25.03.2026
What are the GMP Requirements for Biotechnological Products?

Biotechnologically manufactured medicinal products (often referred to as "biologics" or "biopharmaceuticals") are medicinal products that are manufactured using biological systems. Biotechnology refers to the targeted use of cells, microorganisms or biological molecules to produce defined active substances. This is not an entirely novel principle: Traditional antibiotics are also produced using microorganisms. However, the key difference in modern biotechnology lies in the targeted genetic modification of production organisms, for example through recombinant DNA technology, in order to produce specific proteins such as monoclonal antibodies, hormones or enzymes. The most important biotechnologically produced drugs include recombinant proteins (e.g. insulin, growth hormones), monoclonal antibodies (mAbs), fusion proteins, vaccines, blood and plasma products, biosimilars and, in a broader sense, ATMPs.

Biologics are characterised by their high molecular complexity, post-translational modifications (e.g. glycosylation), their production in living cells and inherent batch-to-batch variability. Unlike chemically synthesised drugs, identical copies are virtually impossible to produce. Even minor process changes can affect the structure, activity or immunogenicity. These special characteristics are directly reflected in the GMP requirements.

Regulatory framework in Europe

The legal basis in Europe is provided by the relevant EU regulations and directives, particularly Directive 2001/83/EC on medicinal products for human use, as well as national implementations, e.g. in the German Medicines Act (AMG). The binding GMP requirements are summarised in EudraLex Volume 4 (EU GMP Guidelines). These consist of:

• Part I: Basic requirements for medicinal products
• Part II: GMP for active substances (API)
• Part III: GMP-related documents
• Annexes (product-specific requirements)
• Part IV on ATMPs

EU GMP Part II, which is based on ICH Q7, is particularly relevant for biotechnologically manufactured active ingredients. Chapter 18 ("Biotech Chapter") contains specific requirements for APIs derived from cell culture or fermentation. For the finished medicinal product (drug product, DP), Part I also applies. Specific requirements for biological medicinal products are regulated in Annex 2 ("Manufacture of Biological Medicinal Substances and Products for Human Use"), and requirements for sterile active substances and drugs in Annex 1. For investigational medicinal products, Annex 13, Regulation (EU) 536/2014 and Delegated Regulation (EU) 2017/1569 also apply. The EMA "Guideline on quality, non-clinical and clinical requirements for investigational ATMPs" from 2022 describes the data required for an investigational medicinal product (IMP).

Internationally, ICH guidelines are also central, specifically for biologics: ICH Q5A (virus safety), ICH Q5C (stability), ICH Q5D (cell banking systems), ICH Q6B (specifications for biotechnology products) and ICH Q8-Q11 (QbD, risk management, pharmaceutical quality system).

The production of biotechnological APIs typically begins with a cell bank system. Annex 2 and ICH Q5D require clear characterisation, documentation and control of master and working cell banks. The cell bank must be established in a controlled environment. Its history, genetic stability and freedom from adventitious agents must be demonstrated. Details on the quality of cell banks can also be found in the European Pharmacopoeia.

A key GMP issue is virus safety. Biotechnological products, especially those derived from animal or human cell lines, carry the risk of viral contamination. Therefore, ICH Q5A requires validation of virus inactivation or virus removal steps with demonstrable reduction performance. Annex 2 also emphasises the need to systematically avoid cross-contamination and microbiological contamination.

Part II Chapter 18 describes requirements for fermentation, harvesting, purification, and viral inactivation and removal steps. The focus here is on process control: Parameters such as pH, temperature, oxygen supply and feed strategies are considered critical process parameters (CPPs) because they directly affect critical quality attributes (CQAs). CQAs include, for example, potency, purity, aggregation behaviour, glycosylation patterns and immunogenicity.

Analytical characterisation is particularly extensive. According to ICH Q6B, identity, purity, content, biological activity and process- and product-related impurities must be assessed. Host cell proteins, host cell DNA, media components or chromatography ligands are typical process-related impurities that must be minimised and controlled. The development and validation of analytical methods follows ICH Q14 and ICH Q2.

Biotechnological processes are often microbial or cell culture-based and therefore highly susceptible to contamination. Annex 2 therefore requires a risk assessment of contamination hazards throughout the entire process, including a risk-based definition of hygiene areas and cleanroom classifications, which in turn are described in Annex 1. There are no rigid cleanroom classification requirements for active ingredient manufacturing (API); rather, the classification must be appropriate for the respective process stage and microbiological risk. For the manufacturing steps involved in obtaining sterile active ingredients, reference is made to Annex 1. This concerns cleanroom classes (A/B for aseptic filling), environmental monitoring, media fills (APS), contamination control strategy and quality risk management.

Biotechnological APIs are typically transferred to sterile filling with low bioburden. A clear separation between the API and DP areas is essential. Annex 2 requires the implementation of appropriate measures to prevent cross-contamination. This usually involves the use of separate HVAC systems for fermentation (upstream) and purification (downstream), as well as a clear separation of pre- and post-viral process steps.

Closed systems and single-use technologies are becoming increasingly important. These also require a formal risk analysis, especially with regard to extractables/leachables, biocompatibility and microbiological quality.

Cleaning validation is mandatory for multi-product systems. In addition to Part II, Annex 15 and the HBEL/PDE guideline for deriving health-based limit values also apply here. Special considerations apply to proteins, as they can denature at extreme pH values or temperatures and are then difficult to clean.

Due to the natural variability of biological systems, the "state of the art" is not static, but is constantly evolving. The German AMG specifically requires that manufacturing and quality control comply with the latest scientific and technical standards.

Conclusion

The GMP requirements for biotechnological medicinal products are more complex and scientifically demanding than those for chemically synthetic products. They are based on a dense network of European and international regulations (in particular EU GMP Part II, Annex 2, Annex 1 and ICH Q5A-Q6B). The focus is on process understanding, virus safety, control of biological variability, comprehensive analytical characterisation and a risk-based quality system. Biotechnological GMP is therefore not so much a rigid set of rules as it is a scientifically sound, risk-based control system with the aim of providing reproducible, safe and effective medicinal products despite inherent variability.

Source: https://www.gmp-compliance.org/gmp-news/what-are-the-gmp-requirements-for-biotechnological-products