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


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Vol 26-4A Oct 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, PIC/S and Australian regulatory authorities.


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



MHRA

  • Consultation on the future regulation of medical devices in the United Kingdom

  • Marketing Authorisation Holders' submission of Nitrosamine risk evaluation, risk assessment and confirmatory testing

  • Guidance on GxP data integrity


  • GMP updates

  • New measures to minimise animal testing during medicines development

  • Reflection paper on methods found suitable within the EU for demonstrating freedom from extraneous agents of the seeds used for the production of immunological veterinary medicinal products

  • Guidance on the details of the classification of variations requiring assessment according to Article 62 of Regulation (EU) 2019/6 for veterinary medicinal products and on the documentation to be submitted pursuant to those variations.

  • Nitrosamine impurities Q&A

  • Integration of EudraGMPD and OMS

  • Risk of the presence of mutagenic azido impurities in losartan active substance

  • Certification of suitability: revised terms of reference and rules of procedure

  • New general chapter on balances in European Pharmacopoeia Supplement 10.6

  • Ph. Eur. reference standards


  • Microbiological quality considerations in non-sterile drug manufacturing

  • New and revised draft Q&As on biosimilar development and the BPCI Act (Revision 3)

  • Q2(R1) validation of analytical procedures: text and methodology guidance for industry

  • Q3B(R) Impurities in New Drug Products (Revision 3)

  • Q&A on quality related controlled correspondence

  • Benefit-Risk Assessment for new drug and biological products



Australia TGA

  • TGA international engagement strategy 2016-2020: Highlights and achievements report

  • Data protection scheme for assessed listed medicines


PIC/S

  • China / NMPA applies for PIC/S pre-accession


  • Increase in manufacturing capacity for COVID-19 vaccine from BioNTech/Pfizer

  • EMA evaluating data on booster dose of COVID-19 vaccine Spikevax


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


UK


MHRA

Consultation on the future regulation of medical devices in the United Kingdom

MHRA is inviting members of the public to provide their views on possible changes to the regulatory framework for medical devices in the UK. MHRA wants to develop a future regime for medical devices which enables:

  • Improved patient and public safety;

  • Greater transparency of regulatory decision making and medical device information;

  • Close alignment with international best practice, and;

  • More flexible, responsive and proportionate regulation of medical devices.

The views of patients, medical device researchers, developers, manufacturers and suppliers, clinicians, other healthcare professionals and the wider public will help shape MHRA’s future approach to regulating medical devices in the UK.

Two webinars will provide more background to this consultation.one is aimed at industry and one at patients and the wider public.

Marketing Authorisation Holders' submission of Nitrosamine risk evaluation, risk assessment and confirmatory testing

MHRA has updated this guidance in relation to additional information about submission under section 'Step 2 – Risk assessment and confirmatory testing'.

Guidance on GxP data integrity

This document provides guidance on the data integrity expectations that should be considered by organisations involved in any aspect of the pharmaceutical lifecycle or GLP studies regulated by MHRA.

The guidance is intended to be a useful resource on the core elements of a compliant data governance system across all GxP sectors (good laboratory practice, good clinical practice, good manufacturing practice, good distribution practice and good pharmacovigilance practice).

It addresses fundamental failures identified by MHRA and international regulatory partners during GLP, GCP, GMP and GDP inspections; many of which have resulted in regulatory action.


Europe


EMA

GMP & GDP updates

EMA has updated two sections of it’s GMP pages. The updates concern:-

  • Q&A on Regulatory expectations for medicinal products (human & veterinary) during the COVID-19 pandemic where, In this context, for sites in the European Economic Area (EEA), GMP certificates and time-limited manufacturing and import authorisation are automatically extended until the end of 2022.

  • EMA Role, where From 1 October 2021, marketing authorisation holders and applicants need to use EMA's IRIS system to communicate with EMA on GMP inspections requested by the Agency’s scientific committees.

A similar change has been made on the GDP Q&A where for sites in the EEA, GDP certificates and time-limited wholesale authorisations are automatically extended until the end of 2022.

New measures to minimise animal testing during medicines development

EMA is putting in place special support to developers to replace, reduce and refine animal use for the development, manufacturing and testing of human and veterinary medicines. The Agency is promoting these three principles — replace, reduce and refine; commonly referred to as 3Rs — through EMA’s Innovation Task Force (ITF). This action will facilitate the development and implementation of New Approach Methodologies (NAMs) that are in line with the EU Legislation on the protection of animals used for scientific purposes. ITF is a dedicated forum for early dialogue between regulators and developers of medicines to discuss innovative aspects such as emerging therapies, methods and technologies.

The ITF’s service is free of charge and any NAMs adhering to the 3Rs principles that can be used to fulfil testing requirements are eligible for consideration.

Alternative approaches to animal models, such as improved tests based on human and animal cells, organoids, organ-on-chips and in silico modelling, provide opportunities to develop better and more predictive scientific tools to protect human and animal health as well as the environment.

Reflection paper on methods found suitable within the EU for demonstrating freedom from extraneous agents of the seeds used for the production of immunological veterinary medicinal products

This updated Reflection Paper comes into force on 9 March 2022.

Immunological veterinary medicinal products and materials of biological origin used in their production should be demonstrated to be free from contamination with extraneous agents. The suitability of cells and methods used for the detection of extraneous agents is an essential prerequisite. In this context, the following points need to be considered:

  • The capacity of the test method(s) to detect the relevant extraneous agents.

  • The limit of detection of the chosen test method(s).

Based on available data from already EU-assessed and EU-approved seeds, examples of suitable cells and methods for testing for freedom from a range of extraneous agents are shown in the annex to this reflection paper. Each testing laboratory must demonstrate their suitability to perform the relevant test. The annex of the document covers only cells and other substrates as well as suitable test methods for porcine, bovine, feline, canine, equine, ovine and caprine extraneous agents. The annex can be updated whenever necessary, in particular to take into account new extraneous agents or additional cells and techniques for which sufficient experience and/or validation data become available to justify their inclusion into the annex.

Guidance on the details of the classification of variations requiring assessment according to Article 62 of Regulation (EU) 2019/6 for veterinary medicinal products and on the documentation to be submitted pursuant to those variations.

This guidance is intended to explain the practice of Articles 60 to 68 of Regulation (EU) 2019/6 of the European Parliament and of the Council of 11 December 2018 on veterinary medicinal products, laying down rules for the placing on the market, manufacturing, import, export, supply, distribution, pharmacovigilance, control and use of veterinary medicinal products and to categorise the variations requiring assessment. The Annex to this guidance provides a list of variations, which require assessment according to Article 62 of Regulation (EU) 2019/6 and indicates, where appropriate, the timetable proposed to be applied, the data to be submitted and how this data should be documented. The Annex to this guidance will be regularly updated. This guidance shall come into effect from the date of application of Regulation (EU) 2019/6.

Nitrosamine impurities Q&A

The EMA has updated section 10 “Which limits apply for nitrosamines in medicinal products?” of this Q&A

Integration of EudraGMPD and OMS

The new regulatory framework for veterinary medicines requires several changes to EudraGMDP. (European Inspections Database) The most notable change is the integration of EudraGMDP with EMA’s Organisation Management Service (OMS)

From 28 January 2022, users of EudraGMDP from national competent will no longer introduce organisational data (organisation name and location address details) directly into the relevant fields on the EudraGMDP database. Instead, they will select the relevant organisation name and location address details, including the legally registered address, of the manufacturers/importers/distributors from the Agency’s organisation dictionary (so-called OMS).

It is therefore necessary that all organisations currently regulated through EudraGMDP (which appear on documents within EudraGMDP, including EU and non-EU manufacturers, importers and distributors of human and veterinary medicinal products and active substances are registered in OMS.

[a webinar on 12 Oct 2021 for industry users covers:-

  • Integration of EudraGMDP and OMS – implications for industry users;

  • OMS services and activities;

  • OMS change request process;

  • customer service (EMA Service Desk)

  • data quality management.

Registration details are available from the above hyperlink]


EDQM

Risk of the presence of mutagenic azido impurities in losartan active substance

In April 2021, the EDQM reported that it had received information about the possible presence of potentially mutagenic azido impurities in certain sartan active substances. Investigations requested by the EDQM indicated that only a few sources were impacted. A number of measures were taken to ensure that any active substance containing these impurities above the acceptable level would not be released onto the market. In addition, any impacted holders of a Certificate of Suitability (CEP) were requested to take corrective action to ensure that such impurities do not exceed their acceptable limits in the future. The EDQM review of these actions in the impacted sources has been completed for some manufacturers and is well advanced for others.

These recent investigations recently resulted in the identification of another azido impurity that has so far only been detected in losartan potassium: 5-[4'-[(5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl)methyl]-[1,1'-biphenyl]2-yl]-1H-tetrazole (CAS 727718-93-6) (“losartan azido impurity”). This impurity has tested positive in a bacterial mutagenicity (Ames) test.

In the absence of additional information from in vivo studies, it is necessary to ensure that this azido impurity is controlled at or below the Threshold of Toxicological Concern (TTC). The sources impacted by this azido issue have been identified and the EDQM’s review of any necessary corrective action taken by companies is currently either complete or well advanced.

Addressing the presence of azido impurities in sartan active substances – and ensuring users of such medicines are protected from any potential risk – is of the highest priority to the EDQM. The EDQM will therefore take any necessary action on CEPs (e.g. suspension) when CEP holders are considered not to be fully engaged in meeting these objectives.

Certification of suitability (CEP): revised terms of reference and rules of procedure

A revised version of the terms of reference and rules of procedure for the CEP procedure has been adopted and is available on the EDQM website.

New general chapter on balances in European Pharmacopoeia Supplement 10.6

At its 168th session (November 2020), the European Pharmacopoeia (Ph.Eur.) Commission adopted a new general chapter: Balances for analytical purposes (2.1.7). This new chapter is included in Supplement 10.6 of the Ph. Eur., published in July 2021.

This addition to section 2.1. Apparatus fills a long-standing gap by setting out clear requirements for a piece of equipment that is the cornerstone of every analytical procedure described in the Ph. Eur. Weighing is one of the most common but also most critical tasks in a laboratory, as even the smallest weighing error can propagate throughout the whole analysis, affecting the accuracy of reported results.

After a brief overview of the principles of balances and recommendations on their installation and use, including good practices for weighing vessels, the chapter provides detailed information on calibration and carrying out performance checks during routine use and between calibrations.

This new general chapter complements existing guidelines for the use and qualification of balances published elsewhere.

Ph. Eur. reference standards

Two new and fifteen replacement Ph. Eur. reference standards batches were released in August 2021


United States of America


The US Food and Drug Administration (USFDA)

Microbiological quality considerations in non-sterile drug manufacturing

This draft guidance is intended to assist manufacturers in assuring the control of microbiological quality of their non-sterile drugs (NSDs). The recommendations herein apply to solid non-sterile dosage forms, as well as semi-solid, and liquid non-sterile dosage forms (e.g., topically applied creams, lotions and swabs, and oral solutions and suspensions). NSDs can be prescription or nonprescription drugs, including those marketed under approved new drug applications (NDAs) or abbreviated new drug applications (ANDAs), and nonprescription drugs without approved new drug applications which are governed by the provisions of section 505G of the FD&C Act (often referred to as over-the-counter (OTC) monograph drugs). These recommendations, if followed, will also assist manufacturers in complying with the current good manufacturing practice (CGMP) requirements for finished pharmaceuticals and active pharmaceutical ingredients (APIs).

This guidance was developed, in part, as a result of the Agency’s review of FDA Adverse Event Reports (FAERs) and recalls involving contamination of non-sterile dosage forms. A review of FAERs that occurred between 2014 and 2017 revealed 197 FAERs associated with intrinsic microbiological or fungal contamination, and of those, 32 reported serious adverse events. Because spontaneous reports in FAERs are voluntary by definition, the Agency anticipates a degree of underreporting. The actual number of incidents associated with microbiological contamination is likely significantly higher than the number of events reported. The review of voluntary recall actions during the same time period revealed over 50 events associated with objectionable microbiologically contaminated NSDs. The recalls showed that a wide range of objectionable microorganisms were found in both aqueous and non-aqueous NSDs.

All written comments should be submitted by 29 Nov 2021 and identified with the docket number: FDA-2021-D-0432.

New and revised draft Q&As on biosimilar development and the BPCI Act (Revision 3)

This draft guidance document provides answers to common questions from prospective applicants and other interested parties regarding the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). The question and answer (Q&A) format is intended to inform prospective applicants and facilitate the development of proposed biosimilar products and proposed interchangeable products, as well as describe FDA’s interpretation of certain statutory requirements added by the BPCI Act. FDA believes that guidance for industry that provides answers to commonly asked questions regarding FDA’s interpretation of the BPCI Act will enhance transparency and facilitate the development and approval of biosimilar and interchangeable products. In addition, these Q&As respond to questions the Agency has received from prospective applicants regarding the submission of biologics license applications (BLAs) for biosimilar and interchangeable products. FDA may provide additional Q&As through draft guidance as appropriate.

Q2(R1) Validation of analytical procedures: text and methodology guidance for industry

This Final Guidance consists of two previously published FDA guidances that were developed and finalized before the implementation of FDA’s good guidance practices regulation (21 CFR 10.115)

This document presents a discussion of the characteristics for consideration during the validation of the analytical procedures included as part of registration applications submitted within the European Union, Japan, and United States. This document does not necessarily seek to cover the testing that may be required for registration in, or export to, other areas of the world. Furthermore, this text presentation serves as a collection of terms, and their definitions, and is not intended to provide direction on how to accomplish validation. These terms and definitions are meant to bridge the differences that often exist between various compendia and regulators of the European Union, Japan, and United States. The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose. A tabular summation of the characteristics applicable to identification, control of impurities and assay procedures is included. Other analytical procedures may be considered in future additions to this document.

Q3B(R) Impurities in New Drug Products (Revision 3)

This guidance provides recommendations for registration applications on the content and qualification of impurities in new drug products produced from chemically synthesized new drug substances not previously registered in a region or member state. This guidance revises the ICH guidance of the same title that was issued in May 1997 and first revised in February 2003. The first revision clarified the 1997 guidance and included other changes. The revision also provided consistency with more recently published ICH guidances (e.g., Q3A(R) Impurities in New Drug Substances, Q3C Impurities: Residual Solvents, and Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances). This second revision provides clarification to Attachment 2. This guidance complements the ICH Q3A(R) guidance, which should be consulted for basic principles along with ICH Q3C when appropriate.

Related Controlled Correspondence

This Q&A guidance provides FDA’s current thinking on quality-related scientific and regulatory topics that appear frequently in controlled correspondence submissions. The Office of Pharmaceutical Quality (OPQ) reviews correspondence from generic drug manufacturers and related industry or their representatives related to generic drug development (i.e., controlled correspondence submissions) requesting information regarding chemistry, manufacturing, and controls,(CMC) as well as product quality microbiology for generic drugs. OPQ also reviews controlled correspondence inquiries related to Type II drug master files for drug substances submitted in support of generic drug applications. OPQ has observed that the same questions are frequently received in multiple controlled correspondence submissions. These Q&A are intended to proactively respond to those scientific and regulatory topics that appear frequently in controlled correspondence addressed by OPQ, thereby allowing industry to move forward with certain generic drug development activities without the need to submit controlled correspondence to FDA.

Benefit-Risk Assessment for new drug and biological products

The intent of this draft guidance is to clarify for drug sponsors and other stakeholders how considerations about a drug’s benefits, risks, and risk management options factor into certain premarket and postmarket regulatory decisions that the FDA makes about NDAs submitted under section 505(c) of FD&C Act as well as biologics license applications (BLAs) submitted under section 351(a) of the Public Health Service Act (PHS Act). This guidance first articulates important considerations that factor into the Center for Drug Evaluation and Research’s (CDER) and the Center for Biologics Evaluation and Research’s (CBER) benefit-risk assessments, including how patient experience data can be used to inform the benefit-risk assessment. It then discusses how sponsors can inform FDA’s benefit-risk

assessment through the design and conduct of a development program, as well as how they may present benefit and risk information in the marketing application. It also discusses opportunities for interaction between FDA and sponsors to discuss benefit-risk considerations in connection with the development of an NDA or BLA. This guidance concludes with additional considerations on benefit-risk assessments that inform regulatory decision-making in the postmarket setting.


International


Australia TGA


TGA international engagement strategy 2016-2020: Highlights and achievements report

This report highlights TGA’s achievements under its International Engagement Strategy 2016-2020.

As reported. In a previous edition of ‘The Update’ the goals for the period 2021 – 2025 have already been published.

[It is probably sensible to read both of these documents consecutively MBH]

Data protection scheme for assessed listed medicines

The TGA has implemented a Data Protection Scheme for Assessed listed medicines. This Scheme was developed in response to Recommendation 50 of the Medicines and Medical Devices Regulation (MMDR) review and is enabled under section 26AF of the Therapeutic Goods Act 1989.

The purpose of the Scheme is to:

  • Incentivise innovation by protecting the results of investment in the development of new works and technology.

  • Prevent competitors seeking market authorisation of generic forms of an L(A) medicine by preventing competitors from relying on clinical trials that were generated and used by the sponsor of the originator medicine to obtain market authorisation.

  • Encourage further research and development activities by preventing others from capitalising on a sponsor's investment and innovation.


PIC/S


China / NMPA applies for PIC/S pre-accession

China’s National Medical Products Administration (NMPA) has submitted an application for “pre-accession” to PIC/S. This is a voluntary but highly recommended assessment step that can be completed prior to submitting an application to become a PIC/S Participating Authority. The Pre-Accession Procedure provides up to 2 years to identify any gaps between PIC/S membership requirements and the system used by the interested Competent Authority. This step helps in understanding of PIC/S’ expectations in terms of membership and compliance to facilitate success in any future membership application under the PIC/S Accession Procedure.



Products


Increase in manufacturing capacity for COVID-19 vaccine from BioNTech/Pfizer

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

One site, located in Frankfurt am Main, Germany, is operated by Sanofi-Aventis Deutschland GmbH. The other in Hameln, also in Germany, is operated by Siegfried Hameln GmbH. Both sites will manufacture finished product.

These sites will provide up to 50 million additional doses in 2021.

The sites can become operational immediately.

EMA evaluating data on booster dose of COVID-19 vaccine Spikevax

EMA has started evaluating an application for the use of a booster dose of Spikevax (Moderna’s COVID-19 vaccine) to be given at least 6 months after the second dose in people aged 12 years and older. Based on this review, the CHMP will recommend whether updates to the product information are appropriate. EMA will communicate the outcome of the assessment in due course. Although EMA and ECDC do not consider the need for COVID-19 vaccine booster doses to be urgent in the general population, EMA is evaluating the present application to ensure evidence is available to support further doses as necessary.



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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