First and foremost, the new EU regulation on medical devices generated numerous documents along with all the resulting adaptions throughout Europe. The same applies to new forms of inspections and necessary guidelines that come along with it: While they are still largely carried out remote, hybrid inspections have also made their entrance into the GMP world. To name another one, the breakaway of the UK from the EU likewise caused a flood of new regulations. Take advantage of this compilation as your easy-at-hand overview!
Note: This is an abridged version.
The detailed version is available to the GMP Compliance Adviser costumers.
This long version is also available for download. Just click on the button below.
> Download now: The GMP Regulations Report 2021 – long version
The following questions were added or updated to the Q&A over the year:
Chapter C.8.2.1 GMP Compliance Adviser
Q&A Safety Features, Version 19
The following amendments have been published in the Official Journal of the European Union to Delegated Regulation (EU) 2016/161. The amendments concern an exemption for export to the United Kingdom, as well as Article 47 and Annex I:
Chapter C-8.2 GMP Compliance Adviser
Commission Delegated Regulations (EU) 2016/161
Amendment to Delegated Regulation (EU) 2016/161 (January 2021)
Amendment to Delegated Regulation (EU) 2016/161 (July 2021)
The European medicines regulatory network has announced the automatically applied extension of the validity of GMP and GDP certificates for sites in the EEA (European Economic Area) until the end of 2022, unless there are restrictions on the validity period stated in the clarifying remarks of the certificate. This extension also applies to time-limited manufacturing and import and wholesale authorisations.
The Q&A guidance document has been adapted, accordingly:
Regulatory expectations and flexibility during Covid-19, Q&A
The document considers the latest regulatory requirements for nitrosamine impurities and is revised continuously. The revisions made in 2021 relate to questions 3 and 10:
Question 3 “For the ‘call for review’ for chemically synthesised and biological medicinal products, when and how should MAHs report steps 1 and 2 to competent authorities?”
The question refers to the submission templates for Step 2 “Confirmatory testing”. The template should only be used in addition to the "Step 2 – Nitrosamines detected response template" if
Please note: The Step 2-template provides two options for alternative indication of limit values of newer nitrosamines not considered in the "Assessment report" (according to Article 5(3) of Regulation EC 726/2004) of the CHMP of June 2020:
Important deadlines for MAHs to submit their confirmatory tests under step 2:
Question 10 “Which limits apply for nitrosamines in medicinal products?”
Newly listed:
Chapter C.19 GMP Compliance Adviser
EMA: Q&A on nitrosamine impurities
The revision of the FDA nitrosamine guidance details the recommended timeframe for API manufacturers for a risk assessment of nitrosamine impurities.
“Confirmatory testing should start as soon as the risk of nitrosamine is identified from the risk assessment and should begin immediately for products considered at high risk. To ensure the safety of the U.S. drug supply, confirmatory testing of drug products and submission of required changes in drug applications should be concluded within 3 years of publication of the original guidance, with a recommended completion date of on or before October 1, 2023.”
Unlike the European Q&A paper on the subject, US manufacturers do not need to submit risk assessment documents to the agency, but they should retain these documents to be available if requested.
Chapter D.27 GMP Compliance Adviser
FDA: Control of Nitrosamine Impurities in Human Drugs – Guidance for Industry
FDA: Information about Nitrosamine Impurities in Medications
The Permitted Daily Exposure (PDE) values for the following substances were added:
Chapter E.3.C GMP Compliance Adviser
ICH: Impurities: Guideline for Residual Solvents Q3C(R8)
After five years of drafting, PIC/S has now published the final version of a new guideline on data integrity, the PIC/S Guidance on Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (PI 041-1). The document has already been applied in practice on a trial basis during this time and has been modified twice.
With 63 pages, the document covers all aspects that are to be considered when handling data in the GMP/GDP field. From basic principles, such as ALCOA, to considerations for paper-based or computerized systems or the handling of so-called "findings" and potential risks, all areas are covered. Outsourcing activities and resulting actions such as audits, secure supply chain considerations or document verifications are discussed in a separate section. This also applies to necessary regulatory interventions: Possible "deficiencies" in data management are categorized and suggestions are made on how to address them. A comprehensive glossary concludes the document.
Chapter F.28 GMP Compliance Adviser
PIC/S: Q&A on Data Management and Integrity
This guideline replaces the WHO Guidance on good data and record management practices (Annex 5, WHO Technical Report Series, No. 996, 2016). It includes "GxP for medical devices". In the interest of harmonisation, the document has been aligned to other existing DI guidances. In terms of content, the wheel has not been reinvented, but a clear structure and language speak for the document. Particularly noteworthy are the listed examples for quality risk management and data integrity assessments and the ten examples of good documentation practices in data integrity.
Chapter H.17 GMP Compliance Adviser
WHO TRS Nr. 1033, 2021, Annex 4
This document is a revision of the Guideline on good manufacturing practices: water for pharmaceutical use, which was previously published in the WHO Technical Report Series, No. 970, Annex 2, 2011. It considers water for pharmaceutical use (WPU) that is manufactured, stored, and distributed in bulk. Included are recommendations
Excluded from the document are the production, storage, and use of water in quality control laboratories.
Chapter H.4 GMP Compliance Adviser
WHO TRS Nr. 1033, 2021, Annex 3
The International Coalition of Medicines Regulatory Authorities, ICMRA, has published a comprehensive Reflection paper on experiences with different inspection models to maintain GCP and GMP inspections during the covid pandemic. Chaired by the UK MHRA, the working group gathered representatives from the US FDA, EMA, Health Canada and Swissmedic, German Pei, TGA Australia, PMDA Japan, ANVISA, Saudi FDA, WHO and regulators from Spain, Ireland, France, and Singapore.
The conclusion:
As the pandemic still restricts most onsite inspections the FDA further clarifies general questions on remote inspections.
What’s new?
With an overall inspection backlog the FDA is taking additional steps to bridge the gap. A “resiliency roadmap” addresses the various challenges.
The focus of the 22-page document is on product-specific quality aspects of a medical device and/or part of a medical device that may have an impact on the quality, safety or efficacy of a medicinal product, whether of chemical, biological or radiopharmaceutical type. It is of interest not only for MAHs, but also for manufacturers of such “combination products”.
The guidance is applicable for:
Chapter C.20 GMP Compliance Adviser
Guideline on quality documentation for medicinal products when used with a medical device
As of 26 May 2021, the EU rules on medical devices (EU MDR) entered into force. The new regulation is considered a big step forward to improve the safety and quality of medical devices. It involves fundamental changes in the regulation of medical devices for all European Member States.
Along with the announcement, the European Commission issued a Q&A document on the application of MDR. The document summarises
With the content being held rather general resembling a basic overview, it is noted, that some EU MDR provisions will not be in place until 2025, to allow a smooth transition. The regulation for in vitro diagnostic medical devices will enter into force on 26 May 2022.
Chapter C.10.1 GMP Compliance Adviser
Note: This is an abridged version.
The detailed version is available to the GMP Compliance Adviser costumers.
This long version is also available for download. Just click on the button below.
> Download now: The GMP Regulations Report 2021 – long version
The GMP Compliance Adviser is an online publication that covers all aspects of Good Manufacturing Practice (GMP) in one source.
It is divided into two parts:
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