June 2023 Pharma News Update

On 10 May, the U.S. Food and Drug Administration issued a discussion paper, “Using Artificial Intelligence and Machine Learning in the Development of Drug and Biological Products.” The discussion paper is intended to initiate communication surrounding artificial intelligence and machine learning (AI/ML) with stakeholders, including industry and academia, to promote mutual learning and discussion. It follows on from a Discussion Paper on “Artificial Intelligence in Drug Manufacturing” that was published on 1 March 2023.

FDA is soliciting feedback on the opportunities and challenges with utilizing AI/ML in drug development and medical device development for drugs. This discussion paper will complement and inform future guidance on AI/ML in drug development. Specifically, the questions in Section B aim to initiate a discussion with stakeholders and solicit feedback on three key areas in the context of AI/ML in drug development. These areas are:

1. human-led governance, accountability, and transparency
2. quality, reliability, and representativeness of data
3. model development, performance, monitoring, and validation

For more information on the draft guidance and how to comment, please see the Federal Register notice and visit the Artificial Intelligence and Machine Learning for Drug Development webpage.

On 10 May the U.S. Food and Drug Administration announced the availability of an immediately-in-effect final guidance, Testing of Glycerine, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol. This guidance replaces the 2007 guidance and provides advice on how industry can comply with applicable regulatory requirements.

The guidance also outlines recommendations to help pharmaceutical manufacturers, re-packers, other suppliers of high-risk drug components, and compounders prevent the use of drug components contaminated with diethylene glycol (DEG) and ethylene glycol (EG).

Throughout history, DEG and EG have occasionally been used inappropriately as inexpensive, odourless, sweet-tasting ingredients in the manufacturing of medications. Most recently, in 2022 and 2023, the World Health Organization (WHO) announced cases of DEG and EG contamination in medications in at least seven countries. Investigations linked the contaminations to more than 300 deaths, most occurring in young children under the age of five.

Whilst FDA has no indication that any products described in the WHO alerts have been introduced into the U.S. supply chain, the agency is implementing this guidance document immediately to alert the industry to the potential public health hazard of DEG and EG contamination for certain drug components more than the safety limit for drug products. It is critical for safeguarding the quality and safety of medicines that all manufacturers, and others using high-risk drug components to manufacture or prepare drug products, are aware of the importance of detecting and preventing the use of DEG- and EG-contaminated components.

Comments may be submitted to the docket at any time for agency consideration. Identify all comments with the docket number FDA-2023-D-1573.

there were not significant differences between the final published documents and the previously leaked versions, although the organisation of the published versions is changed.

The proposed revision of the pharmaceutical legislation consists of two legislative proposals:

• A new Directive, repealing Directives 2001/83/EC and 2009/35/EC and incorporating and amending relevant parts of the paediatric Regulation (EC) 1901/2006
• A new Regulation, repealing Regulations (EC) No 726/2004, 141/2000 (orphan medicines) and 1901/2006 (paediatric use) and incorporating and amending Regulations 1394/2007 (ATMPs) and 536/2014 (CTs).

The following are amongst the changes contained in the proposed new human medicines

Directive:

Point-of-Care or decentralised medicines manufacture

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 central site will hold an MIA, with a QP, and be responsible for managing decentralised sites that will not be required to hold a MIA.

Qualified Person qualifications and duties

The list of qualifications and experience that will permit someone to act as a QP is largely unchanged and the detail is given in Annex III of the Directive, including the list of subjects that a qualifying degree should cover that were not in the leaked version.

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 legal duties of the QP are unchanged except that a new section has been added to cover the duties of the QP at the central site when point-of-care, decentralised manufacturing operations are adopted.

Cyprus, Ireland, Malta, and Northern Ireland

There is a whole new Chapter providing specific provisions concerning Cyprus, Ireland, Malta, and the United Kingdom in respect of Northern Ireland. This reproduces the provisions that are in Directive 2022-642 that was implemented in April 2022.

However, I would expect that provisions for Northern Ireland are very likely to be changed in the final version providing the ‘Windsor framework’ is adopted by both the EU and the UK.

Excipients

A new definition of a ‘functional excipient’ has been added:

“… an excipient that contributes to or enhances the performance of a medicinal product or performs an action ancillary to that of the active substance but does not have a therapeutic contribution on its own.”

The proposed Directive clarifies that competent authorities are empowered to inspect excipient suppliers and will do so where there are grounds for suspecting non-compliance with GMP or GDP.

SoHO-derived medicinal product

About medicines where the starting material is derived from substances of human origin (SoHO) there is an interface with the proposed EU SoHO regulation and there is a new definition of a SoHO-derived medicinal product:

‘SoHO-derived medicinal product other than ATMPs’ means any medicinal product containing, consisting of, or deriving from a substance of human origin (SoHO), as defined in Regulation [SoHO Regulation], other than tissues and cells, that is of standardised consistency and is prepared by:

(a) a method involving an industrial process which includes pooling of donations; or

(b) a process that extracts an active ingredient from the substance of human origin or transforms the substance of human origin by changing its inherent properties.

The following are amongst the changes contained in the proposed new human medicines Regulation:

Changes to EMA Committees

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 organised 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).

Changes to EMA role

An inspectorate will be established within EMA to reinforce Member States' capacities, for inspections in third countries to build efficiency in surveillance and support marketing authorisation procedures.

The mandate of the EMA and its Executive Steering Group on Shortages and Safety of Medicinal Products, as established by Regulation 2022/123, will be extended with respect to the management of critical shortages and the security of supply of critical medicines.

Marketing Authorisation (MA) changes

The requirement for 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 regulatory review time for centralised MA applications to be reduced from 210 days to 180 days. The time for the Commission to make the decision on MAs is also reduced from 67 days to 46 days.

A new temporary emergency marketing authorisation for future health crisis-related medicines.

Shortage Prevention

MA holders to be required to have in place and keep up to date a shortage prevention plan, for any medicinal product placed on the market. The details of what to include in this plan are given in Part V of Annex IV.

In addition to the changes listed above, the proposals in the draft legislation include several that are far more controversial and are likely to spark a lively debate between the R&D based pharmaceutical companies, and their political supporters, and those advocating earlier access to cheaper generic medicines:

• A reduction in the statutory regulatory data protection period from eight years to six, to be followed by two years of market exclusivity,
• For orphan drugs, the standard period of market exclusivity would be cut from 10 years to nine,
• A transferable exclusivity voucher intended to encourage R&D into new antimicrobials.

To be approved, these proposals will need to be scrutinised by the European Parliament (EP) and the Council of the EU. It is expected that substantial amendments will be made because of this scrutiny. How long this review will take is difficult to determine but it will not be helped by the fact that there are fresh elections to the EP in 2024.

The speculation is that it could up to 3 years before the final legislation is agreed and this likely to be followed by an implementation period that could add several more years before the changes become effective.

The proposed revisions can be found on the Commission’s website