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


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Vol27.2C June 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:


UK


MHRA

  • Compliance Monitor Process (Part 2)– CM role and application process

  • Medicines shortages: regulatory processes to manage supply disruptions

  • The Northern Ireland MHRA Authorised Route (NIMAR)


EU

  • Public Consultation concerning the physical attendance and the location of personal residency of the Q P.

  • EMA guidance supports development of new antibiotics

  • External whistleblowing policy

  • ICH guideline Q3D (R2) on elemental impurities Step 5

  • Synchron Research Service: suspension of medicines over flawed studies

  • Frequently asked questions about parallel distribution

  • Ph. Eur. Commission adopts first “horizontal standard” for monoclonal antibodies

  • OMCLs participate in international regulatory collaboration on the analysis of nitrosamines in metformin containing medicines

  • 2021 Highlights – EDQM annual report


USA

  • Benefit-Risk Considerations for Product Quality Assessments

  • Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production - Level 2 revision

  • Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors

  • Risk Management Plans to Mitigate the Potential for Drug Shortages

  • Importation of Prescription Drugs Final Rule Q&A


International


International coalition of medicines regulatory authorities (ICMRA)

  • International regulators and WHO: support healthcare professionals to enhance public confidence in COVID-19 vaccines



RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


UK


MHRA

See the product section of this report.



Europe


EMA

Public Consultation concerning the physical attendance and the location of personal residency of the Q P.

The COVID-19 pandemic required manufacturers and importers of medicinal products and regulatory authorities to operate under business continuity mode, impacting the standard way of working. As a result, it was necessary to publish guidance on regulatory expectations and flexibility during the pandemic to minimise risks of shortages while ensuring that the high standards of quality, safety and efficacy of medicines made available to patients in the EU were maintained. The guidance recognised that the work of the Qualified Person required adaptation, permitting remote batch certification when on site presence was not possible.

The GMDP Inspectors Working Group is currently reviewing the flexibilities concerning requirements for the QP’s physical attendance at the authorised manufacturing site when performing batch certification or batch confirmation on a routine basis, outside of an emergency situation.

A set of Q&As has been drafted reflecting on the conditions which should apply and the appropriate technical requirements to facilitate remote certification and confirmation. The Q&As also addresses the location of personal residency of the QP.

The Q&A was open for 1 month only until 13 June 2022.

EMA guidance supports development of new antibiotics

As part of its efforts to support a global approach to the development of new antimicrobial medicines, EMA has published the final revised guideline on the evaluation of human medicines for the treatment of bacterial infection

As antimicrobial resistance (AMR) is a global threat, regulators in the EU, the United States and Japan have agreed to align as much as possible their respective data requirements so that medicine developers can design clinical trials that meet the evidence needs of multiple regulatory agencies. The revised document reflects the outcome of these discussions, and also includes :-

  • clarifications on recommended clinical development programmes for antimicrobials intended to address an unmet need;

  • guidance on clinical trials to support treatment of uncomplicated urinary tract infections and uncomplicated gonorrhoea;

  • updated guidance on displaying microbiological and clinical efficacy data in the summary of product characteristics.

The guideline comes into force on 1 Dec 2022.

External whistleblowing policy

EMA's whistleblowing policy provides a framework for assessing reports from external whistleblowers and coordinating any further investigation, while protecting the confidentiality of the reporting person.

EMA revised the policy in April 2022, with changes in the following areas:

  • Definitions of breaches, which include more examples of allegations

  • Reporting process, which includes an interim report that whistleblowers can receive if a longer investigation is required

  • Acknowledgement of receipt for external reports, which is shortened from 15 to 7 days

  • Clarification of the roles of the European Anti-Fraud Office (OLAF) and the European Public Prosecutor's Office (EPPO) in investigating suspected fraud

ICH guideline Q3D (R2) on elemental impurities Step 5

This document was adopted by EMAs Committee for Medicinal Products for Human Use (CHMP) on 24 March 2022 and comes into force on 24 Sept 2022

Synchron Research Service: suspension of medicines over flawed studies

EMA’s CHMP has recommended the suspension of the marketing authorisations of several generic medicines tested by Synchron Research Services, a contract research organisation (CRO) located in Ahmedabad, India. The recommendation comes after irregularities were found in how the CRO carried out bioequivalence studies, which raised serious concerns about the company’s quality management system and the reliability of data from that site. The CHMP looked at all medicines tested by Synchron Research Services on behalf of EU companies and found that for the majority (around 100 medicines) no adequate bioequivalence data were available from other sources. The Committee recommended that these medicines be suspended. In order to lift the suspension, companies relying on data from Synchron Research Services must provide alternative data demonstrating bioequivalence. For a small number of authorised generic medicines (around 20), adequate bioequivalence data were available from other sources, and these medicines are allowed to remain on the EU market.

Frequently asked questions about parallel distribution

This Q&A has recently been updated. Updates made during April and May 2022 include:-

  • 1.3. Are the Agency parallel distribution notification procedures mandatory?

  • 1.8. What are the post-PD notice obligations of a parallel distributor?

  • 1.16. Does the ‘specific mechanism’ apply to parallel distribution?

  • 1.22. Can the PD notice be transferred?

  • 2.3. How to apply for the PD notice?

  • 2.9 What are some examples of grounds for invalidation, negative outcome and common mistakes often made?

  • 3.1. What is the timeframe for the parallel distribution notification check

  • 3.11. Can several languages be combined in one pack?

  • 3.17. What are the requirements for the ‘blue box’?

  • 3.20. Do parallel distributors have to adhere to particular packaging design or/and colour code when repackaging the products?

  • 4.3. Can the Agency request the national competent authorities to perform an inspection of a parallel distributor?

  • 4.4. What are the parallel distributors’ responsibilities regarding quality defects?

  • 5.2. How to submit safety update?

  • 5.10. How to submit an annual update?

EDQM

Ph. Eur. Commission adopts first “horizontal standard” for monoclonal antibodies (mAbs)

The adoption of the new chapter marks an important milestone in the Ph. Eur. Commission’s efforts to develop – in response to stakeholder demand – a set of widely applicable recommendations for analytical testing strategies that cover the needs of different classes and sub-classes of mAbs. The resulting “horizontal standards” or “performance-based standards” comprise well-defined analytical procedures and tools to control performance and facilitate analytical assessment of key quality attributes of mAbs. Cell-based assays are complex procedures that require significant resources to establish and maintain correctly. This new general chapter provides users with analytical tools and practical guidance to further build on and support testing. It will also help establish an accepted and shared analytical language that contributes to standardising the potency determination of TNF-alpha antagonists, both currently available and in the pipeline.

OMCLs participate in international regulatory collaboration on the analysis of nitrosamines in metformin containing medicines

In 2020, batches of metformin-containing medicines were recalled because they contained N-nitrosodimethylamine (NDMA), a probable human carcinogen, above the acceptable daily intake (AI) of 96 ng/day. Prior to the recalls, Official Medicines Control Laboratories (OMCLs) from the OMCL Network participated in an international collaboration of regulatory laboratories to analyse metformin active pharmaceutical ingredients (APIs) and finished dosage forms (FDFs) for this impurity.

Overall, 215 APIs and 875 drug products were analysed between November 2019 and July 2020 by 10 regulatory laboratories using multiple procedures.

Regulatory agencies continue to collaborate extensively and work with marketing authorisation holders to understand the root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches.

A scientific article presenting an overview on the results obtained was published recently in The AAPS Journal and is available online

2021 Highlights – EDQM annual report

The EDQM 2021 annual report is now available, providing a comprehensive overview of its activities and achievements. New to this edition is a four-page summary of key facts and figures in the introductory section, allowing readers to find essential information about 2021 at a glance. Among the many accomplishments of the EDQM in 2021, the European Pharmacopoeia Commission adopted more than 200 texts, reference standard availability was ensured at a level of over 99%, and the production of reference standards as fully maintained. Two major projects were also completed: the real time remote inspection pilot, which has been successfully integrated as a routine inspection system, and the EDQM reference standards contingency stock project, involving the recently completed secondary site. The EDQM also held numerous virtual events and training sessions.



United States of America


The US Food and Drug Administration (USFDA)

Benefit-Risk Considerations for Product Quality Assessments

This draft guidance describes the benefit-risk principles applied by FDA when conducting product quality-related assessments of chemistry, manufacturing, and controls (CMC) information submitted for FDA assessment as part of original new drug applications (NDAs) under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), original biologics license applications (BLAs) under section 351 of the Public Health Service Act (PHS Act), or supplements to such applications, in addition to other information (e.g., inspectional findings) available to FDA during its assessment.

This guidance discusses how FDA assesses risks, sources of uncertainty, and possible mitigation strategies for a product quality-related issue and how those considerations inform FDA’s understanding of the potential effect on a product. The product quality assessment determines whether an applicant’s product development studies, manufacturing process, and control strategy will consistently result in a finished product of acceptable quality when manufactured at the facilities named in the application. When a regulatory decision regarding the approval of an NDA or BLA is made, FDA considers the overall benefit(s) and risk(s) identified for the product, including any residual risk related to unresolved product quality issues. This guidance also discusses how unresolved product quality issues may be addressed in the context of regulatory decision-making.

Comments on the draft should be submitted by 7 Oct 2022.

Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production - Level 2 revision

This guidance for industry provides the FDA’s current thinking on how to evaluate out-of- specification (OOS) test results. For purposes of this document, the term OOS results includes all test results that fall outside the specifications or acceptance criteria established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications.

Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors

The purpose of this guidance is to help human prescription drug and biological product sponsors, application holders, and applicants minimize medication errors associated with their products. This guidance focuses on safety aspects of the application holder’s container label and carton labeling design. It provides a set of principles and recommendations for ensuring that critical elements of a product’s container label and carton labeling are designed to promote safe dispensing, administration, and use of the product.

Risk Management Plans to Mitigate the Potential for Drug Shortages

This guidance is intended to help stakeholders develop, maintain, and implement risk management plans (RMPs) to proactively assist in the prevention of human drug product and biological product shortages. RMPs can provide stakeholders with a framework to proactively identify, prioritize, and implement strategies to mitigate hazards that can cause a supply disruption. Such a supply disruption may lead to a drug shortage. Effective quality risk management can facilitate better, more informed decisions; can provide FDA with greater assurance that stakeholders understand and can manage the associated risks; and can potentially affect the extent and level of direct regulatory oversight. Based on recent publications and reports, the majority of drug shortages are associated with quality issues. This guidance describes a framework for stakeholders to consider when developing RMPs that aligns with principles stated in the International Council for Harmonisation (ICH) guidance for industry Q9 Quality Risk Management (June 2006). In addition, FDA also recommends risk factors to consider when developing the content of the RMPs.

Comments should be submitted by 19 July 2022

See:-draft guidance

Importation of Prescription Drugs Final Rule Q&A

The final rule became effective November 30, 2020. This guidance document restates in plain language the legal requirements set forth in the final rule and is intended to assist small entities in complying with the final rule.



International


International coalition of medicines regulatory authorities (ICMRA)

International regulators and WHO: support healthcare professionals to enhance public confidence in COVID-19 vaccines

The statement is aimed to help healthcare professionals answer questions about the role of regulators in the oversight of COVID-19 vaccines and to reassure medical staff about the safety of COVID-19 vaccines that undergo a robust scientific evaluation to determine their quality, safety and efficacy.

The statement also contains up-to-date information as well as Q&As on:

  • clinical trial data (including effectiveness studies);

  • COVID-19 virus variants;

  • commonly reported adverse events for each vaccine type;

  • the latest advice on vaccine boosters and vaccine safety in children and pregnant women.

ICMRA and WHO will continue to monitor data on COVID-19 vaccines and their safety and provide any updates as they become available.

The development of the joint statement, which was lats updated in January 2021, followed a series of discussions among ICMRA members and WHO on the importance of public confidence in COVID-19 vaccines.



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.