consecutive batches (full

production scale) should be validated, to demonstrate consistency. Worst case situations

should be considered.

There should be a clear distinction between in-process controls and validation. In-process

tests are performed during the manufacture of each batch according to specifications and

methods devised during the development phase. Their objective is to monitor the process

continuously.

When a new manufacturing formula or method is adopted, steps should be taken to

demonstrate its suitability for routine processing. The defined process, using the materials

and equipment specified, should be shown to result in the consistent yield of a product of the

required quality.

Manufacturers should identify what validation work is needed to prove that critical aspects of

their operations are appropriately controlled. Significant changes to the facilities or the

equipment, and processes that may affect the quality of the product should be validated. A


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risk assessment approach should be used to determine the scope and extent of validation

required.12

1.6 Pre-Requisites for Successful Validation

There are some elements or tools that are required for conducting effective validations. Each are

presented and discussed in the following sections:

Understanding

The single most important element required is a good understanding of what validation is.

This understanding activity goes beyond the basic definition of validation, beyond the

concept of requiring a minimum of three runs and understanding must be anchored by

sufficient years of practical experience and knowledge. It will permit sound and logical

decisions even under most intense situations.13

Communication

Communication is one of the best methods of improving environment understanding. It is

essential for any activity that requires more than one resource to complete. This point is

understandable considering that conducting effective validation involves multi-departments.

Co-operation and Focus

Multi departments that sometimes interact during the course of executing validation program

are project management, accounting, quality control, project engineering, process

engineering, quality assurance, facilities; regulatory etc should have a commendable co-

operation.

Experience

A firm must have resources with solid validation experience to get success in their validation

program.

Resources

Resources mean personnel who will plan and execute equipment on which validations will be

performed on materials with which to conduct validations. Laboratories that will perform

necessary analysis should provide necessary funding for the validations and allocate

sufficient time to perform validations.14

Plan

Conducting validations within most companies will involve a number of departments and

disciplines. These disciplines need a perfect plan in order to get good team synergy.


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Budget

It is important to understand that a successful validation must be done to completion and it

should not be limited by a budget assembled by personnel who have no appreciation for what

is required to successfully complete validation. Further, it is important to understand that

validations cost money.15

Standard Operating Procedures (SOPs)

The SOPs capture activities that routinely occur within an organization. Departments charged

with abiding by or following these SOPs must first be trained against these SOPs.

Quality Control lab support

In most of the validations, some laboratory testing will be required. In most cases this testing

is handled by the QC group. QC is expected to provide results in timely manner. So often, the

wait for the receipt of analytical results cases the entire validation project to come to halt.

Because validations are based on the results obtained.

1.7 Approaches of Validation

According to the WHO, there are two basic approaches to validation; one is based on evidence

obtained through testing (prospective and concurrent validation), and another is based on the

analysis of accumulated (historical) data (i.e. retrospective validation). Whenever possible,

prospective validation is preferred. Retrospective validation is no longer encouraged and is, in

any case, not applicable to the manufacturing of sterile products.

Both prospective and concurrent validation may include following:

Extensive product testing, which may involve extensive sample testing (with the estimation

of confidence limits for individual results) and the demonstration of intra- and inter-batch

homogeneity.

Simulation process trials

Challenge/ worst case tests, which determine the robustness of the process, and

Control of process parameters being monitored during normal production runs to obtain

additional information on the reliability of the process.16

1.8 Phases in Validation17:

The activities relating to validation studies may be classified into three phases mainly. They are

as follows:


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1. Pre-validation Qualification Phase: It covers all activities related to product research and

development, formulating pilot batch studies, scale-up studies, technology transfer to

commercial scale batches, establishing stability conditions and storage, and handling of in-

process and finished dosage forms, equipment; operational and installation qualification,

master production document and process capacity.

2. Process validation phase: It is designed to verify that all established limits of the critical

process parameters are valid and satisfactory products can be produced even under worst

conditions.

3. Validation Maintenance phase: It requires frequent review of all process related documents,

including audit reports, to assure that there have been no changes, deviations, failures and

modifications to the production process and that all SOPs, including change control

procedures have been followed. At this phase, the validation comprising of members from all

major departments assures that there have been no changes/deviations that should be resulted

in requalification and revalidation. A careful design and validation of systems and process

controls can establish a high degree of confidence that all lots of batches produced will meet

their intended specifications. Thus, its assumed that throughout manufacturing and control,

operations are conducted in accordance with the principle of GMP both in general and in

specific reference to sterile product manufacture.

The validation steps recommended in GMP guidelines can be summarized as follows18

:

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


20

implementation of a programme of re-testing in-process equipment should be properly

installed, qualified and maintained.

When appropriate attention is paid to above, the process, if aseptic, may be validated by

means of process simulation studies.

The process should be revalidated at specific time intervals.

Comprehensive documentation should be available to define support and record the overall

validation process.

1.9 Validation Decision Tree:

This model describes a decision tree that helps manufacturer decide on whether processes need

to be validated or not. It is one of the easiest models under consideration.

Each process should have a specification describing both the process parameters and the desired

output. The tree is described below:

A

Is process

Output

Verifiable

B

Is Verification

Sufficient &

Cost Effective

C

Verify &

Control the

Process

D

Validate

E

Redesign

Product and/or

Process

NO NO

Yes YES

Figure- 2: Validation Decision Tree


21

A. The manufacturer should consider whether the output can be verified by subsequent

monitoring or measurement.

B. If the answer is positive, then the consideration should be made as to whether or not

verification alone is sufficient to eliminate unacceptable risk and is a cost effective solution.

C. If yes, the output should be verified and the process should be appropriately controlled.

D. If the output of the process is not verifiable then the decision should be to validate the

process.

E. The product or process should be redesigned to reduce variation, improve product or process

and decrease risk or cost to a point where verification is acceptable decision.


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2. Organizing for Validation

Validation and its role within a pharmaceutical organization have come a long way from its

inception in the 1970s, when the effort was primarily focused on sterilization validation and

demonstrating that the conditions to achieve sterility were met. As a result, it was managed from

within the sterile manufacturing unit using a small team. In the 1980s, validations organizations

were created and began interacting with other groups such as Research, Engineering, Production,

Manufacturing, and Quality Assurance.

Formulating a mission is essential to ensure proper definition of a department role in the

formation. Although there is broad diversity of validation department missions within the

pharmaceutical industry, the mission that is general to all validation departments is the satisfying

of the regulatory requirement to have processes validated. Certainly the validation mission is

influenced by the size of the company as well as its product lines.

2.1 Staffing issues

When staffing a validation group, the mission and the organization exert a degree of influence,

primarily in the academic backgrounds of the members. Because of the aforementioned diversity,

a considerable variety of academic backgrounds are usually found among validation

professionals, such as members having degrees in chemistry, microbiology, pharmacy, statistics,

computer science, biochemistry as well as engineering disciplines. For e.g. when the mission is

directed toward a sterile products focus, having a microbiology degree would be beneficial. In

general sense, the more important than the actual academic background are these 3 skills:

problem-solving capability, interpersonal skills, and oral and written communication abilities.

The technical talent to recognize and solve problems is fundamental to validation. Finally, it is

targeted that the validation members be able to effectively express the validation objectives and

concerns both orally and in written form. If the professional can successfully communicate

orally, esp. during an FDA visit, the strength of validation package is expected to be even

greater.

2.2 Department interactions

Once missions of departments have been formalized and the validation operations are organized,

the main challenge is to implement the plan, which requires interaction with many peer groups.

Within the company, other departments involved in validation taskforce are as follows:


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1. R & D: It is involved with new product and process development and often existing process

improvements. Their key responsibility in validation is to ensure the acceptability (and thus

validatability) of new products or improved process in the manufacturing area. They must

be aware of the validation plan and resulting acceptance criteria.

2. Engineering: It is involved with new or modified equipment or facilities and their start-ups.

Their role is to ensure the acceptability of the processes later on, so their concern must be

built in at the design phase and continued through construction.

3. Production: It is concerned with processes that require validation and stress the benefits of a

validation program.

4. Maintenance: Its concerned with change control, calibration, and preventative maintenance.

This occurs at the instant when an undocumented change is made to a validated piece of

equipment.

5. Quality Control: Its involved with the testing laboratories and ensures that laboratory

personnel know not only the number and type of tests required for the study but also how the

testing fits into the overall validation program.

6. Quality Assurance: Its concerned with GMP compliance to ensure a firms regulatory

compliance. Through the technical competency of the validation staff and the GMP

compliance expertise existing within the QA group, these efforts should be successful. The

key point is to communicate so that the regulatory compliance objective of validation is met.

Whether the process is a bulk process or one of the finishing steps; whether it is a proprietary

purification process, a steam sterilization process, or a conventional non-sterile process; whether

the focus is a clinical manufacturing lot or commercial production; or whether the effort is

accomplished within the firm, contracted out in conjunction with an outsourced manufacturing

agreement, or with the assistance of a consultant, the validation staff must possess 4 things:

i. Technical expertise, allowing a thorough understanding of the process being reviewed.

ii. Understanding of the fundamentals of validation and the ability to apply them to the process.

iii. Interpersonal skills necessary to deal with all of the organizations within and outside of the

firm.

iv. Support from management, which positions the validation effort as a critical element in the

companys success.

These basics ensure that the validation effort is successfully accomplished.19


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2.3 Master planning or planning for Validation

The validation master plan (VMP) has become common practice for all large capital projects

within the global healthcare industry. The master plan has come into vogue to ensure that the

validation requirements for major facilities are adequately addressed. Although its often

described as a regulatory requirement, there is in fact no such requirement in any of the worlds

cGMP regulations; nevertheless, its real value is as a management tool to be used to coordinate

the validation effort. It is an indispensable tool that delineates how the validation effort is to be

executed. The utility of plan diminishes with facility size and complexity, but even small projects

may benefit from the structure that a master plan brings to the validation effort.20

VMP is a good practice to document all validation activities in a document. The FDA does not

specifically demand a validation master plan however; inspectors want to know what the

companys approach towards validation is. So, VMP is an ideal tool to communicate this

approach internally and to inspectors.21

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 VMP. It should comprise all prospective,

concurrent and retrospective validations as well as revalidation.22

The VMP should reflect the

key elements of the validation programme. It should be concise and clear and contain at least the

following:

A validation policy

Organizational structure of validation activities

Summary of facilities, systems, equipment and processes validated and to be validated.

Documentation format (e.g. protocol and report format)

Planning and scheduling

Change control

References to existing documents

2.4 Benefits of Master Planning

Numerous benefits are derived from a VMP which can substantially enhance the firms

validation posture for the project. A well-structured plan will provide following advantages to a

firm:


25

i. Codify decisions regarding how cGMP requirements will be satisfied.

ii. Allow detailed definition of validation activities necessary for the successful operation of the

facility.

iii. Serve as an important document in regulatory compliance and interaction.

iv. Serve as a communication document on the validation for use with third parties.

v. Be easily converted into a Drug Master File

vi. Serve as an excellent tool for audit preparation (either internal or external).

vii. Define project execution through the definition of requirements.

viii. Help determine resource needs for personnel, materials, equipment, components and

laboratory analysis.

ix. Ease protocol and report preparation through the definition of accepted formats.

x. Be used as a bid document when soliciting bids for contract execution.

2.5 Validation Process

Each part of the validation process should be documented. There should be a written plan for

performing each validation to specify who is responsible for managing and performing the

various validation tasks such as production of validation protocols and approvals of validation

documentation. Validation protocols should be written for each phase of the validation to include

acceptance criteria. The validation plan and the validation protocols may be combined into a

single document. The outcome of each phase of validation should be recorded and the overall

conclusions, with a scientific assessment of any failures should be documented in a validation

summary report. The validation records and summary report must be reviewed and approved

before putting the process or system affected into use.

2.6 Validation Plan

The plan should first identify the following things:

What is being validated

Where the validation will take place

Why the validation is taking place providing reference to any relevant change control

records, risk assessments, URS and FDS.

The validation stages required


26

Validation time-frames

The plan should also identify the validation team and define responsibilities for :

Overall management of the validation

Production of protocols

Performing the validation and recording the outcome

Reviewing and approving the protocols and validation records

Reviewing the validation outcomes and signing off the validation as acceptable.23

2.7 Typical validation master plan structure

There is no standard format for master plans. Various authors used different types of plans with

appropriate adaptations to suit to specific requirements of a particular project. The most

successfully used plans basic template is given in table below (table 3)24. It can be readily

modified to different project types and scales. With changes in the facility type, there is a

corresponding change in the focus of the master plan.

Table 3 Validation master plan template

Introduction Introduction to the project scope, location, and timing. Includes

responsibilities for protocol, SOP, report and other documentation

preparation and approval. Identifies who is responsible for the

various activities. A general validation SOP or policy statement may

be included.

Plant/Process/Product

Development

A concise description of the entire project is provided. It will

provide information on layout and flow of personnel, materials, and

components; utility and support systems; description of the

processes to be performed and products to be made in the facility.

Major equipment is also described.

Computerized System

and Process Control

Description (If needed)

Computerized information, laboratory and process control systems

are described in sufficient detail to delineate the validation

requirements. This section may be omitted if the level of automation

is minimal.


27

List of Systems/

Processes/Products to

be validated

Equipment, systems, and products are listed in a matrix format that

describes the extent of validation required (i.e. IQ, OQ, or PQ) as

part of the project. Additional breakout of computerized, cleaning

and sterilization validation requirements can be added.

General and Specific

Acceptance Criteria

Key acceptance criteria (general and specific) for the items listed in

the prior section are provided. Emphasis should be placed on

quantitative criteria throughout. To merely state the general

requirements provides no substantial benefit to either those

responsible for the validation or for those involved in the design

process.

Special Issues (if

needed)

Sections can be included describing in greater detail the validation

requirements of an element of the project where additional

clarification may be warranted. Typical subjects include automation,

cleaning, containment, isolation, or lyophilization.

Protocol and

Documentation format

The format to be used for protocols, reports, and operating

procedures is described. This particularly useful in a new

organization where such formats have not yet been defined. It can

also be beneficial when working with an outside contractor to ensure

that all documentation is in the correct format.

Required procedures List of SOPs (new or existing) necessary to operate the facility.

Manpower planning

and scheduling

An estimate of the staffing requirements to complete the validation

effort described in the plan. A preliminary schedule of required

activities is prepared to help estimate appropriate manning levels.

2.8 Validation Protocol

Validation protocol is the step that comes after validation plan. It is an integral element of the

validation plan. The protocol describes:

The qualification/validation phase (IQ,OQ, PQ or method process validation)


28

The tests that will be performed

The test procedures

The objectives of the validation in terms of acceptance criteria for each test

Records to be completed.

What needs to be tested, how many tests to do and the acceptance criteria at each validation

phase will be specific to each validation and must be founded on the scientific and technical

basis of the processes and systems involved. It should be possible to establish the specific

requirements by reference to the relevant risk assessments, URS, FDS, published standards,

regulations & guidelines.25

The detailed protocols for performing validations are essential to ensure that the process is

adequately validated. It should include the following elements:

Objectives, scope of coverage of the validation study.

Validation team membership, their qualifications and responsibilities.

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.

Process variables and attributes with probable risk and prevention shall be captured.

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.

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.


29

There should also be a description of the way in which the results will be analyzed. The protocol

should be approved prior to use. Any changes to a protocol should be approved prior to

implementation of the change. The validation protocol and report may also include copies of the

product stability report or a summary of it, validation documentation on cleaning, and analytical

methods.

2.9 Validation set up

Validation set up is very essential to establish the desired attributes. These attributes include

physical as well as chemical characteristics. In the case of parenterals, these attributes should

include stability, absence of pyrogens, and freedom from visible particles.

Acceptance specifications for the product should be established in order to attain uniformity and

consistently the desired product attributes, and the specifications should be derived from testing

and challenge of the system on sound statistical basis during the initial development and

production phases and continuing through subsequent routine production.

The process and equipment should be selected to achieve the product specification. For e.g.

design engineers; production and quality assurance people may all be involved. The process

should be defined with a great deal of specificity and each step of the process should be

challenged to determine its adequacy. These aspects are important in order to assure products of

uniform quality, purity and performance.26

2.10 Relationship between validation and qualification

Validation and qualification are essential components of the same concept. The term

qualification is normally used for equipment, utilities and systems, and validation for processes.

In this sense, qualification is part of validation. Qualification is pre-requisite of validation. There

are four phases/stages of qualification for process, equipment, facilities or systems:

Design qualification (DQ);

Installation qualification (IQ)

Operational qualification (OQ)

Performance qualification (PQ)

Component qualification (CQ), only sometimes stated.


30

All SOPs for operation, maintenance and calibration should be prepared during qualification.

Training should also be provided to operators and training records be maintained.

2.10.1 Design Qualification (DQ)

DQ is defined as Providing documented verification that all key aspects of the design,

procurement and installation adhere to the approved design intention and that all the

manufacturers recommendations have been suitably considered.27 It defines the functional and

operational specifications of the instrument and details the conscious decisions in the selection of

the supplier.28

DQ covers all aspects of the design and procurement of facility and equipment. It

is intended to encompass all those activities that might take place in the design phase, detailed

and development, including activities associated with procurement of equipment and checkout at

the suppliers works. It is a verification that the design meets user requirements with a particular

focus on those requirements that relate to GMP and product quality. The extent of DQ may

depend on the contract arrangements. Design may be subcontracted to suppliers or

subcontractors and how this is covered should be defined in the plan. DQ is not a regulatory

requirement but a smart activity to include in the qualification process. It is essential that aspects

of design are demonstrated in the qualification process as the existing regulations require that

facility and equipment are of suitable design and appropriate to purpose.

DQ should also provide documented evidence that the design specifications were met. Any

validation should start with setting and documenting the specifications for user requirements,

instrument functions and performance. The specifications of the instruments design should be

compared with the user requirement specifications. It is a simple rule of thumb: without

specifications there is no validation. DQ is the most important step in the validation process.

Errors made in this phase can have a tremendous impact on the workload during later phases.

Steps for design qualification: The recommended steps that should be considered for inclusion in

a design qualification are listed below:

Description of the analysis problem.

Selection of the analysis technique.

Description of the intended use of the equipment.

Preliminary selection of functional and performance or operational specifications (technical,

environmental, safety).


31

Preliminary selection of the supplier.

Instrument tests (if the technique is new).

Final selection of the equipment.

Final selection of the supplier.

Development and documentation of the final functional and operational specifications.

Role of vendor for design qualification

Although the user of a system has ultimate responsibility for validation, the vendor also plays a

major role. The validation covers the complete life of a product, starting with the design and

development. For commercial off the shelf systems, the user has hardly any influence on how the

software is being developed and validated, but he can check through documentation to see if the

vendor followed in acknowledged quality process.

Tasks of the vendor: The vendor should

Develop and validate software following documented procedures.

Test the system and document test cases, acceptance criteria and test results.

Retain the tests protocols and source code for review at the vendors site.

Provide procedures for IQ and OQ/PV.

Implement a customer feedback, change control and response system.

Provide fast telephone, e-mail and/ or on-site support.

Qualification of the vendor

As a part of the qualification process, the vendor should be qualified. The question is, how

should this be done? Is an established and documented quality system enough, for e.g. ISO

9001? Should there be a direct audit? Is there another alternative between these two extremes?

There may be situations where a vendor audit is recommended: for e.g. when computer systems

are being developed for a specific user. However, this is rarely the case for analytical equipment.

Typically, off-the-shelf systems are purchased from a vendor with little or no customization for

specific users.

The exact procedure to qualify a vendor depends very much on the individual situation, for e.g.

is the system in mind employing mature or new technology? Is the specific system in widespread

use either within your own laboratory or your company, or are there references in the same

industry? Does the system include complex computer hardware and software?


32

2.10.2 Installation Qualification (IQ)

It can be defined as process of obtaining and documenting evidence that equipment has been

provided and installed in accordance with the specification. IQ establishes that the instrument is

received as designed and specified, that it is properly installed in the selected environment, and

that this environment is suitable for the operation and use of the instrument. This involves

verification of good engineering practice in installation of equipment, and should consider

electrical safety, safety issues, location siting, and maintenance/calibration schedules and should

confirm that the installation has been carried out as specified with the appropriate supporting

documentation. This activity can be delegated to the supplier, provided that the content of the IQ

document is approved in advance by the laboratory.

IQ should provide documented evidence that the installation was complete and satisfactory. It

should also clearly define those areas and items of equipment systems that are to be qualified.

The purpose specifications, drawings, manuals, spare parts lists and vendor details should be

verified during installation qualification. Also, control and measuring devices be calibrated.

Steps for IQ: Steps for IQ include activities prior and during installation of the equipment. The

recommended steps are as follows:

a) Before installation

Obtain manufacturers recommendations for installation site requirements.

Check the site for the fulfillment of the manufacturers recommendations (utilities such

as electricity, water and gases and environmental conditions such as humidity,

temperature and dust).

Allow sufficient shelf space for the equipment, SOPs, operating manuals and software.

b) During installation

Compare equipment, as received, with purchase order (including software, accessories,

spare parts)

Check documentation for completeness (operating manuals, maintenance instructions,

and standard operating procedures or testing, safety and validation certificates).

Check equipment for any damage.

Install hardware (computer, equipment, fittings and tubings for fluid and gas connections

columns in HPLC and GC, power cables, data flow and instrument control cables).


33

Switch on the instruments and ensure that all modules power up and perform an

electronic self-test.

List equipment manuals and SOPs.

Prepare an installation report.

2.10.3 Operational Qualification (OQ)

It can be defined as process of obtaining and documenting evidence that installed equipment

operates within predetermined limits when used in accordance with its operational procedures.

OQ is the process of demonstrating that an instrument will function according to its operational

specification in the selected environment. It should provide documented evidence that utilities,

systems or equipment and all its components operate in accordance with operational

specifications. Tests should be designed to demonstrate satisfactory operation over the normal

operating range as well as at the limits of its operating conditions (including worst case

conditions). Operation controls, alarms, switches, displays and other operational components

should be tested and measurements made in accordance with a statistical approach should be

fully described.29

It should prove that the instrument is suitable for its intended use. It is not

required to prove that the instrument meets the manufacturers performance specifications.

Frequently, people misunderstand and prefer to use the manufacturers specifications because

usually these are readily available.

Moreover, this is the verification of process, equipment and facilities over its operating range and

is assessed against the specifications as defined in the URS. During this stage, a range of tests

will be carried out to demonstrate the integrity and functionality of the system, including the

ability to operate under worst case conditions. Confirmation that all calibration, operating and

cleaning processes have been defined and tested will be required. Definition of the required

programme of planned preventative maintenance (PPM) should be considered. It can be carried

out by the supplier and/or by laboratory, or a combination of both. In any case, this must be

performed using and agreed OQ protocol.

Steps for OQ

Define intended functions to be tested.


34

Define test cases and acceptance criteria. For an HPLC system such tests include precision of

retention times and peak areas, wavelength accuracy of UV detectors, gradient accuracy and

precision, system carry over, baseline noise and detector linearity.

Perform tests and compare the results with the acceptance criteria.

2.10.4 Performance Qualification (PQ)

It is defined as process of obtaining and documenting evidence that the equipment, as installed

and operated in accordance with operational procedures, consistently performs in accordance

with predetermined criteria and thereby yields product meeting its specifications. Successful

completion of IQ and OQ is followed by PQ. It can also be defined as documented verification

that all aspects of a facility, utility or equipment perform as intended in meeting predetermined

acceptance criteria. This is performed to demonstrate that the process, equipment or facility

performs as required under routine operational conditions and as defined in the URS. This is

sometimes referred to as Process validation and is the stage of the exercise when the equipment

or process is assessed in its practical application, with operational outputs/product being assessed

for acceptability.30

It should provide documented evidence that utilities, systems or equipment

and all its components can consistently perform in accordance with the specifications under

routine use.

This is generally applicable to those systems that require extended testing over a period of time

such as water systems, heating, and ventilation systems such as those applicable to clean rooms

and the actual performance of the clean room to meet the defined standards of operation over

periods of time. Some organizations may include PQ in the OQ.

PQ should include following, however, it is not exclusive.

Tests using production materials, substitutes or simulated product.

Tests to include condition(s) with upper and lower limits. It will be useful to briefly discuss

process capability design and testing and process qualification.

Check actual product and process parameters and procedures established in OQ.

Test acceptability of the product.

Check process repeatability, and long term process stability.


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2.10.5 Component Qualification (CQ)

It is relatively new term developed in 2005. This refers to the manufacturing of auxiliary

components to ensure that they are manufactured to the correct design criteria. This could

involve packaging components such as folding cartons, shipping cases, labels or even phase

change material. All of these components must have some type of random inspection to ensure

that the third party manufacturers process is consistently producing components that are used in

the world of GMP at drug or biologic manufacturer.31

2.10.6 Requalification

Requalification should be done in accordance with a defined schedule. The frequency of

requalification may be determined on the basis of factors such as the analysis of results relating

to calibration, verification and maintenance. There should be periodic requalification, as well as

requalification after changes (such as changes to utilities, systems, equipment; maintenance

work; and movement). It should be considered as part of the change control procedure.

2.10.7 Revalidation

Revalidation can be defined as repeating the original validation effort or any part of it, which

includes investigative review of existing data. It is essential to maintain the validated status of

the plant, equipment, manufacturing processes and computer systems. Processes and procedures

should be revalidated to ensure that they remain capable of achieving the intended results. There

should be periodic revalidation, as well as revalidation after changes. It should be done in

accordance with a defined schedule. The frequency and extent of revalidation should be

determined using a risk based approach together with a review of historical data.

Periodic revalidation should be performed to assess process changes that may occur gradually

over a period of time, or because of wear of equipment. The following should be considered

when periodic revalidation is performed:

Master formulae and specifications

SOPs

Records (e.g. of calibration, maintenance and cleaning)

Analytical methods


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2.10.8 Revalidation after change

Revalidation should be performed following a change that could have an effect on the process,

procedure, quality of the product and/or the product characteristics. Revalidation should be

considered as part of the change control procedure. The extent of revalidation will depend on the

nature and significance of the changes. Changes should not adversely affect product quality or

process characteristics. The changes requiring revalidation should be defined in the validation

plan, and it may include following:

Changes in starting materials (including physical properties, such as density, viscosity or

particle size distribution that may affect the process or product)

Change of starting material manufacturer

Transfer of processes to a different site (including change of facilities and installations which

influence the process)

Changes of primary packaging material (e.g. substituting plastic for glass)

Changes in the manufacturing process (e.g. mixing times or drying temperatures)

Changes in the equipment (e.g. addition of automatic detection systems, installation of new

a reveiw on pharmaceutical validation

Documents

validation plan

validation process

successful validation

history of validation

scopes of validation

approaches of validation

validation protocol

validation decision