Review of Developments in GMP and the Regulation of Medicines September 2020


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Volume 25-3 C September-2020
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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 Australian, EU, PIC/S, UK and USA regulatory authorities.


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


Europe

  • New reference standards / replacement batches.

  • Nitrosamines risk assessment: update for CEP holders

  • Nitrosamine impurities in human medicinal products

  • Post-authorisation procedural advice for users of the centralised procedure

  • Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs) including recommendations regarding contamination of herbal medicinal products with Pas

  • Big data


United Kingdom

  • Consultation document: changes to Human Medicine Regulations to support the rollout of COVID-19 vaccines

  • Cross Contamination Control in Shared Facilities and Equipment


USA

  • Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency - Q&A.

  • Compliance policy for the quantity of bioavailability and bioequivalence samples retained under 21 CFR 320.38(c)

  • Marketing status notifications under section 506i of the Federal Food, Drug, and Cosmetic Act (FD&C act)


International


Australia

  • TGA business plan 2020/2021

  • Disinfectants: FAQ for new sponsors

  • Faecal microbiota transplant (FMT) products regulation


PIC/S

  • Azerbaijan applies for pre-accession


Products

  • Ranitidine containing products


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


Europe

EDQM

New reference standards / replacement batches.

EDQM has announced the availability of 6 new European Pharmacopoeia (Ph. Eur.) reference standards plus 20 replacement batches for existing Ph. Eur. reference standards.


Nitrosamines risk assessment: update for CEP holders

In June 2020, the EMA finalised a review to provide guidance to Marketing Authorisation Holders (MAHs) on how to avoid the presence of nitrosamines in human medicinal products. As part of the outcome of this review, the European medicines regulatory network agreed new deadlines to implement the Article 5(3) opinion. However, the EDQM has decided not to change the deadline for CEP holders, which remains therefore 31 July 2020.

Moreover, from 1 October 2020, applicants and CEP holders should systematically include a risk assessment regarding the potential formation of nitrosamines in any new CEP application, sister file or renewal application, as well as in any revision where a risk of nitrosamine formation may be introduced (i.e. changes to the manufacturing process, change of suppliers of starting materials or intermediates, etc.).


EMA

Nitrosamine impurities in human medicinal products

The CHMP considers that there is also a risk of presence of nitrosamines in biological medicinal products, in particular for the biological medicines with the following risk factors:

  • biologicals containing chemically synthesised fragments, where risk factors similar to chemically synthesised active substances are present;

  • biologicals using processes where nitrosating reagents are deliberately added;

  • biologicals packaged in certain primary packaging material, such as blister packs containing nitrocellulose.

For the above reasons the current call for review has been extended to cover also all biological medicinal products for human use


Post-authorisation procedural advice for users of the centralised procedure

EMA has posted, on its Grouping of Variations Q&A page, this post authorisation procedural advice. This advice is contained in a 296 page document. Most helpfully the Agency has included a Track Changes version of the document where changed sections can be readily identified, It would appear that the following sections were changed in August 2020:-3.7, 5,3, 7.1.2, 13.2, 15.4, 16.4, 17.20 & 19.6

In addition although sections 13.16 and 16.1 are not marked in the title line as being revised Aug 2020, both do contain “red” revised text.

[The inclusion of the “Track Changes” document is indeed most helpful but at 296 pages might this be a case for Red Tape reduction?MBH]


Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs) including recommendations regarding contamination of herbal medicinal products with PAs

Draft Revision 1 of this document has been adopted by the Committee on Herbal Medicinal Products (HMPC) for release for public consultation. The consultation period ends 15 November 2020.


Big data

EMA is inviting organisations with a potential interest in setting up and operating a European Union-wide database network and healthcare data analysis platform, to complete an online market consultation survey.

This survey will allow EMA to identify organisations interested in delivering the Data Analysis and Real-World Interrogation Network in Europe (DARWIN EU) and gauge high-level market capabilities ahead of implementing a procurement strategy.

More information on the project and on data protection are available in the survey.

The survey closes at 12:00 (CET) on 3 September 2020.


UK

MHRA

Consultation document: changes to Human Medicine Regulations to support the rollout of COVID-19 vaccines

The independent Joint Committee on Vaccination and Immunisation (JCVI) will advise the UK government on which COVID-19 vaccine/s the UK should use, and on the priority groups to receive the vaccine based on the best available clinical, modelling and epidemiological data.

The preferred route to enable deployment of a new vaccine for COVID-19 is through the usual marketing authorisation (product licensing) process. However, if there is a compelling case, on public health grounds, for using a vaccine before it is given a product licence, given the nature of the threat we face, the JCVI may take the very unusual step of advising the UK government to use a tested, unlicensed vaccine against COVID-19, and there is therefore a need to ensure that the right legislative measures are in place to deal with that scenario.

This consultation document has laid out the proposals for changes to the Human Medicine Regulations 2012 to ensure that, in particular, the UK is able to administer a COVID-19 vaccine effectively once it is available, as well as support the upscaling of flu vaccination and providing in the future for the mass distribution of treatments for pandemic diseases.

Although the earliest date by which a COVID-19 vaccination programme could start is uncertain, preparations are underway. Therefore, there is a need to share information on how the necessary changes to medicines legislation to support the vaccination programme might look.

The consultation covers:-

  • authorising temporary supply of an unlicensed product

  • civil liability and immunity

  • expanding the workforce eligible to administer vaccinations

  • promoting vaccines

  • making provisions for wholesale dealing of vaccines

This consultation closes on Friday 18 Sept. 2020.


Cross Contamination Control in Shared Facilities and Equipment

A new post, “Cross Contamination Control in Shared Facilities and Equipment. Reflection on common deficiencies and expectations as seen in recent PIC/S guidance.” has just been published on the MHRA Inspectorate blog.

During this period where MHRA has been conducting predominantly remote inspections, it has reflected on some of the common factors in critical deficiencies that it has seen in control strategies for cross contamination between products in shared facilities. As a result, MHRA has posted this new blog to help make Industry aware of certain elements of control strategy that should be addressed.

[Readers should also familiarise themselves with the PIC/s Aide Memoire PIC/S PI 052 – inspection of health based exposure limit (hbel) assessments and use in quality risk management and the original PIC/s PI 053-1 Q&A on Implementation of Risk-based Prevention of Cross-contamination in Production and ‘Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities’MBH]


United States of America

The US Food and Drug Administration (USFDA)

Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency - Q&A.

FDA recognizes that the COVID-19 public health emergency is not only impacting public health, but also drug development programs, ongoing manufacturing operations, and FDA’s ability to conduct inspections. FDA also recognizes that sponsors and applicants have many questions related to this impact. Therefore, FDA has developed this guidance to provide answers to a number of frequently asked questions.

FDA has issued guidance on how to implement manufacturing process and facility changes; relevant guidances that describe the process for reporting changes to an application can be found in section V., References. The Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Office of Regulatory Affairs (ORA) remain fully capable of continuing daily activities, such as application assessments, including facility evaluation and certain inspection activities, while responding to public health needs related to the current COVID-19 pandemic. As this remains an evolving and very dynamic situation, FDA will continue to be flexible and as transparent as possible.

The Q&A has sections on inspections and on manufacturing & supply chain requests.

This guidance document is being implemented immediately, without prior public participation, but it remains subject to comment in accordance with the Agency’s good guidance practices.


Compliance policy for the quantity of bioavailability and bioequivalence samples retained under 21 CFR 320.38(c)

This procedural guidance, which is for immediate implementation, describes FDA’s compliance policy related to the retention of reserve samples of the test article and reference standard used in an in vivo bioavailability (BA) and in vivo or in vitro bioequivalence (BE) study. Specifically, this guidance:

  • Addresses the requirement at 21 CFR 320.38(c) to retain reserve samples of sufficient quantity to permit FDA to perform five times all the release tests required in an application or supplemental application

  • Describes the conditions under which the Agency does not generally intend to take enforcement action against an applicant or contract research organization (CRO) for retaining less than the quantity of reserve samples of the test article and reference standard that were used in the BA or BE study as specified in 21 CFR 320.38(c).

This guidance applies only to the requirements for retention of reserve samples contained in 21 30 CFR 320.38(c). This guidance does not apply to the other requirements for retention of reserve samples contained in 21 CFR 320.38, such as how testing facilities must select samples for testing, how the reserve samples must be retained, and whether reserve samples are in fact representative of the test article and reference standard used in the BA or BE study. Additionally, this guidance does not apply to the requirement in 21 CFR 211.170 to retain samples under CGMP.


Marketing status notifications under section 506i of the Federal Food, Drug, and Cosmetic Act (FD&C act)

FDA is announcing the availability of a draft guidance for industry entitled “Marketing Status Notifications Under Section 506I of the Federal Food, Drug, and Cosmetic Act (FD&C Act); Content and Format.” This draft guidance is intended to assist holders of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) approved under the FD&C Act with their submission of required marketing status notifications.


International


Australia

TGA business plan 2020/2021

This document has now been published. Key priorities are implemented through different activity streams:

  • Product regulation and safety – through core regulatory activity and business process improvements.

  • Regulatory reform – including activities associated with the final year of implementation of recommendations from the Review of Medicines and Medical Devices Regulation and the Action Plan for Medical Devices.

  • International engagement – through activities that promote international information sharing, work sharing and regulatory convergence, as well as programs for regulatory strengthening and medicines testing in our region.

  • Regulatory education and compliance – through education, monitoring, targeted compliance and enforcement activities and appropriate action.

The plan also provides a table indicating major regulatory reform activities, Work related to the COVID-19 pandemic is also included in this section.


Disinfectants: FAQ for new sponsors

Some sponsors may be seeking to supply disinfectants for the first time during the COVID-19 pandemic. This page answers frequently asked questions for new sponsors in relation to the supply of these products.


Faecal microbiota transplant (FMT) products regulation

FMT products are typically used to repopulate the bacterial microenvironment in a recipient's bowel with healthy microorganisms. Currently, FMT products have sound clinical evidence of efficacy for the treatment of recurrent Clostridium difficile infection (CDI), an often serious bacterial infection of the gut, and emerging evidence of efficacy for treatment of ulcerative colitis (UC), a chronic relapsing-remitting mucosal inflammatory bowel disease (IBD). There is also increasing interest in the use of FMT products for a range of other conditions.

TGA provided clarity for the new regulatory model for FMT products. Most FMT products are regulated as biologicals. This includes significantly processed products that are derived from stool. 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.

More information about how TGA regulates FMT products and the regulatory requirements for sponsors is described in the Australian Regulatory Guidelines for Biologicals.


PIC/S

Azerbaijan applies for pre-accession

On 18 August 2020, the Analytical Expertise Center (AEC) – Ministry of Health of Azerbaijan applied for PIC/S pre-accession. The Rapporteurs will be appointed by written procedure.


Products

Ranitidine containing products

One of the companies that markets ranitidine has requested a re-examination of the CHMP’s April 2020 opinion. Upon receipt of the grounds for the request, the CHMP will re-examine its opinion and issue a final recommendation.


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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