“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.
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
