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Review of Developments in GMP and the Regulation of Medicines May 2022


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Vol27.2B May 2022
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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 MHRA, EU, USA and Australian regulatory authorities.


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



MHRA



  • Facilitating global access to diabetes treatments for non-EU patients

  • Procedural advice for veterinary vaccine antigen master file (VAMF) certification

  • Compilation of Union Procedures on Inspections and Exchange of Information

  • ICH guideline Q9 (R1) on quality risk management – overview of comments received.

  • Annual report of the Good Manufacturing and Distribution Practice Inspectors Working Group 2021

  • Frequently asked questions about parallel distribution

  • Good manufacturing practice

  • ICH Q14 Analytical procedure development

  • Digital application dataset integration (DADI) and Product Management Service (PMS) webinar

  • New (Ph. Eur) general text on comparability of alternative analytical procedures.

  • New Pharmeuropa Bio & Scientific Notes article now online: Human immunoglobulin for ACA BRP

  • Proceedings of Workshop on alternatives to animal testing in Quality Control of Veterinary Vaccines

  • EDQM sticker no longer to appear on Certificates of suitability

  • Outcome of the 172nd session of the European Pharmacopoeia Commission


  • Application of the principles of the ICH m7 guideline to calculation of compound-specific acceptable intakesAddendum to M7(R2)

  • Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use

  • Bioavailability Studies Submitted in NDAs or INDs – General Considerations



Australia


Therapeutic Goods Administration (TGA)

  • Webinar: Medicinal cannabis reforms

Pharmaceutical Inspection Co-Operation Scheme (PIC/s)

  • Pre-accession And Accession Guidelines

  • PIC/s annual report 2021



  • UK MHRA approves ‘Spikevax’ for use in 6 - 11-year olds

  • UK MHRA approves Valneva COVID-19 vaccine.

  • ECDC and EMA issue advice on fourth doses of mRNA COVID-19 vaccines


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


UK


MHRA

See the product section of this report.



Europe


EMA

Facilitating global access to diabetes treatments for non-EU patients

EMA’s human medicines committee (CHMP) has given a recommendation for two diabetes mellitus treatments, Actrapid and Insulatard, for use outside the European Union (EU).

The two diabetes medicines were submitted to EMA under a regulatory procedure (Article 58 of Regulation (EC) No 726/2004) known as EU Medicines for all (EU-M4All). Any medicine assessed under this procedure must meet the same standards as medicines intended for EU citizens.

Actrapid and Insulatard are human insulins that have been centrally authorised in the EU since 2002. According to the EU marketing authorisation, unopened insulin products must be stored in a refrigerator (2–8°C). These strict storage conditions are difficult to adhere to when temperature conditions are challenging and access to refrigeration is limited, for example in countries experiencing conflict or a humanitarian emergency situation. This adds an extra burden to the care of diabetes patients who live under these conditions.

The company applied for an assessment of these two medicines with changed storage time, to include storage without refrigeration when used in countries outside the EU. Following the evaluation of stability data submitted by the company in support of their request, the CHMP concluded to allow storing the two insulin products at temperatures up to 30°C for a maximum of four weeks before they are taken into use or carried as a spare.

This positive opinion by the CHMP paves the way towards increased access to treatment for diabetes patients worldwide.

Procedural advice for veterinary vaccine antigen master file (VAMF) certification

This document is intended to provide advice to marketing authorisation (MA) applicants and marketing authorisation holders (MAHs) on issues associated with the submission, evaluation, certification and use of a veterinary vaccine antigen master file (VAMF) by the EMA. A VAMF is a stand-alone part of the marketing authorisation application dossier for a vaccine, which contains all relevant information on quality for one given vaccine antigen or active substance. The stand-alone part may be common to one or more monovalent and/or combined vaccines presented by the same applicant or marketing authorisation holder The use of the VAMF certification system is optional. For combined vaccines, the vaccine antigen(s) to be included in VAMF(s) shall be specified and a separate VAMF shall be required for each of those selected by the applicant.

This document focusses on the first step of the VAMF certification which consists of a centralised assessment of the VAMF application dossier submitted by the applicant/MAH, which results in a certificate of compliance to Union legislation, issued by the EMA. This certificate is valid throughout the European Union

Compilation of Union procedures on inspections and exchange of information

EMA has issued v10 corr. of this document

[A valuable and extremely useful document which is regularly updated. MBH]

ICH guideline Q9 (R1) on quality risk management – overview of comments received.

EMA has published this overview of comments. [There are 41pages of them so this remains a hot topic., just as it was for the original document. MBH]

Annual report of the Good Manufacturing and Distribution Practice Inspectors Working Group (GMDP IWG)2021

This document is the annual report for the year 2021.There was no annual report from 2018 to 2020 as a result of the EMA Business Continuity Plan (BCP) due to the effects of the UK withdrawal from the European Union. The BCP was extended in 2020 due to the public health emergency due to COVID-19. The impact of the BCP on the work of the GMDP IWG has meant a prioritisation in activities and shorter meetings, although the meeting frequency has been maintained. The GMDP IWG currently meets virtually via remote meeting platforms. The GMP/GDP IWG provides input and recommendations on all matters relating directly or indirectly to GMP ) and GDP. The GMP/GDP IWG focuses on harmonisation and co-ordination of GMP and GDP related activities at EU level and maintains close co-operation with international partner authorities.

Frequently asked questions about parallel distribution

This FAQ was updated in April 2022

Good manufacturing practice

EMA has updated its web pages on this topic. Included is a new guidance document for applicants/MAHs involved in GMP and GCP inspections coordinated by EMA

ICH Q14 Analytical procedure development

EMA’s CHMP has issued this step 2 ICH guidance, on analytical procedure development, for comment.

The closing date for comments is 31 July 2022

Digital application dataset integration (DADI) and Product Management Service (PMS) webinar

16/05/2022 Online, 10:00 - 12:00 Amsterdam time (CEST)

The DADI project will replace PDF electronic application forms (eAF) used for regulatory submissions with online forms, making the future form-filling and submission-handling process more efficient. The variations form for human medicinal products will be the first form to be released by DADI, with an expected go-live in October 2022.This event is a joint DADI-PMS webinar for business and technical audiences from industry and national competent authorities wishing to learn more about what will happen when the DADI web-based form for human medicinal products will go live.

Topics addressed in this webinar include:

  • The process for selecting products, creating and submitting the variation form;

  • Data in the form coming from PMS;

  • The process after the approval of the variation;

  • Electronic submission requirement to the Extended Eudravigilance Medicinal Product Dictionary

New general text on comparability of alternative analytical procedures.

The European Pharmacopoeia (Ph. Eur) launches a public consultation and is seeking feedback on its new general text on the comparability of alternative analytical procedures (5.27).

The draft text elaborates on the requirement expressed more succinctly in the Ph. Eur. General Notices, according to which a user may – with the agreement of the competent authority – use alternative analytical procedures for control purposes provided that they enable an unequivocal decision to be made with regard to compliance with the standards of the monographs if the official procedures were used.

Once adopted by the Ph. Eur. Commission, this new general text will represent a major addition to the Ph. Eur. as it provides more detailed information on one of the processes that offers users greater flexibility in their demonstration of compliance with the Ph. Eur. monographs. It is also expected to prove valuable both to users who choose to employ alternative analytical procedures and to assessors during evaluation.

The new general text is published in Pharmeuropa vol. 34.2 for public consultation from April until the end of June 2022. [Readers will need to log onto the Pharmeuropa site to access the document MBH]

New Pharmeuropa Bio & Scientific Notes article now online: Human immunoglobulin for ACA BRP

A new scientific article on the outcome of a recently concluded Biological Standardisation Programme (BSP) study has been published.

Four replacement batches of the European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) for Human immunoglobulin for anticomplementary activity were established in a collaborative study and adopted by the Ph. Eur. Commission in June 2021.

The published article includes details of the method used, statistical analysis and study results

Proceedings of Workshop on alternatives to animal testing in Quality Control of Veterinary Vaccines

The proceedings of the workshop "Novel in-vitro model as alternative to in-vivo toxoid vaccines testing: Clostridium septicum vaccine as proof of concept" have been published in FreePub, a free online EDQM journal. The proceedings include summaries of the webinar presentations and discussions. It provides a key reference for those who are interested in implementing Vero cell-based testing for Clostridium septicum and other cytotoxic antigens as well as an interesting insight into the work of the Biological Standardisation Programme and the revision of the Ph. Eur veterinary vaccine monographs.

EDQM sticker no longer to appear on Certificates of suitability

As of the 1 May 2022, the EDQM sticker will no longer appear on Certificates of suitability to the Ph. Eur monographs (CEPs). This adhesive sticker will no longer be pasted on CEPs next to the wet signature.

Any certificate granted from this date on the specific EDQM paper and without the EDQM sticker shall be considered to be a valid certificate.

Outcome of the 172nd session of the European Pharmacopoeia Commission,

The Commission adopted 78 texts at this session, to be published in Ph. Eur. Supplement 11.1 and be effective as of 1April 2023. These 78 texts included six new monographs and one new general chapter. The Ph. Eur. Commission adopted revised versions of 71texts and also decided to engage on the revision of a number of texts, including the monographs on Water, purified (0008) and Water for injections (0169), to add the possibility to use recombinant factor C when testing for bacterial endotoxins. The Ph. Eur. Commission approved this revision process, which will lead to an enquiry in the July 2022issue of Pharmeuropa (34.3). The Commission also approved revised versions of the following guides:

  • Technical guide for the elaboration of monographs on medicinal products containing chemically defined active substances, to capture recent changes in the policies for salts and solvates;

  • Guide for the elaboration of monographs on homoeopathic preparations.



United States of America


The US Food and Drug Administration (USFDA)

Application of the principles of the ICH m7 guideline to calculation of compound-specific acceptable intakes, Addendum to M7(R2)

At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate ICH Expert Working Group, is transmitted by the ICH Assembly to the regulatory authorities of the ICH regions for internal and external consultation, according to national or regional procedures.

This document contains only the list of the revisions to the M7(R1) Guideline as well as the new monographs for the 7 new compounds Acetaldehyde, Dibromoethane, Epichlorohydrin, Ethyl Bromide, Formaldehyde, Styrene, and Vinyl Acetate, which are submitted for public consultation. Further to reaching Step 4, these revisions would be integrated into a complete M7(R2) Guideline and Addendum documents.

Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use

This guidance describes how FDA intends to evaluate a request for a waiver, with regard to a pH adjuster, under 21 CFR 314.99(b) of the requirement in 21 CFR 314.94(a)(9)(iii) and (iv) that a drug product intended for parenteral, ophthalmic, or otic use generally “must contain the same inactive ingredients and in the same concentration as the reference listed drug identified by the applicant.” This guidance also provides recommendations regarding the timing and process for requesting such a waiver of the requirement.

Bioavailability Studies Submitted in NDAs or INDs – General Considerations

This guidance provides recommendations to sponsors and applicants submitting bioavailability (BA) information for drug products in investigational new drug applications (INDs), new drug applications (NDAs), and NDA supplements. This guidance contains recommendations on how to meet the BA requirements set forth in 21 CFR part 320 as they apply to dosage forms intended for oral administration. The guidance is also applicable to non-orally administered drug products when it is appropriate to rely on systemic exposure measures to determine the BA of a drug (e.g., transdermal delivery systems and certain vaginal, rectal, and nasal drug products).

The guidance provides recommendations on conducting BA studies during the investigational period for a drug intended to be submitted for approval in an NDA and bioequivalence (BE) studies during the postapproval period for certain changes to drug products with an approved NDA.



International


Australia


Therapeutic Goods Administration (TGA)

Webinar: Medicinal cannabis reforms

This webinar of 6 April was presented by Jennifer Burnett, Assistant Secretary, Manufacturing Quality Branch, TGA and Paul Crossley, Assistant Director, Manufacturing Quality Branch, TGA,

The intent was to provide information on the transition periods and how importers and sponsors can comply with the new requirements, due to reforms having been made to the manufacturing, labelling and packaging requirements for Medicinal Cannabis Products manufactured or supplied in Australia.

Pharmaceutical Inspection Co-Operation Scheme (PIC/s)

Pre-accession and Accession Guidelines

PIC/s has issued revisions of these two documents

PIC/s annual report 2021

PIC/s has issued this report covering another year of operating on a virtual basis.



Products


UK MHRA approves ‘Spikevax’ for use in 6 - 11-year olds

Use of the Moderna COVID-19 vaccine or ‘Spikevax’ has been approved for 6 to 11s after meeting the required safety, quality and effectiveness standards, This approval takes into account the extension to use in children aged 6 to 11 years already approved by the European Medicines Agency on 2 March 2022, as the original GB licence for Spikevax in adults was approved by relying on the EU decision.

UK MHRA approves Valneva COVID-19 vaccine.

The UK’s independent medicines regulator is the first in the world to approve the Valneva vaccine which becomes the sixth COVID-19 vaccine to be granted an MHRA authorisation.

It is also the first, whole-virus inactivated COVID-19 vaccine to gain MHRA regulatory approval.

With this type of vaccine, the virus is grown in a lab and then made completely inactive so that it cannot infect cells or replicate in the body but can still trigger an immune response to the COVID-19 virus. This process is widely used already in the production of flu and polio vaccines.

ECDC and EMA issue advice on fourth doses of mRNA COVID-19 vaccines

The European Centre for Disease Prevention and Control (ECDC) and EMA’s COVID-19 task force (ETF) have concluded that it is too early to consider using a fourth dose of mRNA COVID-19 vaccines (Pfizer’s Comiranty and Moderna’s Spikevax) in the general population.

However, both agencies agreed that a fourth dose (or second booster) can be given to adults 80 years of age and above after reviewing data on the higher risk of severe COVID-19 in this age group and the protection provided by a fourth dose.

ECDC and EMA also noted that there is currently no clear evidence in the EU that vaccine protection against severe disease is waning substantially in adults with normal immune systems aged 60 to 79 years and thus no clear evidence to support the immediate use of a fourth dose.

Authorities will continue to monitor data to determine if there is an increasing risk of severe illness among those who are vaccinated.




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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