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All Pharmaceutical Guidelines Available on www.pharmapathway.com Email [email protected]
All Pharmaceutical Guidelines Available on www.pharmapathway.com Email [email protected]
Page 1 of 43
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