Q.01

What is EudraLex Volume 4?

EudraLex Volume 4 is the European Commission's Guide to Good Manufacturing Practice (GMP). Its full title is "The Rules Governing Medicinal Products in the European Union – EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use" [1]. National competent authorities use it to assess applications for manufacturing authorisations, and as the basis for inspecting manufacturers of medicinal products [2].

Approach: I read the Introduction and the document index of the EU GMP Guide (EudraLex Volume 4) held in the datasets.

Legal basis and scope

  • The Guide gives the detailed guidelines that go with two GMP directives: Directive 2003/94/EC for medicines for human use and Directive 91/412/EEC for veterinary medicines [2].
  • It applies to all operations that need the authorisations in Article 40 of Directive 2001/83/EC, Article 44 of Directive 2001/82/EC and Article 13 of Directive 2001/20/EC. It is also "relevant for" manufacturing done in hospitals. EU manufacturers need a manufacturing authorisation whether they sell inside or outside the Union [2].
  • GMP requirements are the same for human and veterinary medicines. Some veterinary-specific adjustments are set out in two annexes [2].
  • The Guide assumes that the marketing authorisation's requirements are built into the manufacturer's manufacturing, control and release arrangements. It does not cover worker safety, which other EU or national law governs. Other validated methods that give at least an equivalent level of quality management are acceptable [3].

Structure

  • Part I: basic requirements for medicinal products. Nine chapters: 1 Pharmaceutical Quality System, 2 Personnel, 3 Premise and Equipment, 4 Documentation, 5 Production, 6 Quality Control, 7 Outsourced activities, 8 Complaints and Product Recall, 9 Self Inspection [4][5]. Each chapter opens with a principle and then gives detailed guidance [2].
  • Part II: GMP for active substances used as starting materials. It is based on ICH Q7A and covers both human and veterinary use [2][6].
  • Part III: GMP-related documents. These are not detailed guidelines under the GMP directives. They clarify regulatory expectations and describe current best practice [3]. The datasets hold seven:
    • ICH Q9 Quality Risk Management [7]
    • Site Master File [8]
    • MRA Batch Certificate [9]
    • Template for the "written confirmation" for active substances exported to the EU [10]
    • Template for IMP (investigational medicinal product) batch release [11]
    • Guideline on the sponsor's responsibilities for handling and shipping IMPs [12]
    • Reflection paper on GMP and marketing authorisation holders (EMA/INS/3094/2022) [13]
  • Part IV: GMP specific to Advanced Therapy Medicinal Products (ATMPs) [14]. The 2010 Introduction describes only three parts, so Part IV was added after it.
  • Annexes: guidance for specific activities. More than one annex can apply to the same process (for example sterile manufacture plus radiopharmaceuticals) [3]. The datasets hold 17:
    • 1 Sterile medicinal products [15]
    • 2 Biological active substances and medicinal products for human use [16]
    • 3 Radiopharmaceuticals [17]
    • 6 Medicinal gases [18]
    • 7 Herbal medicinal products [19]
    • 8 Sampling of starting and packaging materials [20]
    • 9 Liquids, creams and ointments [21]
    • 10 Pressurised metered dose inhalers [22]
    • 11 Computerised systems [23]
    • 12 Ionising radiation [24]
    • 13 Investigational medicinal products under Regulation (EU) No 536/2014 [25]
    • 14 Products derived from human blood or plasma [26]
    • 15 Qualification and validation [27]
    • 16 Certification by a Qualified Person and batch release [28]
    • 17 Real time release testing and parametric release [29]
    • 19 Reference and retention samples [30]
    • 21 Importation of medicinal products [31]
  • Glossary, placed after the annexes [32].

History

  • 1989: first edition, with an annex on sterile manufacture.
  • January 1992: second edition, implementing Directives 91/356 and 91/412, with 12 additional annexes.
  • August 2004: legal references updated.
  • October 2005: split into Part I and Part II, implementing Directives 2004/27/EC and 2004/28/EC.
  • December 2010: Part III introduced.

[1]

The Commission revises the Guide regularly and publishes revisions on its EudraLex Volume 4 web page [3].

Q.02

What are the parts and annexes?

EudraLex Volume 4 has four parts and a set of numbered annexes, plus an Introduction and a Glossary. The datasets hold all four parts and 17 annexes.

Approach: I listed every document in the European Commission's EU GMP Guide (EudraLex Volume 4), grouped the way the Commission's index page groups them. The datasets hold Annexes 1-3, 6-17, 19 and 21, so this list may not cover every annex the Commission publishes.

Part I: Basic requirements for medicinal products (9 chapters)

  1. Pharmaceutical Quality System [33]
  2. Personnel [34]
  3. Premise and Equipment [35]
  4. Documentation [36]
  5. Production [37]
  6. Quality Control [38]
  7. Outsourced activities [39]
  8. Complaints and Product Recall [40]
  9. Self Inspection [5]

Part II: Basic requirements for active substances used as starting materials [41]

Part III: GMP-related documents (7)

  • Q9 Quality Risk Management [42]
  • Site Master File [43]
  • MRA Batch Certificate [44]
  • Template for the "written confirmation" for active substances exported to the EU for medicinal products for human use [45]
  • Template for IMP batch release (applies from the date Regulation (EU) No 536/2014 on Clinical Trials started to apply) [11]
  • Guideline on the sponsor's responsibilities for handling and shipping investigational medicinal products for human use, under GCP and GMP [46]
  • Reflection paper on GMP and Marketing Authorisation Holders [47]

Part IV: GMP specific to Advanced Therapy Medicinal Products [48]

Annexes (17 held)

No.Title
1Manufacture of Sterile Medicinal Products [49]
2Manufacture of Biological active substances and Medicinal Products for Human Use [50]
3Manufacture of Radiopharmaceuticals [51]
6Manufacture of Medicinal Gases [52]
7Manufacture of Herbal Medicinal Products [53]
8Sampling of Starting and Packaging Materials [54]
9Manufacture of Liquids, Creams and Ointments [21]
10Manufacture of Pressurised Metered Dose Aerosol Preparations for Inhalation [55]
11Computerised Systems [56]
12Use of Ionising Radiation in the Manufacture of Medicinal Products [57]
13Detailed Commission guideline of 8 December 2017 on GMP for investigational medicinal products under the second paragraph of Article 63(1) of Regulation (EU) No 536/2014 [58]
14Manufacture of Products derived from Human Blood or Human Plasma [59]
15Qualification and validation [60]
16Certification by a Qualified Person and Batch Release [61]
17Real Time Release Testing and Parametric release [62]
19Reference and Retention Samples [63]
21Importation of medicinal products [64]

Other sections: the Introduction [3] and the Glossary [32].

Q.03

How is it different from US cGMP?

The two cover much the same ground but are built differently. US cGMP (21 CFR Parts 210 and 211) is binding regulation: a drug made without complying is "adulterated" under section 501(a)(2)(B) of the FD&C Act. EU GMP (EudraLex Volume 4) is a set of detailed guidelines under the principles in Directive 2003/94/EC, and it is much more explicit about quality systems and risk management. The biggest practical difference is batch release: in the EU a named Qualified Person (QP) certifies each batch, while in the US the firm's quality control unit approves it.

Approach: I compared the current eCFR text of 21 CFR Parts 210/211 with the EU GMP Guide (Introduction, Part I, Part II and Annexes 11, 16 and 19). FDA guidance documents that expand on Parts 210/211 are not in the datasets I can search, so the US side here is the regulation text only.

Legal nature

  • US: Parts 210/211 set the "minimum current good manufacturing practice" for making, processing, packing and holding drugs [65]. Failing to comply "shall render such drug to be adulterated", and both the drug and the person responsible face regulatory action [66].
  • EU: the Guide gives detailed guidelines under Directive 2003/94/EC (human) and 91/412/EEC (veterinary). Authorities use it to assess manufacturing authorisations and to inspect [2]. It accepts other methods that reach "a level of Quality Management at least equivalent" [3]. Most clauses use "should".

Main differences

TopicUS 21 CFR 210/211EU GMP Guide
Who releases a batchThe quality control unit approves or rejects all materials and drug products, including those made under contract [67]. It reviews and approves production and control records before a batch is released [68].A QP (Article 51 of Directive 2001/83/EC) "must certify in a register or equivalent document" that each batch complies before release. Batches from third countries must be fully re-analysed in a Member State. QP duties can only be delegated to other QPs [69]. Annex 16 gives the detail [61].
Quality system and managementBuilt around the quality control unit and its written responsibilities [70]. Neither Part uses the words "risk", "quality system", "audit" or "self-inspection".A defined Pharmaceutical Quality System with a Quality Manual [71]. Senior management carries "ultimate responsibility" [72] and holds periodic management review [73]. ICH Q10 is in Part III [74].
Risk managementNot stated in the text.Quality risk management, with effort matched to the level of risk and ICH Q9 in Part III [33].
Annual product reviewRecords must allow an evaluation "at least annually". It covers a representative number of batches plus complaints, recalls, returns, salvage and investigations [75][76][77].The Product Quality Review lists at least 12 elements. These include supply-chain traceability of active substances, CAPA effectiveness, marketing authorisation variations, equipment and utility qualification status, and contracts [78].
Self-inspectionNot stated in the text.A dedicated chapter: a pre-arranged programme covering all GMP areas [79].
RecallsResponsible officials must be notified in writing of recalls and FDA observations [80].Chapter 8 in detail. Recalls may start before the root cause is known [81]. Shortage risk must be considered, and decisions not to act must be agreed with the competent authority [82].
Batch record retentionAt least 1 year after the batch's expiry date. For exempt OTC products without an expiry date, 3 years after distribution [83].1 year after expiry or at least 5 years after QP certification, whichever is longer. For IMPs, 5 years after the last trial ends [84].
Retained samples1 year after expiry, at least twice the quantity needed for testing [85][86]. Active ingredient samples are kept per lot in each shipment [87].Reference and retention samples kept at least 1 year after expiry [88].
Computerised systemsA short provision: calibration, change control by authorised staff, checking input and output, backups [89].Annex 11: risk-based validation over the system lifecycle [90]. Operator identity and timestamps are recorded, electronic signatures are covered, and only QPs can certify release in the system [91].
OutsourcingThe quality control unit approves or rejects products made under contract [67].A written contract between contract giver and acceptor is required, and it must say how the certifying QP exercises full responsibility [92].

Scope differences

  • Active substances: Part 211 covers drug products [93]. The EU Guide has a separate Part II for active substances, based on ICH Q7 [94]. The datasets don't hold an FDA counterpart for active-substance GMP, so I couldn't compare that.
  • Products excluded from Part 211: PET drugs and medical gases are left out of Part 211 and sent to Part 213 [93]. The EU covers both inside the Guide (Annexes 3 and 6).
  • Investigational products: in the US, Phase 1 investigational drugs are exempt from Part 211 until the drug is used in Phase 2 or 3 or is lawfully marketed [95]. In the EU, GMP applies from the manufacture of investigational medicinal products onward [74], with Annex 13 on top.
  • Human and veterinary: both cover both. Part 211 applies to drugs for "humans or animals" [93]. The EU treats veterinary GMP as the same as human GMP, with two veterinary annexes [2].

Where they overlap: both require written procedures with recorded deviations [96], process and aseptic validation [97], a written stability programme [98], and a quality control function that is independent of production. The EU side of that is the head of Quality Control [99].

Q.04