1. Introduction
Validation is an essential part of good manufacturing practices (GMP). It is, therefore, an element of the quality assurance programme associated with a particular product or process. The basic principles of quality assurance have as their goal the production of products that are fit for their intended use.
These principles are as follows:
• Quality, safety and efficacy must be designed and built into the product.
• Quality cannot be inspected or tested into the product.
• Each critical step of the manufacturing process must be validated. Other steps in the process must be under control to maximize the probability that the finished product consistently and predictably meets all quality and design specifications.
Validation of processes and systems is fundamental to achieving these goals. It is by design and validation that a manufacturer can establish confidence that the manufactured products will consistently meet their product specifications.
Documentation associated with validation includes:
— specifications
— qualification protocols and reports
— validation protocols and reports.
The implementation of validation work requires considerable resources such as:
• Time: generally validation work is subject to rigorous time schedules.
• Financial: validation often requires the time of specialized personnel and expensive technology.
• Human: validation requires the collaboration of experts from various disciplines
(e.g. a multidisciplinary team, comprising quality assurance, engineering, manufacturing and other disciplines, depending on the product and process to be validated).
These guidelines aim to give guidance to inspectors of pharmaceutical manufacturing facilities and manufacturers of pharmaceutical products on the requirements for validation. The main part covers the general principles of and qualification. In addition to the main part, appendices on validation
and qualification (e.g. cleaning, computer and computerized systems, equipment, utilities and systems, and analytical methods) are included.
2. Scope
2.1 These guidelines focus mainly on the overall concept of validation and are intended as a basic guide for use by GMP inspectors and manufacturers. It is not the intention to be prescriptive in specific validation requirements.
This document serves as general guidance only, and the principles may be considered useful in its application in the manufacture and control of active pharmaceutical ingredients (APIs) and finished pharmaceutical products. Validation of specific processes and products, for example in sterile product manufacture, requires much more consideration and a detailed approach that is beyond the scope of this document.
2.2 There are many factors affecting the different types of validation and it is, therefore, not intended to define and address all aspects related to one particular type of validation here.
2.3 Manufacturers should plan validation in a manner that will ensure regulatory compliance and ensuring that product quality, safety and consistency are not compromised.
2.4 The general text in the main part of these guidelines may be applicable to validation and qualification of premises, equipment, utilities and systems, and processes and procedures. More specific principles of qualification and validation are addressed in the appendices. Semi-automatic or fully automatic clean-in-place (CIP) systems and other special cases should be treated separately.
3. Relationship between validation and qualification
Validation and qualification are essentially components of the same concept.
The term qualification is normally used for equipment, utilities and systems, and validation for processes. In this sense, qualification is part of validation.
4. Validation
4.1 Approaches to validation
4.1.1 There are two basic approaches to validation — one based on evidence obtained through testing (prospective and concurrent validation), and one based on the analysis of accumulated (historical) data (retrospective validation). Whenever possible, prospective validation is preferred. Retrospective validation is no longer encouraged and is, in any case, not applicable to the manufacturing of sterile products.
4.1.2 Both prospective and concurrent validation, may include:
• extensive product testing, which may involve extensive sample testing (with the estimation of confidence limits for individual results) and the demonstration of intra- and inter-batch homogeneity;
• challenge/worst case tests, which determine the robustness of the process; and
• control of process parameters being monitored during normal production runs to obtain additional information on the reliability of the process.
4.2 Scope of validation
4.2.1 There should be an appropriate and sufficient system including organizational structure and documentation infrastructure, sufficient personnel and financial resources to perform validation tasks in a timely manner. Management and persons responsible for quality assurance should be involved.
4.2.2 Personnel with appropriate qualifications and experience should be responsible for performing validation. They should represent different departments depending on the validation work to be performed.
4.2.3 There should be proper preparation and planning before validation is performed. There should be a specific programme for validation activities.
4.2.4 Validation should be performed in a structured way according to the documented procedures and protocols.
4.2.5 Validation should be performed:
— for new premises, equipment, utilities and systems, and processes and procedures;
— at periodic intervals; and
— when major changes have been made.
(Periodic revalidation or periodic requalification may be substituted, where appropriate, with periodic evaluation of data and information to establish whether requalification or revalidation is required.)
4.2.6 Validation should be performed in accordance with written protocols. A written report on the outcome of the validation should be produced.
4.2.7 Validation should be done over a period of time, e.g. at least three consecutive batches (full production scale) should be validated, to demonstrate consistency. Worst case situations should be considered.
4.2.8 There should be a clear distinction between in-process controls and validation. In-process tests are performed during the manufacture of each batch according to specifications and methods devised during the development phase. Their objective is to monitor the process continuously.
4.2.9 When a new manufacturing formula or method is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to result in the consistent yield of a product of the required quality.
4.2.10 Manufacturers should identify what validation work is needed to prove that critical aspects of their operations are appropriately controlled. Significant changes to the facilities or the equipment, and processes that may affect the quality of the product should be validated. A risk assessment approach should be used to determine the scope and extent of validation required.
5. Qualification
5.1 Qualification should be completed before process validation is performed.
The process of qualification should be a logical, systematic process
and should start from the design phase of the premises, equipment, utilities
and equipment.
5.2 Depending on the function and operation of the equipment, utility or system, only installation qualification (IQ) and operational qualification (OQ) may be required, as the correct operation of the equipment, utility or system could be considered to be a sufficient indicator of its performance (refer to Section 10 for IQ, OQ and performance qualification (PQ)). (The equipment, utility and system should then be maintained, monitored and calibrated according to a regular schedule.)
5.3 Major equipment and critical utilities and systems, however, require IQ, OQ and PQ.
6. Calibration and verification
6.1 Calibration and verification of equipment, instruments and other devices, as applicable, used in production and quality control, should be performed at regular intervals.
6.2 Personnel who carry out calibration and preventive maintenance should have appropriate qualifications and training.
6.3 A calibration programme should be available and should provide information such as calibration standards and limits, responsible persons, calibration intervals, records and actions to be taken when problems are identified.
6.4 There should be traceability to standards (e.g. national, regional or international standards) used in the calibration.
6.5 Calibrated equipment, instruments and other devices should be labelled, coded or otherwise identified to indicate the status of calibration and the date on which recalibration is due.
6.6 When the equipment, instruments and other devices have not been used for a certain period of time, their function and calibration status should be verified and shown to be satisfactory before use.
7. Validation master plan
The validation master plan (VMP) should reflect the key elements of the validation programme. It should be concise and clear and contain at least the following:
— a validation policy
— organizational structure of validation activities
— summary of facilities, systems, equipment and processes validated and to be validated
— documentation format (e.g. protocol and report format)
— planning and scheduling
— references to existing documents.
8. Qualification and validation protocols
8.1 There should be qualification and validation protocols describing the qualification and validation study to be performed.
8.2 As a minimum the protocols should include the following significant background information:
— the objectives of the study
— the site of the study
— the responsible personnel
— description of SOPs to be followed
— equipment to be used; standards and criteria for the relevant products and processes
— the type of validation
— the processes and/or parameters
— sampling, testing and monitoring requirements
— predetermined acceptance criteria for drawing conclusions.
8.3 There should be a description of the way in which the results will be analysed.
8.4 The protocol should be approved prior to use. Any changes to a protocol should be approved prior to implementation of the change.
9. Qualification and validation reports
9.1 There should be written reports on the qualification and validation performed.
9.2 Reports should reflect the protocols followed and include at least the title and objective of the study; reference to the protocol; details of material, equipment, programmes and cycles used; procedures and test methods.
9.3 The results should be evaluated, analysed and compared against the pre-determined acceptance criteria. The results should meet the acceptance criteria; deviations and out-of-limit results should be investigated. If these deviations are accepted, this should be justified. Where necessary further
studies should be performed.
9.4 The departments responsible for the qualification and validation work should approve the completed report.
9.5 The conclusion of the report should state whether or not the outcome of the qualification and/or validation was considered successful.
9.6 The quality assurance department should approve the report after the final review. The criteria for approval should be in accordance with the company’s quality assurance system.
9.7 Any deviations found during the validation process should be acted upon and documented as such. Corrective actions may be required.
10. Qualification stages
10.1 There are four stages of qualification:
— design qualification (DQ);
— installation qualification (IQ);
— operational qualification (OQ); and
— performance qualification (PQ).
10.2 All SOPs for operation, maintenance and calibration should be prepared during qualification.
10.3. Training should be provided to operators and training records should be maintained.
Design qualification
10.4 Design qualification should provide documented evidence that the design specifications were met.
Installation qualification
10.5 Installation qualification should provide documented evidence that the installation was complete and satisfactory.
10.6 The purchase specifications, drawings, manuals, spare parts lists and details should be verified during installation qualification.
10.7 Control and measuring devices should be calibrated.
Operational qualification
10.8 Operational qualification should provide documented evidence that utilities, systems or equipment and all its components operate in accordance with operational specifications.
10.9 Tests should be designed to demonstrate satisfactory operation over the normal operating range as well as at the limits of its operating conditions (including worst case conditions).
10.10 Operation controls, alarms, switches, displays and other operational components should be tested.
10.11 Measurements made in accordance with a statistical approach should be fully described.
Performance qualification
10.12 Performance qualification should provide documented evidence that utilities, systems or equipment and all its components can consistently perform in accordance with the specifications under routine use.
10.13 Test results should be collected over a suitable period of time to prove consistency.
Requalification
10.14 Requalification should be done in accordance with a defined schedule. The frequency of requalification may be determined on the basis of factors such as the analysis of results relating to calibration, verification and maintenance.
10.15 There should be periodic requalification, as well as requalification after changes (such as changes to utilities, systems, equipment; maintenance work; and movement). (See also point 4.2.5 above and section 11 below.)
10.16 Requalification should be considered as part of the change control procedure.
Revalidation
10.17 Processes and procedures should be revalidated to ensure that they remain capable of achieving the intended results.
10.18 There should be periodic revalidation, as well as revalidation after changes. (See also points 4.2.5 above, point 10.21 below and section 11 below.)
10.19 Revalidation should be done in accordance with a defined schedule.
10.20 The frequency and extent of revalidation should be determined using a risk-based approach together with a review of historical data.
Periodic revalidation
10.21 Periodic revalidation should be performed to assess process changes that may occur gradually over a period of time, or because of wear of equipment.
10.22 The following should be considered when periodic revalidation is performed:
— master formulae and specifications;
— SOPs;
— records (e.g. of calibration, maintenance and cleaning); and
— analytical methods.
Revalidation after change
10.23 Revalidation should be performed following a change that could have an effect on the process, procedure, quality of the product and/or the product characteristics. Revalidation should be considered as part of the change control procedure.
10.24 The extent of revalidation will depend on the nature and significance of the change(s).
10.25 Changes should not adversely affect product quality or process characteristics.
10.26 Changes requiring revalidation should be defined in the validation plan and may include:
• changes in starting materials (including physical properties, such as density, viscosity or particle size distribution that may affect the process or product);
• change of starting material manufacturer;
• transfer of processes to a different site (including change of facilities and installations which influence the process);
• changes of primary packaging material (e.g. substituting plastic for glass);
• changes in the manufacturing process (e.g. mixing times or drying temperatures);
• changes in the equipment (e.g. addition of automatic detection systems, installation of new equipment, major revisions to machinery or apparatus and breakdowns);
• production area and support system changes (e.g. rearrangement of areas, or a new water treatment method);
• appearance of negative quality trends;
• appearance of new findings based on current knowledge, e.g. new technology;
• support system changes.
Changes of equipment which involve the replacement of equipment on a “like-for-like” basis would not normally require a revalidation. For example, installation of a new centrifugal pump to replace an older model would not necessarily require revalidation.
11. Change control
11.1 Changes should be controlled in accordance with a SOP as changes may have an impact on a qualified utility, system or piece of equipment, and a validated process and/or procedure.
11.2 The procedure should describe the actions to be taken, including the need for and extent of qualification or validation to be done.
11.3 Changes should be formally requested, documented and approved before implementation. Records should be maintained.
12. Personnel
12.1 Personnel should demonstrate that they are appropriately qualified, where relevant.
12.2 Personnel requiring qualification include, for example:
— laboratory analysts;
— personnel following critical procedures;
— personnel doing data entry in computerized systems; and
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