December 2022 Pharma News Update

MHRA is now resuming its program of international on-site GMP inspections. However, there will still be restrictions on the countries they can travel to, particularly those that still require international travelers to quarantine on arrival.

MHRA will be adopting a risk-based approach, prioritizing inspections with the greatest impact on UK public health and patient safety. They will do this in conjunction with their product license assessors and using existing risk-based inspection (RBI) tools. While they are implementing this return to international inspections, they ask that sites do not contact them asking to arrange a routine inspection or to inquire about when they can expect their inspection to be; MHRA will make contact when they can arrange each inspection.

It has been over two years since MHRA performed routine on-site international inspections, and therefore many international sites in their risk-based inspection program have not been inspected in line with the frequency indicated. Throughout the pandemic, MHRA has taken a pragmatic approach to the “expiry” of GMP certificates, with these initially extended to the end of 2021 and then to the end of 2022. MHRA has now confirmed that the expiry of GMP certificates will again be extended until the end of 2023. They will work through the outstanding inspections as quickly as they can, without compromising the integrity or rigor of their inspection process.

Revision 2 of ICH Q5A achieved step 2b approval on September 29, 2022, and now moves to step 3, public consultation. The revised guideline adds key coverage of new product types that are amenable to viral clearance, like genetically engineered viral vectors and viral vector-derived products, such as virus-like particles, protein subunits and nanoparticle-based vaccines and therapeutics.

A new Section 7 provides viral safety points to consider for continuous manufacturing, including when batch processes could suffice as scale-down models, which should be read in parallel with the new ICH Q13 guideline on continuous manufacturing.

On October 10, 2022, version 12 of the EMA nitrosamines Q&A was published. This revision updates the answer to Q10 (“Which limits apply for nitrosamines in medicinal products?”) and adds a new Q&A 21 (“What is the approach to control the presence of nitrosamines until a substance-specific AI is established?”).

The new answer 21 states that if N-nitrosamines are identified without sufficient carcinogenicity data to derive a substance-specific limit for lifetime exposure as recommended in the ICH M7(R1) guideline, and the class-specific Threshold of Toxicological Concern (TTC) for nitrosamines of 18 ng/day is not used for controlling the levels of the nitrosamine in the finished product, an acceptable intake (AI) limit agreed by the Non-clinical Working Party (NcWP) and adopted by the CHMP is required to decide on control options for the nitrosamine in the finished product.

The Q/A allows the adoption of a temporary AI (t-AI) of 178 ng/day, which is more achievable compared to the original 18 ng/day and provides flexibility until the final AI is announced.

In practice, this means that when competent authorities are notified about a product containing a new N-nitrosamine exceeding the TTC limit of 18 ng/day, no market actions may be required for batches with N-nitrosamine levels ≤178 ng/day pending the agreement of the AI, but this limit can be used only for 12 months and will need additional consultation if used further. Also, the Q/A highlights that it should not be used as a target of development.

On October 19, 2022, the U.S. FDA’s Center for Veterinary Medicine issued new guidance titled “Animal Cells, Tissues, and Cell- and Tissue-Based Products.” This guidance provides establishments that manufacture animal cells, tissues, and cell- and tissue-based products meeting the definition of a new animal drug (ACTPs) with recommendations for meeting current Good Manufacturing Practice (cGMP) requirements.

This 45-page cGMP guidance addresses the methods, facilities and controls used for manufacturing ACTPs, including steps in recovery, processing, storage, labeling, packaging and distribution.

As part of its Framework for Advanced Manufacturing Evaluation (FRAME) initiative, on October 14, 2022, the FDA launched a consultation on point-of-care drug manufacturing, similar to the one initiated by the UK MHRA in August 2021. As with the UK consultation, the reason given by the FDA is that the traditional model of drug product manufacturing and distribution does not work for some of the new products currently in development, such as cell- and gene-based therapies. These types of product-distributed manufacturing (DM) and point-of-care (POC) manufacturing technologies have the potential to improve the reliability and robustness of the drug supply chain.

The FDA has identified certain areas of consideration in a discussion paper (attached) and is asking for public feedback on some key questions identified in that paper:

• How often might a DM unit move to a new location, and what might an applicant report to the agency when doing so?
• What locations are envisioned for POC unit operation?
• How might a centralized quality system (i.e., at a “parent location”) ensure that each manufacturing unit complies with regulatory requirements and quality standards?
• What type of business relationship is envisioned between companies developing POC manufacturing platforms and health care facilities?

Interested stakeholders can provide input at a public workshop on November 14-16 and to the public docket under docket number FDA-2022-N-2316.

On November 16, 2022, the EMA and the PIC/S published a joint concept paper proposing to revise GMP Annex 11 on computer systems. Comments on the concept paper should be submitted by January 16, 2023.

The current version of this annex was issued in 2011, so it is not surprising that it is now thought to need updating. The concept paper lists a total of 33 improvements that may be necessary. Prominent on this list are the following:

• The document should be updated to replace relevant parts of the Q&A on Annex 11 and the Q&A on data integrity on the EMA GMP website.
• An update of the document with regulatory expectations to “digital transformation” and similar newer concepts.
• Guidelines should be included for the classification of critical data and critical systems.
• An audit trail functionality that automatically logs all manual interactions on GMP critical systems, where users, data or settings can be manually changed, should be regarded as mandatory, not just “considered based on a risk assessment.”
• The audit trail should positively identify the user who made a change, and it should give a full account of what was changed.
• It should not be possible to edit audit trail data or to deactivate the audit trail functionality for normal or privileged users working on the system.
• The audit trail review should focus on a review of the integrity of manual changes made on a system.
• The revised document will include guidelines for acceptance of AI/ML algorithms used in critical GMP applications.

The timetable for the revision of Annex 11 given in the concept paper anticipates a draft revised annex being published in December 2024 and the final version being adopted in September 2026.

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