GMP Compliance Adviser Update No. 6/2020

With this GMP Compliance Adviser UPDATE you have direct access to all prime regulatory changes and to our GMP expert interpretations. Here are the new features at a glance:

GMP in Practice

Chapter 20

Active Pharmaceutical Ingredients

20.B Regulatory principles


Chapter 21

Inspections and drug safety

21.B Official inspections


GMP Regulations

Chapter C 

EU Directives and Guidelines


C.8.2.1 Safety features for medicinal products for human use – Questions and Answers – Version 18

C.19 Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products

Chapter D

USA: CFR and FDA Guidelines


D.27 Control of Nitrosamine Impurities in Human Drugs – Guidance for Industry


GMP in Practice

Chapter 20 Active Pharmaceutical Ingredients

20.B Regulatory principles

The ICH Q7 Guideline constitutes the central regulation for GMP-compliant manufacturing of active substances worldwide. It has been implemented in Europe as the legally binding EU GMP Guide Part II. The distribution and trade of active ingredients must also be legally binding in Europe in accordance with the EU GDP Guidelines for active ingredients.

More detailed information on the manufacture and testing of biotechnological active substances can be found in Annex 2 of the EU-GMP Guide and in numerous international guidelines. The instructions of the European Pharmacopoeia should also be considered.

Registration with the competent national authority is mandatory in Europe for manufacturing, importing and distributing active substances. However, in contrast to medicinal products, no manufacturing or import authorisation requirement for active substances has been implemented in Europe.

Written confirmation has been a requirement since 02 July 2013 for the import of active substances into the European Union from third countries.

With regard to the release of active substances for distribution to third parties it should be noted that the prerequisites to be met here have been greatly reduced in comparison to the release of medicinal products.

Manufacturers of active ingredients are subject to the audit obligation of the pharmaceutical entrepreneur or the pharmaceutical manufacturer commissioned by the company (contract manufacturer).

The manufacture, import and distribution of active pharmaceutical ingredients are subject to supervision by the competent national authority. To this end, official GDP or GMP inspection must be conducted in accordance with the guidelines for performing inspections.

Active ingredient manufacturers in the EU are generally supervised by the national competent authorities. There are different case constellations for supervising third country manufacturers depending on the type of active ingredient to be imported and the EU member state in which the import takes place. (Rainer Gnibl, PhD)

Chapter 21 Inspections and drug safety

21.B Official inspections

The requirements for the qualification of inspectors are uniformly defined within the EU in the Compilation of Community Procedures on Inspections and Exchange of Information (CoCP). The training comprises theoretical and practical parts and ends with an inspection carried out as lead inspector. Inspectors must undergo regular further training in order to keep up to date with the latest scientific and technical developments. In order to be able to carry out their supervisory duties effectively, the EU regulations grants inspectors extensive powers.

Official inspections are divided into GMP inspections, third country inspections and inspections by licensing authorities/departments.

Depending on the occasion, GMP inspections can be divided into general GMP inspections, product or process related GMP inspections, for-cause inspections and follow-up inspections.

Inspections by the licensing authority/department can relate to new marketing authorisations, official batch release, investigational medicinal products or pharmacovigilance.

General inspections are carried out on the basis of a defined inspection plan. The inspection plan is based on a risk assessment of the sites to be inspected. The risk classification decides on the frequencies and duration of the inspections.

The preparation of inspections in EU inspectorates shall be carried out in accordance with the CoCP. An inspection plan shall be established. General inspections are usually announced in advance so that the inspected site can prepare for the inspection. By contrast, for-cause inspections are unannounced.

An inspection begins with an opening meeting, followed by a plant tour with interviews on site and subsequent documentation review. If necessary, official sampling may take place as part of the inspection. At the final meeting, observations and deficiencies are summarised and evaluated with regard to their criticality.

After the inspection, the authority shall write an inspection report. The inspected establishment may comment on it within a specified period. (Michael Hiob, PhD, Sabine Paris, PhD)

GMP Regulations

Chapter C EU Directives and Guidelines

C.8.2.1 Safety features for medicinal products for human use – Questions and Answers – Version 18

On August 12, 2020, the European Commission published version 18 of this document. With the second update this year, it has now grown to 34 pages.

New questions: 4.6, 5.12, 5.13, 6.9

Q&A 4.6: A manufacturer may outsource the application of safety features to a packaged medicinal product to another manufacturer, provided this is done in accordance with the requirements of the EU GMP Guide Part I, Chapter 7 and the manufacturer has a manufacturing authorization. The contracted manufacturer must be included in the marketing authorization.

Q&A 5.12: A wholesaler with multiple locations must be clearly identifiable from any location and therefore must not use a single access to the NMVS system for verification and deactivation of security features.

Q&A 5.13: Medicinal products purchased from a third party do not need to be verified according to Article 20(b) of the Commission Delegated Regulation (EU) 2016/161 based on the unique identifier if they are shipped directly from the manufacturer, marketing authorisation holder or a designated wholesaler.

Q&A 6.9: The pharmacy branch must also be clearly identifiable when connecting to the NMVS system.

Questions 1.8, 2.14, 4.4 were added:

Q&A 1.8: The importer of a medicinal product who imports a product into a Member State according to Article 5(1) of Directive 2001/83/EC does not have to upload the unique identifiers into the national database of the country of destination.

Q&A 2.14: If the application of the unique identifier on the packaging of a medicinal product is outsourced to third parties, this must be done in accordance with the principles described in the EU-GMP Guideline Part I Chapter 7.

Q&A 4.4: A manufacturer may use packaging that carries a unique identifier applied by a packaging manufacturer. If pre-printed cartons are used, a written agreement is required that defines the respective responsibilities. The supplier of the packaging materials must be audited and qualified. It is expected that the manufacturer of the finished medicinal product will carry out appropriate checks on the quantity and quality of the unique identifiers in accordance with EU GMP principles.


C.19. Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products

Shortly after the publication of the EMA's final assessment report on nitrosamine impurities in medicinal products (https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf) this 15-page Q&A for marketing authorisation holders and applicants was published on 6 August 2020. It replaces the meanwhile withdrawn document 'Information on nitrosamines for marketing authorisation holders' EMA/428592/2019 published in September 2019.
The 18 questions and answers on the topic of "risk assessment" deal with the expectations that will be placed on marketing authorisation holders and applicants in the future. They should

  • design their manufacturing processes and controls to prevent or mitigate the presence of N-nitrosamines in their API and FP(s);
  • assess the risk of presence nitrosamine impurities in their API(s) and FP(s) and introduce any resultant changes to the dossier as needed (e.g. changes to their manufacturing processes);
  • ensure that active substances and excipients used in their FPs are manufactured in compliance with good manufacturing practices in line with Article 46(f) of Directive 2001/83/EC.

The following questions, among others, are answered:

  • What is the “call for review” and which three steps have to be followed?
  • What are the currently known causes for the presence of nitrosamines?
  • What factors should be considered in prioritizing the risk evaluation and how should the evaluation be performed?
  • How should the confirmatory tests be conducted by MAHs and manufacturers?
  • What are the requirements for the analytical methods?
  • Which limits apply for nitrosamines in medicinal products?
  • What are the responsibilities of MAHs for active substances with Certificates of Suitability (CEPs) and Active Substance Master Files (ASMFs)?
  • What are the regulatory requirements in other regions?

Chapter D CFR and FDA Guidelines

D.27 Control of Nitrosamine Impurities in Human Drugs – Guidance for Industry

This document is the FDA’s equivalent to the assessment report and the corresponding Q&A by the EMA. Published on 1 September 2020, the guidance is based on the FDA’s current understanding of the chemistry and discusses the potential causes for the formation of nitrosamines. Along with this, the docu00_ment presents a comprehensive risk assessment strategy to detect and prevent their presence. Acceptable intake (AI) limits for the nitrosamine impurities NDMA, NDEA, NMBA, NMPA, NIPEA, and NDIPA are recommended.
Furthermore, circumstances leading to an external introduction of nitrosamines are described as possible sources of contamination. These may origin from catalysts, reagents or recovered solvents. If a contamination is detected in a finished drug, the FDA has to be notified once confirmatory tests have been performed. The guideline provides a step by step instruction.

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