• EJPPS

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


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Vol25-2 C June-2020
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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, Chinese, EU, UK and PIC/s regulatory authorities.


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


Europe

  • COVID-19: What's new

  • EU actions to support availability of medicines during COVID-19 pandemic – update #5

  • Decision on fee reductions (GMP) on-site inspections due to COVID-19 pandemic

  • Q&A- regulatory expectations for medicinal products for human use during the COVID-19 Pandemic (rev 1)

  • Deadline postponed for the second targeted consultation on Annex 1

  • Post-authorisation measures: Q&A

  • Risk management plan (RMP): Q&A

  • Transfer of marketing authorisation: Q&A

  • Renewal and annual re-assessment of marketing authorisation

  • Checklist for Initial Notifications for Parallel Distribution

  • Minutes of the 107th meeting of the EMA Management Board


United Kingdom

MHRA

How to manage temporary GDP process changes and risks through the COVID-19 pandemic


USA

  • General considerations for pre-IND meeting requests for COVID-19 related drugs and biological products

  • Recommendations for the permitted daily exposures for three solvents—2-methyltetrahydrofuran,cyclopentyl methyl ether, and tert-butyl alcohol—according to the maintenance procedures for the guidance Q3C (R8)impurities:residual solvents

  • Orange Book Q&A Guidance for Industry (draft)


International


Australia

  • Update to Manufacturing Principles for medicines, APIs & sunscreens

  • Reuse of face masks and gowns during the COVID-19 pandemic


China

  • National Medical Products Newsletter 2020 Volume 3


PIC/S

  • Adoption and Entry into Force of New PIC/S Guidance Documents (PI 052-1 and PI 053-1)


Products

  • New vaccine for prevention of Ebola virus disease recommended for approval in the EU


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


Europe

EMA

COVID-19: What's new

The latest updates on the Covid-19 pandemic from the European Medicines Agency (EMA), including all news and press releases, are available

From the above, readers may be particularly interested in the following recent items:-


EU actions to support availability of medicines during COVID-19 pandemic – update #5

The steering group members and the heads of the National Competent Authorities (NCAs) discussed if the current way in which the supply of medicines used in intensive care units (ICUs) matches the demand at national level could be further improved in view of the reported shortages of ICU medicines. The heads of the NCAs agreed to explore how national data models to forecast the demand can be shared within the EU medicines regulatory network. The first step of this project would involve sharing best practices regarding the estimation of future needs by different Member States and exploring whether joint principles for data collection and analysis could be established. The steering group members and the heads of the NCAs agreed to further discuss this project and a reasonable timeline for its possible implementation at their next meeting.

The steering group also received an update from EMA on the progress of the i-SPOC (industry single point of contact) system, the fast track monitoring system for crucial medicines used in the context of COVID-19 that was set up by the Agency. The data collected so far through the system indicates that current or anticipated shortages of some of these medicines are mainly driven by the unexpected surge in demand and by changes in prescribing behaviours. EMA will keep updating the steering group on a regular basis as more data are gathered through the i-SPOC system in order for the steering group to discuss possible options for resolution of the reported shortages.


Decision on fee reductions (GMP) on-site inspections due to COVID-19 pandemic

This Decision by the EMA Executive Director provides that reduced fee levels shall be introduced for GMP on-site inspections, in cases where a distant assessment had been conducted for the said site during the period where access to sites for inspections were restricted due to the COVID-19 pandemic, but where based on this distant assessment GMP compliance could not be confirmed due to the limitations of a distant assessment, consequently no GMP certificate could be issued, and thus a subsequent on-site inspection is required to confirm compliance. Plasma Master Files inspections are also in the scope of this initiative and will follow the same principle, if applicable.


Q&A on regulatory expectations for medicinal products for human use during the COVID-19 Pandemic (revision 1)

The current COVID-19 pandemic has a considerable impact on citizens, patients and businesses. It may force marketing authorisation holders of medicinal products and regulatory authorities to operate under business continuity mode, impacting the standard way of working. Moreover, public health needs may require quick actions or re-prioritisation of operations. This document provides guidance to marketing authorisation holders of medicinal products for human use (“MAH”) on regulatory expectations and flexibility during the COVID-19 pandemic. The document will be updated to address new questions and to adjust the content thereof to the evolution of the pandemic. For queries related to specific products that are not specifically addressed in this document, MAHs are invited to address the EMA (for centrally authorised products) or the relevant national competent authorities (for nationally authorised products). This document remains valid until further notice.

New sections of this document are:-

  • 2.2-Which measures will be taken in respect of GMP certificates and authorisations to manufacture/import in light of difficulties to conduct on-site GMP inspections?

  • 2,3-Which measures will be taken in respect of GDP certificates and wholesale authorisations in light of difficulties to conduct on-site inspections?

  • 2.4-Which adaptations to the work of the QP are possible considering travelling and other restrictions?

  • 4.1-Is there any impact on reporting into EudraVigilance of Individual Case Safety Reports (ICSRs)?

Deadline postponed for the second targeted consultation on Annex 1

Due to the challenges posed by COVID-19, the timeline for the second targeted consultation has been extended until 20 July 2020.

Those who have already submitted their comments are welcome to revise their contribution if they would like to. Only their latest comments will be considered.


Post-authorisation measures: Q&A

This page lists questions that marketing-authorisation holders (MAHs) may have on post-authorisation measures. It provides an overview of the EMA's position on issues that are typically addressed in discussions or meetings with MAHs in the post-authorisation phase.

(Several of these Post Authorisation topics which may be considered of particular interest to readers are covered in the subsequent 3 sections below.[MBH])


Risk management plan (RMP): Q&A

This Q&A is intended to provide advice to Marketing Authorisation Holders (MAHs) of centrally authorised medicinal products about procedural and regulatory aspects to the Risk Management Plan (RMP) lifecycle during the post authorisation phase. It addresses the classification of changes to the RMP, submission requirements and aspects to be considered in the management of parallel procedures affecting RMP.


Transfer of marketing authorisation: Q&A

This page lists questions that MAHs may have on transfers of marketing authorisations. It provides an overview of the EMA's position on issues that are typically addressed in discussions or meetings with MAHs in the post-authorisation phase.


Renewal and annual re-assessment of marketing authorisation

This page lists questions that MAHs may have on renewals of marketing authorisations, annual renewals of conditional marketing authorisations and annual re-assessments of marketing authorisations granted in exceptional circumstances.


Checklist for Initial Notifications for Parallel Distribution

The Agency recommends that this checklist is used in advance of submission of initial notifications for parallel distribution. You should be able to answer “Yes” to every item listed below unless a specific point is not applicable to the application in question. Please note that this checklist should not be included in the actual submission.


Minutes of the 107th meeting of the EMA Management Board

EMA has published the minutes of this meeting which was held virtually on March 19 2020


UK

MHRA

How to manage temporary GDP process changes and risks through the COVID-19 pandemic

A new blog post, “How to manage temporary GDP process changes and risks through the COVID-19 pandemic” has just been published on the MHRA Inspectorate blog.

During the Covid-19 pandemic you may need to adjust how you operate, for example using temporary process deviations and temporary staff. Such changes should be documented either as deviations, change controls or similar and incorporate quality risk management principles. They may be documented either as single reports or an over-arching one specific to COVID-19. The ultimate aim should be to ensure the medicines provided to patients remain safe and effective and the integrity of the supply chain is maintained. Identified risks and mitigation should reflect differences compared to non-pandemic conditions, e.g. the need to use alternative suppliers and distribution networks. Application of quality risk management principles should include risk control measures where necessary. It is important to understand that ‘risk assessment’ does not itself reduce risk and should not be used with the aim of justifying an unsuitable practice.

There is a link within the blog to a GDP flexibilities document which MHRA has published as exceptional guidance to assist with distribution of medicines during the COVID-19 outbreak,in order to help maintain the medicines supply chain.These cover:-

  • Supply chain

  • Transportation

  • Responsible Persons (RP)

  • Facilities and equipment

  • Reporting your use of this guidance


United States of America

The US Food and Drug Administration (USFDA)

General considerations for pre-IND meeting requests for COVID-19 related drugs and biological products

FDA is issuing this guidance to facilitate a sponsor’s preparation of, and FDA’s review of, a pre-IND (Investigational New Drug Application) meeting request. Well-prepared pre-IND meeting requests should enable more timely initiation of clinical trials under an IND. The general principles set forth in this guidance apply to drugs; however, for cellular and gene therapies, blood products, vaccines, and other complex biological products regulated by the Center for Biologics Evaluation and Research (CBER), there may be additional considerations. FDA encourages sponsors to contact the CBER Product Jurisdiction Office for additional information.

During the current public health emergency, with the large number of potential therapeutics for COVID-19 related illness, it is essential that the review process for investigational drugs be as efficient as possible. To facilitate this, FDA are urging sponsors to submit a pre-IND meeting request that allows early and thorough review and discussion between the sponsor and FDA, which can lead to more rapid review of the subsequent IND and assurance of subject safety, which in turn can facilitate faster clinical trial initiation for programs that proceed to that phase. Given the range in clinical manifestations of COVID-19 and the large number of drugs and mechanisms of action being evaluated for use in this disease, the Center for Drug Evaluation and Research (CDER) has established a multispecialty, multidisciplinary team focused on review of drug development proposals.


Recommendations for the permitted daily exposures for three solvents—2-methyltetrahydrofuran, cyclopentyl methyl ether, and tert-butyl alcohol—according to the maintenance procedures for the guidance Q3C(R8) impurities:residual solvents

FDA has now published this ICH Q3C(R8) document which was Endorsed by the Members of the ICH Assembly under Step 2 and released for public consultation (document dated 14 February 2020)


Orange Book Q&A Guidance for Industry

This guidance is intended to assist interested parties (including prospective drug product applicants, drug product applicants, and approved application holders) in utilizing the Approved Drug Products With Therapeutic Equivalence Evaluations publication (The Orange Book). This guidance provides answers to commonly asked questions that FDA has received from these interested parties regarding the Orange Book. The Orange Book identifies (1) drug products approved by FDA under the Federal Food, Drug, and Cosmetic Act (FD&C Act) and

(2) patent and exclusivity information related to approved drug products. In particular, the main criteria for the inclusion of a drug product in the Orange Book are that the drug product is the subject of an approved application and that FDA has not determined the drug product to have been withdrawn from sale for safety or effectiveness reasons. The Orange Book is composed of four main parts:

  • The Prescription Drug Product List, which is a list of approved marketed prescription drug products with therapeutic equivalence evaluations (which along with the OTC Drug Product List is referred to as the “Active Section”);

  • The OTC Drug Product List, which is a list of marketed over-the-counter (OTC) drug products that have been approved in new drug application (NDAs) or abbreviated new drug applications (ANDAs) ( which along with the Prescription Drug Product List is referred to as the “Active Section”);

  • The Drug Products with Approval under Section 505 of the FD&C Act Administered by 50 the Center for Biologics Evaluation and Research List; and 51 52

  • The Discontinued Drug Product List,


International


Australia

Update to Manufacturing Principles for medicines, APIs & sunscreens

The TGA's Manufacturing Quality Branch (MQB) is responsible for the assessment, inspection and licensing/certification of manufacturers of medicines supplied to, or exported from Australia.

The current manufacturing principles adopted by the TGA for the manufacture of medicines, active pharmaceutical ingredients and sunscreens is the PIC/S Guide to GMP, (PE009-13) issued 1 January 2017 (excluding Annexes 4, 5 and 14). This guide was adopted by the TGA in 2018.

The intent of this notice is to provide early notification that the TGA intends to adopt the current version of the PIC/S Guide to GMP for Medicinal Products (PE009-14) issued, 1 July 2018, as the manufacturing principles for medicines, active pharmaceutical ingredients and sunscreens.

A 12 month graduated transition period will be provided to allow manufacturers time to assess the new supplementary requirements contained in the new Manufacturing Principles and implement changes to procedures and practices to fully comply with the new guide.

An incremental adoption plan has been developed which outlines incrementally increasing expectations for compliance throughout the 12 month transition period. The incremental adoption plan explains the position an inspector will adopt during inspection of a manufacturer at each time point. This plan will be published by the TGA prior to the initial adoption date.


Reuse of face masks and gowns during the COVID-19 pandemic

TGA has updated this guidance to include new section on reprocessing of PPE by healthcare facilities.


China

National Medical Products Newsletter 2020 Volume 3

Readers involved in supplying pharmaceutical products to China may be interested in this newsletter from China Center for Food and Drug International Exchange (CCFDIE) and Servier (Tianjin) Pharmaceutical Co., Ltd.

Issues covered are:-

  • Provisions for drug registration and for the supervision and administration of drug production pertaining to the current administration on drug distribution

  • The implementation of the provisions for drug registration

  • The implementation of the newly revised provisions for the supervision and administration of drug production

  • Regulations for administration of medical device extended clinical trials (Interim)

  • Medical device unique identification database shared externally


PIC/S

Adoption and Entry into Force of New PIC/S Guidance Documents (PI 052-1 and PI 053-1)

The following new PIC/S guidance documents have been successfully adopted: -

  • PI 052-1 Aide-memoire - Inspection of Health Based Exposure Limit (HBEL) Assessments and Use in Quality Risk Management

  • PI 053-1 Questions and Answers 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’

The documents, which have been successfully developed by the PIC/S Expert Circle on Controlling Cross-Contamination in Shared Facilities, led by UK / MHRA, entered into force on 1 June 2020.



Products

New vaccine for prevention of Ebola virus disease recommended for approval in the EU

EMA’s human medicines committee (CHMP) has recommended granting a marketing authorisation in the European Union for a new Ebola vaccine that provides active immunisation to prevent Ebola virus disease in individuals aged 1 year and older. The recommendation to grant a marketing authorisation for the new vaccine follows the approval of the first Ebola vaccine in November 2019. The new Ebola vaccine consists of two components, Zabdeno and Mvabea. Zabdeno is given first and Mvabea is administered approximately eight weeks later as a booster.

As protection against Ebola virus disease is considered to be of major public health interest, Zabdeno and Mvabea were evaluated under EMA's accelerated assessment mechanism, a tool which aims to speed up patients' access to new medicines if there is an unmet medical need.

Currently, there are no therapies approved for Ebola. EMA is working together with regulatory authorities around the world to support WHO and to advise on possible pathways for the development, evaluation and approval of medicines and vaccines to fight Ebola.


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.