Using microbiological criteria for risk management should only occur when they can be shown to be effective and can contribute to the provision of safe products.

To access, see: https://assets.publishing.service.gov.uk/media/66debd72e87ad2f1218265e1/UKHSA-ready-to-eat-guidelines-2024.pdf 

In addition, the European Commission (EC) has passed Regulation (EU) 2024/1756, amending and correcting Regulation (EU) 2023/915 on the maximum levels for certain contaminants in food. This new regulation introduces several important changes aimed at enhancing food safety standards across the EU.

See: https://eur-lex.europa.eu/eli/reg/2024/1756/oj 

Metagenomics

The European Commission has recently provided an update on developments in metagenomics.

Metagenomes comprise enormous reservoirs coding for proteins with useful activities. Unfortunately, harvesting this reservoir is difficult, because useful candidates are rare and hidden in an overwhelming majority of irrelevant genes. Screening campaigns of metagenomic libraries requires massive capital-expenditure for robotic systems and much manpower. This makes them expensive, slow and available to very few users. 

Exploration and exploitation of the metagenome will be made faster and more successful by:

• Ultrahigh-throughput screening in picoliter droplets that dramatically lower the cost per assay to well below 0.01 cents and allows throughput of 10e7 assays per hour
• Workflows that streamline and increase the yield of library construction and functional expression
• Workflows for efficient bioinformatic analysis of hits based on user-friendly software solutions for metagenome analysis

See: https://ec.europa.eu/info/funding-tenders/opportunities/portal/screen/opportunities/projects-details/31045243/685474/H2020

Good Clinical Practice

Draft ICH E6(R3) guideline for good clinical practice – Annex 2 - Step 2b

ICH E6(R2) is currently under revision. The new guideline will be composed of principles intended to apply across clinical trial types and settings, with annexes that expand on the principles to include specific details for different types of clinical trials.

ICH E6(R3) Annex 2 addresses the GCP considerations that arise from the increased use of a wider range of design elements and data sources. Annex 2 provides additional GCP considerations, focusing on examples of trials that incorporate decentralised elements, pragmatic elements and/or real-world data. This Annex should be read in conjunction with the ICH E6(R3) Principles and Annex 1.

For details, see: https://www.ema.europa.eu/en/ich-e6-r2-good-clinical-practice-scientific-guideline

Annex 1 supplemental

The European Medicines Agency (EMA) has updated its ‘Q&A’ support for EU GMP Annex 1. The latest question relates to bioburden, in relation to the manufacture of sterile medicinal products:

‘When a prefilter is installed, unless otherwise justified, a bioburden limit of 10 CFUs/100 ml before first filtration is achievable in principle and is strongly recommended from a GMP point of view. Higher bioburden limits should not be justified by the high capacity of two consecutive bacteria retaining filters.

‘However, when appropriate justification is submitted (processes involving fermentation or other biological or herbal components, use of purified water for ophthalmic preparations, etc.), a bioburden limit of higher than 10 CFUs/100 ml before prefiltration may be acceptable. In such cases, it should be demonstrated that the first filter has the capability to achieve a bioburden prior to the last filtration of NMT 10 CFUs/100 ml, in line with the notes for guidance on manufacture of the finished dosage form (CPMP/QWP/486/95 and EMEA/CVMP/126/95).’

Good Distribution Practice

The EMA has added a question and answer relating to Good Distribution Practice to its guidance page:

To fulfil the criteria for the process of certification set out in Section 1 of Annex 16, the complete manufacturing and distribution supply chain of the medicinal product and its related active substance up to the stage of certification, should be documented and available for the Qualified Person. Supply chain records should provide adequate traceability and be available in a timely manner, to facilitate amongst others, quality defect investigations and product recalls as provided for in Chapter 8 of Part I of EU GMP, or requests of competent authorities. This means that these records should make it possible to identify, for active substances and medicinal products, all the entities, including suppliers and outsourced activities, involved in the manufacture of a specific batch of the drug product, in line with the registered supply chain.

In addition, and according to Chapter 1 and 5 of Part I of EU GMP, when establishing the supply chain traceability, the associated risks should be formally assessed and periodically reviewed with appropriate risk-mitigation measures determined.

Source: https://www.ema.europa.eu/en/human-regulatory-overview/research-development/compliance-research-development/good-manufacturing-practice/guidance-good-manufacturing-practice-good-distribution-practice-questions-answers

Endotoxin testing: USP RSE Lot Change 

The current lot of Reference Standard Endotoxin (RSE), H0K354, is no longer available from USP and it has been replaced with R172R0. Additionally, the Endotoxin Units per vial has been revised to 11,000 USP Endotoxin Units. 

Artificial intelligence

The U.S. FDA has issued draft guidance to provide recommendations for predetermined change control plans tailored to artificial intelligence (AI)-enabled devices.

The recommendations are intended to support iterative improvement through modifications to AI-enabled devices while continuing to provide a reasonable assurance of device safety and effectiveness. Change controls need to describe the planned device modifications, the associated methodology to develop, validate and implement those modifications, and an assessment of the impact of those modifications. 

See:  https://www.fda.gov/regulatory-information/search-fda-guidance-documents/marketing-submission-recommendations-predetermined-change-control-plan-artificial-intelligence 

GDP: Mean Kinetic Temperature

General Chapter <1079.2> of the United States Pharmacopeia outlines the use of Mean Kinetic Temperature (MKT) to evaluate temperature excursions during the storage and transportation of drug products. While MKT cannot be used to normalise uncontrolled storage conditions, it serves as a valuable tool for assessing short-term excursions. 

The chapter currently includes temperature excursion limits for Climatic Zone II. The revised chapter will add temperature excursion limits for Climatic Zone IVb. A Stimuli Article entitled ‘The Use of Mean Kinetic Temperature and the Need for Allowable Excursion Limits for Climatic Zone IVb’ explains the rationale for this update.

The draft is accessible via the USP (requires registration). 

Residual Host Cell Protein Measurement

USP general chapter <1132.1> Residual Host Cell Protein Measurement in Biopharmaceuticals by Liquid Chromatography-Mass Spectrometry was approved for publication on November 1, 2024, in USP-NF 2025, Issue 1.

However, more changes are to be made through an accelerated revision vehicle:

• The term ‘Residual HCP ELISA’ is being revised to ‘HCP ELISA’ to align with the Expert Committee’s decision on a public comment received
• In the 4.1 Sample Preparation section, the term ‘product’ is being revised to ‘product protein’ in one instance to improve clarity
• In the 5.1 Methods for HCP Quantitation section, the term ‘product’ is being revised to ‘product protein’ in three instances to improve clarity

The draft will be available via the USP (requires registration).