PDA recommended using a risk-based approach to address health-based exposure limits (HBELs) in the presentation, “Key points to recognize quality in Health Based Exposure Limits (HBEL) and associated monograph” at EMA’s June workshop on shared facilities (1). In particular, PDA advocated flexible approaches for products currently manufactured in shared facilities to avoid interrupting the supply of essential medicines.

Hosted by EMA’s Safety Working Party (SWP), this workshop offered industry representatives a chance to discuss the Agency’s Q&A concerning risk-based strategies to prevent cross-contamination in shared facilities (2). The discussions at the workshop were positive and paved the way for continued use of scientifically justified, toxicological, risk-based approaches that rely on documented rationale proportionate to the level of cross-contamination risk.

Background on Shared Facilities

Chapters 3 and 5 of the EU EudraLex Guidelines for Medicinal Products for Human and Veterinary Use require a toxicological evaluation to assess and control cross-contamination risks presented by drug products manufactured in shared production facilities (3, 4). On June 1, 2015, EMA’s regulatory guideline setting Permitted Daily Exposure (PDE) values went into effect for all new human pharmaceutical products. The guideline for existing human pharmaceutical products then went into effect Dec. 1, 2015 (5). Previously, other methods were used to determine an acceptable level of carryover with uncertain levels of patient health protection (6). One of the most frequently used methods was 1/1000 of the minimum daily dose (MinDD). This method has many shortcomings, as has been covered in recent articles (7, 8).

Following implementation of the PDE guideline, EMA issued a Q&A document in response to several open questions (2). While EMA hoped this nonmandatory document would clarify interpretation of the PDE guideline, it reintroduced two criteria that appeared to be a step back. One was the classification of products into two hazard categories; the second related to the continued use of the 1/1000 criteria for nonhazardous drugs. These two points caused significant confusion within industry, and a number of comments have been sent to EMA by industry associations, such as PDA, as well as individual experts.

In its comments, PDA’s Regulatory and Quality Advisory Board (RAQAB) advocated “flexible approaches for products currently manufactured in shared facilities to avoid interruption of supply of essential medicines” (9). PDA recommended use of a scientifically justified, toxicological, riskbased approach relying on a documented rationale. Further, PDA urged EMA to remove references to 1/1000 of the minimum therapeutic dose based on the approach described in the 2015 guideline.

PDA Position Discussed at Workshop

The PDA presentation at the June workshop reiterated the points made in the earlier comments. Following the presentation, attendees raised the following key points in support of PDA’s position:

• Inspectors expect to see the HBEL approach to avoid redundancy of terminology such as “highly hazardous” and the use of 1/1000 MinDD
• Trained and knowledgeable individuals must complete a rigorous methodology to accurately determine a safe/acceptable exposure for a given substance
• Cross-functional users should employ a solid implementation plan to ensure consistent application of practices in complex quality risk management systems (10)
• There are many factors in controlling carryover risks beyond the HBEL, which also need to be done consistently by qualified experts

The discussions at the workshop were positive and paved the way for continued use of a scientifically justified, toxicological, risk-based approach with a documented rationale. While more time is clearly needed for implementation of the PDE/HBEL concepts, future use of toxicological limits is not in dispute. During future inspections, more focus will be given this topic, as well as topics addressed in the Q&A document, such as quality of the PDE documentation, toxicological expertise, responsibilities associated with implementation, and quality of overall GMP risk assessments. A proper and consistent risk assessment of cross-contamination risks has to be available; best practices would include historical process control limits as well as proper training of personnel. The extent of the risk assessment concept must be proportional to the associated risks, which gives some additional opportunities for flexibility to small to medium-sized enterprises with lower cross-contamination risks.

References

1. Barle, E.L. “Key points to recognize quality in HBEL and associated monograph.” Presented at EMA Stakeholder guidance workshop on shared facilities, London, June 20–21, 2017.
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,’ European Medicines Agency, December 2016.
3. European Commission, EudraLex: “The Rules Governing Medicinal Products in the European Union, Part I-Basic Requirements for Medicinal Products. Volume 4. EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. Chapter 3: Premises and Equipment,” August 2014.
4. European Commission, EudraLex: “The Rules Governing Medicinal Products in the European Union, Part I–Basic Requirements for Medicinal Products. Volume 4. EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. Chapter 5: Production,” August 2014.
5. Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities, European Medicines Agency, November 2014.
6. Fourman, G.L. and Mullen, M.V., “Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations.” Pharmaceutical Technology 17 (1993): 54-60.
7. Lovsin Barle E., et al. “Comparison of Permitted Daily Exposure with 0.001 Minimal Daily Dose for Cleaning Validation.” Pharmaceutical Technology 41 (2017): 42-53.
8. Walsh, A., et al. “Cleaning Limits—Why the 10-ppm and 0.001-Dose Criteria Should be Abandoned, Part II.” Pharmaceutical Technology 40 (2016): 45-55.
9. PDA to EMA, May 25, 2017
10. Olson, M. et al., “Issues and approaches for ensuring effective communication on acceptable daily exposure (ADE) values applied to pharmaceutical cleaning,” Supplement. Regulatory Toxicology and Pharmacology 79 (2016):S19- S27.