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


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Vol 26-3A July 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, ICH and PIC/s regulatory authorities.


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


UK


MHRA

Recall of 31 contaminated Irbesartan and 2 Losartan batches as precautionary measure

EU


EU

  • Q&A on labelling flexibilities for COVID-19 vaccines

  • Reflection paper on forecasting demand for medicinal products in the EU/EEA

  • Checklist for annual updates for parallel distribution

  • Highlights of Management Board: June 2021 meeting

  • Success rate for marketing authorisation applications from SMEs doubles between 2016 and 2020

  • Highlights from the second meeting of the Nitrosamine Implementation Oversight Group (NIOG)

  • European Pharmacopoeia Supplement 10.6 now available

  • EDQM reference spectra

  • European Pharmacopoeia to put an end to the rabbit pyrogen test


USA

  • Product identifiers under the drug supply chain security act (DSCSA)- Q&A

  • Definitions of suspect product and illegitimate product for verification obligations under the DSCSA

  • DSCA Implementation: Identification of suspect product and notification

  • Enhanced Drug Distribution Security at the Package Level Under DCSA


International

  • Efforts to engage other ICH pharmacopoeias in the Q4B Annexes maintenance process

  • PIC/S Adapting EU GMP Annex 16 on Authorised Person and Batch Release

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


Products

  • COVID-19 Vaccine Janssen: authorities in EU take steps to safeguard vaccine quality

  • Additional manufacturing capacity for Moderna’s COVID-19 vaccine

  • Two additional manufacturing sites for BioNTech/Pfizer’s COVID-19 vaccine

  • Vaxzevria: EMA advises against use in people with history of capillary leak syndrome


Documents

  • ABPI launches updated Code of Practice


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


UK

MHRA

Recall of contaminated Irbesartan and Losartan batches as precautionary measure

The MHRA has issued a recall for 31 batches of Irbesartan-containing medicinal products and 2 batches of Losartan-containing medicinal products due to contamination with 5-(4’-(azidomethyl)-[1,1’-biphenyl]-2yl)-1H-tetrazole, a substance that can potentially increase the risk of cancer over time.

This is a precautionary measure to prevent further exposure and there is no evidence that this impurity has caused any harm to patients. The recall is for pharmacies and wholesalers and is not a patient-level recall.


Europe


EMA

Q&A on labelling flexibilities for COVID-19 vaccines rev 2

EMA together with the Member States, in the context of the Quality Review of Documents (QRD) group, have developed and updated this Q&A document with the aim to provide operational guidance on labelling flexibilities for COVID-19 vaccines. As this is an evolving topic the present Q&A may be subject to further updates, as deemed appropriate.

The changes in this version (V2) relate to:-

  • Question 2 – France deleted from the list of Member States requiring the printed package leaflet in their national language.

  • Question 6 – France deleted from the list of Member States requiring equal number of printed package leaflets, corresponding to the number of doses.

Reflection paper on forecasting demand for medicinal products in the EU/EEA

As stated in Article 81 of Directive 2001/83/EC ”The holder of a marketing authorisation for a medicinal product and the distributors of the said medicinal product actually placed on the market in a Member State shall, within the limits of their responsibilities, ensure appropriate and continued supplies of that medicinal product to pharmacies and persons authorised to supply medicinal products so that the needs of patients in the Member State in question are covered. The arrangements for implementing this Article should, moreover, be justified on grounds of public health protection and be proportionate in relation to the objective of such protection, in compliance with the Treaty rules, particularly those concerning the free movement of goods and competition...” Therefore, marketing authorisation holders are responsible for the continued supply of medicinal products. Shortages of medicinal products are an important public health issue. They are particular concerns in the context of exceptional (e.g. pandemic) situations that lead to a considerable increase in the demand for certain medicines. This reflection paper has been developed in the context of such an event – the COVID-19 pandemic – and builds on the experience accumulated by the regulatory authorities during the initial months of this pandemic with respect to ICU medicines used in the treatment of COVID-19 patients. It aims at setting recommendations for medicines' demand forecasting, which is essential for correct adjustments in the manufacturing and distribution of medicinal products to avoid or at least mitigate the impact of shortages. Although the focus of the reflection paper is on demand forecasting at national level by EU /EEA Member State authorities during the COVID-19 pandemic, its principles can be also applied for forecasting demand in other situations and/or by other stakeholders. The aim of this reflection paper is to facilitate forecasting demand for medicinal products for human use in the EU/EEA. The reflection paper includes practical recommendations and examples specific to help with the preparations for a further progression of the COVID-19 pandemic. However, many of the general principles set out in this reflection paper could be used in the context of other pandemics where there is a need to forecast demand for medicines. While the reflection paper is intended to support such demand forecasting by the national competent authorities for medicines, such additional forecasting activity is in no way intended to substitute for the responsibilities set in the legislation for marketing authorisation holder

Checklist for annual updates for parallel distribution

The EMA has issued Rev 1 of this checklist.

Highlights of Management Board: June 2021 meeting

EMA about recent developments in response to COVID-19. Since the last update in March, a fourth vaccine (Janssen vaccine) has been granted a conditional marketing authorisation, and a rolling review has started for the Sinovac vaccine, in addition to the ongoing rolling reviews for the Curevac, Novavax and Sputnik V vaccines. EMA continues to provide rapid scientific advice to developers of vaccines and therapeutics.

To address the increasing volume of COVID-19-related assessment procedures, the Agency has implemented additional short term measures to streamline activities in the European medicines regulatory network.

The Board has also initiated a reflection on lessons learnt from the COVID-19 pandemic. This topic will be discussed in further detail at the October Board meeting.

The activities described in the Annual Report formed the basis of the Executive Director’s annual activity report for 2020, which the Board assessed and adopted. The Board noted that although 2020 had been another challenging year for EMA due to the COVID-19 pandemic, the Agency had managed to maintain the high quality and continuity of its core operations whilst also completing the relocation to its permanent headquarters in Amsterdam. The Board also noted the Agency’s responsiveness in managing activities to address the pandemic and mitigating its impact on the supply of medicines in the EU as well as the significant efforts of EMA’s human medicines committee (CHMP) which led to the authorisation of the first COVID-19 vaccine before the end of 2020.

Other achievements highlighted by the Board include the Agency’s activities in the global fight against antimicrobial resistance as well as the publication of the Regulatory Science Strategy to 2025 and the European Medicines Agencies Network Strategy to 2025.

The Board also noted the concerns regarding the Agency’s staffing levels in light of its continuously increasing workload, the significant responsibilities assigned to the Agency over the last few years and the possible new tasks stemming from the European Commission proposal to extend EMA’s mandate.

Success rate for marketing authorisation applications from SMEs doubles between 2016 and 2020

EMA has published today a report highlighting the Agency’s support for micro, small and medium-sized enterprises (SMEs) which develop and market medicines for human or veterinary use in the European Union. The report covers the period from 2016 to 2020.The report features key facts and figures of companies that are registered as SMEs with EMA. SMEs are a major driver of innovation in the pharmaceutical industry and the Agency provides them with access to a number of incentives, including regulatory assistance from a dedicated SME office and reduced fees for certain procedures.

Highlights from the second meeting of the Nitrosamine Implementation Oversight Group (NIOG)


EDQM

European Pharmacopoeia Supplement 10.6 now available

The European Pharmacopoeia (Ph. Eur.) Supplement 10.6 is now available and will be applicable in 39 European countries as of 1 January 2022.

EDQM reference spectra

As of July 2021, EDQM reference spectra will be sent exclusively by email in PDF format and no longer in paper format by courier.

European Pharmacopoeia to put an end to the rabbit pyrogen test.

At its 170th session in June 2021, the European Pharmacopoeia (Ph. Eur.) Commission took the decision to engage on a path that should ultimately lead to the complete replacement of the rabbit pyrogen test (RPT) in the Ph. Eur., within approximately 5 years.

The Ph. Eur. test for pyrogens (general chapter 2.6.8) consists of measuring the rise in body temperature evoked in rabbits by the intravenous injection of a sterile solution of the substance to be examined. It was first published in the Ph. Eur. in 1986.

The majority of pyrogens are bacterial endotoxins and these can be detected using the bacterial endotoxins test (BET) described in Ph. Eur. general chapters 2.6.14. Bacterial endotoxins and 2.6.32. Test for bacterial endotoxins using recombinant factor C. However, in some cases, non-endotoxin pyrogens may also be present and these are not detected by the BET. A test covering all types of pyrogens is therefore required to confirm the absence of non-endotoxin pyrogens.

General chapter 2.6.30. Monocyte-activation test (MAT) was added to the Ph. Eur. in 2009, providing an in-vitro alternative to the RPT that is capable of detecting both endotoxin and non-endotoxin pyrogens.

There are currently 59 Ph. Eur. texts – covering a variety of topics including vaccines for human use, blood products, antibiotics, radiopharmaceuticals and containers – that refer to the RPT and will be affected. The Ph. Eur. is committed, for all these texts, to replacing the test for pyrogens with a suitable in-vitro alternative, ultimately leading to the complete elimination of the RPT. In the meantime, users are actively encouraged to seek alternatives to chapter 2.6.8, the best option being the MAT.


United States of America


The US Food and Drug Administration (USFDA)

Product identifiers under the drug supply chain security act (DSCSA) Q&A

The DSCSA was signed into law on November 27, 2013. It outlines critical steps to build an electronic, interoperable system by November 27, 2023, that will identify and trace certain prescription drugs as they are distributed within the United States. Section 202 of the DSCSA, which added new sections 581 and 582 to the FD&C Act, set forth new definitions and requirements related to product tracing, product identifiers, and verification for manufacturers, repackagers, wholesale distributors, and dispensers to facilitate the tracing of product through the pharmaceutical distribution supply chain. Failure to comply with the requirements of section 582 is a prohibited act and is subject to enforcement action under the FD&C Act.

This guidance is intended to help manufacturers and repackagers understand and satisfy the requirements of section 582(b)(2) and (e)(2) of the FD&C Act, respectively, to affix or imprint a product identifier to each package and homogenous case of product that they intend to introduce in a transaction into commerce. The recommendations in this guidance are intended to assist manufacturers and repackagers in developing standardized formats for the human- and machine-readable information that is contained in the product identifier. The requirements set forth in the DSCSA do not change the linear barcode requirements under 21 CFR 201.25.

Definitions of suspect product and illegitimate product for verification obligations under the DSCSA

This is Revision 1 of the Draft Guidance.

FDA is issuing this guidance to interpret the terms used in the definition of suspect product set forth in section 581(21) of the FD&C Act, and the definition of illegitimate product set forth in section 581(8) of the FD&C Act, to assist trading partners in meeting verification and notification obligations. This guidance revises the draft guidance for industry Definitions of Suspect Product and Illegitimate Product for Verification Obligations Under the Drug Supply Chain Security act issued in March 2018. This revision clarifies certain points of the March 2018 draft guidance, and also adds FDA’s current understanding of the term stolen.

DSCA Implementation: Identification of suspect product and notification

Manufacturers are required to notify FDA and certain immediate trading partners, as applicable, after the manufacturer determines or is notified by FDA or a trading partner that there is a high risk that a suspect product is illegitimate. This guidance identifies specific scenarios that could significantly increase the risk of a suspect product entering the pharmaceutical distribution supply chain; provides recommendations on how trading partners can identify a product and determine whether a product is a suspect product as soon as practicable; and sets forth the process by which trading partners should notify FDA of illegitimate product or products with a high risk of illegitimacy, and how they must terminate the notifications, in consultation with FDA

The contents of this document do not have the force and effect of law and are not meant to bind the public in any way, unless specifically incorporated into a contract. This document is intended only to provide clarity to the public regarding existing requirements under the law.

The DSCSA outlines critical steps to build an electronic, interoperable system over a 10-yearperiod that will identify and trace certain prescription drugs as they are distributed within the United States. For many years, FDA has been engaged in efforts to improve the security of the drug supply chain to protect U.S. patients from unsafe, ineffective, and poor quality drugs. Since at least the formation of the first FDA Counterfeit Drug Task Force in 2003, FDA has strongly supported a multi-layered approach to securing the supply chain. A key component of that approach has been to encourage heightened vigilance and awareness among supply chain partners. The electronic, interoperable system that will be established under the DSCSA will enhance FDA’s ability to help protect U.S. consumers by improving detection and removal of potentially dangerous drugs from the drug supply chain.

Enhanced Drug Distribution Security at the Package Level Under DCSA

Requirements for enhanced drug distribution security, commonly referred to as the “enhanced system” go into effect on November 27, 2023. This guidance clarifies the enhanced system requirements. In addition, this guidance outlines and provides recommendations on the system attributes necessary for enabling the secure tracing of product at the package level, including allowing for the use of verification, inference, and aggregation, as necessary. FDA views these recommendations as an important tool to assist in implementing the robust enhanced system envisioned under the DSCSA.

[The above four Guidances / Draft Guidances should be read together for a comprehensive understanding MBH]


International


ICH


Efforts to engage other ICH pharmacopoeias in the Q4B Annexes maintenance process

At its November 2020 meeting, the ICH Assembly approved the proposal made by the PDG (Pharmacopoeial Discussion Group) on how to include the pharmacopoeias of the non-Founding ICH Regulatory Members in the maintenance of the ICH Q4B Annexes. The expansion of ICH membership provides an excellent opportunity to further promote the global convergence of pharmacopoeial quality standards, through the extended recognition – potentially by all ICH Regulatory Members – of the harmonised pharmacopoeial texts referenced in the Q4B Annexes. The PDG has now reached the first crucial milestone in its efforts to involve the pharmacopoeias of non-Founding ICH Regulatory Members in this work.

The PDG has since contacted the pharmacopoeias of the non-Founding ICH Regulatory Members and asked them to evaluate their own texts versus the PDG sign-off texts and to inform the PDG if they have implemented the PDG sign-off texts or if they consider their own texts as already harmonised with them. They were also asked to provide the PDG with a detailed review of potential residual differences as well as an English version of their pharmacopoeial texts. This process is liable to take several months.

The PDG will review the feedback from these pharmacopoeias and, where appropriate, update the Q4B Annexes with additional information on the acceptance by additional ICH Regulatory Members. The revised Q4B Annexes will be submitted to the ICH secretariat which will then launch a consultation among the ICH Regulatory Members. This consultation will focus on the regulatory considerations in the Q4B Annexes.

The PDG will provide a status update to the ICH Assembly after the PDG Annual Meeting, which will be hosted by the EDQM in October 2021.


PIC/S


Adapting EU GMP Annex 16 on Authorised Person and Batch Release

The PIC/S term of “Authorised Person” and the EU term of “Qualified Person” are strictly equivalent.

Following the revision of EU Annex 16 in 2016, PIC/S re-discussed whether to transpose Annex 16 in order to harmonise internationally requirements regarding product release in line with PIC/S’ mission “to lead the international development, implementation and maintenance of harmonised GMP standards and quality systems of Inspectorates in the field of medicinal products”. The PIC/S Sub-Committee on GMDP Harmonisation (SCH), led by Paul Gustafson (Health Canada), was mandated to transpose a PIC/S version of EU GMP Annex 16 in accordance with a memorandum of understanding with the European Medicines Agency

Following several internal rounds of consultation and extensive discussion between PIC/S Members on draft versions of PIC/S Annex 16, the PIC/S Committee recently agreed to proceed to Step 2 of the PIC/S consultation process. Step 2 of the PIC/S adoption process enables an opportunity for PIC/S Participating Authorities to consult with stakeholders. PIC/S Participating Authorities may take differing approaches to consultation. Some may engage in consultation at later periods through local harmonisation efforts that realize subsequent adaptation of PIC/S GMP into jurisdictional specific GMP guides or requirements.

This consultation will be launched on 15 June 2021 for a period of 3 months. The consultation will focus on national stakeholders of non-EU/EEA Members of PIC/S, considering that EU/EEA Members of PIC/S already apply EU Annex 16.

Where the implementation of PIC/S Annex 16 will affect a jurisdiction, the competent PIC/S Participating Authority will consult pharmaceutical industry associations. This consultation may also be open to the general public and other stakeholders. International professional and industry associations, which are interested to contribute to the PIC/S consultation process, are invited to channel their consolidated comments through one of the PIC/S Participating Authorities

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

These guidance documents have been revised by the PIC/S Working Group on Blood Guidance, led by Switzerland / Swissmedic, on the basis of the Good Practice Guidelines (GPG) for Blood Establishments drafted by the European Directorate for the Quality of Medicines & HealthCare of the Council of Europe (EDQM) and the European Commission.

The revised guidance documents enter into force on 1 June 2021


Products


COVID-19 Vaccine Janssen: authorities in EU take steps to safeguard vaccine quality

Authorities in the EU are aware that a batch of the active substance for COVID-19 Vaccine Janssen had been contaminated with materials for another vaccine manufactured at the same site.

The contamination occurred at a manufacturing site for the active substance in Maryland, United States, owned by Emergent Biosolutions. The batch concerned was not intended for the EU market.

Based on available information, batches of the vaccine released in the EU are not affected by the cross contamination. However, as a precaution and to safeguard the quality of vaccines, the supervisory authorities have recommended not releasing vaccine batches containing the active substance made at around the same time that the contamination occurred.

Additional manufacturing capacity for Moderna’s COVID-19 vaccine

EMA’s committee for human medicines (CHMP) has approved a new manufacturing site for the production of Moderna COVID-19 vaccine finished product. The site, operated by Recipharm, is located in Monts, France.

The CHMP has also given a positive opinion for the addition of several alternative sites responsible for batch control/testing.

Also on 4 June 2021, two new sites for the manufacturing of active substance and finished product intermediates, located in the US (ModernaTX, Inc., Norwood, Massachusetts and Lonza Biologics, Inc., Portsmouth, New Hampshire), were approved by CHMP. Together, these changes are expected to allow the production of an additional one to two million vials of ready-to-use vaccine for the European Union market every month. This will increase the supply of the vaccine in the EU.

This recommendation does not require a European Commission decision and the site in Monts can become operational immediately.

Two additional manufacturing sites for BioNTech/Pfizer’s COVID-19 vaccine

EMA’s CHMP has approved additional manufacturing sites for the production of Comirnaty, the COVID-19 vaccine developed by BioNTech and Pfizer.

One site, located in Reinbek, Germany, is operated by Allergopharma GmbH & Co. KG. The other in Stein, Switzerland, is operated by Novartis Pharma. The sites will perform finished product manufacturing steps at different stages of the process.

The two new sites are expected to support the continued supply of Comirnaty in the European Union.

Vaxzevria: EMA advises against use in people with history of capillary leak syndrome

EMA’s safety committee (PRAC) has concluded that people who have previously had capillary leak syndrome must not be vaccinated with Vaxzevria (formerly COVID-19 Vaccine AstraZeneca). The Committee also concluded that capillary leak syndrome should be added to the product information as a new side effect of the vaccine, together with a warning to raise awareness among healthcare professionals and patients of this risk.


Documents


ABPI launches updated Code of Practice

The Association of the British Pharmaceutical Industry (ABPI) has launched its new Code of Practice, containing updated principles to make the Code ‘easier for companies to use’.

The 2021 APBI Code of Practice, which is set to come into force on 1 July, has also been updated to reflect changes in the environment that pharma companies currently operate in. Changes have also been implemented to reflect updates to the European Code.

The Code is used by the industry to self-regulate its commitments to operate in a professional, ethical and transparent manner for the benefit of both patients and the public.

The new Code aims to increase transparency, while other updates will aim to help companies work with the NHS within an ethical framework.


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.