WHO publishes Guidance on Safe Production and Quality Control of Monoclonal Antibodies

Recommendation

7/8 May 2024

Annex 2 & Co. - GMP Compliance for Biopharmaceuticals - Live Online Training
Regulatory Requirements and Practical Implementation

As early as October 1991, the WHO Expert Committee enacted the first guidelines for the quality assurance of monoclonal antibodies for human use. In the following 30 years, there have been many scientific and technical advances in both the production and quality assurance of monoclonal antibodies (mAbs). In particular, the use of recombinant DNA (rDNA) and cloning technologies have contributed significantly.

As a result, the WHO guidelines for the quality, safety and efficacy of biotherapeutic protein products produced using recombinant DNA technology were published in 2013. Although guidance on the production and quality control of mAbs falls within the scope of these guidelines, there was a further need for additional clarity and more detailed information on this topic as well as guidance on mAbs produced from plant-based systems. This guidance has been developed through an international consultation and is intended to replace the guidance in Annex 3 of the Technical Report Series, No. 822. Based on the significant advances concerning the types and variants of mAbs and related antibody-like proteins, this guidance can be considered applicable to these types of products based on an antibody scaffold. This includes:

•  mAbs of all isotypes, whether they are humanized, human, or chimeric, and regardless of the intended therapeutic mechanism of action,
• antibody fragments, such as single-chain variable fragments (scFv’s) and antigen-binding fragments (Fab),
• single domain antibodies (nanobodies)
• bispecific or multispecific antibodies,
• mAbs or related antibody proteins which have been chemically modified, such as through their conjugation to polyethylene glycol (PEG) or an active drug substance,
• multiple mAb substances pooled within a final product (“antibody cocktail”).

The draft guidelines now available are structured as follows

• Terminology
• General and Regulatory Considerations
• Special Considerations
•  International reference materials
• Part A. Manufacturing recommendations
  A.1 Definitions
  A.2 General manufacturing recommendations
  A.3 Reference preparations
  A.4 Control of source materials
  A.5 Control of mAb production
  A.6 Filling and containers
  A.7 Control of the final product
  A.8 Records
  A.9 Retained samples
  A.10 Labelling
  A.11 Distribution and transport
  A.12 Stability testing, storage and expiry data
• Part B. Recommendations for NRAs
  B.1 General recommendations
  B.2 Release and certification
• Acknowledgements
• References

The WHO defines the applicability of these guidelines as follows:

"For the purposes of this guideline, the term “monoclonal antibody” or “mAb” is used to encompass the breadth of the substances and products represented above unless otherwise stated. Readers are also encouraged to consult with the WHO Guidelines on evaluation of monoclonal antibodies as similar biotherapeutic products (SBPs) for additional guidance on characterization and quality assessment for relevant products.
It should be noted that this guideline is not applicable to nucleic acid-based platforms which use a vector or similar technology for the delivery of the genetic sequence that would encode for antibody production in vivo following their administration. The manufacture and quality assurance of such products is very different from those of mAbs. Although antibody mimetic proteins based on non-immunoglobulin scaffolds (e.g. DARPins, affimers, and anticalins) have some similar manufacturing and quality assurance processes as described in this guideline, they may also have unique regulatory considerations which are outside of the scope of this document. Therefore, manufacturers of such products are encouraged to refer instead to the above-noted guideline regarding biotherapeutics prepared by recombinant DNA technology."

This document is open for comments until the end of November. More detailed information can be found directly in the "WHO Guideline for the safe production and quality control of monoclonal antibodies for use in humans"