- Annex 14 of EudraLex Volume 4, titled Manufacture of Medicinal Products Derived from Human Blood or Plasma, provides Good Manufacturing Practice (GMP) guidance specifically for the collection, processing, testing, storage, and manufacture of human blood or plasma-derived medicinal products. These include a wide range of plasma-derived therapies such as coagulation factors, immunoglobulins, and albumin, which are critical for treating conditions like hemophilia, immune deficiencies, and trauma-related hypovolemia.
- Given the biological origin of these products, Annex 14 emphasizes the inherent risks associated with transmissible agents, particularly blood-borne viruses such as HIV, hepatitis B, and hepatitis C. Therefore, the annex establishes a stringent framework for ensuring the safety, quality, and traceability of blood/plasma-derived medicinal products through comprehensive control of the entire supply chain—from donor selection to final product release.
- One of the core elements of Annex 14 is the requirement for full traceability of every donation. This includes detailed records of donor identity, donation date, processing site, storage conditions, and batch numbers for all intermediate and finished products. This traceability is critical for enabling rapid and effective recall procedures and for conducting investigations in the event of transfusion-transmitted infections or adverse reactions.
- The annex mandates strict donor selection and testing procedures. Donors must be screened and qualified based on medical history, risk factors, and mandatory testing for a defined panel of infectious diseases. Any units testing positive or considered at risk must be immediately excluded. Furthermore, all plasma used must come from approved collection centers, which are themselves subject to regulatory oversight and must operate under GMP and Good Practice Guidelines (GPG) for blood and blood components.
- Virus inactivation and removal are critical processing steps in ensuring the safety of plasma-derived products. Annex 14 requires that multiple complementary viral safety measures be employed. These include donor screening, testing of donations and plasma pools, and validated manufacturing steps known to inactivate or remove viruses, such as pasteurization, solvent/detergent treatment, nanofiltration, or low pH incubation. These steps must be validated not only for known viruses but also for emerging or unknown pathogens, using model viruses or surrogate studies.
- Storage and handling conditions are also tightly controlled under Annex 14. Plasma must be stored at appropriate temperatures (usually frozen at -20°C or colder) to preserve protein functionality and reduce the risk of degradation. Manufacturing and storage facilities must be designed to prevent cross-contamination between batches or product types and must comply with high hygiene standards, often including Grade C or higher cleanroom classifications for specific operations.
- The annex also requires the implementation of a robust quality assurance system, encompassing documented procedures, deviation management, change control, and quality audits. The Qualified Person (QP) is responsible for certifying that every batch of plasma-derived medicinal product meets all regulatory and safety requirements before it is released to the market. This includes ensuring compliance with the product specification file and regulatory authorizations.
- Additionally, Annex 14 emphasizes the need for pharmacovigilance and post-marketing surveillance. Because of the biological complexity and potential long-term effects of these products, manufacturers must monitor for adverse reactions and conduct periodic risk assessments to evaluate the ongoing safety profile of the product. This may involve product recalls, donor look-back procedures, or updates to risk mitigation strategies.
- In summary, EudraLex Volume 4 – Annex 14 outlines a comprehensive and rigorous GMP framework for the manufacture of medicinal products derived from human blood or plasma. It addresses the unique safety challenges, regulatory requirements, and quality controls necessary to ensure that these life-saving therapies are consistently manufactured to the highest standards. Annex 14 places particular emphasis on traceability, viral safety, validated manufacturing processes, and pharmacovigilance, reflecting the vital importance of protecting patients from infectious risks while ensuring access to critical biologic therapies.
Further reading:
- EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines
- EudraLex – The Rules Governing Medicinal Products in the European Union, Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Annex 14: Manufacture of Medicinal Products Derived from Human Blood or Plasma
