The EMA guidance, Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (and follow-up questions and answers) goes against current best practice in the biomanufacturing industry. Roisin Magee at Pfizer identified an opportunity when the follow-up Q&A document was published in 2018, thinking it would make an interesting topic for discussion at the12th Annual CIP/SIP Industry Benchmarking Summit.
Magee’s instinct proved correct when she said, “Everyone at the summit agreed that it would be beneficial to come together as a group to document the extensive controls and risk-based approach to changeover that has been used and accepted within the biopharmaceutical industry”. A fellow contributor and Team Leader for the CIP Summit, Michael Parks at Pfizer, added, “When the topic came up at the summit, we thought we would want to get ahead of this, to make sure we clarified and justified the risk-based approach to changeover that is used and currently accepted in the biopharmaceutical industry”.
For several years, biopharmaceutical manufacturers have been working on best practices and controls for PCO, applying risk management principles to achieve the desired state. This includes cleaning validation to limit or eliminate sampling, use of routine visual inspections and further alignment of industry best practices for PCO. Robust risk-based approaches are used to assess and continually improve established changeover processes. Contributor, Andy Brewer at Roche, notes that “Over the last several years Roche has been working to streamline our cleaning validation programs especially product changeover requirements in an attempt to eliminate non-value-added activities”. The new paper from the BioPhorum Multi-Product Facility Workstream focuses on three stipulations in the EMA guidance, that:
- Health-based exposure limits (HBELs) should be set for all medicinal products
- Analytical testing of all equipment must happen at product changeover, regardless of cleaning validation
- Controls and requirements for conducting invasive visual inspections on a routine basis must be in place, including the implementation of additional programs such as periodic eyesight and competence testing.
The new paper builds on previous BioPhorum publications, Elastomer Change Out – Justification for Minimizing the Removal of Elastomers to Prevent Cross-Contamination in a Multi-Product Facility and Guidelines for Risk-based Changeover of Biopharma Multi-Product Facilities Part 1 and Part II. It sets out the currently accepted practices and controls in an evidence-based justification so companies can validate their practices and continue working towards the industry aligned desired state. The paper proposes the following de facto set of revised standards for PCO, and the rationale for each proposed change:
Limited or no sampling at PCO, supported by cleaning validation
Analytical testing of all equipment post-cleaning validation is unnecessary. Equipment with validated cleanings will typically roll into routine cleaning monitoring programs. These ongoing monitoring programs should be robust enough to support that the CIP systems continue to operate in a validated state and as such similar types of soils should be removed as proven through cleaning validation. Sampling post cleaning validation at PCO can undermine these programs and contradict the meaning of a validated cleaning and the need for ongoing monitoring.
Alternative methods for calculating limits can be used, therefore not requiring a HBEL calculation.
For example, if degradation and inactivation of the biopharmaceutical product can be demonstrated, then calculating a limit based on these factors can be performed making the HBEL calculation unnecessary.
Additional programs (e.g. eye-sight testing) may not be required
Any program for visual inspection should be commensurate with the requirements for visual inspection. If visual inspection is used as an additional verification of cleanliness at PCO following validation with analytical methods (e.g. inline conductivity and TOC or direct sampling), then additional programs around visual inspection (e.g. eye-sight testing) may not be required.
Generation of a robust Risk Assessment is required and should align with industry practices.
The assessment of risk should be performed for all products to confirm the baseline controls that are in place, and to determine the need for additional mitigations over and above the baseline requirements for changeover. The risk assessment should also align with the extensive baseline controls currently defined, justified, used and accepted within the biopharmaceutical industry.
This paper provides immediate practical benefits. As Neti Hansen at Roche notes, it “provides an industry-aligned response to further justify the risk-based controls for product changeover”.
Any manufacturer with an EMA inspection on the horizon now has access to this little diamond in the desk drawer: an evidence-based, industry-aligned justification for current risk-based PCO practices.