Review of Developments in GMP and the Regulation of Medicines December 2021
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INTRODUCTION
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 UK, EU, USA, PIC/S and Australian regulatory authorities.
The topics covered in this edition of the “Update” include:
Q&As Webinar for MAHs on Integration of EudraGMDP and OMS
Overview of comments received on Addendum to the ICH guideline S1B on testing for carcinogenicity of pharmaceuticals
Human Medicines Highlights issue 152
Annual report of the pharmacovigilance inspectors working group for 2019 and 2020
Nitrosamine Implementation Oversight Group (NIOG) – 2nd meeting with pharmaceutical industry
Veterinary medicines info day
Veterinary Medicinal Products Regulation highlights
More than 40% decrease in sales of antimicrobials for use in animals
Webinar - Clinical trials regulation and the clinical trials information system (CTIS)
Procedural advice on the provision of scientific recommendation on classification of advanced therapy medicinal products
EMA’S guide on advanced therapy medicinal products
Irish language derogation ending on 1 January 2022
PDG signs-off on milestone harmonised general chapter on chromatography
Change in EDQM timelines for CEP applications
Ph. Eur. reference standards
Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products
Australia TGA
Review of real world evidence and patient reported outcomes
Importation, manufacture and supply of unapproved medicinal cannabis products
Cracking the code: Developing requirements for data matrix codes on medicines
TGA investigation – potential contamination of medicines with nitrosamine impurities.
GMP approach to overseas manufacturers of medicines and biologicals during the COVID-19 pandemic
Concept papers on the revision of annexes 4 & 5 of the guidelines on GMP for manufacture of veterinary medicinal products
Booster dose of Janssen Covid 19 vaccine (EMA)
Comirnaty COVID-19 vaccine: EMA recommends approval for children aged 5 to 11
Lagevrio (molnupiravir) for treating patients with COVID 19
Concept papers on the revision of annexes 4 & 5 of the guidelines on GMP for manufacture of veterinary medicinal products
Real World Evidence (RWE)
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
Europe
EMA
Q&As Webinar for MAHs on Integration of EudraGMDP and OMS
This helpful document (EMA/587537/2021) published by the Veterinary Medicines Division on 11 November 2021 contains 87 Q&As on the topic.
Overview of comments received on Addendum to the ICH guideline S1B on testing for carcinogenicity of pharmaceuticals
Comments will be sent to the ICH S1B EWG for consideration in the context of Step 2b of the ICH process
Human Medicines Highlights issue 152
This newsletter is addressed primarily to organisations representing patients, consumers and healthcare professionals. It provides a summary of key information relating to medicines for human use published during the previous month by the EMA. Information is selected based on recommendations from consulted patients, consumers and healthcare professionals, and does not necessarily cover all relevant information published by the Agency.
Annual report of the pharmacovigilance inspectors working group for 2019 and 2020
The activities outlined in the annual report for 2019 and 2020 have been carried out in line with the Agency’s business continuity plan and prioritisation of activities for the preparation of the Agency’s relocation and the Covid-19 pandemic and are therefore substantially reduced in comparison with the activities carried out by the PhV Inspectors Working Group in previous years. These matters have resulted in the delay of the publication of this report.
Nitrosamine Implementation Oversight Group (NIOG) – 2nd meeting with pharmaceutical industry
The second meeting of the NIOG with industry stakeholders will take place online on 8 dec 2021. The aim is to provide an update on progress of NIOG workplan and discuss priorities for 2022.
Registration is by invitation only.
Veterinary medicines info day
This meeting was held online 30/11/2021,.
The aim of this second info day is to provide the latest updates to pharmaceutical industry stakeholders responsible for veterinary medicines before the veterinary medicinal products regulations become applicable on 28 January 2022.
Veterinary Medicinal Products Regulation highlights
Issue #8 of this news, views and interviews for the Veterinary Medicinal Products Regulation has been published.
More than 40% decrease in sales of antimicrobials for use in animals
European countries have substantially reduced the use of antimicrobials in animals. According to data from the 25 countries that provided input for the full 2011-2020 period, overall sales of veterinary antimicrobials in European countries were 43% lower in 2020 than in 2011.
While an increase of 6% in overall sales for the 25 countries in 2020 compared to 2019 was registered, data for the next years are necessary to better understand this observation.
Veterinary sales of those antimicrobials that are considered critically important in human medicine, decreased noticeably between 2011 and 2020 and accounted for only 6% of total sales in 2020. In particular, sales of third- and fourth- generation cephalosporins dropped by 33%, polymyxins by 76%, fluoroquinolones by 13% and sales of other quinolones dropped by 85%. These classes include antimicrobials used to treat serious infections in humans that are caused by bacteria resistant to most other antimicrobial treatments. In animals, they should be used with restrictions in order to preserve their effectiveness in humans and mitigate the risk to public health.
Webinar - Clinical trials regulation and the clinical trials information system (CTIS)
The way that clinical trials are conducted in the European Union/EEA will change when the clinical trials regulation becomes applicable on 31 January 2022 and the clinical trials Information System (CTIS) will go live.
EMA organised this webinar on 29/11/2021, to inform small and medium-sized enterprises (SMEs) and academic sponsors of clinical trials on how to prepare for the main changes brought by the Regulation and its impact on their trial-related activities.
Topics presented during the webinar included:
an overview of the clinical trials Regulation
an introduction to the new process for submitting clinical trial information in the European Union/European Economic Area
functionalities of CTIS, including transparency aspects and safety reporting requirements
guidance and training material available for sponsors
Procedural advice on the provision of scientific recommendation on classification of advanced therapy medicinal products in accordance with article 17 of regulation (EC) no 1394/2007
The scientific recommendation on classification of Advanced Therapy Medicinal Products (ATMPs) is an optional procedure for applicants, which involves the Committee for Advanced Therapies (CAT). The purpose of this procedure is to allow applicants to clarify, in case of doubt, whether a given product based on genes, cells or tissues meets the scientific criteria which define ATMPs, in order to address, as early as possible, questions of borderline with other areas such as cosmetics or medical devices, which may arise as science develops. It is recommended that this is done before submission of request for scientific advice/protocol assistance, Paediatric Investigation Plan (PIP) evaluation, certification of quality and non-clinical data for SMEs developing ATMPs, orphan drug designation and Marketing Authorisation Application (MAA). Within 60 calendar days following receipt of a valid request, the CAT shall deliver its ‘scientific recommendation on ATMP classification’ after consultation with the European Commission (EC). The EMA shall also publish summaries of this recommendation, after deletion of all information of commercial confidential nature. This document describes the procedure and gives guidance for the steps to be followed by the applicant and EMA for the ATMP classification. The content of the summaries of recommendations for publication on the EMA website is also presented.
EMA’S guide on advanced therapy medicinal products
To help developers of gene therapy medicinal products (GTMPs) and cell-based medicinal products (CBMPs) navigate the most important regulatory requirements during the clinical development and non clinical phases, EMA has issued two flowcharts. A further flowchart covering how to navigate the most important quality-related regulatory requirements is also available.
[Very useful flowcharts and checklists for these newer and increasingly more evident types of medicines MBH]
Irish language derogation ending on 1 January 2022
The European Commission’s report (EUR-Lex - 52021DC0315 - EN - EUR-Lex (europa.eu), published in June 2021, on whether the Union institutions have sufficient available capacity for the Irish language, relative to the other official EU languages, concluded that Regulation No 11 can apply without a derogation as of 1 January 2022.
To see what this means for:-
EMA opinions and the European Commission decisions.?
What a marketing authorisation holder / applicant have to do to request a language waiver?
What happens in the case of Commission decisions addressed to the Member States
European Directorate for the Quality of Medicines & HealthCare (EDQM)
PDG signs-off on milestone harmonised general chapter on chromatography
The harmonised general chapter Chromatography was signed-off by the Pharmacopoeial Discussion Group (PDG), which brings together the European Pharmacopoeia (Ph. Eur.), Japanese Pharmacopoeia (JP) and the United States Pharmacopeia (USP), on 28 September 2021. The coordinating pharmacopoeia for this text was the Ph. Eur.
During a joint PDG–industry meeting in 2009, the PDG was encouraged to add harmonisation of the three regional chapters on chromatography to the PDG work programme. Although the chapters in question differed in content and format, it was considered feasible to develop a chapter describing core requirements applicable for TLC, HPLC and GC. After discussion, it was agreed not to include more general (textbook type) descriptions of individual techniques as each of the PDG pharmacopoeias has its own approach, decided at regional level.
These harmonised requirements promote the development of individual monographs with a consistent approach and enhance understanding of basic requirements by users in all three regions.
Change in EDQM timelines for CEP applications
On 1 October 2021, the EDQM commenced the use of a new IT tool to manage CEP applications. The implementation of this tool requires that timelines for evaluation of all CEP applications and their revisions/renewal be specified in working days instead of calendar days, which will also provide greater clarity on deadlines for applicants, particularly when the EDQM offices are closed.
In order to avoid disrupting applicants’ internal procedures, the timelines for response to requests for additional information, clarification, etc., for ongoing procedures will continue to be counted in calendar days/months.
Ph. Eur. reference standards
5 new Ph. Eur. reference standards and 19 replacement batches released
United States of America
The US Food and Drug Administration (USFDA)
Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products
FDA is issuing this draft guidance as part of its Real World Evidence (RWE) Program and to satisfy, in part, the mandate under section 505F of the FD&C Act to issue guidance on the use of RWE in regulatory decision making. For the purposes of this guidance, FDA defines real-world data (RWD) and RWE as follows:
RWD are data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources.
RWE is the clinical evidence about the usage and the potential benefits or risks of a medical product derived from analysis of RWD.
Topics covered in this guidance include:
Considerations regarding a registry’s fitness-for-use in regulatory decision-making, focusing on attributes of a registry that support the collection of relevant and reliable data
Considerations when linking a registry to another data source for supplemental information, such as data from medical claims, electronic health records (EHRs), digital health technologies, or other registries
Considerations for supporting FDA review of submissions that include registry data
Whether registry data are fit-for-use in regulatory decision-making depends on the attributes that support the collection of relevant and reliable data (described in this guidance) as well as additional scientific considerations related to study design and study conduct that are beyond the scope of this guidance.
International
Australia TGA
Therapeutic Goods Administration (TGA)
Review of real world evidence and patient reported outcomes
TGA recently commissioned a review into its usage of real world evidence (RWE) and patient reported outcomes (PROs) in the regulation of medicines and medical devices. This considered stakeholders' understanding of what RWE and PROs are, and how TGA and other international regulators use them.
TGA uses both RWE and PROs in premarket and post market evaluations, and the review found that:
there is ambiguity (internally and externally) surrounding our usage of RWE and PROs, which potentially limits its adoption.
stakeholders recommend that TGA improve its communication about how the TGA accepts and uses RWE and PROs.
From these learnings, over 2021-22 TGA will make a number of changes in response to the review.
The TGA will more extensively communicate the current status of use of RWE and PROs, to overcome the perception that they are not currently part of the regulatory landscape. While resources do not permit TGA to fund or undertake research on RWE it will monitor work by comparable regulators and regulatory science coalitions on the use of RWE/ PROs to remain abreast of their evolving status.
Importation, manufacture and supply of unapproved medicinal cannabis products
The importation, manufacture and supply of unapproved medicinal cannabis products is tightly regulated in order to manage the risks of unlawful supply, and to ensure any necessary public health alerts and recalls can be managed appropriately.
To that end, the 'direct control' requirement in the Therapeutic Goods Regulations 1990 is in place to ensure that the sponsor remains responsible for product control and supply decisions throughout the supply chain.
If you import or manufacture finished medicinal cannabis products that are not entered in the Australian Register of Therapeutic Goods, you can only supply those products:
if they are held under your direct control until they are supplied under an approved pathway to an Authorised Prescriber or Special Access Scheme approval holder
if you comply with certain conditions.
Provided you comply with these requirements, you can enter into distribution arrangements with third parties, where they provide services to assist you in supplying finished medicinal cannabis products.
Cracking the code: Developing requirements for data matrix codes on medicines
This presentation paper is provided on the TGA's website solely for the purpose of indicating or suggesting what TGA representatives spoke about to the various conferences and seminars to which it relates. The paper is not legislative in nature and should not be taken to be statements of any law or policy in any way. This particular presentation was made by Tony Manderson, Scientific Operations Management Section, TGA. The presentation discusses implementation of TGO 106 and medicine traceability in markets.
TGA investigation – potential contamination of medicines with nitrosamine impurities.
TGA has been investigating the issue of nitrosamine contamination of medicine since 2018. Information on affected medicines has previously been published (see ‘Related Safety alerts’). This page provides general information for consumers and health professionals.
GMP approach to overseas manufacturers of medicines and biologicals during the COVID-19 pandemic
In collaboration with the TGA-Industry Working Group on GMP (TIWGG), TGA is providing an update on certain temporary measures introduced last year for overseas manufacturers.
Pharmaceutical Inspection Co- Operation Scheme (PIC/S)
Concept papers on the revision of annexes 4 & 5 of the guidelines on GMP for manufacture of veterinary medicinal products
These concept papers address the need to update Annexes 4 (manufacture of veterinary medicinal products other than immunologicals) & 5 (manufacture of immunological veterinary medicinal products) of the Good Manufacturing Practice (GMP) guide. Both Annexes are common to the member states of the EU/ EEA as well as to the participating authorities of the PIC/S. The original version has not been revised since it was originally issued in 1992. Since that time, there has been extensive progress in the use of new technologies, significant changes in GMP following the adoption of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q8, Q9, Q10 and Q11 guidelines, International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) guidelines. Additionally, there have been development of new products (e.g. Advanced Therapy Medicinal Products, Blood products, Cell therapy products, Gene therapy products, Biotechnology products, Animal extracted products, Tissue engineered products, Allergen products ...).
The revision of the current text of Annexes is considered a priority for the following main reasons:
to facilitate the implementation of the principles in these aforementioned ICH guidelines and ad hoc VICH guidelines;
to extend the underlying concepts to include new areas of technology (e.g. novel therapy products), new processing, new products not previously covered;
to clarify areas that have been highlighted as ambiguous due to the age of the document.
As the existing Annex 5 is focused solely on the manufacture of immunological veterinary medicinal products to this day, there is no source of guidance in EU-PIC/S GMP for the conditions of manufacture of other veterinary biological products and for the early stages in the manufacture of a range of these products (GMP Part I vs GMP Part II).
Moreover, since the update and split of GMP Part I and II in 2005, a number of Annexes have been revised (e.g. Annex 2 and 15) or are under revision (Annex 1). This revision has provided the opportunity to indicate if specific requirements are applicable to those described in GMP Part I and II. The current Annexes 4&5 do not similarly indicate if requirements are applicable to Parts I and II.
The publication date was 9 Nov 2021 and the deadline for comments is 9 Jan 2022.
Products
Booster dose of Janssen Covid 19 vaccine
EMA has started evaluating an application for the use of a booster dose of COVID-19 Vaccine Janssen to be given at least two months after the first dose to people aged 18 years and older. EMA’s human medicines committee (CHMP) will carry out an accelerated assessment of data submitted by the company that markets the vaccine. The outcome of this evaluation is expected within weeks, unless supplementary information is needed, and will be communicated by EMA.
Comirnaty COVID-19 vaccine: EMA recommends approval for children aged 5 to 11
EMA’s CHMP has recommended granting an extension of indication for the COVID-19 vaccine Comirnaty to include use in children aged 5 to 11. The vaccine, developed by BioNTech and Pfizer, is already approved for use in adults and children aged 12 and above. The dose will be lower than that used in people aged 12 and above (10 µg compared with 30 µg). As in the older age group, it is given as two injections in the muscles of the upper arm, three weeks apart.
Lagevrio (molnupiravir) for treating patients with COVID 19
EMA has started evaluating an application for marketing authorisation for the oral antiviral medicine Lagevrio (molnupiravir). Lagevrio, which is being developed by Merck Sharp & Dohme in collaboration with Ridgeback Biotherapeutics, is intended for the treatment of COVID-19 in adults.
EMA will assess the benefits and risks of Lagevrio under a reduced timeline and could issue an opinion within weeks if the data submitted are sufficiently robust and complete to show the efficacy, safety and quality of the medicine.
Note also that EMA’s CHMP has issued advice on the use of Lagevrio for the treatment of COVID-19. The medicine, which is currently not authorised in the EU, can be used to treat adults with COVID-19 who do not require supplemental oxygen and who are at increased risk of developing severe COVID-19. Lagevrio should be administered as soon as possible after diagnosis of COVID-19 and within 5 days of the start of symptoms. The medicine, which is available as capsules, should be taken twice a day for 5 days.
EMA issued this advice to support national authorities who may decide on possible early use of the medicine prior to marketing authorisation, for example in emergency use settings, in light of rising rates of infection and deaths due to COVID-19 across the EU.
Paxlovid for treating patients with COVID-19
EMA is reviewing currently available data on the use of Paxlovid (PF-07321332/ritonavir), an oral treatment for COVID-19 developed by Pfizer. EMA is starting this review to support national authorities who may decide on its early use for COVID-19, for example in emergency use settings, prior to marketing authorisation.
Xevudy (sotrovimab) for treating patients with COVID-19
EMA has started evaluating an application for marketing authorisation for the monoclonal antibody Xevudy (sotrovimab). The applicant is GlaxoSmithKline Trading Services Limited, who developed the medicine together with Vir Biotechnology.
Xevudy is intended for the treatment of adults and adolescents with COVID-19 who do not require supplemental oxygen therapy and who are at increased risk of progressing to severe COVID-19.
EMA will assess the benefits and risks of Xevudy under a reduced timeline and could issue an opinion within two months, depending on whether the data submitted are sufficiently robust and whether further information is required to support the evaluation,
COVID-19 vaccine, Nuvaxovid
EMA has started evaluating an application for conditional marketing authorisation for Novavax’s COVID-19 vaccine Nuvaxovid. The assessment will proceed under an accelerated timeline, and an opinion on the marketing authorisation could be issued within weeks if the data submitted are sufficiently robust and complete to show the efficacy, safety and quality of the vaccine.
Such a short timeframe is only possible because EMA has already reviewed a substantial portion of the data on the vaccine during a rolling review.
Documents
Real World Evidence (RWE)
The EMA has been significantly involved in the creation of two recent papers on this topic. The first explains plans to establish methods and standards for high-quality collection and use of RWE, in cooperation with stakeholders. The second examines when and how RWE was used to support Marketing Authorisations and extensions of indications submitted to the Agency in 2018 and 2019. The retrospective analysis shows that 40% of initial MA applications and 18% of applications for extension of indication for products currently on the market contained RWE. The second article also describes the characteristics of RWE included in these applications and identifies areas where further research is required. Both articles aim to support transformation to data-driven regulatory decision-making and to advance patient-centred access to better medicines. They are available through open access:
And finally…
Further information on these and other topics can be found in recent versions of the “Regulatory Update” on the PHSS website (members area) by utilising the hyperlink within that particular Update.
We hope that our readers find our reviews to be both informative and helpful in keeping up to date with pharmaceutical legislation and regulatory guidance.
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