PRINCIPLE
This chapter describes the
principles of qualification and validation which are applicable to the
manufacture of pharmaceutical 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.
PLANNING FOR VALIDATION
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.
The VMP should be a summary
document which is brief, concise and clear.
The VMP should contain data on at
least the following:
validation
policy;
organisational
structure of validation activities;
summary
of facilities, systems, equipment and processes to be validated;
documentation
format: the format to be used for protocols and reports; planning and
scheduling;
change
control; and
reference
to existing documents.
In
case of large projects, it may be necessary to create separate validation
master plans.
DOCUMENTATION
A
written protocol should be established that specifies how qualification and
validation will be conducted. The protocol should be reviewed and approved by
the head of Quality Management (Quality Assurance). The protocol should specify
critical steps and acceptance criteria.
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.
After completion of a satisfactory
qualification, a formal release for the next step in qualification and
validation should be made as a written authorisation.
QUALIFICATION
Design Qualification
The first element of the validation
of new facilities, systems or equipment could be design qualification (DQ).
The
compliance of the design with GMP should be demonstrated and documented.
Installation Qualification
Installation qualification (IQ) should
be performed on new or modified facilities, systems and equipment.
IQ
should include, but not be limited to the following:
installation
of equipment, piping, services and instrumentation checked to current
engineering drawings and specifications;
collection and collation of
supplier operating and working instructions and maintenance requirements;
calibration
requirements; and
verification of materials of
construction.
Operational Qualification
Operational qualification (OQ) is
performed after IQ has been completed, reviewed and approved.
OQ should include, but not be
limited to the following:
tests that have been developed from
knowledge of processes, systems and equipment; and
tests to include a condition or a
set of conditions encompassing upper and lower operating limits, sometimes
referred to as “worst case” conditions.
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
Performance qualification (PQ) is
performed after both IQ and OQ have been completed, reviewed and approved.
PQ should include, but not be
limited to the following:
tests,
using production materials, qualified substitutes or simulated product, that
have been developed from knowledge of the process and the facilities, systems
or equipment;
tests to include a condition or set
of conditions encompassing upper and lower operating limits.
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
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.
PROCESS VALIDATION
General
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 revalidation.
Process
validation should normally be completed prior to the distribution and sale of
the pharmaceutical 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).
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.
Facilities, systems, equipment and
processes should be periodically evaluated to verify that they are still
operating in a valid manner.
Prospective Validation
Prospective
validation should include, but not be limited to the following:
short description of the process;
summary
of the critical processing steps to be investigated;
list of the
equipment/facilities to be used (including measuring/ monitoring/recording
equipment) together with its calibration status;
finished
product specifications for release;
list
of analytical methods, as appropriate;
proposed
in-process controls with acceptance criteria;
additional
testing to be carried out, with acceptance criteria and analytical validation,
as appropriate;
sampling
plan (location and frequency);
methods
for recording and evaluating results;
functions and responsibilities; and
proposed
timetable.
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.
Batches
made for process validation should be the same size as the intended industrial
scale batches.
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 Practices, including the satisfactory outcome of the validation
exercise, and the marketing authorisation.
Concurrent Validation
In exceptional circumstances it may
be acceptable not to complete a validation programme before routine production
starts.
The decision to carry out
concurrent validation must be justified, documented and approved by the head of
Quality Management (Quality Assurance).
Documentation requirements for
concurrent validation are the same as specified for prospective validation.
Retrospective Validation
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.
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.
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 stability results.
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 process.
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.
CLEANING VALIDATION
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.
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.
Normally only cleaning procedures
for product contact surfaces of the equipment need to be validated.
Consideration should be given to non-contact parts. The intervals between use
and cleaning as well as cleaning and reuse should be validated. Cleaning
intervals and methods should be determined.
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.
Typically
three consecutive applications of the cleaning procedure should be performed
and shown to be successful in order to prove that the method is validated.
"Test
until clean" is not considered an appropriate alternative to cleaning validation.
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.
CHANGE CONTROL
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.
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, re-qualification and
re-validation should be determined.
RE-VALIDATION
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.
VALIDATION OF ANALYTICAL
PROCEDURES
The objective of validation of an
analytical procedure is to demonstrate that it is suitable for its intended
purpose.
Types of Analytical Procedure to
be Validated
