process validation Archives - European Industrial Pharmacists Group (EIPG)

A concept paper on the revision of Annex 11


This concept paper addresses the need to update Annex 11, Computerised Systems, of the Good Manufacturing Practice (GMP) guideline. Annex 11 is common to the member states of the European Union (EU)/European Economic Area (EEA) as well as to Read more

What happens after IP loss of protection


by Giuliana Miglierini What does it happen under a competitiveness perspective once intellectual property (IP) protection for medicinal products expired? And what is the impact of the new entries on generics and biosimilars already in the market? The role of competitor Read more

The FDA warns about the manufacture medicinal and non-pharmaceutical products on the same equipment


by Giuliana Miglierini A Warning Letter, sent in September 2022 by the US FDA to a German company after an inspection, addresses the possibility to use the same equipment for the manufacturing of pharmaceutical and non-pharmaceutical products. The FDA reject Read more

The FDA warns about the manufacture medicinal and non-pharmaceutical products on the same equipment

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by Giuliana Miglierini

A Warning Letter, sent in September 2022 by the US FDA to a German company after an inspection, addresses the possibility to use the same equipment for the manufacturing of pharmaceutical and non-pharmaceutical products. The FDA reject this possibility, that is considered a significant violation of cGMP.

The letter addresses the lack of process validation for the manufacturing of over-the counter (OTC) drugs and of qualification documentation proving acceptance criteria were met and the process was under control. Deficiencies were reflected in the batch records missing important pieces of information. Aspects pertaining cleaning validation were also found critical.

The requests of the FDA

The Warning Letter asks the company to provide the FDA with a full qualification programme of the equipment and facility. This should include a detailed risk assessment for all medicinal products manufactured using shared equipment. Plans are also needed on how to separate the manufacturing areas for pharmaceutical and non-pharmaceutical productions.

Furthermore, the program for cleaning validation should be reviewed to include at least (but not limited to) drugs with higher toxicities or potencies, drugs of lower solubility in their cleaning solvents and that may result difficult to clean. Maximum holding times before cleaning and swabbing locations for areas that are most difficult to clean should be also provided. A retrospective assessment of the cleaning process has to be included in the required CAPA plan; change management for the introduction of new manufacturing equipment or a new product should be also discussed.

The FDA also addressed many other violations, such as the lack of robust laboratory controls, identity testing of incoming raw materials including active ingredients (APIs), and the inability to demonstrate the respect of minimum USP monograph specifications and appropriate microbial limits for drug manufacturing. Management and controls on data integrity were also found deficient.

The European perspective

In the EU, the possibility to use the same equipment and premises for the manufacturing of both pharmaceutical and non-pharmaceutical products can be referred to the provisions set forth by Chapter 3 (Premises and Equipment) of the EU GMPs.

The document clearly states that the “premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination”.

The application of Quality Risk Management principles is used to assess the specific risk of cross-contamination and the consequent measures to be put in place. Dedicated premises and equipment may be needed in some cases, especially if the risk cannot be adequately controlled by operational and/or technical measures, the product has an unfavourable toxicological profile, or relevant residue limits cannot be satisfactorily determined by a validated analytical method. Attention should also be paid to the positioning of equipment and materials, so to avoid confusion between different medicinal products and their components, and to guarantee the correct execution of process controls. Particular provisions are needed in the case dusty materials are used, also with respect to cleaning validation.

All cleaning procedures should be available in written form, designed to allow for an easy and thorough cleaning (including drains, pipework, light fittings, ventilation points and other services). In the case of exposed materials, the interior surfaces of the premises should be smooth and easy to clean and disinfect.

All documentation needed to support the above mention requirements should be prepared according to Chapter 4 (Documentation) of the European GMPs.

EMA’s Guideline on shared facilities

The European Medicines Agency (EMA) published in 2014 a guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities.

Threshold values expressed in terms of Permitted Daily Exposure (PDE) or Threshold of Toxicological Concern (TTC) are the key parameters to be used to run the risk assessment. The so determined threshold levels for APIs can also be used to justify carry over limits used in cleaning validation. EMA’s guideline discusses how to address the determination of the PDE, also with respect to specific types of active substances (e.g. genotoxic, of highly sensitising potential, etc.)

The WHO guidelines

The World Health Organisation released in 2011 its GMP guideline Annex 6 (TRS 961) on the manufacturing of sterile pharmaceutical products. Clean areas are the location of choice for such productions. High-risk operative areas for aseptic manufacturing are classified in Grade A, with Grade B representing their background zones. Grade C and D areas are reserved to less critical steps of the production process.

A frequent and thorough sanitation is important, coupled with disinfection with more than one biocide and/or a sporicidal agent, as appropriate. The effectiveness of the cleaning procedure should be closely monitored to exclude the presence of contaminants, both in the form of vital and not vital particulate.

The guideline specifically mentions the case of preparations containing live microorganisms (such as vaccines), that can be prepared in multiuser facilities only if the manufacturer can demonstrate and validate effective containment and decontamination of the live microorganisms. To transport materials, the conveyor belt should be continuously sterilised as a requirement to pass through a partition between a Grade A/B and a processing area of lower air cleanliness.

A “Comparison of EU GMP Guidelines with WHO Guidelines” was published by the German Federal Ministry for Economic Cooperation and Development (BMZ) to support the understanding of differences between the two approaches, and with a special emphasis to the alleged higher costs of implementation and compliance to EU GMPs.

Analysing the requirements relative to premises and equipment, they aim to guarantee the suitability of rooms to the intended tasks, minimise the risk of failure and cross-contamination and ensure easy cleaning and maintenance. According to the BMZ, EU’s and WHO’s requirements are the same, even if the WHO guideline is more detailed in some aspects (to this instance, the BMZ document was published prior to the release of the new Annex 1 to the GMPs). The theme of equipment is also discussed in other WHO guidelines, i.e. the “WHO good manufacturing practices: starting materials” and the WHO guidelines on transfer of technology in pharmaceutical manufacturing.

Cleaning and sanitation should be addressed according to the provisions set forth by the ISO 14644 family of technical standards. Cleaning validation is also treated in Appendix 3 of the WHO TRS 937 Annex 4. Cleaning validation should be used as the main tool to ensure the removal to pre-established levels of all residues of an API of a product manufactured in any equipment with direct contact to the surface, so that the next product manufactured using the same apparatus would be not cross-contaminated.

According to the BMZ, indications on qualification, process validation and cleaning validation contained in Annex 15 of EU GMPs (paragraph 6) should be integrated with the contents of the ICH Q2 guideline. The only two points of the EU GMPs not covered by the WHO’s guide refer to the allowance that toxic or hazardous substances can be substituted under special conditions for the validation process and the indication that “Test until clean” is not considered an appropriate alternative to cleaning validation.


Small-scale models for process development

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by Giuliana Miglierini

There are many steps within a pharmaceutical production that may require the availability of a model of the manufacturing process in order to run targeted simulations. To this instance, a useful approach is represented by the so-called “small-scale models” (SSMs, or “scaled-down models”), that are usually developed to reflect the real working parameters available for a certain large manufacturing facility.
A small-scale model needs to undergo a process qualification (SSMQ) in order to be acceptable from the regulatory point of view. The main features and criticalities of SSMQ have been discussed in a series of articles published on BioProcess Online, and based on the results of a survey run between the representatives of large biopharmaceutical companies participating to the BioPhorum Development Group. A white paper on SSMs is also available.

The main requirements for an SSM
A critical requirement for a small-scale model to be accepted by regulators is its ability to exactly replicate the large-scale manufacturing process. This can be assessed and justified by choosing appropriate process parameters to be used as inputs for the simulation and obtaining outputs showing performance and quality attributes comparable to the large-scale process.
Small-scale models can be used both in early development, for example to support clinical manufacturing, and in late-stage development (e.g. to identify critical process parameters).
The overall quality of the model increases in the passage from early- to late-stage applications, due to the increasing number of data available to simulate the processes. Alternatively, a scientific evaluation of the process without application of a formal statistical method might be used, but a good experience and sufficient platform knowledge is needed in order to obtain valid results.
Other examples of the utility of SSMs in biopharmaceutical manufacturing include media stability and cell line stability studies, qualification of raw materials, impurity clearance validation, postapproval process changes and resolution of deviations.
The clearing of infectious viruses is a particularly critical step in biomanufacturing, and it should be run according to the ICH Q5A8 guideline; to this instance, SSMs may turn useful to validate the process at the laboratory scale. Other points to be kept in mind refer to the possibility of different layouts, mode of operation, geometry or materials for the systems used in small-scale vs large-scale plants.

Validation and qualification of the SSMs
A risk-based assessment of the parameters of choice can be used to validate the representativeness of model, with key performance indicators (e.g., titer, VCD, etc.) and product quality attributes (PQAs) used to run the comparison. A risk-based approach should be the choice also for the design of the small-scale model, taking into consideration both technical and business risks.
More than just one large-stage run (with a minimum of 3) is suggested to support the full qualification of the small-scale models by statistical analysis, according the survey. The choice to assess or qualify the SSM depends on its intended use.
The dimensions of the model can vary according to its specific target use. A benchtop-scale (1 L to 10 L) is common for upstream unit operations, but micro-scale bioreactors (15 to 250 mL) and pilot-scale (50 to 200L) models are other useful options. The benchtop scale of a chromatography
column can be used to model downstream processes, with micro-scale models or pilot plants as other alternatives. The article also reports a table to help identify the correct choice of the scale-independent “scaling parameter”.

In some instances, it might be advisable to use the same media and buffers as in the real manufacturing process, as well as the same raw materials. Procedures to prepare the buffers and other materials should be also comparable.
The BioPhorum Development Group provided examples of how to address qualification, including a satellite or non-satellite approach for upstream unit operations according to the characteristics of the inoculum transfer and scale of the run, the location of the development laboratories and the commercial site. An important parameter to be considered is the temperature for shipping, should it be required a transfer of materials between different locations; shipping at ≤-65°C is the preferred choice for many companies, writes the authors.
Different procedures for filtration have been also addressed, as well as the analytical setup for small-scale experiments; measures may be run in the QC GMP laboratories associated to the manufacturing site or in non-GMP labs for small-scale model qualification. A mix of the two may represent the preferred option in many cases, indicates the article. Training is fundamental to ensure the consistency of small-scale unit operations independent of the operator. Formal documentation should be also produced should the small-scale model undergo new runs of qualification.

The choice of the statistical methods
All data obtained both from the small-scale model and the large manufacturing plant needs to undergo a statistical analysis to be used for the qualification of the production process.
Descriptive statistical methods may depend upon the satellite or non-satellite character of the study, and they may turn useful to provide data in the form of scattered plots to be used for qualification assessment, for example by SMEs or health authorities.
Inferential statistical methods compare data obtained from the small-scale model and the atscale one, which must be representative of populations and referred to stable processes all over the product lifetime. Attention should be paid to the indication of “equivalent” or “notequivalent” results obtained from the applied method, as errors are possible in the 5-10% of cases.
“This is an important fact often overlooked by scientists and health authorities in evaluating the statistical component in a qualification report. It is also an important rationale for not using statistical methods alone to qualify or not qualify a model”, warn the authors of the article. Possible examples of inferential statistical procedures are the difference tests (or null hypothesis significance tests, NHSTs) known as T-test and F-test. Equivalence tests (Two One Sided T-tests, TOST) are also possible to obtain evidence of equivalency, especially in the case of a satellite design of the experiment. Quality range (QR) methods are another available option, useful to establish the population ranges. Multivariate analysis (MVA) provides the possibility to consider different, time-based data sets simultaneously, thus supporting the study of the processes under a time evolution perspective.