18.01.2022 | LOGFILE Feature 02/2022

The GMP Regulations Report 2021

The GMP Regulations Report 2021

13 min. reading time | shortened version


From a regulatory perspective, the year 2021 had plenty in store. Parallel to the omnipresent COVID-19 pandemic, the authorities around the world managed to finalize draft documents that became “sideshows” while the pandemic took centre stage. What topics kept the GMP professionals on their toes?

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

European Commission



FINAL – EC: Q&As on Safety Features Version 19, December 2021

The following questions were added or updated to the Q&A over the year:

  • Question 1.14: Are there mandatory specifications for tamper evidence?
    The citation of EN ISO standard 21976:2020 “Packaging – Tamper verification features for
    medicinal product packaging” as a reference for consideration by manufacturers replaces
    the CEN standard EN 16679:2014 “Tamper Verification Features for medicinal product packaging”
    with Europe-wide relevance. The ISO standard has international validity.
  • Question 1.22: In the case of parallel-traded packs, can parallel traders cover or remove the
    safety features of the original pack?
    Answer: Yes. Parallel traders who cover or remove the existing safety features are required
    to apply equivalent safety features in accordance with Article 47a of Directive 2001/83/EC.
    If the product code or/and batch number change, the original one must be decommissioned
    as a first step. The new individual identifier should comply with the requirements of
    the Member State where the medicinal product is to be placed on the market. In any case,
    traceability must be maintained in the final storage system.
  • New Question 1.29: Do the unique identifiers of reference and retention samples taken
    from stock in compliance with Annex 19 of the EU GMP Guidelines5 and uploaded to the
    EMVS have to be decommissioned? If yes, to what status?
    Answer: Yes, if a sample of a batch is taken as reference or retention sample after uploading
    in EMVS, it should be decommissioned as “sample”. If a sample is taken voluntarily
    by a wholesaler that fall outside the scope of Annex 19, they should be decommissioned as
  • Question 5.8: Can a wholesaler request another wholesaler to verify the authenticity and
    decommission the unique identifiers for medicinal products they intend to distribute outside
    the EU on their behalf?
    Answer: No, this obligation cannot be delegated, as the audit trail would not reflect the
    reality of the supply chain.
  • Question 7.19: Can a marketing authorisation holder delegate the uploading of the information
    laid down in Article 33(2) of Commission Delegated Regulation (EU) 2016/161?
    Answer: Yes, this is possible if there is a written agreement between both parties. However,
    the legal responsibility will remain with the MAH. He must ensure the accuracy, confidentiality,
    and integrity of the data uploaded into the system.


Chapter C.8.2.1 GMP Compliance Adviser

GMP News

Q&A Safety Features, Version 19

EU: Delegated Regulation (EU) 2016/161 on Safety Features, March, September and December 2021

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:

  • The amendment is to exempt the obligation for wholesalers to deactivate the unique identifier of medicinal products exported to the United Kingdom – now a third country.
    Please note: This adjustment was originally scheduled for 2021. In December 2021, an extension of this exemption was granted for an additional three years, until December 2024. This is to ensure the supply of medicines to Cyprus, Ireland, Northern Ireland, and Malta.
  • An alert system is introduced to report in case a verification of a medicine destined for these countries takes place outside of one.
  • The basic objective of Article 47 is to establish rapid action to protect public health in the event of exposure to falsified medicinal products. In the future, corresponding reports (according to Article 46) are to be evaluated by the Commission without delay and within 45 days at the latest.
  • In Annex I, which lists product categories or APIs that in principle may not bear safety features, “Cicatrizants with ATC code D03AX – dosage form fly larvae” has been newly included. Since their shelf life is limited, the risk of counterfeiting is negligible, according to the justification for the inclusion.


Chapter C-8.2 GMP Compliance Adviser

GMP News

Commission Delegated Regulations (EU) 2016/161

Amendment to Delegated Regulation (EU) 2016/161 (January 2021)

Amendment to Delegated Regulation (EU) 2016/161 (July 2021)




FINAL – Validity of GMP and GDP Certificates Extended and Q&A Updated, September 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:

  • Question 2.2 concerning the extension of certificates was updated
  • Questions 4.2-4.4 regarding pharmacovigilance activities were added


GMP News

Regulatory expectations and flexibility during Covid-19, Q&A

EMA: COVID-19, latest updates

Final – Q&A on Nitrosamines, July and September 2021

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

  • the specified acceptable intake limit for the nitrosamine is exceeded
  • the corresponding lifetime excess cancer risk of 1:100000 is exceeded
  • it is a newly identified nitrosamine not covered in CHMP Article 5 (3), irrespective of the amount detected

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:

  1. Application of a general class specific TTC (18 ng/day) in line with CHMP article 5(3) Q&A
  2. Application of substance specific AI limit (including SAR considerations)

Important deadlines for MAHs to submit their confirmatory tests under step 2:

  • for products containing chemically synthesised active substances: by 26 September 2022
  • for products containing biological active substances: by 1 July 2023

Question 10 “Which limits apply for nitrosamines in medicinal products?”

Newly listed:

  • N-nitroso-varenicline, NNV, was added to the table of specific nitrosamines with a limit of 37.0 ng/day.
  • N-nitrosomorpholine, NMOR was added with a limit of 127 ng/g.


Chapter C.19 GMP Compliance Adviser

GMP News

EMA: Nitrosamine impurities

EMA: Q&A on nitrosamine impurities




Revision of Nitrosamine Guidance, February 2021

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

GMP News

FDA: Control of Nitrosamine Impurities in Human Drugs – Guidance for Industry

FDA: Information about Nitrosamine Impurities in Medications




FINAL - ICH Q3C(R8) Guideline for Residual Solvents, April 2021

The Permitted Daily Exposure (PDE) values for the following substances were added: 

  • 2-Methyltetrahydrofuran (50 mg/day), classified in solvent class 3
    Methyltetrahydrofuran was found to be non-genotoxic in a mutation assay with bacteria, human lymphocytes, and rats. No data are available on carcinogenicity. Reproductive toxicity and repeated-dose toxicity were not observed.
  • Cyclopentyl methyl ether (15 mg/day), classified in solvent class 2
    No toxicity in humans was found. Likewise, no genotoxic potential was found. Again, no data are available on carcinogenicity. No statements could be made on reproductive and developmental toxicity based on data available to date.
  • Tertiary butyl alcohol (35 mg/day), classified in solvent class 2
    No genotoxicity was found. The data on carcinogenicity do not allow any precise conclusions to be drawn regarding the effect on humans, while changes in the renal tubules were found in rats. No precise statements could be made on reproductive toxicity either, but moderate transient systemic toxicity was found in rats.


Chapter E.3.C GMP Compliance Adviser

GMP News

ICH: Impurities: Guideline for Residual Solvents Q3C(R8)




Final – Guidline on Data Management and Integrity, July 2021

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

GMP News

PIC/S: Q&A on Data Management and Integrity




Final – WHO Guideline on Data Integrity (TRS No.1033, Annex 4), March 2021

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

FINAL - GMP for Water for Pharmaceutical Use (TRS No. 1033, Annex 3), March 2021

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

  • on various specifications for WPU,
  • good practices for the quality management of water systems,
  • water treatment systems (production),
  • water storage and distribution systems,
  • commissioning, qualification and validation,
  • sampling and testing, and
  • routine monitoring of water.

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

Hybrid & Remote Inspections



FINAL – ICMRA: Authorities Reflections on Global Experiences with Remote Inspections, November 2021

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:

  • Remote inspections enable minimal regulatory oversight during the pandemic but will not be able to replace on-site inspections in the future.
  • Some regulators from the working group are indeed looking at a future use of remote inspections, while others do not believe that the concept of remote inspections will be a permanent solution.
  • Remote and hybrid inspections are overall seen as an "additional tool" for inspections that may be used after the pandemic. But it is seen difficult to replace an inspector's on-site walk-through with visual technology.


GMP News

ICMRA: Reflection Paper

FINAL - FDA: Q&A on Remote Inspections, May 2021

As the pandemic still restricts most onsite inspections the FDA further clarifies general questions on remote inspections.

What’s new?

  • It is clarified under which circumstances a pending application may be approved when a physical inspection cannot be conducted
  • Detailed information is given regarding the issue of "complete response (CR) letters" in case of remote inspections.
  • The action FDA will take if a decision on an application must be deferred due to insufficient information for conducting a remote inspection is described.

With an overall inspection backlog the FDA is taking additional steps to bridge the gap. A “resiliency roadmap” addresses the various challenges.


GMP News

FDA: Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency

Medicinal Product



FINAL - EMA: Guideline on Quality Documentation for “Combination products”, July 2021

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:

  • MPs where the medical device and/or device part and the medicinal product form an integral product that is not reusable (integral) and where the action of the medicinal product is principal
  • MPs placed on the market by the MAH, where the medical device is packed together with the medicinal product (co-packaged)
  • MPs where the product information refers to a specific medical device to be used with the medicinal product, and the medical device is obtained separately by the user of the medicinal product (referenced)


Chapter C.20 GMP Compliance Adviser

GMP News

Guideline on quality documentation for medicinal products when used with a medical device

Final – EC: EU MDR in Frce with New Q&A, May 2021

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

  • the many patient benefits from a new approach for medical device oversight
  • delineates which products are affected by the new regulation and in what way
  • general information on the validity of products certified under the old scheme for which a transitional period is granted until May 2024, or
  • the role of the Notified Bodies and the state of play on EUDAMED

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

GMP News

EC: Press Corner

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


GMP Compliance Adviser

GMP Compliance Adviser

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:

  • GMP in Practice
    "How-to-do" interpretations and knowledge of our renowned industry specialists and according to international GMP rules. It contains 21 chapters and provides practical assistance with checklists, templates and SOP examples.
  • GMP Regulations
    The most important GMP regulations from Europe, the United States, Japan and many other countries (e.g. PIC/S, ICH, WHO, ...).

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