May 2023 Pharma News Update

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:

General Objectives

• Guarantee a high level of public health by ensuring the quality, safety, and efficacy of medicinal products for EU patients
• Harmonise the internal market

Specific Objectives

• Promote innovation, for unmet medical needs
• Create a balanced system for pharmaceuticals in the EU that promotes affordability for health systems while rewarding innovation
• Ensure access to innovative and established medicinal products for patients, with special attention to enhancing security of the supply across the EU
• Reduce the environmental impact of the pharmaceutical product lifecycl
• Reduce the regulatory burden and provide a flexible regulatory framework

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:

• A new Directive, amending and replacing Directive 2001/83/EC and incorporating and amending relevant parts of the paediatric Regulation (EC) 1901/2006
• A new Regulation, amending and replacing Regulation (EC) No 726/2004, incorporating, and amending the orphan Regulation 141/2000/EC, and incorporating and amending relevant parts of the paediatric Regulation (EC) No 1901/2006

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Directive 2001/83/EC, Regulation (EC) No 726/2004, Regulation 141/2000/EC and Regulation (EC) 1901 /2006 would be repealed and replaced by the proposed new Directive and new Regulation.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:

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:

• Process Design and Scale-up
• Advanced Process Control (APC)
• Process Monitoring and Fault Detection
• Trend Monitoring

Areas of Consideration Associated with AI are given as:

1. Cloud applications may affect oversight of pharmaceutical manufacturing data and records.
2. The Internet of Things (IOT) may increase the amount of data generated during pharmaceutical manufacturing, affecting existing data management practices.
3. Applicants may need clarity about whether and how the application of AI in pharmaceutical manufacturing is subject to regulatory oversight.
4. Applicants may need standards for developing and validating AI models used for process control and to support release testing.
5. Continuously learning AI systems that adapt to real-time data may challenge regulatory assessment and oversight.

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:

1. SUSPECT PRODUCT—The term “suspect product” means a product for which there is reason to believe that such product:
   1. is potentially counterfeit, diverted, or stolen.
   2. is potentially intentionally adulterated such that the product would result in serious adverse health consequences or death to humans.
   3. is potentially the subject of a fraudulent transaction; or
   4. appears otherwise unfit for distribution such that the product would result in serious adverse health consequences or death to humans.
2. ILLEGITIMATE PRODUCT—The term “illegitimate product” means a product for which credible evidence shows that the product:
   1. is counterfeit, diverted, or stolen.
   2. is intentionally adulterated such that the product would result in serious adverse health consequences or death to humans.
   3. is the subject of a fraudulent transaction; or
   4. appears otherwise unfit for distribution such that the product would be likely to result in serious adverse health consequences or death to humans.

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:

• Applicants with approved new drug applications (NDAs) or approved abbreviated new drug applications (ANDAs) for certain finished drug products
• Applicants with approved biologics license applications (BLAs) for certain finished biological products other than blood or blood components
• Applicants with approved BLAs for blood or blood components for transfusion that manufacture a significant percentage of the U.S. blood supply
• Manufacturers of certain finished drug products marketed without approved NDAs or ANDAs

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:

• Changes to the drug substance synthesis result in new impurities or increased acceptance criteria for existing impurities
• Changes in the formulation, composition, or manufacturing process result in new degradation products or increased acceptance criteria for existing degradation products
• Changes in indication or dosing regimen are made which significantly affect the acceptable cancer risk level.”

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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