· 9 min read
The European Commission has today finally published their proposed reforms to the human medicines legislation. The publication was originally scheduled for 21 December 2022 but had to be delayed due to the Commission’s Regulatory Scrutiny Board issuing a negative opinion on the impact assessment for the legislative changes. The next date that was given for the publication was 29 March 2023 but this was again delayed on the grounds that the commission had a “busy agenda.” However, it was widely reported that the second delay was due to pressure from the pharmaceutical industry to water down some of the more controversial proposals in the draft legislation.
The objectives of the proposed changes are given as the following:
It had been expected that the revised legislation would be issued as a Regulation, as had already been done with the Directives for clinical trials, veterinary medicines, and medical devices. However, the proposed revision of the pharmaceutical legislation will consist of two legislative proposals:
Under the proposed revision, Directive 2001/83/EC, Regulation (EC) No 726/2004, Regulation 141/2000/EC and Regulation (EC) 1901 /2006 would be repealed and replaced by the proposed new Directive and new Regulation.
There are also links with other EU regulatory frameworks for health products. EU legislation on blood, tissues and cells is relevant as some substances of human origin are starting materials for medicines. The EU regulatory framework for medical devices is also relevant as there are products that combine medicines and medical devices.
The following are amongst the many changes contained in the proposed new human medicines legislation:
The draft proposes a hub and spoke model, as per the UK proposals, where the QP is based at a central, ‘hub’ site and takes responsibility for decentralised manufacture and testing.
The list of degrees that will permit someone to function as a QP is unchanged but the list of subjects that the degree course should cover, which is in Article 49 of Directive 2001/83/EC, has gone. There is a new legal duty for the MA holder and the QP to ensure that “the practical experience acquired is appropriate to the types of products to be certified.” “The Commission may publish guidelines outlining the practical experience requirements.”
The legal duties of the QP are unchanged but a new section has been added to cover QP duties when the point-of-care decentralised manufacturing operations are adopted.
There is a whole new Article specifically dealing with Northern Ireland. However, I would expect that this is likely to be changed in the final version providing the ‘Windsor framework’ is adopted by both the EU and the UK.
There is a new Article specifically for Cyprus, Ireland, and Malta.
The proposal is to just have two human medicines committees: the Committee on Medicinal Products for Human Use (CHMP) and the Pharmacovigilance Risk Assessment Committee (PRAC).
The expertise of the other four scientific committees would be retained and organized into working parties and a “pool of experts” that would give input to the CHMP, the PRAC and the EU Heads of Medicines Agencies’ Co-ordination group for mutual recognition and decentralized procedures – human (CMDh). The four committees that would be discontinued are the CAT (advanced therapies), the COMP (orphan medicines), the PDCO (paediatric medicines) and the HMPC (herbal medicinal products).
The requirement for marketing authorisations (MAs) to be renewed after 5 years is dropped and MAs will be granted for an unlimited period.
The sunset clause that requires companies to place a product on the market in at least one EU member state within three years of an MA being granted, is also to be scrapped.
The proposed revisions can be found on the Commission’s website here.
On 1 March 2023, the FDA published a Discussion Paper on “Artificial Intelligence in Drug Manufacturing”. This paper states “The use of AI to support pharmaceutical manufacturing can be deployed with other advanced manufacturing technologies to achieve desired benefits. AI is an enabler for the implementation of an Industry 4.0 paradigm that could result in a well-controlled, hyper-connected, digitized ecosystem and pharmaceutical value chain for the manufacturer.” This discussion paper presents areas for consideration and potential policy development that CDER identified based on evaluating the application of the existing regulatory framework to use of AI in pharmaceutical manufacturing. Feedback should be sent to CDER.
Potential area where AI might be used are given as:
Areas of Consideration Associated with AI are given as:
Read the AI in Manufacturing Discussion Paper here.
In March 2023 FDA issued final guidance on “Definitions of Suspect Product and Illegitimate Product for Verification Obligations Under the Drug Supply Chain Security Act”.
The guidance contains the following definitions:
On 5 April 2023 FDA issued draft guidance titled “Notifying FDA of a Discontinuance or Interruption in Manufacturing of Finished Products or Active Pharmaceutical Ingredients Under Section 506C of the FD&C Act”, with a 60-day deadline for comments.
This guidance clarifies who must notify FDA of a discontinuance or interruption of supply:
In general, the notification requirements for finished products and APIs apply to each individual manufacturer regardless of market share, number of other manufacturers marketing products that are therapeutically equivalent, or the amount of product that may be in distribution.
In general, manufacturers must submit a notification to FDA at least 6 months in advance of discontinuation or an interruption. If it is not possible to give 6 months’ notice, then the notification must be submitted as soon as practicable and no later than five business days after the discontinuance or interruption in manufacturing occurs.
The draft guidance then lists the information to be provided for both finished products and APIs, how to notify FDA and the consequences of failing to notify the FDA. The draft ends with a section on how FDA communicates information about drugs and biological products in shortage.
The ICH M7(R2) Guideline on the “Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” and the accompanying M7(R2) Addendum “Application of the Principles of the ICH M7 Guideline to Calculation of Compound-Specific Acceptable Intakes” have reached Step 4 of the ICH Process on 3 April 2023.”
This document is intended to provide guidance for new drug substances and new drug products during their clinical development and subsequent applications for marketing. It also applies to post-approval submissions of marketed products, and to new marketing applications for products with a drug substance that is present in a previously approved product, in both cases only where:
In this Addendum to ICH M7, AIs or Permissible Daily Exposures (PDEs) have been derived for a set of chemicals that are considered to be mutagens and carcinogens and are common in pharmaceutical manufacturing or are useful to illustrate the principles for deriving compound-specific intakes described in ICH M7. The set of chemicals include compounds in which the primary method used to derive AIs for carcinogens with a likely mutagenic mode of action is the “default approach” from ICH M7 of linear extrapolation from the calculated cancer potency estimate, the TD50.”
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