Panel Discussion with Regulators on Sustainability, Annex 1 Revision Implementation, Good Engineering Practice
A panel discussion held on 26 April during the 2022 ISPE Europe Annual Conference focused on Sustainability, Annex 1 Revision Implementation, and Good Engineering Practice and highlighted the many linkages among the topics.
Panelists in the room and remote included:
The discussion was moderated by
How can regulators help?
Dimitrios Catsoulacos started by commenting that WHO had initiated work on health impacts of sustainability, for example by examining the potential for effluent from manufacturing plants to make a contribution to the increase in antimicrobial resistance (AMR) (see https://www.who.int/news/item/02-03-2022-world-leaders-and-experts-call-for-action-to-protect-the-environment-from-antimicrobial-pollution).
Brendan Cuddy indicated that sustainability is an important topic in the EU in many areas, for example in finance and health. A revised pharmaceutical legal framework is being adopted with priority being given to the public health impact of AMR. Policies are being developed to promote a strong, competitive, and green pharmaceutical industry in the EU. A network of regulators is examining how the EU can adopt its processes. An example influenced by the International Coalition of Medicines Regulatory Agencies (ICMRA) is use of more bilateral arrangements to reduce the number of GMP inspections. The ongoing review of EU Pharmaceutical legislation will consider the topic of sustainability.
Natalie Moll confirmed that the European pharmaceutical industry is aligned with the WHO initiative and has published policy statements and a white paper on the circular economy (see https://www.efpia.eu/media/554663/circular-economy.pdf) and “green deal” (https://www.efpia.eu/about-medicines/development-of-medicines/regulations-safety-supply/environment-health-safety-and-sustainability/). EFPIA supports safe discharge targets and medicinal product disposal. There should be more consideration of sustainability in all aspects of the pharmaceutical business, for example more general use of electronic patient leaflets rather than issuing paper copies. The circular economy white paper covers many topics.
Is there a need for regulation and inspection?
Dimitrios Catsoulacos said WHO had conducted a limited survey relating to waste management, which is not regulated by National Competent Authorities (NCAs) for pharmaceuticals – it is usually regulated by environmental agencies. There are not harmonized standards for waste management related to AMR and some expectations are needed. This issue is being discussed by a WHO specifications committee. WHO inspectors will be inspecting waste management systems; however, the requirements are in a separate document and not in the GMP regulations. More data is required regarding who is responsible for monitoring.
Carmelo Rosa commented that FDA was seeing contamination in water systems. With regard to the broader topic of sustainability FDA observed a reluctance to change by companies. For example, there is a reluctance to change (reduce) air change rates to reduce energy use, even though such changes could be supported scientifically. It appears that companies were looking for regulatory guidance rather than making company-driven continual improvements. Regulators are sharing information on sustainability topics.
Natalie Moll mentioned the Eco-Pharmaco-Stewardship concept (see https://efpia.eu/media/288586/pie-brochure.pdf), a proposal that strives to protect patient access to medicines while appropriately considering environmental aspects. This industry concept is being progressed in Europe by an inter-association task force with EFPIA working with self-care (OTC)(AESGP) and generic (European Generic and Biosimilar medicines Association (EGA) associations.
EU GMP Annex 1 Revision Implementation
Where do regulators see industry moving with quality risk management?
Abdelaali Sarakha commented that quality risk management (QRM) is an integral part of a contamination control strategy (CCS) and is currently required. QRM, however, is often not applied correctly, which has led to the revision of ICH Q9, Quality Risk Management, particularly for the topics of formality and subjectivity as applied to QRM.
Christina Meissner mentioned that QRM has been applied to support bad positions with QRM exercises not including the correct range of expertise, for example not including operators.
David Churchward agreed with Christina and indicated that the revision of ICH Q9 should be helpful, particularly if accompanied by implementation guidance or examples. He stressed four key points for implementing or changing a process:
- Consider the outcome and prior knowledge
- Design the process
- Design the monitoring scheme
- Integrate into the pharmaceutical quality system.
Carmelo Rosa indicated that QRM needs more practical training. For example, QRM should not be used to justify lack of process understanding and release batches. It is a worrying observation that regulators can quickly identify poor practices simply by observation.
Brooke Higgins also stressed the need to have the correct people (expertise) in QRM exercise teams. As an example, FDA observed a case where a media fill failure investigation was performed without the presence of a microbiologist. From a QRM perspective, humans should be as far as possible “removed” from aseptic operations.
Manuel Ibarra Lorente commented that the risk identification step in QRM should include breadth of knowledge and not just locally available expertise.
Annex 1 revision draft mentions the CCS – how is this to be implemented?
Christina Meissner stressed that companies should not be afraid of implementation – a CCS is already required. The CCS should consider all aspects for example,
- Monitoring techniques
- Sampling points
- Relationship to media fills
- Cleaning strategy
Brooke Higgins confirmed that FDA currently expects CCSs and yet there are deficiencies seen in warning letters where better design of the process and monitoring programs should have been implemented.
Alice Redmond in her role in a consultant company saw deficiencies in the gap assessment which often comes at integration points between steps in an aseptic process.
Carmelo Rosa observed that people movements are insufficiently considered even though the room in unmanned state meets standards e.g.
- People crawling under conveyor belts to enter a sterile area
- People bumping into one another
FDA has observed contamination issues not being shared between sites in an organization.
How has sustainability been included in revised Annex 1?
Abdelaali Sarakha pointed out that use of filtered water as water for injection was being allowed.
Brendan Cuddy said that Annex 1 was being revised in a manner not to hinder innovation and sustainability. It is however not being written as a sustainability standard.
Good Engineering Practice
Alice Redmond opened the session by stressing the importance of good engineering practice (GEP) which should include a thorough and wide-ranging design review taking full consideration of the manufacturing process. This step is often seen as a check box exercise.
What is the expectation for GEP documentation in qualification and validation?
Manuel Ibarra Lorente stressed that GEP is part of a pharmaceutical quality system and should be managed properly. It contains knowledge which should be used in, for example QRM exercises.
David Churchward confirmed that use of vendor documentation was acceptable, however, a company should not have a vendor on site and operating equipment. In his role as an MHRA inspector David had observed a tablet press being operated by a vendor and the company did not know how to use it!
Is there a role for eValidation?
Carmelo Rosa said there needs to be an understanding of what the equipment is doing. eValidation is similar to the data integrity issue in that there needs to be understanding by company personnel as well as appropriate controls of who can get into a system and who can make changes. A company cannot delegate to an external supplier; it must understand the equipment. Quality risk management should be applied early in the validation exercise and should be applied to the whole process, not just individual pieces of equipment.
Manuel Ibarra Lorente pointed out that continuity of supply should be one of the harms identified during the risk identification phase of QRM.
Should sustainability be included in GEP?
Carmelo Rosa confirmed that sustainability should be included in GEP. The right people should be brought to the table.
Christina Meissner said that energy use and re-use should be considerations in GEP as part of sustainability.
Brendan Cuddy commented that ISPE Guidances should include the topic.
Carmelo Rosa said that equipment should be designed to be sustainable, however we do not need to reinvent the wheel.
Brooke Higgins stressed that well designed processes should lead to less waste and reduced manual interventions also should reduce rejections.
Question to Abdelaali Sarakha: how do GEP and GMP link?
He responded that GEP and GMP need to be linked early and where there are uncertainties, regulators should be involved in the design phase. Sustainability should be included in design qualification.
Could regulators produce a detailed guideline for regulatory expectations for QRM?
Manuel Ibarra Lorente said that regulators wished to retain flexibility and thought that industry would also like to retain flexibility.
Brendan Cuddy commented that regulators are often accused of being too prescriptive, however, he agreed with Manuel that flexibility should be retained to use a variety of QRM tools.
Dimitrios Catsoulacos pointed out that there are examples in WHO Technical Reports, which should be readily available.
David Churchward indicated that not all QRM tools work in every situation and hopefully ICH Q9 revision will provide some worked examples.
Alice Redmond noted the ISPE had provided some examples to the ICH Q9 Revision expert working group (EWG) and that more examples had been requested from ISPE by the EWG.
Will Annex 1 revision raise standards and contribute to drug shortages?
Christina Meissner questioned whether Annex 1 revision was raising standards.
Brendan Cuddy stressed that there has been an extensive stakeholder consultation process where comprehensive feedback has been given. Annex 1 has been drafted by a multinational team to take account of multi-regional positions. Training will be needed regarding Annex 1 implementation, and this could occur using conferences.
Conversations with local inspectors should be used to agree timescales for any revisions or changes to processes considered necessary to comply with Annex 1 revision.
Finally, Abdelaali Sarakha as rapporteur of Annex 1 revision could not provide an exact date for issue. The document is in the final stages of Commission approval and may be issued in summer 2022.
This is brief and informal synopsis of a discussion among regulators from various countries and regulatory organizations during the ISPE European Conference on 26 April 2022. It has not been vetted by any of the agencies or regulators cited in this article.