GMP Requirements for Blood Components and Plasma-derived Medicinal Products

Blood products occupy a special status within the regulatory framework. They exist at the intersection of traditional drug manufacturing, transfusion medicine and public health care. A distinction must be made between blood components for transfusion (e.g. erythrocyte concentrates, thrombocytes, plasma) and plasma-derived medicinal products (e.g. albumin, immunoglobulins, coagulation factors).

While plasma-derived products are clearly classified as medicinal products and are subject to European GMP regulations, blood components are primarily regulated by transfusion law. The regulatory complexity will change further with the upcoming SoHO Regulation (EU) 2024/1938.

1. Regulatory framework at European level

1.1 Plasma-derived medicinal products

The central regulatory basis for medicinal products is Directive 2001/83/EC (Community code relating to medicinal products for human use). Industrially manufactured medicinal products derived from human plasma are considered medicinal products for human use and are therefore subject to:

• EU marketing authorisation requirements
• pharmacovigilance
• GMP requirements in accordance with EudraLex Volume 4

At GMP level, the following apply in particular:

• EU GMP Part I (finished medicinal products),
• EU GMP Part II (active substances),
• Annex 14 (May 2011) "Manufacture of Medicinal Products Derived from Human Blood or Plasma"

Among other things, Annex 14 specifies:

• Requirements for plasma quarantine and release
• Pooling strategies
• Documentation and retention samples
• Stability programmes
• Special requirements for supplier qualification and plasma master file (PMF)

The EMA guideline "Note for guidance on plasma-derived medicinal products" (CHMP/BWP/269/95 rev.3) is also relevant, as it describes detailed requirements for donor selection, pooling, virus screening and manufacturing processes.

1.2 Blood components for transfusion

Blood and blood components for transfusion are primarily regulated by Directive 2002/98/EC. This applies to:

• Collection and testing of blood, regardless of its intended use
• Processing, storage and distribution, provided that the blood is intended for transfusion
• Autologous transfusions (with specific regulations)

Blood stem cells are exempt from this.

The directive is specified in more detail by:

• 2004/33/EC (technical requirements)
• 2005/61/EC (traceability, notification of serious adverse reactions and events)
• 2005/62/EC (quality systems for blood establishments)

Blood components are not automatically "sterile medicinal products" within the meaning of Annex 1, but are primarily subject to quality and safety requirements under transfusion law.

2. Regulatory framework in Germany

In Germany, the regulatory framework consists of:

• The Medicinal Products Act (AMG)
• The Transfusion Act (TFG)
• The Medicinal Products and Active Substances Manufacturing Ordinance (AMWHV)

Plasma-derived medicinal products are clearly subject to the AMG and the AMWHV. Blood establishments are also subject to the TFG, which regulates organisational and medical responsibilities in particular. The German Medical Association's (Bundesärztekammer) haemotherapy guidelines specify requirements for donor selection, indication and use.

3. GMP and quality requirements in detail

3.1 Quality system and organisation

Blood establishments must implement a documented quality system in accordance with Directive 2005/62/EC. This includes:

• SOP system
• Validation of critical processes
• Training and qualification of personnel
• Deviation and CAPA management
• Full traceability from donor to recipient

The EU GMP requirements also apply to plasma-derived medicinal products:

• Production management (PM) and quality control management (QCM) must always be organised separately; deviations are only permitted if justified and risk-based.
• The Qualified Person (§ 14 AMG) is responsible for batch release.

In the context of transfusion law, the senior medical officer (§ 4 TFG) is responsible for organisation, donor selection and emergency management.

3.2 Donor selection and testing

The quality of the source material is a key safety criterion. Directive 2004/33/EC sets out detailed requirements for:

• Haemoglobin levels
• Donor criteria and grounds for exclusion
• Testing for HIV, HBV, HCV, syphilis
• Other relevant infection markers

Directive 2005/61/EC requires a comprehensive traceability system and the reporting of serious adverse events (haemovigilance).

3.3 Virus safety in plasma-derived medicinal products

Virus safety is the central GMP focus for plasma-based medicinal products.

Several safety levels are required:

1. Donor selection and individual donation testing
2. Pool testing
3. Validated virus inactivation and removal steps

Typical procedures:

• Solvent/detergent treatment
• Pasteurisation
• Nanofiltration

Validation is carried out by means of virus clearance studies with documented log reduction of suitable model viruses.

3.4 Manufacturing and sterile filling

Blood components are manufactured in controlled hygiene areas in accordance with the quality requirements of transfusion law. Additional GMP requirements apply to plasma-derived medicinal products:

• Part II for active substance manufacturing
• Annex 14 for plasma-derived products
• Annex 1, provided that the finished medicinal product is filled under sterile or aseptic conditions

Annex 1 is therefore particularly relevant for the sterile filling of plasma-derived medicinal products, however, it does not generally apply for blood components for transfusion.

3.5 Traceability and pharmacovigilance

Traceability is essential for blood and plasma.

• Directive 2005/61/EC requires complete traceability from the donor to the recipient
• Pharmacovigilance under pharmaceutical law also applies to plasma-derived medicinal products

The "Graduated plan officer" in Germany (Stufenplanbeauftragter, § 63a AMG similiar to QPPV) coordinates safety reports and recalls. § 19 AMWHV specifies complaint and recall procedures.

4. Personal responsibility

Both pharmaceutical law and transfusion law stipulate clearly defined personal responsibilities.

Responsible persons bear:

• Organisational obligations
• Selection and monitoring obligations
• Documentation obligations
• Liability risks in the event of violations of GMP or transfusion law requirements

Particularly in the area of blood and plasma (with potentially life-threatening risks), organisational deficiencies can have significant criminal and civil law consequences.

5. SoHO Regulation (EU) 2024/1938

The new SoHO Regulation will come into full effect on 7 August 2027, replacing the previous blood and tissue guidelines. Its scope covers all substances of human origin (SoHO) intended for use in humans or for the manufacture of other regulated products. This also explicitly addresses interfaces with medicinal products, in particular plasma-derived products. New features include:

• a Responsible Person (Art. 36)
• a Releasing Officer (Art. 49)
• a mandatory physician (Art. 50)

The SoHO Regulation strengthens life cycle assessment, risk monitoring and systematic safety evaluation.

In summary, the GMP requirements for blood products are characterised by dual regulation: GMP under pharmaceutical law (AMG, EU GMP, Annex 14) on the one hand, and quality and safety requirements under transfusion law on the other. Key elements include a robust quality system, strict donor selection, validated virus inactivation, complete traceability and clearly defined personal responsibilities.

The upcoming SoHO Regulation will harmonise and expand the regulatory framework. For institutions, this means even greater integration of quality systems, clinical monitoring and organisational responsibility - with the aim of raising the safety of substances of human origin to a uniformly high level all across Europe.