BY DR TIM SANDLE | 29 April 2024
Catch up with the latest news from around the pharmaceutical industry with issue 20 of our regulatory review, curated by Dr Tim Sandle.
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Burkholderia Cepacia Complex
On 29th March 2024, the United States Pharmacopeia (USP) published an announcement regarding a proposed compendial approach for the implementation of Burkholderia Cepacia Complex (BCC).
The USP is dedicated to ensuring the highest level of microbiological quality in nonsterile pharmaceutical products. As part of this commitment, they have proposed a new compendial approach for the implementation of <60> Microbiological Examination of Nonsterile Products - Tests for Burkholderia Cepacia Complex (BCC).
A critical aspect of pharmaceutical quality is the mitigation of risks associated with microbiological contamination. BCC represents a significant concern due to its ability to survive in various environments and its association with serious adverse events. The US Food and Drug Administration (FDA) has highlighted the importance of robust testing for BCC in aqueous non-sterile products. In order to strengthen our collective defence against such risks, the USP is planning to revise several General Chapters to clarify the application of this test.
For further details, see: https://www.uspnf.com/notices/bcc-gen-annc-20240329
Data integrity for In Vivo Bioavailability and Bioequivalence studies
The FDA has issued a new draft guidance document titled “Data Integrity for In Vivo Bioavailability and Bioequivalence Studies”.
This guidance is designed to provide recommendations to applicants and testing site management on achieving and maintaining data integrity. This includes clinical and bioanalytical portions of bioavailability (BA) and bioequivalence (BE) studies submitted in support of investigational new drug applications (INDs), new drug applications (NDAs) and abbreviated new drug applications (ANDAs).
To access, see: https://www.fda.gov/media/177404/download
FDA officials discuss strategies for answer-ready controlled correspondence
According to Regulatory Focus, FDA officials have commented that including valid formulation information, a valid letter of authorisation and complete submissions are amongst the best practices that should be followed to ensure that the controlled correspondence of generic drug makers is accepted. In addition, separate controlled correspondence submissions should be submitted for each specific discipline.
To read the assessment, see: https://www.raps.org/News-and-Articles/News-Articles/2024/4/FDA-officials-discuss-strategies-for-answer-ready
Manufacture of batches in support of original NADA's
The FDA has issued draft guidance concerning “Manufacture of Batches in Support of Original NADAs, ANADAs, and CNADAs”.
The information included in this document is intended to provide recommendations for the primary batches of drug product manufactured to support the approval or conditional approval of new animal drug products. This guidance is applicable to all original new animal drug applications (NADAs) and abbreviated new animal drug applications (ANADAs) and their associated investigational new animal drug files (INADs). It also applies to generic investigational new animal drug files (JINADs), as well as applications for conditional approval of new animal drugs (CNADAs).
To access see: https://www.fda.gov/media/176991/download
ATMP guidance
With complexity and risk associated with each stage of assay development, British Pharmacopeia (BP) has put together an Advanced Therapy Medicinal Products (ATMP) best practice guidance document.
The guidance provides a practical and phase appropriate validation tool to help your cell therapy programme succeed. Areas covered include the application of flow cytometry, vector copy number and T Cell and NK cell characterisation assays.
This new guidance, the fourth the BP has produced, was developed in partnership with experts from the cell and gene therapy community including industry, the NHS and academia.
See: https://www.pharmacopoeia.com/content/html/358
PH. Eur. Supplement now available online
The European Pharmacopoeia (Ph. Eur.) Supplement 11.5 is now available. New monographs in Supplement 11.5 include cannabis flower and cannabidiol.
See: https://www.edqm.eu/en/web/edqm/european-pharmacopoeia-ph.-eur.-11th-edition#{%22468819%22:[1]}
PH. Eur. to put an end to all animal tests for histamine and depressor substances
At its 177th session in November 2023, the European Pharmacopoeia Commission (EPC) decided to engage on a path that should ultimately lead to the deletion of the general chapters on histamine (2.6.10) and depressor substances (2.6.11) from the European Pharmacopoeia (Ph. Eur.).
See: https://www.edqm.eu/en/-/european-pharmacopoeia-to-put-an-end-to-all-animal-tests-for-histamine-and-depressor-substances
Public consultation on traceability of medicines in hospital settings
The European Directorate for the Quality of Medicines & HealthCare is seeking comments from interested parties on a draft guidance document on the topic of “Traceability of Medicines in Hospital Settings”.
The objective of this project is to provide regulatory authorities and stakeholders with a guidance document on the minimum requirements to be fulfilled for full in-hospital traceability of medicines, from their arrival on-site until their administration to patients.
To read more, see: https://www.edqm.eu/en/-/public-consultation-on-traceability-of-medicines-in-hospital-settings
EU: Overall quality summary
For the European Union, the template of Quality Overall Summary (QOS) to be submitted for certification applications has been adapted to the current needs. A new version of the QOS template is available.
The QOS (eCTD Module 2) has to be provided along with an initial submission since it is essential in the review of a new CEP application.
For further details, see: https://www.edqm.eu/en/-/the-template-of-quality-overall-summary-qos-to-be-submitted-for-certification-applications-has-been-adapted-to-the-current-needs-
Annual reportable labelling changes for new drug applications
The FDA has issued a new draft guidance document concerning “Annual Reportable Labeling Changes for New Drug Applications and Abbreviated New Drug Applications for Nonprescription Drug Products”.
The document covers certain nonprescription drug products that are new drugs within the meaning of section 201(p) of the Federal Food, Drug and Cosmetic Act (FD&C Act). These are subject to approval on the basis of an NDA or ANDA submitted under sections 505(b) or 505(j) of the FD&C Act, respectively.
A “nonprescription drug” is a drug that is not subject to the requirements of section 503(b)(1) of the FD&C Act.
The draft guidance is provided here: https://www.fda.gov/media/176915/download
Recombinant viral vectored vaccines for human use
The European Pharmacopoeia has published a draft chapter for comment: 5.37. Recombinant viral vectored vaccines for human use.
Recombinant viral vectored vaccines are preparations containing live viruses (the vector) that are genetically engineered to express one or more heterologous antigens or induce the expression of these antigens in human cells. The viral vector may be replication-competent or replication-incompetent. Replication-competent viral vectors can replicate in humans and include viral vectors using yellow fever virus, measles virus, or vesicular stomatitis virus (VSV) as the backbone. Replication-incompetent viral vectors cannot replicate in humans and include viral vectors using adenovirus, or modified vaccinia virus Ankara (MVA) as the backbone.
This is accessible via Pharmeuropa (registration is required).
Cell-based preparations for human use
The European Pharmacopoeia has published a draft chapter for comment: 5.32. Cell-based preparations for human use.
Cell-based preparations are preparations containing cells that are intended to be used in or administered to human beings with a view to treating, preventing or diagnosing a disease.
Cell-based preparations are based on cells which can originate from the recipient (autologous), from another individual (allogeneic) or from an animal (xenogeneic). They encompass stem cell therapies (e.g. embryonic, induced pluripotent and foetal) and somatic cell therapies (e.g. chondrocytes, mesenchymal stromal cells, keratinocytes, hepatocytes, dendritic cells, T-cells, B-cells, Natural Killer cells and myoblasts). Each of these cell-based preparations have particular characteristics that must be determined and the consistency of the production process must be carefully controlled to minimise variability that could affect the safety and efficacy of the preparation.
The principles described in this general chapter also apply to cell-based preparations that undergo further processing, where relevant. This general chapter does not cover the specific considerations related either to genetic modifications and their associated requirements or human haematopoietic stem cells (HSCs), the latter being covered by monograph 2323.
This is accessible via Pharmeuropa (registration is required).
Container content for injections
Pharmacopeial Forum has published a draft chapter for potential inclusion in the United States Pharmacopeial, titled “〈697〉 Container Content for Injections.”
Suspensions and emulsions must be shaken before withdrawal of the contents and before the determination of the density. Oily and viscous preparations may be warmed according to the instructions on the label (if necessary) and thoroughly shaken before removing the contents. The contents are then cooled to 20°–25° before measuring the volume.
Sterile solid formulations must be constituted according to labelled directions before removing the contents. Contents are then to be measured following the procedures for suspensions, emulsions, or solutions.
The proposed changes are noted below.
Single-dose containers:
- Revise to not specify a container number that must be tested. The focus should be on individual decisions based on process variability and lowest possible fill volume.
- Revise to allow any suitable syringe to be used.
- Revise to allow the testing of extractable volume on a per-container basis for small-volume parenterals ≤2 mL.
- Revise so that containers ≥10 mL can be tested as per labelling instructions.
Injections in cartridges or prefilled syringes:
- Revise to not specify a container number that must be tested. The focus should be on individual decisions based on process variability and lowest possible fill volume.
Large-volume intravenous solutions:
- Revise to not specify a container number that must be tested. The focus should be on individual decisions based on process variability and lowest possible fill volume.
The draft chapter is accessible via the Pharmacopeial Forum (registration is required).
Filters and membranes
The USP is proposing to update the chapter “〈1002〉 Filters and Membranes”.
Here it is proposed to add this new chapter with recommendations on the selection and characterisation of filters and membranes used in analytical procedures. This chapter does not address the use of filters and membranes in in-process, manufacturing, and compounding processes.
USP is seeking collaborators to develop a section on the use of filters and membranes in sterility and microbiological testing of pharmaceutical products.
The draft chapter is accessible via the Pharmacopeial Forum (registration is required).
Biological assays
The USP is proposing to update “〈1030〉 Biological Assay Chapters—Overview and Glossary.”
This proposal is based on the version of the chapter official as of December 1, 2013. The Statistics Expert Committee proposes to update and expand the scope of the current chapter by changing the title to “An Introduction to the Biological Assay Chapters—Overview and Glossary” and adding the following new sections:
- Introduction to Biological Assays
- Some Important Characteristics of Bioassays
- Life Cycle Concepts and Framework for the Bioassay Chapters
- Categories and Levels of Variability Throughout the Bioassay Life Cycle
- Brief Description of the Bioassay Chapters
- Bioassay Glossary
This is considered to be a major revision and one designed to assist bioassay professionals in starting with the more technical chapters Design and Development of Biological Assays 〈1032〉, Biological Assay Validation 〈1033〉, and Analysis of Biological Assays 〈1034〉.
The draft chapter is accessible via the Pharmacopeial Forum (registration is required).