GMP Compliance Adviser Update No 2/2022
GMP in Practice
Chapter 1 Quality Management Systems
1.I Batch Record Review
The Batch Record Review (BRR) is an examination of the batch records that is independent of their creation and takes place at the end of the production process. It is an important prerequisite for the release of the finished medicinal product and the issuing of a certificate by the qualified person.
The term ‘Batch Record Review’ is not anchored in the regulations, but the obligation to review batch documentation is.
The responsibilities are located in both manufacturing and quality control. The implementation of the BRR and the responsibilities should be described in detail in an SOP.
The batch documentation is the focus of a BRR. However, peripheral documents can also be used, e.g. relating to deviations, changes or other quality systems.
A checklist is recommended for conducting a BRR. An example is presented. (Nicole Kordek, PhD)
1.J Product Quality Review and Annual Product Review
Product Quality Reviews (PQR) for Europe and Annual Product Reviews (APR) for the United States are tools that play an important role in the assessment of processes and process environments, and of the product. With its cross-system assessment, the PQR in particular provides information that can help improve the quality management system and its elements, such as change control, OOS and CAPA.
For the PQR and APR, the product-specific data is compiled and assessed. This information is available in various systems, for example LIMS or ERP systems. In the PQR, the current regulatory status is reviewed with a view to demonstrating the conformity of the products with their marketing authorisation (regulatory compliance). Where necessary, changes must be initiated. Measures set out in the current review are examined in the subsequent review to ensure that they have been implemented and are effective.
In terms of organisation, the reviews can be both centralised (compilation and assessment of all data) and decentralised. If preparation is decentralised, the data from analytics (e.g. release analytics, supplier assessed, certificates of analysis, in-process control) and production (e.g. yields, qualification, deviations) are collected and evaluated in the areas in which they occur and assessed by a central unit (quality assurance, qualified person).
The process validation status (OPV for the PQR or CPV for the APR) is reviewed.
In the case of contract manufacturing or testing, responsibilities for preparation of the review must be agreed by contract.
When preparing the review, it is important to ensure that it is clear, coherent, and comprehensible. The most important results should be briefly summarised. An assessment of the data constitutes the main body of the PQR, while the data itself is preferably gathered in an annex to ensure overall clarity.
An SOP for the APR/PQR should govern the structure, content, implementation, and responsibilities for the review. Templates with a fixed structure can facilitate the preparation of reviews and at the same time improve comparability. (Christian Gausepohl, PhD)
Chapter 12 Sterile Production
12.H Testing for Endotoxins
Endotoxins are lipopolysaccharides from the outer membrane of the cell wall of Gram-negative bacteria. They can cause fever and other adverse physiological reactions in humans and must therefore not be present in parenterals.
Chapter 2.6.14 of the European Pharmacopoeia describes tests for the detection of bacterial endotoxins, which are presented in their methodological implementations. Validation of the gel-clot test with the test for inhibition and enhancement is discussed in detail. More recent developments in the field of endotoxin detection, such as the test with recombinant factor C and the monocyte activation test, are briefly outlined. The elimination of interference factors and the phenomenon of masking and low endotoxin recovery are also addressed.
The occurrence of OOS results and the procedures required in response are described for practical application. (Michael Rieth, PhD)
GMP Regulations
Chapter C EU Directives and Guidelines
For the following chapters C.2.1 and C.2.2 please note:
As of 31 January 2022, the new Clinical Trials Regulation (EU) No. 536/2014 (CTR) entered into force and the new Clinical Trials Information System (CTIS) has gone live. CTIS serves for the submission and assessment of clinical trial data in all EU and EEA countries.
With this step, Directive 2003/94/EC is repealed and replaced by Directive (EU) 2017/1572 and Regulation (EU) 2017/1569 according to Articles 15, 16 and 17 of Directive (EU) 2017/1572. The GMP requirements for commercial products and for investigational medicinal products are thus regulated separately.
With the repeal of Directive 2003/94/EC, the numbering within Chapter C EU Directives and Guidelines of the GMP Compliance Adviser was adjusted, accordingly:
• C.2.1 Commission Directive (EU) 2017/1572
Directive 2017/1572 supplements Directive 2001/83/EG (Art. 40) on the principles and guidelines of GMP. It lays down provisions on inspections by the competent authorities and on certain obligations of the manufacturer.
• C.2.2 Commission Delegated Regulation (EU) 2017/1569
Regulation 2017/1569 specifies the basic principles of GMP for investigational medicinal products (IMPs) and their monitoring by the authorities. The aim is to achieve a harmonisation of GCP and GMP standards.
C.4.13 Annex 13: Detailed Commission guidelines on good manufacturing practice for investigational medicinal products for human use, pursuant to the second subparagraph of Article 63(1) of Regulation (EU) No 536/2014
Annex 13 of the EU GMP Guide on Investigational Medicinal Products has been revised based on Article 63(1) of the EU Clinical Trials Regulation (CTR) No. 536/2014. It entered into force on 31 January 2022.
With the revision, changes in batch release (Chapter 8) are introduced and the responsibilities of the Qualified Person regarding the release of IMPs are redefined. According to Chapter 8, the QP of the manufacturer or importer must certify batches in accordance with the CTR (Article 62(1)) and according to the principles of Annex 16 of the EU GMP Guide. This is then followed by "regulatory" release through the sponsor for further investigational use in a clinical trial.
C.4.21 Annex 21: Importation of medicinal products
The new Annex 21 was published in its final version on 21 February 2022 and will enter into force on 21 August 2022. The 6-page Annex to the EU GMP Guide summarises the GMP requirements for Manufacturing Import Authorisation (MIA) holders of medicinal products for human, investigational and veterinary use from outside the EU/EEA. Medicinal products entering the EU/EEA for export, and which are neither processed in any way nor released for placing on the EU/EEA market are not covered.
Chapter D CFR and FDA Guidelines
The Code of Federal Regulations is subject to an annual revision. With the current update of the GMP Compliance Adviser we have reviewed the following Title 21 CFRs as of April 1, 2022.
D.1.3 21 CFR Part 11 Electronic Records; Electronic Signatures
The section “Scope” was amended with sub-point (p) on which type of records are subject to 21 CFR 11. Reference is made to Subpart R of 21 CFR 1: Laboratory Accreditation for Analyses of Foods.
D.1.6 21 CFR Part 600 Biological Products: General
In Subpart C which lays down the inspection procedure of an establishment, § 600.22 on the duties of inspectors has been deleted.
Please note: The dates of the following CFRs have been updated without any further regulatory amendments and only a few minor editorial changes:
- D.1.1 21 CFR Part 210 Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General
- D.1.2 21 CFR Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals
- D.1.4 21 CFR Part 820 Quality System Regulation
- D.1.5 21 CFR Part 4 Regulation of Combination Products
- D.1.7 21 CFR Part 606 Current Good Manufacturing Practice for Blood and Blood Components
- D.1.8 21 CFR Part 680 Additional Standards for Miscellaneous Products
- D.1.9 21 CFR Part 601 Licensing
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