Review of Developments in GMP and the Regulation of Medicines June 2021

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Vol 26-2C June 2021
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During the last 4 weeks there have been a number of developments in the regulation of the pharmaceutical industry. This month reported issues have come from the Australian, EU, PIC/s, UK and USA regulatory authorities. There are also two interesting industry associations ‘Way Forward’ papers noted in the document section of the report.

The topics covered in this edition of the “Update” include:



  • See Products section of this report


  • Additional measures to allow experts to focus on COVID-19 activities

  • Frequently asked questions

  • EMA / ANVISA Confidentiality Agreement

  • Minutes of the 111th meeting of the EMA Management Board

  • New Organization First User QPPV/RP or Change of EU QPPV/RP

  • Procedural advice for medicinal products intended exclusively for markets outside the European Union in the context of co-operation with the World Health Organisation (WHO)

  • Addendum to the guideline on testing for carcinogenicity of pharmaceuticals S1B(R1)

  • ICH Q3C (R6) Residual solvents

  • Medical Device Regulation comes into application

  • Particulate contamination: sub-visible particles – PDG revision of general chapter released for public consultation

  • Adoption of the revised General Notices chapter.


  • S5(R3) Detection of reproductive and developmental toxicity for human pharmaceuticals

  • Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

  • ICH Q12: Implementation considerations for FDA-regulated products

  • Q3D(R2) Elemental Impurities

  • Qualified Infectious Disease Product Designation— Q&A

  • ANDAs for certain highly purified synthetic peptide drug products that refer to listed drugs of rDNA origin

  • Bispecific Antibody Development Programs



  • Guidance on the management of GMP compliance signals

  • Faecal microbiota transplant (FMT) products regulation

  • Consultation: Remaking of standards and legislative instruments for human cell and tissue (HCT) products, blood and blood components


  • Revision of PIC/S Blood Guidance Documents (PE 005-4 and PI 008-4)


  • More flexible storage conditions for BioNTech/Pfizer’s COVID-19 vaccine

  • One-dose Janssen COVID-19 vaccine approved by the UK MHRA

  • Safety updates COVID-19 vaccines

  • EMA starts rolling review of COVID-19 Vaccine (Vero Cell) Inactivated

  • EMA issues advice on use of sotrovimab (VIR-7831) for treating COVID-19

  • EMA reply to ‘Doctors for COVID ethics’ letters


  • Call for Advanced Therapies to be exempt from EU GMO legislation

  • Call for postponed application and phased implementation of the in vitro diagnostic Regulation




See Products section of this report



Additional measures to allow experts to focus on COVID-19 activities

The new temporary measures include: -

For Pre-authorisation procedures: -

All initial marketing authorisation applications (MAAs) for COVID-19 vaccines and therapeutics will continue to be given first priority. There will continue to be two independent, simultaneous scientific assessments with separate initial reports for these procedures, with no change to the current responsibilities of the rapporteur and co-rapporteur at EMA’s human medicines committee (CHMP).

For initial MAAs for non-COVID-19 products, unless they are advanced therapy medicinal products (ATMPs) or other very complex medicines to be considered by the CHMP, the co-rapporteur will no longer provide a separate assessment report to the rapporteur in the first phase of the evaluation. Instead, he or she will review the submitted data and give a detailed critique of the rapporteur’s assessment report. These measures will free up some of the co-rapporteur resources to focus on COVID-19 activities.

For all applications, there will temporarily no longer be a separate, formally appointed peer reviewer, but the assessment will rely on the intrinsic peer review that is part of the CHMP’s role in the evaluation process. In the case of COVID-19 products, there are additional reviews by the COVID-19 EMA pandemic Task Force (COVID ETF).

These measures will apply to initial MAAs starting in May 2021.

For Post-authorisation procedures: -

Currently, the involvement of co-rapporteurs in the assessment of post-authorisation procedures to extend indications and extension applications (so-called line extensions) depends on the complexity of the file. The approach to these procedures is being temporarily amended as follows:

For COVID-19 products, the co-rapporteur will be systematically involved in all such procedures; however, the need for two separate assessment reports, or for providing a detailed critique of the rapporteur’s assessment report, will depend on the complexity of the application.

For non-COVID 19 products, when the co-rapporteur is involved, the co-rapporteur will produce comments on the rapporteur’s assessment report but will not draft a full separate report in the first phase of the evaluation.

These changes will take effect from May 2021.

Frequently asked questions

EMA has recently updated its FAQ pages

EMA / ANVISA Confidentiality Agreement

The European Commission, EMA and Brazil’s Agência Nacional de Vigilância Sanitária (ANVISA) signed a confidentiality arrangement in 2021. It is valid for an indefinite period of time, unless terminated by either party.

Minutes of the 111th meeting of the EMA Management Board

EMA has published the minutes of this meeting which took place virtually on 11 March 2021.

New Organization First User QPPV/RP or Change of EU QPPV/RP

If a change of qualified person for pharmacovigilance/responsible person for EudraVigilance (QPPV/RP), named person or legal representative within the organisation occurs, you need to notify EMA. There are 2 possible scenarios,

A) There is still a QPPV/RP in your organisation–change of QPPV/RP

B) There is no QPPV/RP in your organisation–first user QPPV/RP of a new organisation

Procedural advice for medicinal products intended exclusively for markets outside the European Union in the context of co-operation with the World Health Organisation (WHO)

EMA has updated this advice. This document addresses a number of questions that users of Article 58 of Regulation (EC) No 726/2004 may have. It provides an overview of the EMA’s position on issues that are typically addressed in pre-submission meetings. The EMA emphasises the importance of pre-submission meetings with applicants. These meetings are an opportunity for applicants to obtain procedural and regulatory advice to streamline the submission of their application. Together with the guidance in this document, successful pre-submission meetings should enable applicants to submit applications that conform to legal and regulatory requirements and that can be validated speedily. Pre-submission meetings also enable applicants to establish contact with the EMA product team who will be involved with the application as it proceeds. In addition, applicants are actively encouraged to seek scientific advice as early as possible in the development process.

Addendum to the guideline on testing for carcinogenicity of pharmaceuticals S1B(R1)

EMA has published this endorsed draft version ICH guideline.

This Addendum covers all small molecule pharmaceuticals where carcinogenicity evaluations are recommended as described in S1A. This Addendum expands theesting scheme for assessing human carcinogenic risk of small molecule pharmaceuticals by introducing an additional approach that is not described in the original S1B Guideline is an integrative approach that provides specific weight of evidence (WoE) criteria that inform whether or not a 2-year rat study adds value in completing a human carcinogenicity risk assessment. The Addendum also adds a plasma exposure ratio-based approach for setting the high dose in the rasH2-Tg mouse model, while all other aspects of the recommendations for high dose selection in S1C(R2) Guideline would still apply.

ICH Q3C (R6) Residual solvents

EMA has updated its advice on this topic.

Medical Device Regulation comes into application

The Medical Device Regulation (MDR), which was adopted in April 2017, changes the European legal framework for medical devices and introduces new principal and supportive responsibilities for EMA and for national competent authorities in the assessment of certain categories of products. The Regulation entered into force in May 2017 and had a staggered transitional period.

The MDR introduces new or revised responsibilities for EMA for:

  • medicines with an integral device, such as pre-filled syringes and pens, and pre-filled inhalers;

  • medical devices containing an ancillary medicinal substance to support the proper functioning of the device. Examples include drug-eluting stents, bone cement containing an antibiotic, catheters coated with heparin or an antibiotic agent and condoms coated with spermicides;

  • medical devices made from substances that are absorbed by the human body to achieve their intended purpose;

  • borderline products for which there is uncertainty over which regulatory framework applies. Common borderlines are between medicinal products, medical devices, cosmetics, biocidal products, herbal medicines and food supplements.

To support the implementation of the MDR, updated guidance on quality requirements for medical devices in human medicines that include a medical device, as well as an updated Q&A, are currently under preparation and will be published shortly.


Particulate contamination: sub-visible particles – PDG revision of general chapter released for public consultation

A new, revised version of general chapter 2.9.19. Particulate contamination: sub-visible particles has been published in Pharmeuropa 33.2. In addition to applying to solutions for dialysis, the European Pharmacopoeia requires this test to be performed for liquid parenteral preparations (0520), sterilised water for injections (0169) and solutions for organ preservation (1264).

This new version is the result of lengthy and fruitful discussions with experts from the Japanese Pharmacopoeia and the United States Pharmacopoeia within the Pharmacopoeial Discussion Group (PDG). The three pharmacopoeias each made a significant effort to come to a consensus on an updated text that is now undergoing public consultation in all three regions.

Comments to be submitted before 30 June 2021.

Adoption of the revised General Notices chapter

The European Pharmacopoeia (Ph. Eur.) Commission adopted a revised version of chapter 1. General Notices.

The chapter was overhauled to provide greater clarity for users, the structure and content of the chapter have also been reviewed.

The chapter features new additions such as a section on monographs for medicinal products containing chemically defined active substances. This new section also provides information on related substances and impurities taken from the relevant Technical Guide.

The wording and terminology have been further harmonised and clarified. E.g, synonyms have been weeded out, with “medicinal product” selected over the formerly interchangeable “finished product” and “pharmaceutical preparation”.

Further terminological changes include “shelf life” and “re-test period” instead of “period of validity” and “period of use”, in accordance with the ICH guidelines. Definitions have also been added for “freshly prepared solution” and “immediately before use”.

Another addition is a sub-section on “Demonstration of suitability of monographs” that provides useful guidance for users.

The scope of first and second identification series and of alternative identifications described in monographs have been clarified and several changes, including an explanation of the rounding rule, information on chiral substances and an example of equivalents, have been introduced in the tests and assay sections of the General Notices.

Lastly, all the paragraphs concerning monographs on herbal drugs that were previously dispersed throughout the text are now gathered together in a single section, for enhanced readability.

The revised chapter will be published in Ph. Eur. Supplement 10.7, available in October 2021.

United States of America

The US Food and Drug Administration (USFDA)

The US FDA has recently published six ICH documents. Three of these are of particular interest / relevance to readers of The Update and are referenced below.

S5(R3) Detection of reproductive and developmental toxicity for human pharmaceuticals

This guidance revises the ICH guidanceS5 Detection of Toxicity to Reproduction for Medicinal Products (September 1994). This revision brings the guidance into alignment with other ICH guidances, elaborates on the use of exposure margins in dose-level selection, incorporates a section on risk assessment, and expands the scope to include vaccines and biopharmaceuticals. It also describes qualification of alternative assays, describes potential scenarios of use, and provides options for deferral of developmental toxicity studies. To assess a human pharmaceutical’s effect on reproduction and development, there should generally be information available that addresses the potential impact of exposure to a pharmaceutical and, when appropriate, its metabolites (ICH M3 (ref. 1), ICH S6 (ref. 2)) on all stages of reproduction and development. No guidance can provide sufficient information to cover all possible cases, and flexibility in testing strategy is warranted.

Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

This guidance provides a framework to facilitate the management of post approval chemistry, manufacturing, and controls (CMC) changes in a more predictable and efficient manner. A harmonized approach regarding technical and regulatory considerations for lifecycle management will benefit patients, industry, and regulatory authorities by promoting innovation and continual improvement in the pharmaceutical sector, strengthening quality assurance, and improving supply of medicinal products. The concepts outlined in prior ICH Quality guidances for industry (ICH Q8(R2), Q9, Q10, and Q11) provide opportunities for science- and risk-based approaches for use in drug development and regulatory decisions. These guidances are valuable in the assessment of CMC changes across the product lifecycle. ICH Q8(R2) and Q11 guidances focus mostly on early stage aspects of the product lifecycle (i.e., product development, registration, and launch). This guidance addresses the commercial phase of the product lifecycle (as described in ICH Q10) and it both complements and adds to the flexible regulatory approaches to post approval CMC changes described in ICH Q8(R2) and Q10 Annex 1.This guidance is also intended to demonstrate how increased product and process knowledge can contribute to a more precise and accurate understanding of which post approval changes should result in a regulatory submission as well as the definition of the levels of reporting categories for such changes (i.e., a better understanding of risk to product quality). Increased knowledge and effective implementation of the tools and enablers described in this guidance should enhance industry’s ability to manage many CMC changes effectively under the company’s Pharmaceutical Quality System (PQS) with less need for extensive regulatory oversight prior to implementation. This approach can incentivize continual improvement by providing an opportunity for greater flexibility in making post approval changes. It could also result in fewer associated post approval submissions to the Marketing Authorization Application (MAA) and less associated regulatory burden. The extent of this operational and regulatory flexibility and its adequate implementation is subject to the regulatory framework in place, as well as product and process understanding (ICH Q8(R2) and Q11), application of quality risk management principles (ICH Q9), and an effective PQS (ICH Q10).

Also published is an Annex to Q12. The examples provided in sections I.A through I.F of the ICH Q12 Annexes are mock examples provided for illustrative purposes. They only suggest how the tools described in sections III, IV, and V of the ICH Q12 guidance could be applied, and should not be used as a template or the sole basis for a regulatory submission. In addition, the reporting categories, as described in section II of the ICH Q12 guidance, may differ across regions depending on regional legislation; the nature of the product; and the Marketing Authorization Holder’s (MAH’s) demonstrated understanding of the product, process, and analytical procedure.

ICH Q12: Implementation considerations for FDA-regulated products

This draft guidance should be read in conjunction with ICH Q12, which this guidance complements by clarifying how the ICH Q12 tools and enablers can be implemented within the U.S . regulatory system. These guidances apply to drug substances and drug products that are the subject of new drug applications (NDAs), biologics license applications (BLAs), abbreviated new drug applications (ANDAs), and supplements to these applications regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). They also apply to combination products with device constituent parts that are the subject of NDAs, BLAs, ANDAs, and supplements to these applications regulated by CDER and CBER.

Q3D(R2) Elemental Impurities

This draft document for public consultation is comprised of extracts of the Q3D(R2) Guideline with the revisions to the Q3D(R1) Guideline:

  • Part 1 - Extract of Appendix 2: Correction of PDEs for Gold, Silver and Nickel

  • Part 2 - Extract of Appendix 3: Correction of Gold monograph

  • Part 3 - Extract of Appendix 3: Correction of Silver monograph

  • Part 4 - New Appendix 5

development of bispecific antibodies, which are genetically-engineered, recombinant antibodies that consist of two distinct binding domains capable of binding two different antigens or two different epitopes of the same antigen A scientific rationale often exists for engaging two targets in the therapeutic strategy for a specific disease. Bispecific antibodies can target multiple disease-modifying molecules with one drug, with possible advantages over combination therapy or the use of antibody mixtures. The possibility of immune cell retargeting through the delivery of an effector or effector cell to a specific target cell or the possibility of synergistic efficacy through engagement of multiple targets gives bispecific antibodies the potential to advance the development of antibody-based therapies. Challenges may arise in developing bispecific antibodies such as immunogenicity related to novel structures and complex structural and functional characterization.

This final guidance provides recommendations to assist industry and other stakeholders involved in the development of bispecific antibodies. In addition to general considerations, the guidance provides recommendations for specific regulatory, quality, nonclinical, and clinical considerations for bispecific antibody development programs. Although this guidance is intended for bispecific antibodies, the principles discussed in this guidance may also inform the development of other types of bispecific protein products and multi-specific products.



Australia Therapeutic Goods Administration (TGA)

Guidance on the management of GMP compliance signals

The guidance outlines the GMP compliance requirements for manufacturing biologicals and medicines intended for supply in Australia and our framework for managing GMP compliance signals.

This guidance applies to:

  • licensed manufacturers in Australia

  • sponsors responsible for any overseas site in the manufacture of a Medicine or active pharmaceutical ingredient supplied to Australia.

Faecal microbiota transplant (FMT) products regulation

On 1 January 2020, TGA provided clarity for the new regulatory model for FMT products. Following an 18-month transition period, the new regulatory requirements for FMT products commenced on 1 July 2021.

Most FMT products are regulated as biologicals. This includes significantly processed products (e.g. capsules) that are derived from stool. How an FMT product will be regulated by TGA depends on the level of clinical oversight and external governance in its preparation.

As a general principle, most FMT products will currently be regulated as either Class1 or Class 2 biologicals depending on whether or not they are:

  • manufactured in a hospital

  • minimally manipulated

However, where a strain(s) of microorganisms, known to be present in stool, is characterised and grown from established isolates with standardised consistency, it may be regulated as a medicine rather than a biological.

From 1 July 2021, the supply of FMT products can only occur in Australia where:

  • TGA has included the product in the Australian register of therapeutic goods (ARTG) or

  • TGA has granted approval or been notified utilising the ‘unapproved’ product pathways where specific criteria are met

Consultation: Remaking of standards and legislative instruments for human cell and tissue (HCT) products, blood and blood components

is conducting a public consultation seeking feedback on a proposal to remake some of the legislative instruments relating to human cell and tissue (HCT) products (including blood and blood components), which sunset in October 2021.

The TGOs relevant to this consultation can be broadly categorised into three groups:

  • Product-specific standards: TGO 83,84,85 & 86.

  • Labelling requirements: TGO 87

  • General donor selection and testing requirements: TGO 88

This consultation will also consider two other legislative instruments: Therapeutic goods -Things that are not biologicals and Therapeutic goods -Things that are biologicals

The consultation opens on 27 May 2021. Interested parties should respond by close of business 11 July 2021