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The year 2020 will stay with us for a long time; and so most likely will 2021. Life was full of changes and restrictions, not only in the private aspect. The working world and focal points of the regulatory authorities have also changed, in some cases considerably. Many activities now had to be performed online; including audits, inspections and batch release. And hovering over everything was the Brexit. The following article summarizes a few of the highlights.

Remote Certifications

The European Commission, the European Medicines Agency (EMA), and the heads of national medicines agencies (HMAs) agreed on a series of measures to mitigate the impact of the problems and challenges caused by the COVID-19 pandemic.

One interesting outcome is the question-and-answer document1 on regulatory expectations, which is updated regularly1. One Q&A addresses the role and responsibilities of Qualified Persons (QP) and remote batch certification. These may be possible under certain circumstances, "remote batch certification is permissible under EU GMP rules, provided that the QP has access to all information necessary to enable them to certify the batch."

While the document acknowledges that some member states may have additional or different requirements that prevent remote certification, it also states that "considering the current restrictions of travelling linked to the COVID-19 pandemic, the remote certification should be acceptable in all EEA Member States."

Distant Assessments

Until recently, almost all audits conducted were on-site. From time to time, auditors used questionnaires and checklists. But these were or are more or less an addition in the qualification process.
When the GMP specifications and regulations were written and introduced, it wasn't with the thought of a pandemic in mind. Some of the requirements to perform on-site audits are therefore clear, for example in Article 46(f) EU Directive 2001/83/EC:
"the holder of the manufacturing authorisation shall verify compliance by the manufacturers and distributors of active substances with good manufacturing practice and good distribution practices by conducting audits at the manufacturing and distribution sites..."

Distant assessments, as we have come to understand them lately, e.g. with direct video and audio communication, were so far not addressed or regulated. Here, however, the above-mentioned questions and answers document1 helps us.

Question and answer 2.2 deals with GMP certificates and manufacturing/ import authorisations. Due to the current difficulties in performing on-site GMP inspections, it is often not possible for authorities to extend the validity of GMP certificates accordingly. However, this should be possible now to avoid difficulties in the availability of medicines - until the end of 2021. The validity of manufacturing/ import authorisations should also be extended (if they are time-limited).

For new sites, a distant assessment by a competent EU/EEA authority may be an option. A GMP certificate can then be issued depending on the outcome of the assessment. However, it should be specified that the certificate was issued on the basis of a Distant Assessment. In addition, an on-site inspection should be conducted as soon as circumstances permit. Limited or brief on-site inspections in the EEA should also be considered at this time if compatible with travel restrictions, health measures, and other limitations.

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Where on-site audits of active ingredient manufacturers are not possible, the QP may refer to paper-based audits and also consider the results of inspections by competent authorities. Decisions should be based on a scientific approach and an adequate and documented risk assessment.

Because of the COVID-19 pandemic, almost all inspectorates have postponed routine inspections both domestically and internationally. Alternative approaches including distant assessments were also increasingly used. A harmonized procedure was not discernible for some time. Then, in November, the EMA published a GMP/ GDP guidance document (EMA/335293/2020)2 for such distant assessments to provide guidance for inspectors. In addition to a detailed definition, it also describes prerequisites and the most important points in preparation and implementation. However, the authors clearly point out that Distant Assessments are not intended as a substitute for on-site inspections outside of crisis situations and that on-site inspections should be carried out as soon as circumstances allow.

The US FDA has not yet carried out any Distant Assessments, as we define them.

The companies themselves currently have little choice but to resort to these options. It is advisable for each company to carry out an individual risk assessment and to document the result achieved in detail. This should include plans for what to do when restrictions are lifted to ensure that on-site audits are resumed and repeated in a timely manner.

Thus, a Distant Assessment is a possible (and currently sensible) way to assess a supplier's GMP compliance when an on-site audit is not possible, but it cannot fully replace an on-site audit.


The approaching Brexit and the long uncertainty also kept us busy in 2020. Despite the uncertainties, the authorities have tried to formulate and set their expectations as far as possible.

EU expectations

The European Commission had published a notice3 for businesses, governments and citizens in summer 2020 to prepare them for the end of the transition period. The document is appropriately titled "Ready for change - Communication to prepare for the end of the transition period between the European Union and the United Kingdom."

And even with a successfully concluded agreement, the future relationship will be very different from the previous situation in the single market with a customs union. For example, on January 1, 2021, the United Kingdom (UK) also exited the Union's regulatory system for medicines and medical devices.

After intensive negotiations, the European Union (EU) and the United Kingdom (UK) agreed on a provisional Trade and Cooperation Agreement on 24 December 2020. By the end of the year, all remaining EU member states have given their consent to the agreement and its provisional application. For the agreement to finally enter into force, the approval of the European Parliament is still required.

What does the document say?

Primarily, the document is about an economic partnership and trade regulations. It provides a free trade agreement which contains neither tariffs nor quotas for goods that comply with the relevant rules of origin. Furthermore, it also deals with topics such as services, professional qualifications, environmental and energy issues, freight transport as well as regulations on social security or research and development. A fairly good overview of the regulations can be found here.

Only a few of the regulations relate directly to medicinal products and the associated requirements. There is a dedicated annex (TBT- 2: Medicinal Products), but it mainly refers to cooperation, the recognition of inspections, the exchange and recognition of official GMP documents and the establishment of a working group - but nothing that could change the situation communicated by the EU Commission, EMA and MHRA already last year.

This is not a Mutual Recognition Agreement (MRA), as many had hoped. Neither the mutual recognition of batch testing nor the batch certification and release of medicinal products is covered. This means that for medicinal products imported from the UK, batch certification must be carried out by an EU based Qualified Person (QP) according to EU GMP.

A possible mutual recognition of marketing authorisation decisions was also not agreed on, nor was a transition period.

The document goes on to say that "in specific circumstances" an authority may "opt not to accept an official GMP document issued by an authority of the other Party for manufacturing facilities located in the territory of the issuing authority", e.g. in the case of inconsistencies or inadequacies in an inspection report or quality defects. The authorities on both sides of the channel thus exchange all the information necessary for the recognition of inspections and of official GMP documents. However, this is not a guarantee any authority has "the right to conduct its own inspection of manufacturing facilities that have been certified as compliant by the other Party".

The Annex also states that the EU and UK "shall endeavour to consult one another" in the development and adoption and implementation of internationally agreed scientific or technical guidelines. This is probably intended to prevent a slow drift apart of new GMP requirements. However, it is not a guarantee. In the case of planned changes to applicable laws, regulations and administrative provisions, the contracting party must be notified at least 60 days "before adopting any new measures or changes relating to Good Manufacturing Practice".

Guidance for UK

The MHRA has currently updated or created a set of guidance. For example, guidance documents in the area of medicines approval and new assessment routes have been updated. This has introduced changes to national licensing procedures, including procedures to prioritise access to new medicines that will benefit patients, an accelerated assessment procedure and new routes of evaluation for novel products and biotechnological products. Details can all be found on the MHRA website.

The challenges of centralised marketing authorisations and ongoing marketing authorisation procedures are also addressed and new guidance is published, such as "Guidance on the handling of applications for Centrally Authorised Products (CAPs)" and "Procedural advice for Northern Ireland on applications for European Commission Centralised Marketing Authorisations". Guidance on the handling of Decentralised and Mutual Recognition Procedures which are approved or pending has also been published in an updated form.

The MHRA has also published guidance on the location of marketing authorisation holders and QPPVs (Qualified Person responsible for Pharmacovigilance). This somewhat unwieldy document states that the required QPPV for nationally authorised products can be based not only in the UK but also in the EU or EEA. Marketing authorisation holders for UK marketing authorisations must be established in the UK or in the EU or EEA. However, if the QPPV is not based in the UK, a UK contact person for pharmacovigilance is required.

Caution! Conversely, a QPPV established in the UK will not be accepted in the EU Member States.

Northern Ireland - an (as yet) unresolved problem?

In early November, the Ireland/Northern Ireland Technical Committee held a video conference4 to share updates on the implementation of the so-called Northern Ireland Protocol. The meeting was co-chaired by officials from the British government and the EU Commission. Also part of the British delegation was a representative of the Northern Ireland Executive.

The committee noted that "an agreed approach had been reached on a phased process for implementing medicines regulation in Northern Ireland up to 31 December 2021, providing the additional time needed for businesses to prepare in relation to batch testing, importation and Falsified Medicines Directive requirements."

Toward the end of the year, the discussion picked up steam once again. Following an online webinar for invited stakeholders (including representatives from ECA and EQPA) on December 1, a Q&A paper5 was published immediately after. The questions and answers cover the most important areas for medicinal products and APIs, e.g. approval procedures, clinical trial procedures and also GMP-related issues. Additionally, the question of whether batch release control, batch release, and batch certification must be performed by a manufacturer located in Northern Ireland was clarified.

End of January, the EU Commission published a new notice entitled "Application of the Union's pharmaceutical acquis in markets historically dependent on medicines supply from or through Great Britain after the end of the transition period" (2021/C 27/08)6.

In this document, a good summary is given on the situation:

  • Medicinal products (in the scope of the abovementioned legislation) placed on the market in Northern Ireland must comply with the regulatory requirements laid down in Union law;
  • Medicinal products must have a valid marketing authorisation in the EU or in Northern Ireland;
  • Trade in medicinal products from Great Britain to Northern Ireland or to the Union constitutes an import in the sense of applicable Union law;
  • Trade in medicinal products from the Union or Northern Ireland to any other part of the United Kingdom (Great Britain) or any other third country constitutes an export in the sense of applicable Union law;
  • Authorisations issued by UK authorities are, in principle, not valid under Union law, but can only be recognised in Northern Ireland if adopted in accordance with applicable Union law;
  • Any steps in the supply of medicines which must be carried out in the Union (e.g. batch release) in order to allow for the placing on the market of medicinal products in accordance with Union law must occur in the (geographical) scope of Union law, i.e. in the Union or Northern Ireland, and only actions that may be carried out in third countries may occur in Great Britain.

The Role of the Qualified Person:
Further Guidance entitled "Acting as a Responsible Person (import) from 1 January 2021" states that the RPi should ensure that written evidence is available that each batch of product has been QP certified in accordance with Article 51 of Directive 2001/83/EC.

  • This batch certification by a QP can be confirmed by the following evidence:
  • Batch certificate confirming QP certification in accordance with Article 51 of Directive 2001/83/EC.
  • A copy of the 'Control Report' (Appendix II to Annex 16 of EU Good Manufacturing Practice).
  • Certification statement (ad-hoc, confirming certification according to Article 51 of Directive 2001/83/EC)
  • Reference to internal company systems (e.g. global enterprise resource planning system) indicating batch certification.
  • Confirmation that the last manufacturing step (other than batch certification) of an approved drug product was performed by a manufacturing and import license holder in a listed country. A copy of the authorization and technical agreement with the manufacturer should be available to rely on this supply chain control.
  • For medicines approved in a listed country (see above), batch certification can be verified by confirming that the medicine was purchased from an approved wholesaler after it was placed on the market in the listed country.

Import: Annex 21 finally published

On March 20, after several delays, Annex 21 to the EU GMP Guide was published in draft form. The document is titled "Importation of medicinal Products." The concept paper was already published here on May 13, 2015 (EMA/238299/2015) and the consultation period ended in August 2015. The first draft for regulatory consultation was then available in November 2016. Since then, no further activities or versions have been published.

The document is aimed at Marketing Authorization Holders (MIA Holders) who import medicinal products for human or veterinary use from third countries. It does not cover products that do not have a marketing authorization in the EU/EEA and are directly reexported. The following points are to be regulated with the new annex:

  • Physical transfer from a third country to the EU/EEA.
  • Physical receipt of the product
  • Certification by a Qualified Person/ QP
    - Interlinking with the requirements of Annex 16 to the EU GMP Guideline
  • Pharmaceutical quality system
    - Including deviation, complaint and recall system
  • Requirements for buildings and facilities
    - Reference to chapters 3 and 5 of the EU-GMP Guidelines
  • Documentation
  • Requirements for documentation to be submitted to the QP for certification and the PQR
    - Scope and frequency of the audit
    - Provision of documents in a language that can be understood by all parties involved.
  • GMP requirements for third country manufacturers and exporters
    - Qualification and audits under the responsibility of the importing facility.
  • Inspection at import, if not from a third country with MRA or ACAA
    - Reference to the detailed regulations in Annex 16
  • Contractual regulations between manufacturer in third country, all companies involved in import (e.g. testing facilities) and marketing authorization holder

The issue of "fiscal import" when the product physically remains in the EU but changes ownership to a third country is no longer addressed in the current second draft, neither is the issue of re-importation.

Annex 1: The new draft (still) under discussion

The draft of Annex 1 to the EU GMP Guidance was published on December 20, 2017 already (Annex 1 "Manufacture of Sterile Medicinal Products; Targeted stakeholders consultation"). The GMP Journal has already provided comprehensive information about the planned changes, so that they will not be discussed here again. The final version is still pending and there may still be some adjustments.

There were comments from 140 companies and organizations during the comment period, but no consistent comment from the pharmaceutical industry.

Following the analysis and evaluation of the comments and after consultation with PIC/S and WHO, version 12 was published by the Commission on February 20, 2020 for a "targeted stakeholder consultation". Selected associations were asked to provide their comments on specific points that were still critical. Due to the Corona pandemic, the comment period was extended by three months to July 20, 2020. ECA, along with EQPA, was also invited to comment on the final draft. This comment was prepared with the assistance of individual members7 and included 62 separate items.

Consolidated GMP guidelines for Marketing Authorisation Holders

Early in 2020, the European Medicines Agency (EMA) published a so-called Reflection Paper (EMA/457570/2019) containing the consolidated GMP requirements for Marketing Authorisation Holders. The comment period ended in July 2020, and not much has been heard since.

Section 5 of the document describes, or at least summarizes, each GMP requirement applicable to the marketing authorization holder. These are:

  • Outsourcing and technical agreements
  • Audits and qualification activities
  • Communication with manufacturing sites (e.g., information on marketing authorization dossiers, deviations, commitments to the regulatory authority, etc.)
  • Product quality assessments
  • Quality defects, complaints and product recalls
  • Maintaining the supply of medicines
  • Continuous improvement activities

In addition, Chapter 6 discusses responsibilities related to the Falsified Medicines Directive (FMD), including responsibilities for safety features, the repository system, uploading serialization data, and posting serialization numbers.

Corona: Flexibility in the GMP/GDP system

The European Commission, the European Medicines Agency (EMA), and the Heads of Medicines Agencies (HMAs) also updated their question-and-answer document1 previously described here on regulatory expectations for necessary changes during the Covid 19 pandemic. A revision added a new section on "Additional temporary GMP and GDP flexibility."

This section discusses the possibility of temporary changes to certain planned quality-related tasks. These changes to certain elements of the quality system are now possible for shifting resources to ensure the supply of essential medicines during the pandemic (and only then!). With proper justification, certain routine activities could be postponed, such as:

  • Maintenance, re-qualification, re-validation, re-calibration
  • Regular review of PQS documents
  • Re-audits of suppliers on site and replacement by remote audits
  • Regular trainings
  • Stability tests

However, some prerequisites must be taken into account:

  • The changes do not adversely affect the quality, efficacy and safety of medicinal products
  • The changes should be transparently managed and documented as part of the pharmaceutical quality system (PQS)
  • A quality risk management system should be in place
  • The Qualified Person (QP) should be informed of planned changes
  • Changes cannot be used to facilitate certification of batches affected by noncompliance with registered specifications

Veterinary Medicinal Products

Directive 2001/82/EC - EU Codex for Veterinary Medicinal Products will be repealed with effect from 28 January 2022 and replaced by Regulation (EU) 2019/6. This contains directly applicable, harmonized rules for veterinary medicinal products and is based on the experience that veterinary medicinal products are subject to different requirements than medicinal products for human use. The most important changes at a glance:

  • Veterinary prescriptions may only be issued by veterinarians (with a few exceptions).
  • Establishment of a central EU database of all authorized veterinary medicinal products.
  • Pharmacovigilance data recording adverse events to be made available to all veterinarians.
  • Reporting system to be made more user-friendly.
  • Internet sales only for medicines that do not require a prescription (with national exceptions).
  • The transfer of veterinary medicinal products from another member state will be simplified
  • Repurposing of human medicines will only be allowed if no veterinary medicine is available in the EU for that indication and species.
  • To combat antibiotic resistance, certain antibiotics that are important for treating humans can be restricted or banned for use in animals.
  • The ban on the use of growth-promoting antimicrobials and antibiotics reserved for treatment in humans also applies to imported animals and animal products from third countries.

Nitrosamines: EMA informs about new deadline for risk assessment

Following the discovery of N-nitrosodimethylamine (NDMA) and other nitrosamines in numerous medicines, the EMA has asked marketing authorization holders (MAHs) to take precautions to reduce the risk of the formation or presence of nitrosamines in the manufacture of all medicines containing chemically synthesized active ingredients. Marketing authorization holders were required to submit their risk assessments for medicinal products to the authorities within 6 months. Within this timeframe, it became apparent that meeting the March 26, 2020 deadline for submission of these risk assessments was a major challenge. Most problematic was obtaining all relevant information from suppliers of active ingredients, raw materials, and other indirect materials. Another major obstacle was the closure of some sites due to the COVID 19 pandemic.

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The EMA had then agreed to extend the deadline for submission of risk assessments to October 1, 2020. However, as before, marketing authorization holders were required to inform national competent authorities as soon as possible if tests confirmed the presence of nitrosamines, regardless of the amount detected.

Then, at the end of October, the EMA presented a plan to implement the recommendations to reduce drug impurities from nitrosamines ("Lessons learned from presence of N-nitrosamine impurities in sartan medicines - Implementation Plan")8. The comprehensive implementation plan also proposes amendments and adaptations to chapters and annexes of the EU GMP Guide, including a timeframe for their implementation.

WHO publishes GMP standards for pharmaceutical development

Given the need for rapid development of medicines to treat COVID- 19, the World Health Organization (WHO) has published new Good Manufacturing Practice (GMP) guidance for development batches9. The deadline for comments on this was quite tight (January 6, 2021). According to the WHO, there have been no previous guidelines addressing this issue. The main focus of the document is on pharmaceutical formulation and development. Thus, the WHO document is intended to provide research and development (R&D) facilities with a form of GMP guidance.

In addition, WHO had shortly before published for comment a new GMP Guideline for Investigational Medicinal Products10, which specifically addresses the requirements and recommendations for products used in clinical trials (IMPs). According to WHO, the update to the document, "WHO Good manufacturing practices for investigational pharmaceutical products for clinical trials in humans" (WHO Technical Report Series, No. 863), is intended to bring the guideline in line with current expectations (e.g., in Annex 13 of the EU GMP Guide) and trends in good manufacturing practice (GMP).


Revision of Chapter 4 and Annex 11 EU-GMP Guidelines

The revision of Chapter 4 and Annex 11 to the EU-GMP Guideline is approaching. The last update of Chapter 4 (Documentation) and Annex 11 (Computerised Systems) took place in 2011, but in recent years there has been a considerable further development in many areas, e.g. the increased use and storage of electronic data and documents, automation in production and laboratories, electronic management of data also in the cloud, and much more. Adaptation has therefore become necessary.

ICH Q9(R1) - Quality Risk Management

Since 2005, ICH Guideline Q9 has been the state of the art when it comes to quality risk management (QRM) in the GMP environment. Now it is to be revised.

ICH has published what is planned regarding the revision in a concept paper. As a justification for the revision, the Council states that the benefits of quality risk management are not yet fully realized. In particular, digitalization in the GMP environment and new (emerging) technologies (such as continuous manufacturing and PAT) should also be able to benefit from the revision.

It is planned to develop specific, officially accessible, training material beyond the already available "briefing pack". The development of this training material is stated as the main revision goal. Furthermore, there will be specific adaptations in selected chapters and annexes in 4 areas

  • The excessive level of subjectivity in risk assessments and QRM outputs.
  • Assessment of product availability risks
  • Lack of understanding of the level of formality required
  • Lack of clarity about risk-based decision making.

The concept paper also cites more clarification on maintaining risk assessments and implementing the "Risk Review" as other suggestions for change. The "Risk Review" should also be more linked to continuous improvement, as mentioned in ICH Q10, and life cycle management from ICH Q12/14.


Wolfgang Schmitt
... is Vice President at CONCEPT HEIDELBERG and organises and conducts courses and conferences on behalf of the ECA Academy
in the areas QA and GMP.


1 Notice to Stakeholders: Questions and answers on regulatory Expectations for medicinal products
for human use during the COVID-19 pandemic (

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