“Documented
evidence which provides a high degree of assurance that a specific process will
consistently produce a product meeting its predetermined specifications and
quality attributes.”
QUALIFICATION
The
premises, the supporting utilities, the equipment and the processes have been
designed in accordance with the requirements of GMP. This normally constitutes
Design Qualification or DQ.
Design qualification
The
first element of the validation of new facilities, systems or equipment could
be design qualification (DQ). Design qualification should provide documented
evidence that the design specifications were met.
The
premises, the supporting utilities, the equipment and the processes have been
designed in accordance with the requirements of GMP. This normally constitutes
Design Qualification or DQ. The compliance of the design with GMP should be
demonstrated and documented.
Installation
qualification
Installation
qualification (IQ) performed in new or modified facilities, systems and
equipment.
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
Operational
qualification (OQ) should follow Installation qualification.
OQ
should include, but not be limited to the following:
(a)
Tests that have been developed from knowledge of processes, systems and
equipment;
(b)
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
finalization 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) should follow successful completion of Installation
qualification and Operational qualification.
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.
Although
PQ is described as a separate activity, it may in some cases be appropriate to
perform it in conjunction with OQ.
PROCESS VALIDATION
General
For
purposes of this guidance, process validation is defined as the collection and
evaluation of data, from the process design stage through commercial
production, which establishes scientific evidence that a process is capable of
consistently delivering quality product. Process validation involves a series
of activities taking place over the lifecycle of the product and process. This
guidance describes process validation activities in three stages.
•
Stage 1 – Process Design: The commercial manufacturing process is defined
during this stage based on knowledge gained through development and scale-up
activities.
•
Stage 2 – Process Qualification: During this stage, the process design is
evaluated to determine if the process is capable of reproducible commercial
manufacturing.
•
Stage 3 – Continued Process Verification: Ongoing assurance is gained during
routine production that the process remains in a state of control.
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 re-validation.
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).
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:
(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.
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 Practice, including the satisfactory outcome of the validation exercise,
and with the marketing authorization.
Concurrent validation
In
exceptional circumstances it may be acceptable not to complete a validation programmed
before routine production starts.
The
decision to carry out concurrent validation must be justified, documented and
approved by authorized personnel.
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 storage 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.
Re-validation
Re-validation
provides the evidence that changes in a process and/or the process environment,
introduced either intentionally or unintentionally, do not adversely affect process characteristics and
product quality.
There
are two basic categories of Re-validation:
(a)
Re-validation in cases of known change (including transfer of processes from
one company to another or from one site to another),
(b)
Periodic Re-validation carried out at scheduled intervals.
Reference:
1. Final
Version of Annex 15 to the EU Guide to Good Manufacturing Practice, July 2001 ;
Qualification and validation
2. Process
Validation: General Principles and Practices, January 2011;
U.S.
Department of Health and Human Services ,Food and Drug Administration
3. Validation
Master Plan Installation And Operational Qualification Non-Sterile Process
Validation Cleaning Validation ; PI 006-3, 25 September 2007
4. FDA Guidance for Industry
Sterile Drug Products Produced by Aseptic Processing Guideline, Published
September 2004
5. Agalloco
J. P. (ed.), Carleton F. J. (ed.) - Validation of Pharmaceutical Processes ,
third edition, 2007
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