[Stability Testing related News – vol.67]

◆  Publication of EMA Document on the Establishment of a Guideline on mRNA Vaccines (12-Sep-23 ECA)

The published document from the European Medicines Agency addresses the need to establish a guideline on the quality aspects of mRNA vaccines. In recent years, the number of applications for clinical trials for human medicinal products as well as for marketing authorization for mRNA-containing medicinal products has increased significantly and is expected to continue to increase in the near future. From an analytical and regulatory perspective, mRNA vaccines are of interest because their classification depends on the target and/or whether they are derived by chemical or biological means. mRNA vaccines against infectious diseases must comply with the current guidelines for human vaccines. However, this new technology is not fully addressed in the existing documents. It is therefore proposed that a guideline be developed to address the specific aspects of the manufacturing process, characterization, specifications, and analytical control, as well as the definition of the active ingredient and finished product for mRNA vaccines for the prevention of infectious diseases.

The scope of the guideline will be limited to mRNA vaccines against infectious diseases (including self-amplifying mRNA). mRNA-based therapeutics do not fall within the scope of the document. For now, It is not intended to address specific requirements for mRNA vaccines for clinical trials; however, the scientific principles described may also be applied to pharmaceutical development.

Because the manufacturing of mRNA vaccines must be compliant with the general guidelines for human vaccines, special quality considerations may apply to these novel products. The proposed guideline is based on the structure of CTD Module 3, where relevant. In addition, finished product considerations (e.g., excipient selection, formulation and manufacturing aspects) relevant to mRNA-containing finished product formulations are addressed. The guide provides information and regulatory considerations on the following key aspects of manufacturing and quality control:

• Definitions of terms: Starting materials, active ingredient, finished product intermediate, excipients and finished product
• Control of starting materials
• Development of an integrated control strategy for the active ingredient and finished product
• Manufacturing process to ensure consistent quality of mRNA vaccines, based on relevant critical quality attributes (CQAs)
• Characterization approaches including investigation of impurity profile
• Contamination control strategy: process- and product-related impurities as well as other potential impurities and methods to control them
• Active ingredient and finished product specifications
• Efficacy testing: various tests may be required to control different aspects of efficacy, including functionality (e.g., mRNA expression, protein expression in transduced cells)
• Various aspects related to formulation strategies, including considerations for lipid nanoparticle (LNP) formulation and manufacturing process and stability
• Stability studies for active ingredient and finished product

Other regulatory considerations and challenges

The guidance described also addresses the following regulatory considerations and challenges:

• The development and testing of bivalent and multivalent vaccines, and modifications to existing strains of mRNA vaccine
• Self-amplifying mRNA (sa-mRNA) packaged in LNPs
• Other carrier systems (i.e., non-LNPs)

EMA is requesting assistance with this document and needs your expertise. The comment period for this document ends on September 30, 2023.

For the full original EMA document, see “Concept Paper on the development of a Guideline on the quality aspects of mRNA vaccines“.

◆  WHO Draft Working Document on Good Practices for Quality Control Laboratories published for Comments (27-Sep-23 ECA)

End of August 2023, the World Health Organization (WHO) has published a draft working document entitled “WHO good practices for pharmaceutical quality control laboratories (QAS/21.882)”.

The WHO invites all experts who may be interested in the subject to review the document, which was posted on the WHO Medicines website under “Working documents in public consultation“. The WHO asks that comments should be submitted through the online platform PleaseReview™ by 06 October 2023. It is mentioned that only comments received by this deadline will be considered. Further information on the commenting process can be found on the first page of the new document.

The PDF file is quite extensive, with a total of 83 pages.

Document History

Already in 1999, the WHO Expert Committee on Specifications for Pharmaceutical Products (ECSPP) adopted the WHO good practices for national pharmaceutical control laboratories guidelines. These were published as Annex 3 of the WHO Technical Report Series, No. 902, 2002.

These guidelines were subsequently revised, renamed as “WHO good practices for pharmaceutical quality control laboratories” and finally published as Annex 1 of the WHO Technical Report Series, No 957, 2010.

The draft now published states: “Since the last revision of the guidelines, the experience from inspections of pharmaceutical quality control laboratories has enabled WHO to identify sections requiring clarification and the necessity to add new sections. Also, the COVID-19 pandemic has made clear that risk management, crisis management and business continuity are subjects which should be addressed to ensure that laboratories are prepared to face similar situations.”

The purpose of the document is described as follows: “The present document provides advice on the quality management system (QMS) within which the analysis of pharmaceutical products by quality control laboratories (QCL) should be performed to ensure that accurate and reliable results are obtained. Compliance with the commendations provided in these guidelines will help promote international harmonization of good laboratory practices for pharmaceutical quality control laboratories and facilitate mutual recognition of test results.”

Main Chapters of the new Document

The document is divided into the following main chapters:

• 1 General considerations
• 2 Glossary
• 3 Organization and management system
• 4 Planning and strategic management
• 5 Resources
• 6 Technical activities
• 7 Safety rules
• Appendix 1: Equipment for a first-stage and medium-sized pharmaceutical quality control laboratory
• Appendix 2: Recommendations for the target uncertainty and the maximum admissible uncertainty for normal analytical practice
• Appendix 3: Examples of the uncertainty estimation on compliance with normal analytical practice (the “worst case”) for assay of pharmaceutical substances by chromatography

Updates

Compared to the version published as Annex 1 of the WHO Technical Report Series, No 957, 2010, some of the contents have been renumbered . The new draft also contains a number of extensions.

For example, the definition of the following terms have been added:

• acceptance criterion for an analytical result
• crisis management
• data integrity
• expanded uncertainty
• level of confidence
• risk
• target uncertainty

These topics are addressed accordingly in the newly added or enlarged subchapters, for example:

• 3.6 Control of data
• 4.4 Quality Risk management
• 4.5 Crisis management
• 6.7 Measurement uncertainty

These recognition routes will be in place by early 2024.