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.