Non Sterile Process Validation
Non Sterile Process Validation
Non Sterile Process Validation
Supplementary guidelines on good manufacturing practices: validation. In: WHO Expert Committee on
1
Specifications for Pharmaceutical Preparations: fortieth report. Geneva: World Health Organization; 2006:
Annex 4 (WHO Technical Report Series, No. 937).
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WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-ninth report
2. Glossary
WHO Technical Report Series No. 992, 2015
The definitions given below apply to the terms used in these guidelines. They
may have different meanings in other contexts.
at-line. Measurement where the sample is removed, isolated from, and
analysed in close proximity to the process stream.
concurrent validation. Validation carried out during routine production
of products intended for sale in exceptional circumstances when data from
replicate production runs are unavailable because only a limited number of
batches have been produced, batches are produced infrequently or batches are
produced by a validated process that has been modified. Individual batches may
be evaluated and released before completion of the validation exercise, based on
thorough monitoring and testing of the batches.
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real-time release testing. The ability to evaluate and ensure the quality of
in-process and/or final product based on process data, which typically include a
WHO Technical Report Series No. 992, 2015
3. Introduction
Process validation data should be generated for all products to demonstrate the
adequacy of the manufacturing process. The validation should be carried out in
accordance with GMP and data should be held at the manufacturing location
whenever possible and should be available for inspection.
Process validation is associated with the collection and evaluation of data
throughout the life cycle of a product – from the process design stage through
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Figure A3.1
Phases of process validation
4. Process design
Under the life-cycle approach, the focus of validation is shifted from commercial-
scale batches to development. Product development activities provide key inputs
WHO Technical Report Series No. 992, 2015
to the process design stage, such as the intended dosage form, the quality attributes
and a general manufacturing pathway. Laboratory or pilot-scale models designed
to be representative of the commercial process can be used to estimate variability.
Process design should normally cover design of experiments, process
development, the manufacture of products for use in clinical trials, pilot-scale
batches and technology transfer. Process design should be verified during product
development.
Process design should cover aspects for the selection of materials,
expected production variation, selection of production technology/process and
qualification of the unitary processes that form the manufacturing process as a
whole, selection of in-process controls, tests, inspection and its suitability for the
control strategy.
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5. Process qualification
Personnel, premises, utilities, support systems and equipment should be
appropriately qualified before manufacturing processes are validated. Materials,
environmental controls, measuring systems, apparatus and methods should
be considered during validation. The stages of qualification of equipment may
include design, installation, operation and performance of equipment (for more
details see (WHO Technical Report Series, No. 937, Annex 4 (1)).
Traditionally, three batches have been considered the normal and
acceptable number for process validation; however, the number of batches should
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be justified and based on a risk assessment that includes, for example, variability
of results from the process design stage, variability of materials, product history,
where the product is being transferred from and where it will be produced.
Manufacturers should define the stage at which the process is considered to be
validated and the basis on which that decision was made. The decision should
include a justification for the number of batches used based on the complexity
and expected variability of the process and critical quality attributes (CQAs).
Successful completion of process performance qualification stage of the life cycle
is required for commercial distribution.
A risk assessment should be performed for the change from scale-up
to commercial batch size. Process qualification should confirm that scale-up in
batch size did not adversely affect the characteristics of the product and that a
process that operates within the predefined specified parameters consistently
produces a product which meets all its CQAs and control strategy requirements.
The process should be verified on commercial-scale batches prior to
marketing of the product.
Extensive in-line and/or online and/or at-line controls may be used to
monitor process performance and product quality in a timely manner. Results
on relevant quality attributes of incoming materials or components, in-process
material and finished products should be collected. This should include the
verification of attributes, parameters and end-points and assessment of CQA and
critical process parameter (CPP) trends. Process analytical technology applications
and multivariate statistical process control can be used.
Manufacturers are encouraged to implement the new validation approach
to ensure that processes are of known and acceptable capability. As full
implementation of this approach may take time, the traditional approach
of prospective validation and concurrent validation (used infrequently and
restricted to the scenarios described in section 2) may be acceptable in the interim.
A combination of elements of the traditional process validation approach and the
new continuous process verification approach may be considered appropriate,
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collected and assessed to verify the validity of the original process validation or
to identify changes required to the control strategy.
The scope of continued process verification should be reviewed
periodically and modified if appropriate throughout the product life cycle.
7. Change management
Manufacturers should follow change control procedures when changes are
planned to existing systems or processes.
The change control procedure and records should ensure that all aspects
are thoroughly documented and approved, including regulatory approval where
appropriate (variation).
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References
1. Supplementary guidelines on good manufacturing practices: validation. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations: fortieth report. Geneva: World
Health Organization; 2006: Annex 4 (WHO Technical Report Series, No. 937).
2. WHO good manufacturing practices for active pharmaceutical ingredients. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations: forty-fourth report. Geneva: World
Health Organization; 2010: Annex 2 (WHO Technical Report Series, No. 957).
3. WHO good manufacturing practices for sterile pharmaceutical products. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations: forty-fifth report. Geneva: World
Health Organization; 2011: Annex 6 (WHO Technical Report Series, No. 961).
4. ICH harmonised tripartite guideline, pharmaceutical development Q8(R2), Current Step 4 version,
dated August 2009 (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/
Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf, accessed 15 January 2014).
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Further reading
Guideline on process validation. London: Committee for Medicinal Products for Human Use
(CHMP), Committee for Medicinal Products for Veterinary Use (CVMP); 2012 (EMA/CHMP/CVMP/
QWP/70278/2012-Rev1) (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_
guideline/2012/04/WC500125399.pdf, accessed 15 January 2015).
Guidance for industry. Process validation: general principles and practices. Silver Spring (MD): US
Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation
and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Veterinary
Medicine (CVM); 2011 (Current Good Manufacturing Practices (CGMP) Revision 1).
ICH harmonised tripartite guideline, quality risk management, Q9, Current Step 4 version, dated
9 November 2005.
ICH harmonised tripartite guideline, pharmaceutical quality system, Q10, Current Step 4 version, dated
4 June 2008 (http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html, accessed
15 January 2014).
Quality assurance of pharmaceuticals. WHO guidelines, related guidance and GXP training materials.
Geneva: World Health Organization; 2014 (CD-ROM).
WHO good manufacturing practices: main principles for pharmaceutical products. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations: forty-eighth report. Geneva: World Health
Organization; 2014: Annex 2 (WHO Technical Report Series, No. 986 (http://www.who.int/medicines/
areas/quality_safety/quality_assurance/GMPPharmaceuticalProductsMainPrinciplesTRS961Annex3.pdf,
accessed 15 January 2015).
WHO guidelines on quality risk management. In: WHO Expert Committee on Specifications for
Pharmaceutical Preparations: forty-seventh report. Geneva: World Health Organization; 2013: Annex 2
(WHO Technical Report Series, No. 981).
WHO Technical Report Series No. 986, 2014
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