supplementary guidelines on good manufacturing practices...

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Pharmapathway.com

SUPPLEMENTARY GUIDELINES ON

GOOD MANUFACTURING PRACTICES (GMP):

VALIDATION



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1. INTRODUCTION

Validation is an essential and integral part of Good Manufacturing Practice (GMP).

It is, therefore, an element of the quality assurance programme associated with a particular

product or process. It is accepted that the basic principles of quality assurance have as their goal

the production of products that are fit for their intended use. These principles may be stated as:

(1) quality, safety and efficacy must be designed and built into the product;

(2) quality cannot be inspected or tested into the finished product; and

(3) each step of the manufacturing process must be controlled to maximize the

probability that the finished product meets all quality and design specifications.

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

It is by design and validation of both process and process controls that a manufacturer can

establish confidence that all manufactured products from successive lots will be acceptable.

The documentation associated with validation includes:

- a quality manual

- Standard Operating Procedures (SOPs)

- specifications

- Validation Master Plan (VMP)

- validation and qualification protocols

- validation and qualification reports

The implementation of validation work requires considerable resources in terms of:

- time: generally validation work is submitted to rigorous time schedules;

- finance: validation studies require time of highly specialized personnel and expensive

technology; and

- personnel: collaboration of experts of various disciplines. A good validation team is

a multidisciplinary team, comprising quality assurance, engineering, manufacturing,

and other disciplines, depending on product and process.

This guideline aims to give guidance to inspectors of pharmaceutical manufacturing facilities

on the requirements for validation, the design of a validation protocol, recording of validation

data and implementation of a system based on the outcome of the validation report.

2. GLOSSARY

The definitions given below apply to the terms used in this guideline. They may have different

meanings in other contexts.

Calibration

The performance of tests and retests to ensure that measuring equipment (e.g. for temperature,

weight, pH) used in a manufacturing process or analytical procedure (in production or quality

control) gives measurements that are correct within established limits.



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Computer validation

Documented evidence which provides a high degree of assurance that a computerized system

records data correctly and that data processing complies with predetermined specifications.

Concurrent validation

Validation carried out during routine production of products intended for sale.

Cleaning validation

Documented evidence to ensure that cleaning procedures are removing residues to

predetermined levels of acceptability, taking into consideration i.e. batch size, dosing,

toxicology, equipment size, etc.

Design qualification (DQ)

Documented evidence that the premises, supporting utilities, equipment and processes have

been designed in accordance with the requirements of GMP.

Installation qualification (IQ)

IQ is the documentary evidence to verify that the equipment has been built and installed in

compliance with design specifications.

Operational qualification (OQ)

OQ is the documentary evidence to verify that the equipment operates in accordance with its

design specifications in its normal operating range and performs as intended throughout all

anticipated operating ranges.

Performance qualification (PQ)

PQ is the documentary evidence which verifies that the equipment or system operates

consistently and gives reproducibility within defined specifications and parameters for

prolonged periods. (The term “process validation” may also be used.)

Process validation

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

characteristics.

Prospective validation

Validation carried out during the development stage by means 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.



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Qualification

Qualification is the planning, carrying out and recording of tests on equipment and systems,

which form part of the validated process, to demonstrate that it will perform as intended.

Retrospective validation

Involves the examination of past experience of production on the assumption that composition,

procedures, and equipment remain unchanged.

Re-validation

Involves the repeat of the initial process validation to provide assurance that changes in the

process and/or in the process environment, whether intentional or unintentional, do not adversely

affect process characteristics and product quality.

Validation Documented series of actions that prove that any procedure, process, equipment,

material, activity or system performs its intended functions adequately and consistently, and lead

to the expected results of uniform batches that meet the required specifications and quality

attributes.

Validation Protocol (VP)

The VP is 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.

Validation Report (VR)

The VR is a written report on the validation activities, the validation data and the conclusions

drawn.

Validation Master Plan (VMP)

VMP is a high level document that establishes an umbrella validation plan for the entire project

and summarizes the manufacturer’s overall philosophy and approach, to be used for establishing

performance adequacy. It provides information on the manufacturer’s validation work

programme and defines details of and time-scales for the validation work to be performed,

including stating the responsibilities relating to the plan.

Worst case

A condition or set of conditions encompassing upper and lower processing limits 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.



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3. SCOPE OF DOCUMENT

The guideline focuses mainly on the overall concept of validation and is intended as a basic

guide for use by GMP inspectors. It is not very prescriptive in specific validation requirements.

There are many parameters affecting the different types of validation and it is, therefore, difficult

to define and address all aspects related to one particular type of validation.

Manufacturers should realistically set their validation parameters for each project, with the view

to create a cost-effective process, yet still complying with all the regulatory standards and

ensuring that product quality, safety and uniformity are not compromised.

The aspects addressed in this guideline include the validation team, validation master plan, types

of validation and change control associated with validation.

4. VALIDATION

4.1 Approaches to validation

There are two basic approaches to validation - the experimental approach and an approach based

on the analysis of historical data.

The experimental approach, which is applicable to both prospective and concurrent validation,

may involve:

- extensive product testing, which may involve extensive sample testing, with the

estimation of confidence limits for individual results and batch homogeneity;

- simulation process trials, which involve mainly aseptic sterilization with the target

contamination level of microbial growth not exceeding 0.1%;

- challenge/worst case tests, which determine the robustness of the process; and

- controls of process parameters being monitored during normal production runs to obtain

additional information on the reliability of the process.

The approach based on the analysis of historical data, which is applicable to retrospective

validation, combines all available historical data of a number of batches with the outcome of the

results, indicating whether the process is under control. No experiments are performed.

Retrospective validation is not applicable to the manufacturing of sterile products.

4.2. Scope of validation

Validation is not considered to be a one-off process.

Validation requires meticulous preparation and careful planning of the various steps in the

process. All work involved should be carried out in a structured way according to the

documented procedures to ensure that the set objectives are met.

The accumulation of documentary evidence relating to a process, item of equipment, or facility

is achieved by means of a validation protocol which should exist for every product and which

details the tests to be carried out, and the accumulation and review of data against agreed

acceptance criteria.



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Validation should be performed for new processes and new equipment, and when major changes

have been made or implemented to premises, systems, equipment, materials and/or processes.

When any new manufacturing formula or method of preparation is adopted steps should be taken

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

equipment specified, should be shown to yield a product consistently of the required quality. In

this phase the extent to which deviations from the chosen processing parameters can influence

product quality should also be evaluated. In general the final batch size should not be more than

10 times the batch size of the representative development batches.

Validation in the production unit mainly comprises the determination and evaluation of the

process parameters applied for the scale-up to final batch size. The control of all critical process

parameters, results of the in-process controls, final controls and stability tests should prove the

suitability of the important individual steps of a procedure. At least three batches (including at

least two production batches in the final batch size) should be validated, to show consistency.

Worst case situations should be considered.

When certain processes or products have been validated during the development stage it is not

always necessary to re-validate the whole process or product if similar equipment is used or

similar products have been produced, provided that the final product conforms to the in-process

control and final product specifications.

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

are performed each time on a batch-to-batch basis, using specifications and methods devised

during the development phase. The objective is to monitor the process continuously.

Validation can be prospective, concurrent, or retrospective, depending on when validation is

performed. A written report should be available after completion of the validation. The results

should be evaluated, analysed and compared with acceptance criteria. All results should meet

the criteria of acceptance and satisfy the stated objective. If necessary further studies should be

performed. If found acceptable the report should be approved and authorized (signed and dated).

Levels where validation and qualification must be performed should be established, with the

type of product to be validated, determining the intensity of the validation. Normally it should

be least for liquid preparations (solutions) and most for parenteral preparations, and for solid

dosage forms it should depend on the criticality of the product to the patient.

4.3 Benefits of validation

Processes consistently under control require less process support, will have less down time,

fewer batch failures, and may operate more efficiently, with greater output. In addition timely

and appropriate validation studies will transmit a commitment to product quality, which may

facilitate pre-approval inspections and expedite the granting of marketing authorizations.

Successfully validating a process may reduce the dependence upon intensive in-process and

finished product testing.



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5. QUALIFICATION

Validation and qualification are essentially the same concept.

Qualification is considered to be the act of planning, carrying out and recording the results of

tests on equipment to demonstrate that it will perform as intended.

Qualification should be completed before process validation is performed. The process of

qualification is a logical, systematic process and should start from the design phase of buildings,

equipment and instruments. There should be a specific programme for qualification of equipment

For systems and equipment performance qualification (PQ) is often synonymous with validation.

Depending on the function and operation of some equipment, only installation qualification (IQ)

and operational qualification (OQ) would be required, as the correct operation of the equipment

could be considered to be a sufficient indicator of its function (refer to Section 12 for IQ, OQ

and PQ). (The functions should then be monitored and calibrated according to a regular

schedule.)

Major equipment and critical systems, however, require IQ, OQ and PQ.

6. CALIBRATION AND VERIFICATION

Regular calibration, validation and verification of all equipment, instruments and other devices

used to measure the physical properties of substances, must be performed at regular intervals

according to the SOPs (having regard to the extent to which they are used). The following are

some examples:

- balances;

- infrared spectrophotometers; and

- HPLC.

A calibration programme should be available.

Equipment should be listed, together with the following information for each piece of equipment:

calibration standards and limits, responsibilities for performing calibration, intervals between

calibration, record-keeping requirements and logs, and actions to be taken when problems are

identified.

After calibration each piece of equipment, instruments and other devices under the control of the

laboratory, and requiring calibration, should be labelled, coded or otherwise identified to indicate

the status of calibration and the date when re-calibration is due.

When the equipment, instruments and other devices are outside the direct control of the

laboratory for a certain period of time, the laboratory should ensure that their function and

calibration status are verified and shown to be satisfactory before they are taken into service

again.

There is a link between equipment calibration and preventative maintenance. Preventative

maintenance assures that the equipment is in good working condition within calibration intervals.

Personnel who provide calibration and preventative maintenance should have appropriate

training.



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7. VALIDATION TEAM

In compliance with Good Validation Practice requirements, a validation team and validation

steering committee should be appointed which will be responsible for the policy and

performance of all validation respectively.

The validation team should consist of a representative from at least the following sections of the

company:

- Regulatory Affairs;

- Quality Assurance; and

- Finance,

The validation team should meet regularly, in accordance with a defined schedule, to discuss

issues relating to validation and to assess progress and compliance with the validation plan and

schedule.

The validation team should maintain records of the meetings and should inform management of

progress in terms of the validation plan and schedule.

The validation team should be responsible for liaison with any third party contract acceptors and

for approving or rejecting all validation protocols and reports. The team should make the final

recommendation regarding the performance of validation, the type of validation, and the

acceptance of the reports and recommendations by the validation steering committee.

The validation steering committee should consist of members of staff who are responsible for

the act of performing the validation in the different sections on site. The steering committee

should, at regular intervals, report to the validation team on progress made regarding the

performance of the validation.

8. VALIDATION MASTER PLAN (VMP)

8.1 General requirements

The Validation Master Plan (VMP) complements the manufacturer’s site master file and should

be the first document to be reviewed during inspection by a regulatory authority.

The VMP reinforces the commitment of the company to GMP. It is a formal policy document

which describes the overall philosophy of the company towards validation and which also

describes the key elements of the validation programme, organizational structure of validation,

schedules and responsibilities. It should describe: “Why, what, where, by whom, how and

when?”.

The VMP should direct to the more specific, detailed documents such as protocols, reports and

documentation preparation and their control, SOPs, and personnel training records.

The VMP should identify which systems, facilities, equipment and processes are subject to

validation, the nature and extent of such testing and the applicable validation and qualification

protocols and procedures. It should outline the test procedures and protocols to be followed to

accomplish validation.



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It should serve as a guide to the validation team, steering committee and personnel who are

responsible for implementing the validation protocols, and should be a source document to

identify tasks and responsibilities and should assist regulatory inspectors to understand the

manufacturer's approach to validation and how the validation activities are organized and

managed. It should help management to know what the validation programme involves with

respect to time, people and money, and to understand the necessity for the programme.

8.2 Specific requirements

The VMP should be concise and should typically include the following:

- table of contents;

- introduction, policy and objectives;

- description of facilities, including plans;

- constitution of the validation committee;

- glossary of terms;

- description and history of equipment;

- description and listing of protocols;

- preventative maintenance programme;

- personnel training programme;

- process and cleaning validation;

- laboratory instrument qualification;

- analytical method validation;

- facility/utility qualification;

- computer system validation;

- re-validation intervals;

- new process cycles validation;

- reasonable unexpected events (worst case), e.g. power failure, computer crash and recovery,

filter integrity test failure;

- key acceptance criteria;

- documentation format to ensure a systematic approach to the layout and format of these

documents, e.g. training record, raw data retention record, calibration record, validation

protocol, validation report, etc.;

- list of relevant SOPs (how?);

- planning and scheduling (when?);

- location where the validation activity is to be performed (where?);

- estimate of staffing requirements to complete the validation effort described in the plan (who?);

- time plan for the project, showing detailed planning of sub-projects (when?);

- change control identifying the company’s commitment to controlling critical changes; and

- approvals.



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9. VALIDATION PROTOCOL

The Validation Protocol (VP) should clearly describe the procedure to be followed for

performing validation.

The VP should include at least significant background information, the objectives of the

validation and qualification study, site of the study, the responsible personnel, description of

SOPs to be followed, equipment (including calibration before and after validation), standards

and criteria for the relevant products and processes, the type of validation, and frequency.

The processes and/or parameters to be validated (e.g. mixing times, drying temperatures, particle

size, drying times, physical characteristics, content uniformity, etc.) should be clearly identified.

Pre-determined acceptance criteria for drawing conclusions should be provided, as well as a

description on how the results will be analysed.

10. VALIDATION REPORT

A written report (VR) should be available after completion of the validation.

The report should include the title and objective of the study, and should refer to the protocol,

details of material, equipment, programmes and cycles used, procedures and test methods.

Recommendations on the limits and criteria to be applied to all future production batches, which

should form part of the basis of the future batch manufacturing document, should be included.

The results should be evaluated, analysed and compared with the acceptance criteria. All results

should meet the criteria of acceptance and satisfy the stated objective. If necessary further studies

should be performed. If found acceptable the report should be approved and authorized (signed

and dated).

11. RELATIONSHIP BETWEEN VALIDATION AND QUALIFICATION

Validation and qualification are essentially the same concept.

Validation is the documented act of proving that any procedure, process, equipment, material,

activity or system actually leads to the expected results.

Qualification is the act of planning, carrying out and recording of tests on equipment and

systems, that form part of the validation process, in order to demonstrate that it will perform as

intended.

Validation, therefore, refers to the overall concept of validation, including process validation,

while qualification refers to the validation part of equipment and systems. In this sense,

qualification is part of validation.

The scheduling of validation should only be done once qualification is complete.

Validation is, therefore, a multifaceted activity that relates to various aspects, of which some are

summarized below.



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11.1 Premises

Manufacturing and packing facility premises should be subjected to qualification as part of

validation, where relevant.

In areas where required, such as sampling and dispensing rooms, room qualification should be

performed.

Some of the basic criteria to be considered during room qualification should include:

- building finish and structure;

- air filtration;

- air change rate or flushing rate;

- room pressure;

- location of air terminals and directional airflow;

- temperature and humidity;

- material and personnel flow; and

- equipment movement.

11.2 Systems

The prevention of contamination and cross-contamination is an essential design consideration of

the architectural components of the manufacturer and should be considered at the design stage

of the facility.

Supporting facilities should be subjected to the different stages of qualification (e.g. Design

Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ) and

Performance Qualification (PQ)) and should be recorded. Supporting facilities/systems include

waste systems, e.g. process drain systems, hazardous waste, solid waste disposal systems, air

handling systems such as Heating Ventilation and Air Conditioning (HVAC), air filtration,

laminar flow hoods, water systems such as RO water; gas systems such as compressed air, gas

supply (nitrogen, oxygen and other gases), and electrical systems such as electrical emergency

power and back-up power.

All supporting systems should have been validated before a specific system is subjected to PQ,

e.g. the steam system should be validated before the autoclave is validated.

A realistic approach to differentiating between critical and non-critical parameters should be

followed.

Systems and components, which are non-critical components, should be subject to Good

Engineering Practice (GEP) reviews in lieu of OQ and PQ.

There should be a relationship between the design conditions, operating range and validated

acceptance criteria (action limits and alert limits). During system OQ all parameters should fall

within the design condition range. However, during normal operating procedures it is acceptable

for the conditions to fall out of the design conditions range, but they should remain within the

operating range.



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Re-qualification of parameters should be done at regular intervals, e.g. at least annually.

11.2.1 Heating, Ventilation and Air Conditioning (HVAC) system

The HVAC system plays an important role in product protection, personnel protection and

environmental protection.

For all HVAC installation components, sub-systems or parameters, critical parameters and

noncritical parameters should be determined. If the component comes into direct contact with

the product, or if the parameter affects the quality of the drug product, it should then be classified

as a critical parameter.

Some of the typical HVAC system parameters that should be qualified include:

- room temperature and humidity;

- supply air and return air quantities;

- room pressure, air change rate, flow patterns, particle count and clean-up rates; and

- laminar flow velocities and HEPA filter penetration tests

11.2.2 Water system

All water-treatment systems should be subject to planned maintenance, validation and

monitoring.

Validation of water systems should consist of at least three phases:

· Phase 1: Investigational phaseDuring the first 2-4 weeks of the commissioning of the plant the

DQ, IQ and OQ should be performed. Operational parameters should be established and the

cleaning and sanitization procedures, including frequencies for cleaning and sanitization, should

be determined.

Daily sampling should be performed at each point of use. On completion of the phase the SOP

for the water system should be developed.

· Phase 2:Short-term control

During the following 4-5 weeks the control of the system should be verified. Sampling should

be performed as during Phase 1.

· Phase 3: Long-term controlDuring the following year the objective should be to demonstrate

that the system is in control over a long period of time. Sampling may be reduced to weekly.The

validation performed and re-validation requirements should be included in the Water Quality

Manual.

11.3 Equipment

Requirement for qualification should be applied to equipment used in production as well as in

quality control laboratories.

The Design Qualification (DQ) should define the functional and operational specifications of the

instrument and should detail the conscious decisions in the selection of the supplier.

Prior to use and to ensure that the equipment is fit for its intended use the different stages of

qualification should be performed, e.g. IQ, OQ, and PQ (refer to Section 12 for detail).



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In addition, the equipment should be well maintained and routinely calibrated.

Certain stages of the equipment qualification may be done by the supplier or a third party. Each

major piece of equipment should have a logbook which should detail at least, the supplier’s

name, module, model and serial number, date of installation, all qualification performed,

maintenance performed and reference to records, and routine use.

11.4 Processes

Production processes should be validated. Process validation should only begin when

qualification is complete.

Process validation should be organized and administered in the same way as qualification. It

should be associated with the writing and issuing of process validation protocols, and the

accumulation and review of data against agreed acceptance criteria.

The level of validation should reflect the complexity of the process. The critical process

parameters should be defined during the course of pre-formulation, pharmaceutical development

and scale-up studies, and the validation protocol should challenge and explore them.

Prospective, concurrent or retrospective validation may be applied. Re-validation should be

performed as identified per schedule and product (refer to Section 13 for detail).

In some cases process validation may be conducted concurrently with performance qualification,

for example, where an item of equipment is dedicated to one process producing one product.

11.5 Procedures

11.5.1 Analytical method

Analytical results should be accurate and reproducible.

Critical factors that should be validated include:

- specificity;

- accuracy;

- precision;

- recovery;

- linearity;

- system suitability for chromatographic determination (refer to Section 15 for detail); and

- robustness.

The method may or may not be stability indicating.

The validated analytical method from development should be transferred to quality control.

Additional validation or re-validation studies may be required if equipment differs.

11.5.2 Packaging component

Packaging material should be evaluated and selected for drug products to provide the required

properties of compatibility, stability, security and sterility.

Their validation should be considered as part of the process validation of the product.



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11.5.3 Cleaning validation

Validation of cleaning methods is an important element of qualification and process validation

for drug substances and drug product manufacture (refer to Section 16 for detail).

The establishment of acceptance criteria for contaminant levels in the sample should be practical

and achievable. Each situation should require individual assessment. However, it is often

considered that a cleaning procedure, that consistently reduces the contaminants to a level not

exceeding one-thousandth of its lowest daily therapeutic dose in the highest daily therapeutic

dose of the product, can be regarded as validated.

Worst case situations should be investigated.

Cleaning validation should be documented either as part of an OQ or process validation protocol,

or separately if appropriate.

11.6 Computer systems validation

Computerized systems should be considered as equipment.

A written validation plan should be available. Specifications should be identified and design

review should be performed. The system should be tested (IQ, OQ and PQ should be performed

and documented). Results should be reviewed, and validation outcome concluded (refer to

Section 14 for detail).

12. QUALIFICATION STAGES

There are different stages in the performance of qualification. These include:

- Design Qualification (DQ);

- Room Qualification (RQ);

- Installation Qualification (IQ);

- Operational Qualification (OQ);

- Performance Qualification (PQ); and

- Re-Qualification (RQ).

The qualification protocol should provide the specific procedure to be followed, the acceptance

criteria, list of materials, equipment and documentation needed to perform the validation.

12.1 Design Qualification

Design Qualification (DQ) constitutes the assurance that the premises, supporting utilities,

equipment and processes have been designed in accordance with the requirements of GMP.

12.2 Installation Qualification

Installation Qualification (IQ) is associated with the performance of tests to ensure that the

installation of machines, measuring devices, utilities and manufacturing areas used in the

manufacturing processes are:

- appropriately selected;

- correctly installed; and



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- will be operating in accordance with the established specifications.

An IQ protocol should be used to document the specific (static) attributes of a facility or item of

equipment, in order to prove that the installation of the unit has been correctly performed and

that the installation specifications of the manufacturer have been met.

The IQ protocol should be numbered, dated, and approved for issue by appropriately authorized

personnel. The IQ protocol should contain at least an introduction and objectives, plant inventory

number, standard operating procedure number, purpose of the facility or equipment, design and

construction details, details of services required and provided, addenda such as chart recorder

traces, technical drawings, and acceptance criteria.

The protocol should be written for all critical processing equipment and systems used within a

manufacturing/packing/testing facility. It should list all the identification information, location,

utility requirements and safety features of the equipment.

During the IQ process it should be verified that the item matches the purchase specification and

that all the drawings, manuals, spare parts list, vendor address and contract numbers, and other

important documentation are available.

The IQ data should be reviewed and approved before operational qualification commences.

12.3 Operational Qualification

Operational Qualification (OQ) is associated with the performance of the equipment to ensure

that the function of machines, measuring devices, utilities and manufacturing areas operate

according to its operational specification in the selected environment.

An OQ protocol is used to document specific (dynamic) attributes of a facility or item of

equipment to prove that it operates as expected throughout its operating range.

As with the IQ protocol, the OQ protocol should be numbered, dated and formally approved.

Tests should be designed to demonstrate that the unit performs properly at the limits of its

operating conditions, as well as within its normal operating range. Measurements made on a

statistical basis should be fully described in the protocol.

The OQ protocol should outline the information required to provide evidence that all the

components of the system or equipment operate as specified. It should include verification of all

the operation controls, alarm points, switches and displays. The protocol should reflect all SOPs

for operation, maintenance and calibration, and training of operators.

The OQ protocol should include an introduction and objective, identification information, visual

inspection parameters, functioning of switches and indicator lights, check and calibration of

sensors, probes, gauges, recorders, air flow rates, direction, pressures, temperatures, filter

integrity and efficiency tests, cleaning procedures, details of qualification instrumentation used,

acceptance criteria, actions resulting from the OQ (what to do when out-of-specification results

are obtained), re-qualification time scales and triggering factors.

The OQ data should be formally reviewed and approved before process validation can

commence.



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12.4 Performance Qualification

Performance Qualification (PQ) is done after both IQ and OQ have been completed, reviewed

and approved.

The PQ protocol describes the procedure to be followed for demonstrating that a system or

equipment can consistently perform and meet required specifications under routine operation (or

worst case conditions).

The PQ protocol may be used in cases where performance data are gathered over a long period

of time. Under these circumstances, it may be difficult to “sign off” the operational qualification

(OQ) as complete. One solution is to define and approve the OQ at a single point in time, and to

create a PQ protocol which is then used as the vehicle for amassing the ongoing data.

12.4 Re-qualification

Equipment should be subject to re-qualification in accordance with a defined schedule. The

frequency of re-qualification is dependent on the analysis of results relating to calibration,

verification, and maintenance.

Re-qualification is subdivided into periodic re-qualification, and re-qualification after change.

These changes include adaptation of equipment, maintenance, movement and repairs (refer to

Section 17 for detail).

12.5 Qualification report

A written report should be available after completion of the validation/qualification.

The results should be evaluated, analysed and compared with acceptance criteria. All results


should be performed.

The report should include the title and objective of the study, reference to the protocol, details

of material and equipment, programmes and cycles used, details of procedures and test methods.

The report should include a conclusion and recommendation as to the suitability of the

equipment and whether the qualification was considered to be satisfactory. If found acceptable

the report should be approved and authorized (signed and dated).

13. PROCESS VALIDATION

By definition process validation requires the accumulation of documentary evidence relating to

a process.

Types of process validation include:

- prospective validation;

- concurrent validation; and

- retrospective validation.



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13.1 Prospective validation

Prospective validation is carried out during the development stage of a product.

If the validation programme is designed and the protocol issued before the equipment or facility

comes on stream, or before the product manufactured by the process being validated is

distributed, then it constitutes prospective validation. It should be performed by means of a risk

analysis of the production process which is broken down into individual steps. It should involve

the establishment of documented evidence that a process, procedure, system, equipment or

mechanism used in manufacture does what it purports to do, based on a pre-planned validation

protocol.

Prospective validation is required for new manufacturing formulae or methods of preparation

where the latter are adopted. Steps should be taken to demonstrate their suitability for routine

processing.

The purpose is to ensure that the defined process, using the materials and equipment specified,

should be shown to yield a product that is consistently of the required quality.

In this phase the extent to which deviations from the chosen processing parameters can influence

product quality should also be evaluated.

In general the final batch size should not be more than 10 times the batch size of the

representative development batches.

The process should include the identification and evaluation of individual steps, the

identification of critical situations, design of trial plans and set of priorities, performance of trials

and recording of results, and finally assessment and evaluation of results. If the results are

unsatisfactory then the processes are modified and improved until acceptable results are

obtained. This is essential to limit the risk and errors that may occur on production scale.

11.2 Concurrent validation

Concurrent validation is carried out during normal production.

This method of validation can only be successful if the development stage has resulted in a proper

understanding of the fundamentals of the process. It is carried out during normal production of

products intended for sale. It should involve close and intensive monitoring of the steps and

critical points in at least the first three production scale batches. The results of inprocess controls

can be used to provide some of the evidence required for validation but these are no substitute

for validation.

Validation in the production unit mainly comprises of the determination and evaluation of the

process parameters of the facilities applied for the scale-up to final batch size. The control of all

critical process parameters, the results of the in-process controls, final controls and stability tests

should prove the suitability of the important individual steps of a procedure.



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11.3 Retrospective validation

Retrospective validation is based on a review of historical manufacturing and testing data, and

is the analysis of accumulated results from past production to assess the consistency of a process.

It is assumed that the composition, procedures and equipment remained unchanged.

During retrospective validation results of in-process and final control tests are evaluated.

It should include trend analysis of test results and a close examination of all recorded process

deviations. Quality control charts could be used when performing retrospective validation. A

total of 10-25 batches (or more), manufactured over a period of 12 months, should be used when

reviewing the results, to provide a statistically significant picture. Trend analysis should be

conducted.

Rejected batches should not be included in the analysis. Failure investigations should however,

be performed separately.

All difficulties and failures recorded should be analysed to determine limits of process

parameters. Product-related problems should be analysed. These should include rejections,

complaints, returns and unaccountable ADR.

As retrospective validation is not considered to be a quality assurance measure it should not be

applied to new processes or products. It is not the preferred method of validation and should be

used in exceptional cases only.

When the results of retrospective validation are positive it is considered to be an indication that

the process is not in need of immediate attention, and may be validated later in accordance with

the normal schedule.

Steps during retrospective validation include:

- choosing a critical quality parameter (e.g. assay value, unit dose uniformity, disintegration

time, dissolution);

- extracting the analytical results from each batch (the results of a batch are grouped as

subgroups);

- pooling the results from the batches;

- calculating the grand average (process average) and control limits; and

- plotting the results on graphs or charts.

The process may be considered reliable if the plotted data are within the control limits and the

variability of individual results is stable (or tends to decrease). Where the existing data are

inadequate additional tests should be performed.

Acceptance criteria must be set before validation, and NOT after the experimental phase of the

work has been completed. This is another reason why retrospective validation is not encouraged

since the acceptance criteria are set after all the analytical work has already been performed.



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14. COMPUTER VALIDATION

14.1 General

Computer systems should be validated in accordance with the level appropriate for their use and

application. This is of importance in production as well as in quality control.

The utilization of a computer system includes different stages. These are planning, specification,

programming, testing, commissioning, document operation, monitoring and modifying.

The purpose of computer system validation is to ensure a degree of evidence (documented, raw

data), confidence (dependability and thorough, rigorous achievement of predetermined

specifications), intended use, accuracy, consistency and reliability.

Aspects to be validated include both the system specifications and functional specifications.

Periodic (or ongoing) evaluation should be performed after the initial validation.

There should be written procedures for performance monitoring, change control, programme and

data security, calibration and maintenance, personnel training, emergency recovery and periodic

re-evaluation.

Aspects of computerized operations that should be considered include:

- networks;

- manual back-ups;

- input/output checks;

- process documentation;

- monitoring;

- alarms; and

- shutdown recovery.

14.2 System specification

There should be a control document or system specification.

The control document should contain the objectives of a proposed computer system, the data to

be entered and stored, the flow of data, how it interacts with other systems and procedures, the

information to be produced, the limits of any variable and the operating programme and test

programme. [Examples of each document produced by the programme should be included.]

System elements in computer validation that need to be considered include hardware

(equipment), software (procedures) and people (users).

14.3 Functional specification

A functional or performance specification should provide instructions for testing, operating, and

maintaining the system, as well as names of the person(s) responsible for its development and

operation.

The following general aspects should be kept in mind when using computer systems: location,

power supply, temperature, and magnetic disturbances. Fluctuations in the electrical supply can

influence computer systems and power supply failure can result in loss of memory.



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The following general GMP requirements are applicable to computer systems:

- Verification and re-validation. (After a suitable period of running a new system it should be

independently reviewed and compared with the system specification and functional

specification.)

- Change control. (Alterations should only be made in accordance with a defined procedure

which should include provision for checking, approving and implementing the change.)

- Checks. (Data should be checked periodically to confirm that they have been accurately and

reliably transferred.)

14.4 Security

This is of importance in production as well as in quality control.

Data should only be entered or amended by persons authorized to do so. Suitable security

systems should be in place to prevent unauthorized entry or manipulation of data. The activity

of entering data, changing or amending incorrect entries and back-ups should all be done in

accordance with written, approved SOPs.

The security procedures should be in writing. Security should also extend to devices used to

store programmes, such as tapes, disks and magnetic strip cards. Access should be controlled.

Traceability is of particular importance and it should be able to identify the persons who made

entries/changes, released material, or performed other critical steps in manufacture or control.

The entry of critical data into a computer by an authorized person (e.g. entering a master

processing formula) requires an independent verification and release of use by a second

authorized person.

SOPs should be validated for certain systems or processes, e.g. the procedures to be followed if

the system fails or breaks down should be defined and tested. Alternative arrangements should

be developed by the validation team, and a disaster recovery procedure should be available for

systems which need to be operated in the event of a breakdown.

14.5 Back-ups

Regular back-ups of all files and data should be made and stored in a secure location to prevent

intentional or accidental damage.

14.6 Validation

Planning, which should include the validation policy, project plan and SOPs, is one of the steps

in the validation process.

The computer-related systems and vendors should be defined and the vendor and product should

be evaluated. The system should be designed and constructed, taking into consideration the

types, testing and quality assurance of the software.

After installation of the system it should be qualified. The extent of the qualification should

depend on the complexity of the system. The system should be evaluated and performance



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qualification, change control, maintenance and calibration, security, contingency planning,

SOPs, training, performance monitoring and periodic re-evaluation should be addressed.

14.7 Validation of hardware and software

The following summary indicates aspects of computer systems that should be subjected to

validation:

Table 14.1. Summary of validation requirements for computer systems

HARDWARE SOFTWARE

1. Types

1.1 Input device

1.2 Output device

1.3 Signal converter

1.4 Central Processing Unit (CPU)

1.5 Distribution system

1.6 Peripheral devices

1. Level

1.1 Machine language

1.2 Assembly language

1.3 High level language

1.4 Application language

2. Key aspects

2.1 Location

environment

distance

input devices

2.2 Signal conversion

2.3 I/O operation

2.4 Command overrides

2.5 Maintenance

2. Software Identification

2.1 Language

2.2 Name

2.3 Function

2.4 Input

2.5 Output

2.6 Fixed set point

2.7 Variable set point

2.8 Edits

2.9 Input manipulation



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2.10 Programme overrides

3. Validation

3.1 Function

3.2 Limits

3.3 Worst case

3.4 Reproducibility/consistency

3.5 Documentation

3.6 Re-validation

3. Key aspects

3.1 Software development

3.2 Software security

4. Validation

4.1 Function

4.2 Worst case

4.3 Repeats

4.4 Documentation

4.5 Re-validation

14.7.1 Hardware

As part of the validation process appropriate tests and challenges to the hardware should be

performed.

Static, dust, power feed voltage and electromagnetic interference could influence the system.

The depth of validation should depend on the complexity of the system. Hardware is considered

to be equipment, and focus should be placed on location, maintenance and calibration of

hardware, as well as on validation/qualification.

The validation/qualification of the hardware should prove :

- the capacity of the hardware matches its assigned function (e.g. foreign language);

- that it operates within the operational limits (e.g. memory, connector ports, input ports);

- that it performs under worst case conditions (e.g. long hours); and

- reproducibility/consistency (e.g. at least three runs covering different conditions).

The validation should be done in accordance with written qualification protocols and the results

should be recorded in the qualification reports.

Re-validation should be performed when significant changes are made.

Much of the hardware validation may be performed by the computer vendor. However, the

ultimate responsibility for suitability of equipment used remains with the company.

Hardware validation data and protocols should be kept by the company. When validation

information is produced by an outside firm, e.g. computer vendor, the records maintained by the

company need not be all inclusive of voluminous test data; however, such records should be

reasonably complete (including general results and protocols) so as to allow the company to



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assess the adequacy of the validation. A mere certification of suitability from the vendor, for

example, will be inadequate.

14.7.2 Software

Software is the term used to describe the total set of programmes used by a computer which

should be listed in the menu or main menu.

Records are considered as software with focus placed on accuracy, security, access, retention of

records, review, double checks, documentation and reproduction accuracy.

Identification

The company should identify the following key computer programmes: language, name,

function (purpose of the programme), input (determine inputs), output (determine outputs), fixed

set point (process variable that cannot be changed by the operator), variable set point (entered

by the operator), edits (reject input/output that does not conform to limits and minimize errors,

e.g. four- or five-character number entry), input manipulation (and equations) and programme

overrides (e.g. stop a mixer before time).

Persons should be identified who have the ability and/or are authorized to write, alter or have

access to programmes.

Software validation should provide assurance that computer programmes (especially those that

control manufacturing/processing) will consistently perform as they are supposed to, within pre-

established limits. When planning the validation, the following points should be considered:

- function: does the programme match the assigned operational function (e.g. generate batch

documentation, different batches of material used in a batch listed, etc.)?

- worst case: perform validation under different conditions (e.g. speed, data volume,

frequency);

- repeats: enough times (replicate data entries);

- documentation: protocols and reports; and

- re-validation: when significant changes are made.

15. ANALYTICAL VALIDATION

15.1 General

During manufacturing of any product it is a requirement that specifications be available for the

materials, components and in-process material as well as the finished product. Test methods

should be available to enable the quality control section to perform tests.

Pharmacopoeias provide specifications for the materials in the monographs, as well as official

test methods. It is not compulsory or mandatory to follow the test methods described in the

pharmacopoeia. Suitable alternative methods may be used if these give results of equivalent

significance.

Only methods as approved for use in registration dossiers may be used for registered products.

Before material or products are released or rejected the results obtained should be checked to

make sure that they are consistent with all other information and specifications.



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15.2 Pharmacopoeia methods

When pharmacopoeia methods for starting materials (APIs and excipients) are chosen as the

method of choice in the registration dossier, authorities normally only require laboratories to

verify the method, with the laboratory proving that the method can be performed in the

laboratory environment.

Validation is not required. The verification of pharmacopoeia methods used for determination

of content or impurities in pharmaceutical products should demonstrate that the methods are

specific with respect to the product (no placebo interference).

15.3 Non-pharmacopoeia methods

Non-pharmacopoeia methods can be used once approved by the authorities. These methods are

normally developed during the developmental phase of the product.

Validation is required.

15.4 Method validation

Methods used in routine analysis should be simple to use, give results quickly and inexpensively,

but they should be accurate, precise and robust.

When an in-house method is to be developed and used - as opposed to using a pharmacopoeia

method - justification of the proposed test procedure in comparison with other possible methods

must be given (including comparative data), a description of the procedure should be given with

as much detail as is deemed necessary to allow properly trained workers to carry it out in a

reliable manner (reagents needed, reference standards, formula for calculation of results), and

validation data need to be submitted to the authorities.

Re-validation may be required when there have been any changes, including transfer of methods

from site to site, from laboratory to laboratory, or changes to materials, etc.

Tests that could be subjected to validation are identity tests, tests for related substances, and

assay.

Validation should be performed in accordance with the validation protocol. The results should

be documented in the validation report.

15.5 Validation report

A written report should be available after completion of the validation.

The results should be evaluated, analysed and compared with acceptance criteria. All results


should be performed. If found acceptable the report should be approved and authorized (signed

and dated).

The report should include the title and objective of the study, reference to the protocol, details

of materials used, description of the equipment, programmes and cycles used where applicable,

details of procedures, including description of the test conditions, precautions, reagents,

reference materials, verification (e.g. system suitability), formulae for calculations of results and



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statistical routines.

The data generated and recorded or documented in log books or worksheets should be

maintained, as these may be used during inspections for verification purposes.

15.6 Characteristics of analytical procedures

Critical parameters that should be included as part of the analytical procedure validation include

accuracy, precision, repeatability, reproducibility, robustness, linearity and range, specificity,

limit of detection, and limit of quantitation.

Accuracy is the degree of agreement of test results with the true value, or the closeness of the

results obtained by the procedure to the true value. Sometimes referred to as the difference

between the experimental and true values.

It is the comparison with the established reference method (e.g. pharmacopoeia method), or

alternatively the procedure can be applied to samples of the material to be examined that have

been prepared to quantitative accuracy. [It is acceptable that “spiked” placebo be used where

known quantities or concentration of a reference material is used.]

Precision (repeatability) is the degree of agreement among individual results. The complete

procedure is applied repeatedly to separate, identical samples drawn from the same

homogeneous batch of material.

It is measured by the scatter of individual results from the mean (good grouping) and usually

expressed as the standard deviation (RSD). The minimum number of repeats used to assess

precision should be at least five (single or multiple samples).

Repeatability (within laboratory variation) is the precision of the procedure when repeated by

the same operator under the same conditions (reagents, equipment, settings and laboratory)

within a short interval of time. It is normally a measure of consistency.

Reproducibility is the precision of the procedure when it is carried out under different conditions

(usually a different laboratory, analysts, equipment or at different times).

Robustness (or ruggedness) is the ability of the procedure to provide analytical results of

acceptable accuracy and precision under a variety of conditions. Results from separate samples

are influenced by changes in the operational or environmental conditions. Factors that can have

an effect:

- variation in analyst experience,

- humidity,

- temperature,



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- stability of test and standard samples,

- reagents (e.g. different suppliers),

- columns (different batches).

Linearity and range indicate the ability to produce results that are directly proportional to the

concentration of the analyte in samples.

A series of samples are prepared having analyte concentrations spanning the claimed range of

the procedure.

Range is an expression of the lowest and highest levels of analyte that have been demonstrated

to be determinable for the product.

Specificity (selectivity) is the ability to measure the analyte in a manner that is free from other

components in the sample being examined (e.g. impurities and excipients).

Sensitivity is the capacity of the test procedure to record small variations in concentration.

Limit of detection is the lowest level of an analyte that can be detected, and not necessarily

determined, in a quantitative fashion.

Limit of quantitation is the lowest level of an analyte in a sample that may be determined with

acceptable accuracy and precision.

Characteristics that should be considered for different types of analytical procedures are

summarized in Table 15.1.

Table 15.1. Characteristics to consider during analytical validation

Class A Class B Class B Class C Class D

Quantitative tests Limit tests

Accuracy X X X

Precision X X X

Robustness X X X X X

Linearity and range X X X

Selectivity X X X X

Limit of detection X

Limit of Quantitation X X

Whereas tests can be classified as summarized in Table 15.2.

Table 15.2. Classification of tests

Class Tests

A To establish identity

B To detect and quantitate impurities

C To determine quantitatively the concentration of a substance in a finished dosage form



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D To assess characteristics of finished dosage forms

16. CLEANING VALIDATION

16.1 General

Cleaning, like any other critical process, should be validated.

The objective of cleaning validation is to prove that the equipment is consistently cleaned from

product, detergent and microbial residues to an acceptable level, to prevent contamination and

cross-contamination.

These guidelines address the general requirements on cleaning validation, excluding specialized

cleaning or inactivation that may, e.g. be required for viral or mycoplasma removal in the

biological manufacturing industry.

There should be written SOPs detailing the cleaning process for equipment and apparatus.

The SOP for cleaning a piece of equipment should only be written once the cleaning process has

been validated. The validated procedure should thus be followed consistently, adhered to,

appropriately documented and recorded in cleaning logs and maintained to ensure that the

equipment is always cleaned as required.

Before the cleaning procedure is validated a written SOP should be available, detailing how the

cleaning processes will be validated, and referring to accountabilities, acceptance criteria,

microbiological aspects (bio-burden control) and re-validation requirements. The complexity

and design of the equipment, training of operators, size of the system and time delay between

end of processing and cleaning should be kept in mind when designing the cleaning SOP.

The greater the risk of the product, or the greater the drug potency or toxicity, the more effort is

required on the validation of cleaning methods.

Pharmaceutical products can be contaminated by a variety of substances such as contaminants

associated with previous products (both API and excipient residues), residues of cleaning agents,

airborne matter such as dust and particulate, lubricants and ancillary material, such as

disinfectants, and decomposition residues which include:

- product residue breakdown occasioned by, e.g. use of strong acids and alkalis during the

cleaning process; and

- breakdown products of the detergents, acids and alkalis that may be part of the cleaning process.

Detergents residues

Detergents are not part of the manufacturing process and are only added to facilitate cleaning

during the cleaning process. Detergents should facilitate the cleaning process and should be

easily removable. If not, a different detergent should be used.



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Detergents found to have persistent residues are, e.g. cationic detergents, which adhere very

strongly to glass and are difficult to remove. Detergent composition should be known and

removal demonstrated. Acceptable limits should be defined for detergent residues after cleaning.

The possibility of detergent breakdown should also be considered when validating cleaning

procedures. Detergents should be acceptable to the QA/QC departments and should preferably

be able to meet local food industry standards.

The manufacturer should have a strategy on cleaning validation covering:

- product-contact surfaces;

- cleaning after product changeover (when one pharmaceutical formulation is being changed

for another, completely different formulation);

- between batches in campaigns (when the same formula is being manufactured over a period of

time, and on different days). It seems acceptable that a campaign can last a working week, but

anything longer becomes difficult to control and define;

- bracketing products for cleaning validation. This often arises where there are products

containing substances with similar properties (such as solubility) or the same substance in

different strengths. An acceptable strategy is to manufacture the more dilute form (not

necessarily the lowest dose) and then the most concentrated form. There are sometimes

“families” of products which differ slightly as to actives or excipients; and

- periodic evaluation and re-validation of the number of batches required should be included.

At least three consecutive applications of the cleaning procedure should be performed and shown

to be successful in order to prove that the method is validated.

The practice of re-sampling should not be utilized and is acceptable only in rare cases. Constant

re-testing and re-sampling can show that the cleaning process is not validated since these re-tests

actually document the presence of unacceptable residue and contaminants from an ineffectual

cleaning process.

The cleaning validation protocol should be formally approved by the Quality Unit and other

appropriate management.

Records of the cleaning validation, which include all raw data of the test results together with,

e.g. the cleaning record (signed by the operator, checked by production and reviewed by QA),

should be kept and a final validation report should be prepared. The final outcome should be

stated, e.g. “all the acceptance criteria were met”.

Personnel/operators who perform cleaning routinely should be trained and should have effective

supervision.

Equipment

Normally only cleaning procedures for product-contact surfaces of the equipment need to be

validated. Consideration should be given to non-contact parts into which product or any process

material may migrate.



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Critical areas should be identified (independently from method of cleaning), particularly in large

systems employing semi-automatic or fully automatic clean-in-place systems.

Dedicated equipment should be used for products which are difficult to clean, equipment which

is difficult to clean, or for products with a high safety risk where it is not possible to achieve the

required cleaning acceptance limits via a validated cleaning procedure.

16.2 Sampling

There are two methods of sampling that are considered to be acceptable. A combination of the

two methods is generally the most desirable.

(a) Surface sampling

This direct method of sampling is the most commonly used and involves taking an inert material

(usually cotton wool or similar) on the end of a probe and rubbing it methodically across a

surface. The type of sampling material used and its impact on the test data is important. It is

known that the sampling material may interfere with the test. For example, the adhesive used in

swabs has been found to interfere with the analysis of samples.

Factors that should be considered include the supplier of the swab, area swabbed, number of

swabs used, wet or dry swabs, swab handling and swabbing technique.

The swab location is important, taking into consideration the material of the equipment (e.g.

glass, steel) and the location (e.g. blades, tank walls, fittings). Worst case locations should be

considered. The protocol should identify the swab locations.

Therefore, the validation programme should ensure that the sampling medium and solvent (used

for extraction from the medium) are satisfactory and can be readily used.

Advantages of direct sampling include:

- areas hardest to clean and which are reasonably accessible can be evaluated (leading to

establishing a level of contamination or residue per given surface area); and

- residues that are “dried out” or are insoluble can be sampled by physical removal.

Some disadvantages of using swabs include:

- inability to access some areas;

- presumes uniformity of contamination surface;

- must extrapolate sample area to whole surface; and

- reproducibility is suspect due to the human involvement and extraction efficiency.

(b) Rinse samples

This indirect method allows sampling of a large surface, of inaccessible areas or those that cannot

be routinely disassembled and provides an overall picture.



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Rinse samples give sufficient evidence of cleaning where accessibility of equipment parts ca

preclude direct surface sampling. However, as a norm, rinse sample should be used in

combination with other sampling methods such as swabs. Rinse samples are also useful for

checking cleaning agent residues, e.g. detergents.

Disadvantage of rinse samples:

- residue or contaminant may not be soluble or may be physically occluded in the equipment.

(c) Other methods

Batch placebo method

A less frequent sampling method, due to its high cost. The method relies on the manufacture of

a placebo batch and then checking it for carry-over of the previous product. It is an expensive

and laborious process.

It should be used in conjunction with rinse and/or swab samples. It is difficult to provide

assurance that the contaminants will be dislodged from the equipment surface uniformly.

Additionally, if the contaminant or residue is of large enough particle size, it may not be

uniformly dispersed in the placebo. Samples should be taken throughout manufacture. Traces of

the preceding products are sought in these samples. The sensitivity of the assay may be greatly

reduced by dilution of the contaminant.

Scrubbing by hand

Manual cleaning methods are difficult to replicate.

Clean-In-Place (CIP) systems

Critical areas, i.e. those hardest to clean, should be identified, particularly in large systems that

employ semi-automatic or fully automatic CIP systems.

16.3 Analytical methods

Validated analytical methods, having sensitivity to detect residues or contaminants, should be

used.

The analytical method should be validated before the cleaning validation is started. Aspects that

should be checked are:

_ precision, linearity, selectivity (the latter if specific analytes are targeted). Note that

interference by another analyte will make the validation fail rather than pass;

_ Limit of Detection (LOD);

_ Limit of Quantitation (LOQ);

_ recovery, by spiking with the analyte; and



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_ reproducibility.

The detection limit for each analytical method should be sufficiently sensitive to detect the

established acceptable level of the residue or contaminants.

A non-specific assay method is not a disadvantage where total contaminants are being studied

as opposed to just specific analytes. Suitable methods could include:

_ Chromatographic: HPLC, GC, High Performance Thin-Layer Chromatography (HPTLC) are

all very sensitive and also very specific. TLC may not be sensitive enough.

_ TOC: total organic carbon analysers are very sensitive, but not specific. Should be used with

pH and conductivity.

_ pH: very sensitive to hydrogen ions. Used for trace levels of acids and alkalis that may be used

as part of the cleaning process.

_ Conductivity: sensitive for total ions. (TOC, pH and conductivity, when used in combination,

are proving very powerful cleaning validation assay methods.)

_ UV spectroscopy: moderate specificity, not quantitative.

_ ELISA (Enzyme-linked immuno sorbent assay): very sensitive and specific for

biopharmaceuticals; expensive, labour-intensive, long sample turn-around.

Establishment of limits

The validation team should set limits.

The rationale for the residue limits established should be logical, based on the knowledge of the

materials involved. They should be practical, achievable, and verifiable.

Limits may be expressed as a concentration in a subsequent product (ppm), limit per surface area

(mcg/cm2), or in rinse water as ppm . (It is important to define the sensitivity of the analytical

methods in order to set reasonable limits.)

The manner in which limits are established should be carefully considered. In establishing

residual limits it may not be adequate to focus only on the principal reactant, since other chemical

variations may be more difficult to remove. There are circumstances where TLC screening, in

addition to chemical analyses, may be needed.

Looking only for evidence of the absence of the previous compound during cleaning validation

would be considered inadequate. Evidence (from TLC tests on the rinse water) of the presence

of residues of reaction by-products and degradants from the previous process is considered

unacceptable. Any residues from the cleaning process itself (detergents, solvents, etc.) also have

to be removed from the equipment.

It should be noted at the outset that regulatory authorities do not set limits for specific products.

The limits must be practical, achievable and verifiable. The limit setting approach can be:

- product specific;



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- grouped into product families, e.g. all those products containing multiple ingredients and one

common, low-level ingredient, and choosing a worst case product;

- collected into similar risk groups, e.g. very soluble products, similar potency, highly toxic, or

difficult to detect products; and

- Different safety factors for different dosage forms based on physiological response (method is

essential for potent materials).

Setting limits on carry-over

The rationale for selecting limits of carry-over of product residues, cleaning agents and microbial

contamination should be scientifically justified, based on the materials involved.

Certain allergenic ingredients (e.g. penicillins, cephalosporins) and highly potent material (e.g.

anovulent steroids, potent steroids and cytotoxics) should not be detectable by best available

analytical methods. In practice this may mean that dedicated manufacturing facilities are used

for these products. It should be kept in mind that uniform distribution of contaminants is not

guaranteed and that decomposition products should be checked.

The three most common methods of setting cleaning criteria are:

- visually clean (first criterion) [not suitable for high potency, low dosage drugs]. Reports of

consistent results of 4 micrograms per cm2 are available;

- 10ppm in another product [basis for heavy metals in starting materials]; and

- 0.1% of therapeutic dose [assumption that the proportion of the MINIMUM daily dose of the

current product carried over into the MAXIMUM daily dose of a subsequent product should be

not more than 0.1%] with the most stringent of three options: dose-based, 10 ppm default or the

visually clean standard to be used.

Grouping

Grouping may be allowed under certain conditions. Strategies that could be followed include

grouping by product or grouping by equipment.

The grouping by product may be allowed when the products are similar in nature or property

and will be processed in the same equipment. Identical cleaning processes should then be used

for these products (cleaning agent, cleaning method, process parameters).

When a representative product is chosen it should be the most difficult to clean.

Grouping by equipment may be allowed if it is similar equipment, or the same equipment in

different sizes (e.g. 300l, 500l and 1000l tanks). An alternative is validating separately by using

the smallest and the largest size.

Cleaning validation protocol

There should be a cleaning validation protocol for each product and for each piece of equipment.

In drafting the protocol, the following should be considered:



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- disassembly of system;

- pre-cleaning;

- cleaning agent, concentration, solution volume, water quality;

- time and temperature;

- flow rate, pressure, and rinsing;

- complexity and design of the equipment;

- training of operators; and

- size of the system.

The cleaning validation protocol, which should be written before the experimental section of the

work commences, laying down the procedure on how the cleaning process will be validated,

should include:

(a) the objectives of the validation process;

(b) the responsibilities for performing and approving the validation study;

(c) the description of the equipment to be used, including the list of equipment, make, model,

serial number or other unique code;

(d) the interval between the end of production and cleaning and the commencement of the

cleaning procedures (interval may be part of the validation challenge study itself)

– the manufacturer is to take into account the maximum period that equipment will be left dirty

before being cleaned as well as the establishment of the time after cleaning and before use;

(e) microbiological levels (bio-burden);

(f) the cleaning procedures (documented in an existing SOP, including definition of any

automated process) to be used for each product, each manufacturing system or each piece of

equipment;

(g) all routine monitoring equipment used, e.g. conductivity meters, pH meters, total organic

carbon analysers;

(h) number of cleaning cycles to be performed consecutively;

(i) the sampling procedures used (direct sampling, rinse sampling, in-process monitoring,

sampling locations) and the rationale;

(j) data on recovery studies (efficiency of the recovery of the sampling technique should be

established);

(k) analytical methods (specificity and sensitivity) including the limit of detection and the limit

of quantification;

(l) the acceptance criteria (with rationale for setting the specific limits) including a margin for

error and for sampling efficiency;

(m) choice of the cleaning agent should be documented and approved by the Quality Unit and

should be scientifically justified based on, e.g.:

· solubility of the materials to be removed

· the design and construction of the equipment and surface materials to be cleaned

· safety of the cleaning agent

· ease of removal and detection



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· product attributes

· knowledge gained through experience

· the minimum temperature and volume of cleaning agent and rinse solution

· manufacturer's recommendations; and

(n) re-validation requirements.

Cleaning validation report

A validation report should be available, approved by the validation team, and stating whether or

not the cleaning process is valid.

The data should support a conclusion that residues have been reduced to an “acceptable level”.

As with validation of other processes there may be more than one way to validate a cleaning

process. In the end the test of any validation process is whether scientific data show that the

system consistently does as expected and produces a result that consistently meets predetermined

specifications.

16.4 Evaluation

When evaluating the validation data focus should be upon the objective of the validation process,

as specified in the Validation Protocol.

Ideally a piece of equipment or system should have one process for cleaning. This will depend

on the products being produced, whether the clean-up occurs between batches of the same

product (as in a large campaign) or whether the clean-up occurs between batches of different

products.

Normally cleaning validation would be applicable for critical cleaning such as cleaning between

products, product-contact surfaces, drug products and active pharmaceutical ingredients (API).

Cleaning validation is not necessarily required for non-critical cleaning such as between batches

of the same product (or different lots of the same intermediate in a bulk process), floors, walls,

outside of vessels, and some intermediate steps. The company need only meet a criteria of

“visibly clean” for the equipment. Such between-batch cleaning processes do not require

validation.

However, validation is an important part in facilities of high flexibility. It will be required for at

least the equipment, sanitization, garment laundering and general cleaning.

The design of equipment may influence the effectiveness of the cleaning process. Consideration

should be given to the design of the equipment in drafting a validation protocol for cleaning, e.g.

V blenders, transfer pumps, filling lines, etc.

Operators responsible for performing cleaning operations should be aware of problems and have

special training in cleaning these systems and equipment. The cleaning operators should have

knowledge of these systems and the appropriate level of training and experience in cleaning

them.

Drying of residues

A critical element in the documentation of the cleaning processes is the identification and

controlling of the length of time between the end of processing and each cleaning step. This is



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especially important for topical, suspensions, and bulk drug operations. In such operations the

drying of residues will directly affect the efficiency of a cleaning process.

Microbiological aspects of equipment cleaning

Microbiological aspects of equipment cleaning should be considered. This consists largely of

preventive measures rather than removal of contamination once it has occurred. There should be

some evidence that routine cleaning and storage of equipment does not allow microbial

proliferation.

Control of the bio-burden through adequate cleaning and storage of equipment is important to

ensure that subsequent sterilization or sanitization procedures achieve the necessary assurance

of sterility, and the control of pyrogens in sterile processing. Equipment sterilization processes

may not be adequate to achieve significant inactivation or removal of pyrogens.

The period and conditions of storage of unclean equipment before cleaning, and the time between

cleaning and equipment re-use, should form part of the validation of cleaning procedures.

Documented evidence should indicate that routine cleaning and storage of equipment does not

allow microbial proliferation. Equipment should be stored dry and under no circumstances

should stagnant water be allowed to remain in equipment after cleaning operations.

Recovery studies

Validation of recovery: swabs and rinse sampling

A plate should be spiked with a known amount of substance. This should be removed by means

of a swab or rinse procedure. The sample should be analysed. This should be performed at and

below the acceptance limit in the test solution.

Acceptable recovery:

> 80% good

>50% reasonable

<50% questionable

17. RE-VALIDATION

Processes and procedures should undergo periodic critical re-validation to ensure that they

remain capable of achieving the intended results.

It is necessary to ensure that changes in the process (whether intentional or unintentional) do not

adversely affect product quality or process characteristics. The nature of the changes that require

re-validation should be stated in the VMP. Re-validation involves a repeat of the process

validation.

If any of the following are changed the process becomes invalid and the process could be viewed

out of control, even if the finished product meets the marketing authorization specifications for



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finished products:

- changes of starting materials (physical properties, such as density, viscosity or particle size

distribution may affect the process or product);

- transfer of processes to another site (change of facilities and installations which influence the

process);

- change of starting material manufacturer;

- changes of packaging material (e.g. substituting plastic for glass);

- changes in the process (e.g. mixing times, drying temperatures);

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

equipment, major revisions to machinery or apparatus and breakdowns);

- changes of equipment which involve the replacement of equipment on a “like-for-like” basis

would not normally require a re-validation. For example, a new centrifugal pump replacing

an older model would not necessarily mean re-validation;

- production area and support system changes (e.g. rearrangement of areas, new water treatment

method);

- appearance of negative quality trends; and

- appearance of new findings based on current knowledge, e.g. sterilization where the

frequency of checking is dependent on sophistication of in-process methodology.

NOTE: The extent of re-validation will depend on the nature and significance of the changes.

There are two basic categories of re-validation:

(a) re-validation in cases of known change (change having a bearing on product quality),

including transfer of processes from one pharmaceutical manufacturer to another, or from one

site to another; and

(b) periodic re-validation carried out at scheduled intervals.

17.1 Periodic re-validation

Periodic re-validation is required as process changes may occur gradually over a period of time

or because of wear of equipment. The decision on the time interval for re-validation is based on

the results following review of historical data.

The following points should be considered when periodic re-validation is performed:

- review the master formula and specifications;

- check the calibration records;

- review the SOP;

- review the cleaning records;

- review the analytical methods; and

- review the records regarding planned preventative maintenance.

17.2 Re-validation after changes

Re-validation after changes should be performed when these changes could have an effect on

the quality of the product, or the product characteristics.



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These include changes in:

- raw material;

- packaging material;

- manufacturing process;

- equipment;

- manufacturing areas; and

- support system changes.

The extent of re-validation could be the same as the initial validation. This will be decided by

the validation team.

18. CHANGE CONTROL

The manufacturer should have a “change control” procedure.

Change control is a formal system by which qualified representatives of appropriate disciplines

review proposed or actual changes that might affect a validated status. The intent is to determine

the need for action that would ensure and document that the system is maintained in a validated

state.Change control is an important element in any Quality Assurance system.

Written procedures should be in place to describe the actions to be taken if a change is proposed

to a product component, process equipment, process environment (or site), method of production

or testing, or any other aspect that may affect product quality or support system operation. All

changes should be formally requested, documented and accepted by representatives of

production, QC/QA, R&D, engineering and regulatory affairs, as appropriate.

The likely impact (risk assessment) of the change on the product should be evaluated and the

need for and extent of re-validation discussed. The change control system should ensure that all

notified or requested changes are satisfactorily investigated, documented and

authorized.Products made by processes subjected to changes should not be released for sale

without full awareness and consideration of the change by the responsible staff.

Failure to properly document changes to the system means invalidation.

19. PERSONNEL

Validation of personnel is not always considered in the pharmaceutical industry. Where relevant

personnel should be subjected to validation.

Personnel should undergo health checks before employment and at regular intervals thereafter.

The manufacturer must demonstrate that personnel possess the necessary levels of competence.

The signatories of the validation work must have appropriate training, experience, education and

qualifications. Microbiologists should sign microbiological work, engineers, engineering, etc.

The final report should be co-signed by the person responsible for the project.

Training requirements need to be identified for personnel who will maintain or carry out the

processes that have been validated. Personnel should be trained in GMP and procedural activities

in accordance with an SOP.



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Examples of validation of personnel applicable to the manufacture and control of sterile

products, analysis and related activities that may have a direct impact on the quality of a product

include:

- aseptic technique: media fills;

- validation of analysts in laboratories for performing certain analyses;

- validation of personnel performing activities in accordance with SOPs;

- performing visual inspection of sterile injectable products ; and

- personnel working on computerized systems.

REFERENCES

Fourman, G. L., Mullen, M.V. Determining cleaning validation acceptance limits for

pharmaceutical manufacturing operations. Pharmaceutical Technology, 1993, 54:1-6.

1. Hwang, R. Process design and data analysis for cleaning validation. Pharmaceutical

Technology, 1997, 62-68.

2. Pharmaceutical Inspection Convention Scheme. Guide to Good Manufacturing Practice for

Medicinal Products. PH 1/97 (rev. 3), 15 January 2002..

3. Pharmaceutical Inspection Convention Scheme. In: The Inspection of Quality Control

Laboratories Seminar. Training provided on GMP Guidelines for the inspection of

Pharmaceutical Quality Control Laboratories. Lecturers provided at the GMP Training Seminar,

Bratislava, 3-6 June 2003.

4. Proprietary Association of South Africa.. Guide to Good Manufacturing Practice.

Pharmaceutical Manufacturers Association of South Africa (Scientific Advisory Subcommittee)

and Proprietary association of South Africa (Legislative Subcommittee Medicines),

Johannesburg, 1996.

5. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirtyfourth

Report. Geneva, World Health Organization, 1996. WHO Technical Report Series, No. 863,

Annex 6. Good Manufacturing Practices: guidelines on the validation of manufacturing

processes.

6. Quality Assurance of Pharmaceuticals: A Compendium of Guidelines and Related Materials.

Volume 1. Geneva, World Health Organization, 1997, pp. 119-124.

7. Quality Assurance of Pharmaceuticals: A Compendium of Guidelines and Related

Materials. Good Manufacturing Practices and Inspection. Volume 2. Geneva, World

Health Organization, 1999, pp. 53-70.



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Format for an Installation Qualification Protocol and Report

The following format outlines the requirements for an Installation Qualification protocol.

Name and address of site:___________________________ Page __of __

Validation Protocol # ________________________________IQ Protocol number: ___

Title: ________________________________________________________________

Protocol written by: _______________________

Protocol approved by: _______________________ Date: _______________________

QA Approval: _______________________ Date: _______________________

Objective

To ensure that __________ (system/equipment) installed conforms to the purchase

specifications and the manufacturer details and literature, and to document the information that

___________ (system/equipment) meets its specifications.

Equipment inventory number: ____________________

Scope

To perform installation qualification as described in this IQ protocol at the time of installation,

modification and relocation.

Responsibility

___________ (post/person) overseeing the installation will perform the qualification and records

results.

___________ (post/person) will verify results and write the report.

Quality Assurance will review and approve the IQ protocol and report.



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Validation Protocol ___________Installation Qualification Page __of __

Title: ___________ Name and address of site:___________________________

System/Equipment _____________________________ Code no.: ___________________

a. Description of the system/equipment being installed: general description of the

function and the main components.

___________________________________________________________________________

___________________________________________________________________________

_______________________

b. List of the main components:

1. ___________________________ Code no.: ____________________________

2. ___________________________ Code no.: ____________________________

3. ___________________________ Code no.: ____________________________

4. ___________________________ Code no.: ____________________________

c. Description of supporting utilities (e.g. piping, connections, water supply)

1. ___________________________ Code no.: ____________________________

2. ___________________________ Code no.: ____________________________

3. ___________________________ Code no.: ____________________________

4. ___________________________ Code no.: ____________________________

Procedure

1. Prepare a checklist of all components and parts, including spare parts according to the

purchase order and manufacturer’s specifications.

2. Record the information for each actual part, component, auxiliary equipment, supporting

facilities, and compare to the manufacturer’s specifications.

3. Record any deviations to the system/equipment.

4. Prepare a deviation report including justification of acceptance and impact on the function.

5. Prepare a IQ report.*

6. Submit the report to QA for review and approval.

* IQ report should at least include the date of the study initiation, date completed, observations

made, problems encountered, completeness of information collected, summary of deviation

report, results of any tests, sample data if appropriate, location of original data, other information

relevant to the study, and conclusion on the validity of the installation.



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Annex

Validation Protocol ________Installation Qualification __________ Page __of __

Title: _______ Name and address of site___________________________

Checklist for component no. _________ Name: _______________ Code no.: __________

Component function: _______________________________________________________

Require/Order Actual Deviations

1 Model/serial no.

2 Specification

3 Manual

4 Drawing

5 Wiring/cabling

6 Power, fusing

7 SOP (operation)

SOP (maintenance)

SOP (calibration)

8 Input/output control

9 Environment

10 Test equipment or instruments

11 Utilities and service

12 Spare parts list, part number

and supplier

13 Other

Performed by: _____________________________ Date: _________________

Deviations: _____________________________ Date: _________________

Verified by: _____________________________ Date: _________________



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Annex

Validation Protocol ___________Installation Qualification ______page __of __

Title: ___________ Name and address of site:___________________________

Deviation report

Deviations: ______________________________________________________________

____________________________________________________________________________

____________________________________________________________________________

__________________________________________________________________________

____________________________________________________________________________

____________________________________________________________________________

__________________________________________________________________________

Justification for acceptance

__________________________________________________________________________

____________________________________________________________________________

____________________________________________________________________________

__________________________________________________________________________

____________________________________________________________________________

____________________________________________________________________________

__________________________________________________________________________

Impact on operation:

__________________________________________________________________________

____________________________________________________________________________

____________________________________________________________________________

__________________________________________________________________________

Report written by: __________________________________ Date: _________________



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Annex

Validation Protocol ___________Installation Qualification ______page __of __

Title: ___________ Name and address of site:__________________________

Installation Qualification Report

Results: ______________________________________________________________

____________________________________________________________________________

____________________________________________________________________________

__________________________________________________________________________

____________________________________________________________________________

____________________________________________________________________________

__________________________________________________________________________

Conclusions:

__________________________________________________________________________

____________________________________________________________________________

____________________________________________________________________________

__________________________________________________________________________

____________________________________________________________________________

____________________________________________________________________________

__________________________________________________________________________

__________________________________________________________________________

___________________________________________________________________________

____________________________________________________________________________

____________________________________________________________________________

__________________________________________________________________________

Report written by: __________________________________ Date: ________________

QA approved by: __________________________________ Date: ________________

* * *

supplementary guidelines on good manufacturing practices...

Documents