Qualification and validation

1. This Annex describes the principles of qualification and validation which are
applicable to the manufacture of medicinal products. It is a requirement of
GMP that manufacturers identify what validation work is needed to prove
control of the critical aspects of their particular operations. Significant
changes to the facilities, the equipment and the processes, which 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.
2. All validation activities should be planned. The key elements of a validation
programme should be clearly defined and documented in a validation master
plan (VMP) or equivalent documents.
3. The VMP should be a summary document which is brief, concise and clear.
4. The VMP should contain data on at least the following:
(a) validation policy;
(b) organisational structure of validation activities;
(c) summary of facilities, systems, equipment and processes to be validated;
(d) documentation format: the format to be used for protocols and reports;
(e) planning and scheduling;
(f) change control;
(g) reference to existing documents.
5. In case of large projects, it may be necessary to create separate validation
master plans.
6. A written protocol should be established that specifies how qualification and
validation will be conducted. The protocol should be reviewed and approved.
The protocol should specify critical steps and acceptance criteria.
7. A report that cross-references the qualification and/or validation protocol
should be prepared, summarising the results obtained, commenting on any
deviations observed, and drawing the necessary conclusions, including recommending
changes necessary to correct deficiencies. Any changes to the
plan as defined in the protocol should be documented with appropriate justification.
8. After completion of a satisfactory qualification, a formal release for the next
step in qualification and validation should be made as a written authorisation.
Design qualification
9. The first element of the validation of new facilities, systems or equipment
could be design qualification (DQ).
10. The compliance of the design with GMP should be demonstrated and
Installation qualification
11. Installation qualification (IQ) should be performed on new or modified
facilities, systems and equipment.
12. IQ should include, but not be limited to the following:
(a) installation of equipment, piping, services and instrumentation checked to
current engineering drawings and specifications;
(b) collection and collation of supplier operating and working instructions and
maintenance requirements;
(c) calibration requirements;
(d) verification of materials of construction.
Operational qualification
13. Operational qualification (OQ) should follow Installation qualification.
14. OQ should include, but not be limited to the following:
(a) tests that have been developed from knowledge of processes, systems and
(b) tests to include a condition or a set of conditions encompassing upper and
lower operating limits, sometimes referred to as “worst case” conditions.
15. The completion of a successful Operational qualification should allow the
finalisation of calibration, operating and cleaning procedures, operator
training and preventative maintenance requirements. It should permit a
formal "release" of the facilities, systems and equipment.
Performance qualification
16. Performance qualification (PQ) should follow successful completion of
Installation qualification and Operational qualification.
17. PQ should include, but not be limited to the following:
(a) tests, using production materials, qualified substitutes or simulated product,
that have been developed from knowledge of the process and the facilities,
systems or equipment;
(b) tests to include a condition or set of conditions encompassing upper and
lower operating limits.
18. Although PQ is described as a separate activity, it may in some cases be
appropriate to perform it in conjunction with OQ.
Qualification of established (in-use) facilities, systems and equipment
19. Evidence should be available to support and verify the operating parameters
and limits for the critical variables of the operating equipment. Additionally,
the calibration, cleaning, preventative maintenance, operating procedures and
operator training procedures and records should be documented.
20. The requirements and principles outlined in this chapter are applicable to the
manufacture of pharmaceutical dosage forms. They cover the initial
validation of new processes, subsequent validation of modified processes and
21. Process validation should normally be completed prior to the distribution
and sale of the medicinal product (prospective validation). In exceptional
circumstances, where this is not possible, it may be necessary to validate
processes during routine production (concurrent validation). Processes in
use for some time should also be validated (retrospective validation).
22. Facilities, systems and equipment to be used should have been qualified and
analytical testing methods should be validated. Staff taking part in the validation
work should have been appropriately trained.
23. Facilities, systems, equipment and processes should be periodically evaluated
to verify that they are still operating in a valid manner.
Prospective validation
24. Prospective validation should include, but not be limited to the following:
(a) short description of the process;
(b) summary of the critical processing steps to be investigated;
(c) list of the equipment/facilities to be used (including measuring/
monitoring/recording equipment) together with its calibration status
(d) finished product specifications for release;
(e) list of analytical methods, as appropriate;
(f) proposed in-process controls with acceptance criteria;
(g) additional testing to be carried out, with acceptance criteria and analytical
validation, as appropriate;
(h) sampling plan;
(i) methods for recording and evaluating results
(j) functions and responsibilities;
(k) proposed timetable.
25. Using this defined process (including specified components) a series of
batches of the final product may be produced under routine conditions. In
theory the number of process runs carried out and observations made should
be sufficient to allow the normal extent of variation and trends to be established
and to provide sufficient data for evaluation. It is generally considered
acceptable that three consecutive batches/runs within the finally agreed
parameters, would constitute a validation of the process.
26. Batches made for process validation should be the same size as the intended
industrial scale batches.
27. If it is intended that validation batches be sold or supplied, the conditions
under which they are produced should comply fully with the requirements of
Good Manufacturing Practice, including the satisfactory outcome of the validation
exercise, and with the marketing authorisation.
Concurrent validation
28. In exceptional circumstances it may be acceptable not to complete a validation
programme before routine production starts.
29. The decision to carry out concurrent validation must be justified, documented
and approved by authorised personnel.
30. Documentation requirements for concurrent validation are the same as
specified for prospective validation.
Retrospective validation
31. Retrospective validation is only acceptable for well-established processes
and will be inappropriate where there have been recent changes in the composition
of the product, operating procedures or equipment.
32. Validation of such processes should be based on historical data. The steps
involved require the preparation of a specific protocol and the reporting of
the results of the data review, leading to a conclusion and a recommendation.
33. The source of data for this validation should include, but not be limited to
batch processing and packaging records, process control charts, maintenance
log books, records of personnel changes, process capability studies, finished
product data, including trend cards and storage stability results.
34. Batches selected for retrospective validation should be representative of all
batches made during the review period, including any batches that failed to
meet specifications, and should be sufficient in number to demonstrate process
consistency. Additional testing of retained samples may be needed to
obtain the necessary amount or type of data to retrospectively validate the
35. For retrospective validation, generally data from ten to thirty consecutive
batches should be examined to assess process consistency, but fewer batches
may be examined if justified.
36. Cleaning validation should be performed in order to confirm the effectiveness
of a cleaning procedure. The rationale for selecting limits of carry over
of product residues, cleaning agents and microbial contamination should be
logically based on the materials involved. The limits should be achievable
and verifiable.
37. Validated analytical methods having sensitivity to detect residues or contaminants
should be used. The detection limit for each analytical method
should be sufficiently sensitive to detect the established acceptable level of
the residue or contaminant.
38. Normally only cleaning procedures for product contact surfaces of the
equipment need to be validated. Consideration should be given to noncontact
parts. The intervals between use and cleaning as well as cleaning and
reuse should be validated. Cleaning intervals and methods should be determined.
39. For cleaning procedures for products and processes which are similar, it is
considered acceptable to select a representative range of similar products and
processes. A single validation study utilising a “worst case” approach can
be carried out which takes account of the critical issues.
40. Typically three consecutive applications of the cleaning procedure should be
performed and shown to be successful in order to prove that the method is
41. "Test until clean". is not considered an appropriate alternative to cleaning
42. Products which simulate the physicochemical properties of the substances to
be removed may exceptionally be used instead of the substances themselves,
where such substances are either toxic or hazardous.
43. Written procedures should be in place to describe the actions to be taken if a
change is proposed to a starting material, product component, process
equipment, process environment (or site), method of production or testing or
any other change that may affect product quality or reproducibility of the
process. Change control procedures should ensure that sufficient supporting
data are generated to demonstrate that the revised process will result in a
product of the desired quality, consistent with the approved specifications.
44. All changes that may affect product quality or reproducibility of the process
should be formally requested, documented and accepted. The likely impact
of the change of facilities, systems and equipment on the product should be
evaluated, including risk analysis. The need for, and the extent of, requalification
and re-validation should be determined.
45. Facilities, systems, equipment and processes, including cleaning, should be
periodically evaluated to confirm that they remain valid. Where no significant
changes have been made to the validated status, a review with evidence
that facilities, systems, equipment and processes meet the prescribed requirements
fulfils the need for revalidation.
Definitions of terms relating to qualification and validation which are not given in the
glossary of the current EC Guide to GMP, but which are used in this Annex, are given
Change Control
A formal system by which qualified representatives of appropriate disciplines review
proposed or actual changes that might affect the validated status of facilities, systems,
equipment or processes. The intent is to determine the need for action that would ensure
and document that the system is maintained in a validated state.
Cleaning Validation
Cleaning validation is documented evidence that an approved cleaning procedure will
provide equipment which is suitable for processing medicinal products.
Concurrent Validation
Validation carried out during routine production of products intended for sale.
Design qualification (DQ)
The documented verification that the proposed design of the facilities, systems and
equipment is suitable for the intended purpose.
Installation Qualification (IQ)
The documented verification that the facilities, systems and equipment, as installed or
modified, comply with the approved design and the manufacturer’s recommendations.
Operational Qualification (OQ)
The documented verification that the facilities, systems and equipment, as installed or
modified, perform as intended throughout the anticipated operating ranges.
Performance Qualification (PQ)
The documented verification that the facilities, systems and equipment, as connected
together, can perform effectively and reproducibly, based on the approved process
method and product specification.
Process Validation
The documented evidence that the process, operated within established parameters, can
perform effectively and reproducibly to produce a medicinal product meeting its predetermined
specifications and quality attributes.
Prospective Validation
Validation carried out before routine production of products intended for sale.
Retrospective Validation
Validation of a process for a product which has been marketed based upon accumulated
manufacturing, testing and control batch data.
A repeat of the process validation to provide an assurance that changes in the process/
equipment introduced in accordance with change control procedures do not adversely
affect process characteristics and product quality.
Risk analysis
Method to assess and characterise the critical parameters in the functionality of an
equipment or process.
Simulated Product
A material that closely approximates the physical and, where practical, the chemical
characteristics (e.g. viscosity, particle size, pH etc.) of the product under validation. In
many cases, these characteristics may be satisfied by a placebo product batch.
A group of equipment with a common purpose.
Worst Case
A condition or set of conditions encompassing upper and lower processing limits and
circumstances, within standard operating procedures, which pose the greatest chance of
product or process failure when compared to ideal conditions. Such conditions do not
necessarily induce product or process failure.

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