Reflecting Again on GMP Requirements for Marketing Authorization Holder

In July 2021, the European Medicines Agency (EMA) published their reflection paper entitled “Good Manufacturing Practice (GMP ) and the Marketing Authorisation Holder (MAH)”. This paper, updated in January 2022, serves as an important guideline for MAH to understand their GMP responsibilities, especially in cases where they may not be directly involved in the manufacturing process.

The responsibilities of Marketing Authorization Holders encompass several key areas, including:

1. Audits and Qualification Activities: Conducting audits and ensuring the qualification of manufacturing sites.
2. Communication with Manufacturing Sites: MAHs are responsible for sharing MA dossier information, handling variations, addressing regulatory commitments, and more.
3. Product Quality Reviews: MAHs must conduct periodic reviews to assess and ensure product quality.
4. Quality Defects, Complaints, and Product Recalls: Handling and addressing quality defects, complaints, and product recalls is a crucial part of their responsibilities.
5. Maintenance of Supply of Medicinal Products: Ensuring the uninterrupted supply to the market.
6. Continual Improvement Activities: Implementing process improvements and monitoring outcomes to enhance product quality and safety.
7. Falsified Medicines Directive (FMD)-Related Responsibilities: This includes managing safety features, repository systems, serialisation data uploading, and unique identifier decommissioning in compliance with regulations.

Annex 16 emphazises that the ultimate responsibility for the performance of a medicinal product through its lifecycle, including safety, quality, and efficacy, lies squarely with the Marketing Authorisation Holder.

So how are MAH doing this today with their contract manufacturers?

We will take a closer look at how this could be implemented in practical terms.

What you need to know

The process starts with the creation of a comprehensive  technical agreement that delineates  the responsibilities of both the MAH and the manufacturer in detail. 

• This pivotal document serves as the cornerstone, offering a clear roadmap to both parties regarding their respective obligations. However, this document does not prescribe the precise mechanisms for communication and execution or specify when contact should be initiated.
• Typically, these aspects are managed through a combination of formal and informal check-ins involving key personnel. These meetings involve key personnel responsible for quality, production, subject matter experts (SMEs) and regulatory aspects. For example, the quality individuals responsible for batch release are part of the MAH & Manufacturing supply meetings. Production, Quality and Regulatory personnel are part of change control meetings attended by MAH and Manufacturer to align on changes and the implementation timeframes of changes based on impact assessments, regulatory submissions, and target approvals.
• Formal communication includes senior management reviews, technical improvement meetings, quality meetings, change management meetings, and supply meetings. Informal communication occurs in the form of daily status updates of batch release, deviations raised, complaints received, changes effected etc. via email or calls.
• A shared repository is established to systematically store critical information, encompassing MA registration details, current labeling and artwork, product details, approved variations, impact assessments for proposed alterations, deviation records, audit reports, Certificates of Analysis, and Quality Person (QP) declaration statements. This repository serves as the backbone for facilitating the essential two-way communication between the Marketing Authorization Holder (MAH) and the manufacturer.
• However, it’s imperative to avoid turning the repository into an unstructured data dumping ground. Shared repositories should feature well-defined folders tailored to specific document categories such as Master Batch Records, Test Specifications, Meeting Minutes, and Batch Lists. Additionally, it’s advisable to implement alert notifications to promptly inform key stakeholders when new documents are added, or existing ones are updated within the repository. For clarity and control, ensure these documents are visible and tracked through document indexing or date assignment.
• Removing ambiguity in communication and responsibilities is crucial for maintaining GMP compliance. Consider which interactions are part of a formal procedure and/or part of the technical agreement. Consider when the communication processes need to change over the lifetime of the product – for instance, when product developments, changes, and commitments decrease over time.

Both the MAH and the manufacturer should be prepared to demonstrate the effectiveness of their communication processes during inspections. GMP regulations do not allow for information to be retained by one party or the other, and professionalism and openness within teams is essential.

And what about product supply?

Product quality defects or recalls which lead to supply restrictions or shortage will inevitably place a strain on the MAH and manufacturer.  The MAH bears the responsibility of guaranteeing the ongoing availability of a medicinal product to meet the needs of patients. In such critical scenarios, maintaining open, honest communication between both parties is essential. The technical agreement should comprehensively address the communication protocols in these circumstances, enabling the MAH to promptly notify the competent authorities.

And finally…

Successfully meeting GMP standards requires professional conduct. Both parties must work together seamlessly to ensure compliance.

Clear communication, well-defined responsibilities, and a structured approach to collaboration between MAHs and their contract manufacturers is a requirement to maintain GMP compliance. This level of transparency and professionalism is crucial in the pharmaceutical industry to ensure the quality and safety of medicinal products.