Management and control of biological raw materials - the EBE Concept Paper

Recommendation

22/23 February 2024
Munich, Germany

API Regulatory Starting Materials
Definition, Manufacture, Assessment and handling post-approval Changes

While requirements for the GMP-compliant production of chemically synthesised active substances and their starting materials have existed for many years now, one may search in vain for binding GMP guidelines on biological/biotechnological raw materials. However, without careful examination and risk assessment of raw materials, quality assurance for biological/biotechnological medicines is impossible to attain.

A new concept paper by the Association of European Biopharmaceutical Enterprises, EBE, closes this gap. The document entitled "Management and Control of Raw Materials Used in the Manufacture of Biological Medicinal Products" was published on the EBE's official website roughly a year ago. It describes the principles of a risk-based control strategy for raw materials as part of the risk management for manufacturing biological/biotechnological medicines. The document includes a number of examples for the application of control strategies for various raw materials and thereby takes into account the diversity of biological materials and considers their to some extend very different characteristics.

Below is a brief description of the essential contents of the concept paper's main sections:

Scope
The concept paper applies to raw materials such as cell cultures, buffers, resins and chemicals which are used in the manufacture of proteins, polypeptides and peptide conjugates. These active substances are manufactured by fermentative cell culture-based procedures or by isolation from tissues or body fluids.

This first version of the document does not cover raw materials for manufacturing viral vector-based vaccines and Advanced Therapy Medicinal Products (ATMPs). This is meant for a second, not yet published version of the concept paper.

Definition of raw materials
Typical raw materials for biological/biotechnological manufacturing procedures are essential components, such as cell culture media and additives, enzymes or components of buffer solutions and chromatography resins. Note for classification: recombinant cell lines, tissue, body fluids and primary cells that express the desired active substance which is then isolated and purified, are starting materials.

Risk-based approach
The controls and quality management effort for a raw material must comply with its criticality during the manufacturing process and after the development phase. A key part of the EBE concept paper is a flow chart containing four consecutive steps for assessing the risk of a raw material:

• Collect knowledge on RM
  Information on stability, impurity profiles, toxicity, microbiological status, variability, supplier specifications of the raw material, etc. is collected.
• RM Risk Assessment
  Risk types are defined based on this information; for example, the risk of viral or microbial contamination, toxic impurities or the negative impact on the process performance due to the high variability of the raw material.
• Material Attributes Risk Assessment
  For raw materials with a medium or high risk profile, material attributes are evaluated with regard to their potential impact on product quality. These attributes should be re-evaluated regularly.
• Implement Mitigation Plan
  For raw materials with a medium or high risk profile, actions to reduce the risk are introduced based on the critical material characteristics, like, for example, specific tests for incoming raw materials, sterilisation before use, determination of inhouse-requirements for critical material characteristics and expiration dates. The impact of these risk mitigation measures can be reviewed in the annual periodic quality review (APQR).

Furthermore, the concept paper contains a number of guiding questions, which are supposed to assist in evaluating the risk of various raw materials. This is substantiated by two examples of a biological buffer used in purification procedures - with and without impact on the critical quality attributes of the active substance.

Further precise examples describe

• Internal specifications (as a risk mitigation activity), which were developed for a buffer used late in the process,
• Risk assessment and risk mitigation plan for a chemically defined commercially available medium,
• Risk assessment and risk mitigation plan for a commercially available medium containing undefined components (e.g. hydrolysate),
• Internal specifications (as a risk mitigation activity), which were developed for a chemically defined commercially available medium,
• Internal specifications (as a risk mitigation activity), which were developed for a commercially available medium containing undefined components (e.g. hydrolysate),
• Risk assessment and risk mitigation plan for a "dummy"-resin,
• Internal specifications developed for a "dummy"-resin (as a risk mitigation activity),
• Risk mitigation plan for product development phases 1, 2 and 3 for the supplier qualification and quality testing of high-risk raw materials.

The unique character of the concept paper lies in its comprehensive and practice-oriented description of the risk-based approach to managing and controlling various raw materials used for the manufacture of biological/biotechnological medicines. Many examples provide insights on how to assess these materials considering their risk profile and how to describe and document them during an approval procedure. They are therefore useful for the industry and competent authorities in equal measure - especially considering the lack of guidelines designed for this very purpose.