European Medicines Agency (EMA) Public Workshop

ISPE representatives Bruce Naumann, Stephanie Wilkins, and I joined other trade and professional association delegates at a valuable European Medicines Agency (EMA) public workshop held 20–21 June 2017 in London. The meeting was intended to discuss the establishment and use of health-based exposure limits (HBELs) in quality risk management of cross-contamination in shared manufacturing facilities. Participants included industry toxicologists and quality experts, as well as members of the EMA GMP/GDP (good manufacturing practice/good distribution practice) Inspectors Working Group and the Safety Working Party, representing the workgroup supporting the development and implementation of regulatory guidance on shared facilities. The EMA summary of the workshop was recently published. 1

DAY 1: HOW HBELS ARE ESTABLISHED

Much of the first day’s discussion was prompted by a Q&A document2 on cross-contamination and HBELs in shared facilities published for consultation in December 2016 by the EMA. We heard the background to the questions, especially regulators’ desires to facilitate industry implementation of HBEL concepts in a proportionate way based on potency. Inspectors also shared findings related to HBELs and cross-contamination. Establishing the validity of an HBEL determination could be challenging, they noted. Even when HBELs are established, however, we heard that many companies fail to use them appropriately.

Industry presentations focused on the science of HBELs and their value in determining the hazard of a compound. Bruce Naumann’s discussion of the life cycle approach to HBELs explained that appropriate toxicological expertise is required at all phases. Use of traditional 1/1,000 of the (lowest) clinical dose lacks scientific rigor and was universally opposed. Cleaning limits established using traditional approaches can help set priorities for those still working through their portfolio, but formal HBELs for all compounds being handled should be determined by a qualified toxicologist according to an appropriate standard operating procedure. The HBEL is then used in risk-identification processes.

European requirements are likely to be adopted by the Pharmaceutical Inspection Cooperation Scheme (PIC/S), whose GMP guidelines are aligned with those of the European Union (EU). PIC/S were also reported to be in the process of forming an Expert Circle on the control of cross-contamination. In addition, there was a useful discussion about what inspectors might look for, which could help them assess the validity of an HBEL determination.

A very welcome review of the draft Q&As enabled a shared understanding of industry and regulatory perspectives. While regulators were keen to facilitate simple establishment of HBELs by companies that lack toxicological expertise and handled only low-hazard compounds, industry participants felt that the “highly hazardous” categorization was a retrograde step that lacked scientific rigor.

Toxicological expertise would always be required to establish a robust classification, and relevant data should be readily available for legacy compounds. It was acknowledged that the 1/1,000 of the minimum clinical dose proved appropriately conservative in around 85% of cases, but sufficient exceptions exist such that a toxicology review is recommended to ensure that the categorization is scientifically valid. After such a review, the concept of a “hazard continuum” can be used. The newly revised ISPE Baseline® Guide Volume 7: Risk-Based Manufacture of Pharmaceutical Products (second edition) 3  describes this concept in more detail in its Chapter 5 on Risk Identification. Such a continuum could be helpful to regulators classifying operations at manufacturing sites.

Most companies have already completed their HBEL determinations, but we heard that there are a number of smaller companies with limited ranges of low-hazard products for which the regulators felt it was disproportionate to impose a full toxicological evaluation process. Many of these companies find it challenging to complete the evaluations, but inspectors are generally applying a light touch to enforcement at the present time.

Industry response to this difficulty was to restate concerns over the lack of scientific rigor in the proposed highly hazardous categorization and the dangers of oversimplification, but to support that there may be opportunities for some flexibility with well-established products where hazards are clearly low. It was evident that we all supported the need to protect patients from the risk of cross-contamination with a highly potent or highly hazardous agent. Further discussion among regulators will follow.

Cleaning limits were also a topic of discussion, including the possible misunderstanding that HBELs would become limits for cleaning validation, despite visual cleanliness requirements. Another misperception may have been that 1/1,000 or 10 parts per million represent standard regulatory acceptable limits. Perhaps what added confusion was the reference to additional safety factors that could be misinterpreted as requiring adjustments to factors used in calculating a permitted daily exposure.

Following that, it was clarified that the intention was to ensure that cleaning limits are set sufficiently below the HBEL limit to provide a suitable safety margin to accommodate variability. In many cases, traditional limits would provide this headspace (but this would need to be justified). All agreed that “visually clean” was a minimum requirement for cleaning, but it would need to be shown how the visually clean threshold aligned with an HBEL limit, since the latter could be higher or lower. There is a helpful discussion on these concepts in Chapter 6 of the newly revised Risk-MaPP guide. 3

DAY 2: RISK ASSESSMENT AND USE OF HBELs

Three presentations from inspectors exemplified their rigorous approaches to evaluation of cross-contamination, although the focus was not so much on the determination or use of HBELs. It was somewhat surprising to hear that many of the problems encountered are related to poor application of basic GMP expectations for the control of cross-contamination and not to HBELs.

Three industry case study presentations followed. The first considered the challenges of handling veterinary products. The second, presented by Stephanie Wilkins on behalf of ISPE and drawn from Scenario 4 of the Application Examples within the Risk-MaPP guide, focused on the integration of cross-contamination controls within the overall quality system. In addition, Wilkins clearly answered the question of how to determine margins of safety and set alert, control, and acceptance limits for cleaning validation. The third case study considered a large portfolio of legacy and innovator products. We were reminded of the differences between small and large molecules, particularly with respect to cleaning, where the risk is considerably lessened due to degradation where this can be definitively established.

Conclusions

This extremely valuable workshop, with its science-based focus, concluded with a discussion on next steps. Industry asked for a better understanding of inspectors’ expectations and how they could be met. Inspectors opined that they are unlikely to carry out a detailed examination of HBEL determinations at this time, although their understanding is always increasing so this may happen more in the future. This led to a discussion on training for both inspectors and industry.

ISPE offers training on Risk-MaPP, and the second edition of the Baseline Guide takes into account these latest regulatory developments. Both small and large companies could benefit from Risk-MaPP training, which can help even if HBEL determinations are being outsourced; Risk-MaPP training has also been welcomed by non-EU authorities. Other educational opportunities identified included the publication of case studies on HBEL determinations. ISPE’s Risk-MaPP guide contains a selection of valuable case studies.

Some topics are still to be addressed. These include the chemical manufacture of active pharmaceutical ingredients, where the same approaches may be applicable, except that the impact of intermediates must be addressed. Advanced therapy medicinal products may also need consideration, although they are governed by separate GMP guidance. Further work is required to define so-called “highly sensitizing products” (e.g., beta-lactam antibiotics). Current GMP guidance requires dedicated facilities for these, yet this is becoming open to scientific discussion. It was also clear that more discussion on veterinary facilities would be helpful. Further consultation on these subjects is anticipated.

Finally, the question of whether the draft Q&A document should be withdrawn was considered. Since consultation had already occurred, it should be self-evident that the document does not provide the definitive regulatory position. Nevertheless, the EMA agreed that some might understand it to be a final position, and so will consider their next steps with some urgency. 

• 1European Medicines Agency. “Summary of Discussions at The workshop on the Generation and Use of Health-Based Exposure Limits (HBEL) Held on 20-21 June 2017 at the European Medicines Agency (EMA).” EMA/310936/2017. www.ema.europa.eu/docs/en_GB/document_library/Minutes/2017/08/WC500233051.pdf
• 2———. “Questions and Answers on Implementation of Risk Based Prevention of Cross Contamination in Production and ‘Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in shared Facilities.’” (EMA/CHMP/CVMP/SWP/169430/2012).” 15 December 2016. www.ema.europa.eu/docs/en_GB/document_library/Other/2017/01/WC500219500.pdf
• 3 a b International Society for Pharmaceutical Engineering. Baseline Guide Volume 7: Risk-Based Manufacture of Pharma Products, 2nd ed. https://ispe.org/publications/guidance-documents/risk-mapp-management-plan