• EJPPS

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


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Vol 25-1C March-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, ICH and USA regulatory authorities.


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


Europe

  • Second targeted stakeholders' consultation on the revision of Annex 1, on manufacturing of sterile medicinal products

  • New webpage on nitrosamine contamination

  • Coronavirus disease (COVID-19)

  • International collaboration on GMP inspections

  • European authorities working to avoid shortages of medicines due to Brexit – questions and answers

  • Action Plan on ATMPs

  • Guideline on reproductive toxicology: Detection of Toxicity to Reproduction for Human Pharmaceuticals [ICH S5 (R3)]

  • Implementation of risk assessment requirements to control elemental impurities in veterinary medicinal products

  • ICH M9 on biopharmaceutics classification system based biowaivers

  • Quality of medicines questions and answers: Part 1

  • Pre-authorisation guidance

  • Maintaining control: Remote working and QP certification


USA

  • Biosimilars and Interchangeable Biosimilars: Licensure for Fewer Than All Conditions of Use for Which the Reference Product Has Been Licensed

  • Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications Guidance for Industry


International


Australia

  • Guidance for TGO 101- Standard for tablets, capsules and pills

  • ISO TC 198 Sterilization of health care products


PIC/S

  • Second joint targeted stakeholders' consultation on the revision of Annex 1, on manufacturing of sterile medicinal products, of the PIC/S – EU GMP Guide

  • Saudi Arabia applies to Join PIC/S


Conferences

  • PHSS Aseptic Processing Syndicate Workshops


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


Europe

EC

Second targeted stakeholders' consultation on the revision of Annex 1, on manufacturing of sterile medicinal products, of Eudralex volume 4

A first targeted consultation conducted from 20 December 2017 to 20 March 2018 allowed about 140 companies and/or organizations to comment. The drafting group processed more than 6200 lines of comments.

Due to widespread interest from industry following the first targeted consultation, and because of substantial modifications introduced in several sections, it was agreed to engage with stakeholders a second targeted consultation on the updated draft guidance (version 12) focused on the sections and/or significantly modified paragraphs that raised most concerns by stakeholders.

The second targeted consultation aims at collecting experience from the sectors on certain manufacturing steps. The European Commission therefore expect to receive contribution from the European associations representing the sectors.

In order to maintain the global alignment of standards, achieving at the same time assurance for the highest quality, the document will be, in parallel, subject to a second targeted consultation by WHO and PIC/S.

(Please note that PHSS is now one of the targeted stakeholders MBH)


New webpage on nitrosamine contamination

This new webpage providing centralised access to all information related to nitrosamine contamination is now available on the EDQM website. It presents a general overview of the issue and provides details of the actions taken in the different sectors of activity concerned: the European Pharmacopoeia, the Certification of Suitability to the monographs of the European Pharmacopoeia, and the network of Official Medicines Control Laboratories.

In line with its mandate to promote and protect public health in Europe, the EDQM has been working actively at various levels to address the presence of nitrosamines in active substances and medicines since 2018, when certain types of nitrosamines, known as possible carcinogens for humans, were detected in a number of active substances used in certain medicines.

Since then, the EDQM has regularly published information and updates on its website. This new resource page, which provides concerned parties with all relevant information, will be regularly updated as the situation develops.


EMA

Coronavirus disease (COVID-19)

EMA has activated its plan for managing emerging health threats, which determines how EMA responds to and communicates on serious public health threats.

EMA encourages developers of potential vaccines or treatments for novel coronavirus infection to contact EMA as soon as possible to discuss their strategy for evidence-generation.

EMA has regulatory mechanisms to speed up development and approval, including:

  • scientific advice;

  • the PRIME scheme;

  • accelerated assessment and conditional marketing authorisation procedures.

Scientific advice can be fast-tracked for potential novel coronavirus treatments or vaccines.


International collaboration on GMP inspections

The section on International collaboration on GMP inspections has been updated in regard to manufacturers of sterile medicines.

In December 2019, EMA and its European and international partners launched a pilot programme to share information on GMP inspections of manufacturers of sterile medicines located outside the participating countries and to organise joint inspections of manufacturing sites of common interest.

The products in scope include sterile medicines for human use of chemical origin and certain therapeutic biotechnology - derived products, such as monoclonal antibodies and recombinant proteins.

Vaccines, cell and gene therapies and plasma-derived pharmaceuticals are currently out of the scope of this pilot.


European authorities working to avoid shortages of medicines due to Brexit – Q&A

EMA has updated this Q&A


Action Plan on ATMPs

The European Commission services and the European Medicines Agency, in collaboration with the authorities of the Member States, have initiated a number of initiatives to improve the regulatory environment for ATMPs so as to facilitate the development and authorisation of these products in the EU for the benefit of patients. The actions presented in this document are wide-ranging and target challenges identified by various stakeholders at all stages of development, including manufacturing, early and later phases of development, marketing authorisation process and post-marketing setting. ATMP developers also benefit from existing schemes to support the development of medicinal products in the EU, such as PRIME, or initiatives designed to support SMEs and academia. The EU is committed to support the development of these products and will keep monitoring developments in the field to ensure that the regulatory framework supports —and not hinders — the development of ATMPs. It is expected that the implementation of the proposed actions will increase the opportunity for patients to be treated with novel therapies (through enrolment in clinical trials and authorisation of new products). Moreover, an improved regulatory framework will also contribute to promoting innovation, investments and competitiveness of the EU biotechnology sector, whilst striving to ensure patient access.


Guideline on reproductive toxicology: Detection of Toxicity to Reproduction for Human Pharmaceuticals [ICH S5 (R3)]

The purpose of this document is to recommend international standards for, and promote harmonization of, the assessment of nonclinical developmental and reproductive toxicity (DART) testing required to support human clinical trials and marketing authorization for pharmaceuticals. The guideline describes potential strategies and study designs to supplement available data to identify, assess, and convey risk. General concepts and recommendations are also provided that should be considered when interpreting study data. This is a revision of the ICH guideline “S5 Detection of Toxicity to Reproduction for Medicinal Products” that was originally published in 1993. This revision brings the guideline into alignment with other ICH guidelines, elaborates on the use of exposure margins in dose level selection, incorporates a section on risk assessment, and expands the scope to include vaccines and biopharmaceuticals. It also describes qualification of alternative assays, potential scenarios of use, and provides options for deferral of developmental toxicity studies. To assess a human pharmaceutical’s effect on reproduction and development, there should generally be information available that addresses the potential impact of exposure to a pharmaceutical and, when appropriate, its metabolites (ICH M3, ICH S6) on all stages of reproduction and development. No guideline can provide sufficient information to cover all possible cases, and flexibility in testing strategy is warranted.

This document comes into effect in the EU on 30 July 2020


Implementation of risk assessment requirements to control elemental impurities in veterinary medicinal products

This phased implementation approach applies to veterinary medicinal products containing chemical and biological/biotechnological substances including veterinary medicinal products containing synthetic and semi-synthetic antibiotics and synthetic peptides of low molecular weight. The scope of this approach does not apply to veterinary herbal products, radiopharmaceuticals, immunological products, veterinary medicinal products designed for gene therapy, regenerative medicine, tissue engineering, blood product therapy and phage therapy or to elements that are intentionally included in a veterinary medicinal product for therapeutic benefit. Current control strategies are considered acceptable until a risk assessment is required in line with the phased implementation outlined. For veterinary medicinal products authorised before the respective date of implementation detailed, regulatory action is only expected when the outcome of the risk assessment demonstrates that compliance with the Reflection Paper on risk management requirements for elemental impurities in veterinary medicinal products (EMA/CVMP/QWP/153641/2018) does require additional controls or changes in the dossier. Routine submission of risk assessments via variations, or otherwise, which conclude that no change is required, is not envisaged. The risk assessment should be available at the manufacturing site for inspection


ICH M9 on biopharmaceutics classification system based biowaivers

This new multidisciplinary guideline is proposed to address biopharmaceutics classification system (BCS)-based biowaivers. BCS-based biowaivers may be applicable to BCS Class I and III drugs, however BCS-based biowaivers for these two classes are not recognized worldwide. This means that pharmaceutical companies have to follow different approaches in the different regions. This guideline will provide recommendations to support the biopharmaceutics classification of medicinal products and will provide recommendations to support the waiver of bioequivalence studies. This will result in the harmonisation of current regional guideline/guidance and support streamlined global drug development.


Quality of medicines questions and answers: Part 1

These questions and answers address a number of questions that have been brought to the attention of the Joint Committee for Medicinal products for Human Use / Committee for Medicinal products for Veterinary Use Quality Working Party (QWP) by marketing-authorisation holders (MAHs) or European Economic Area (EEA) competent authorities, on matters related to the quality of medicines. They have been developed and are maintained by the QWP.

These Q&A have been produced to provide clarification or additional information. They provide the EEA's harmonised position on issues that can be subject to different interpretation or require clarification, typically arising from discussions or correspondence during assessment procedures.

If a question is not addressed, marketing-authorisation holders are encouraged to contact the EMA for further information.


Pre-authorisation guidance

These questions and answers (Q&As) provide an overview of the European Medicines Agency's (EMA) advice on issues that are typically addressed in discussions or meetings with marketing authorisation holders (MAH) in the application phase.

Q 3.3.5. What should I submit if my medicinal product contains or consists of genetically modified organisms (GMOs)? Was revised Feb 2020.

(Readers might also wish to refresh their knowledge / re-read Q 5.2 on inspections. MBH)


MHRA

Maintaining control: Remote working and QP certification

This Blog from MHRA notes that it is increasingly common to see flexible, part-time or home working arrangements. Digital connections can allow us to continue to work effectively when we are away from the office. The pharmaceutical industry is no exception, and although some companies employ a part-time or contract Qualified Person (QP), there is still a need to maintain market supply whilst the QP fulfils their other duties or is restricted from travel.

Every organisation has its own way of working. Whatever the arrangements, these need to be specified within the pharmaceutical quality system and in any relevant written agreements with contracted parties. Inspectors will review how this is managed to ensure that control is maintained, and products and patients are protected.

MHRA notes in particular that:-

  • The QP must be able to demonstrate they are fulfilling their wider duties.

  • Where remote QP certification is employed, it must be described and controlled within the pharmaceutical quality system.

  • Accurate and up-to-date information must be available to support batch certification and release.


United States of America

The US Food and Drug Administration (USFDA)

Biosimilars and Interchangeable Biosimilars: Licensure for Fewer Than All Conditions of Use for Which the Reference Product Has Been Licensed

This guidance provides recommendations to applicants seeking licensure under section 351(k) of the Public Health Service (PHS) Act of a proposed biosimilar or proposed interchangeable biosimilar for fewer than all of the reference product’s licensed conditions of use. This guidance also provides recommendations on the submission of a supplement to a licensed 351(k) biologics license application (BLA) seeking to add a condition of use that previously has been licensed for the reference product to the labeling of a licensed biosimilar or interchangeable product, including considerations related to the timing of such submissions. This guidance includes recommendations regarding the following specific issues:

  • Submission of an application seeking licensure of a proposed biosimilar or proposed interchangeable biosimilar for fewer than all of the reference product’s licensed conditions of use.

  • Development of proposed labeling when the applicant seeks licensure of a proposed biosimilar or proposed interchangeable product for fewer than all of the reference product’s licensed conditions of use.

  • Submission of a supplement to an application for a biosimilar or interchangeable biosimilar to seek licensure for a condition of use previously licensed for the reference product. This may occur, for example, when (1) the biosimilar or interchangeable product was initially licensed for fewer than all of the reference product’s licensed conditions of use, or (2) the reference product is licensed for a new condition of use after licensure of the biosimilar or interchangeable product.

  • Timing for the submission of, or supplement to a licensed 351(k) BLA described above with the goal of obtaining licensure of a condition of use for a biosimilar or interchangeable product as soon as possible after the expiration of any relevant exclusivity or patents.

This guidance is one in a series of guidances that FDA is developing to implement the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) and includes references to information from other FDA guidances, where appropriate.


Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications Guidance for Industry

Under section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), at least 24 months after the issuance of a final guidance document in which the Food and Drug Administration (FDA or Agency) has specified the electronic format for submitting submission types to the Agency, such content must be submitted electronically and in the format specified by FDA. , This guidance describes how sponsors and applicants must organize the content that they submit to the Agency electronically for all submission types under section 745A(a) of the FD&C Act. This guidance also references several technical specification documents and the Electronic Common Technical Document Conformance (eCTD) Guide, which provide additional details regarding the organization of content for electronic submissions.


International


Australia

Guidance for TGO 101- Standard for tablets, capsules and pills

This guidance is to help sponsors and manufacturers of medicines understand the role of the Therapeutic Goods Order No. 101 - Standard for tablets, capsules and pills (TGO 101, the Order) in ensuring that these types of therapeutic goods are of appropriate quality. The requirements that applied to tablets and capsules under Therapeutic Goods Order No. 78 Standard for tablets and capsules ( TGO 78) have been adopted into TGO 101. This means that, generally, a transition period is not needed for these medicines. Sponsors can elect to move to alternative testing requirements, where this is permitted under the Order, at any time. Details on how to request this type of change are provided later in this document. The TGO 101 requirements that apply to pills commence on 31 March 2021. Pills were not subject to TGO 78. The delayed commencement allows sponsors two years to update their manufacturing documentation and ensure that their goods will comply with the new requirements by the end of March 2021. A two-year transition period has also been specified in relation to section 16 of the Order. This allows sponsors time to review the manufacturing documentation for their medicines and update them in line with the requirements for elemental impurities and residual solvents in tablets and capsules. All tablets, capsules and pills subject to the Order and released for supply after 30 March 2021 must comply with TGO 101.


ISO TC 198 Sterilization of health care products

This presentation ‘Revising ISO 13408 aseptic processing standards to reflect best practice’ was given by Karen Longstaff, Director, Microbiology Section Laboratories Branch Medical Devices and Product Quality Division, TGA.


PIC/S

Second joint targeted stakeholders' consultation on the revision of Annex 1, on manufacturing of sterile medicinal products, of the PIC/S – EU GMP Guide

Please view detail in the EC section of this edition of ‘The Regulatory Update’ MBH)

Saudi Arabia applies to Join PIC/S

On 17 February 2020, the Saudi Food & Drug Authority (SFDA) applied for PIC/S membership. The Rapporteurs will be appointed by written procedure.


Conferences

PHSS Aseptic Processing Syndicate Workshops

Registration is open for these PHSS workshops to be held at the Marriott Worsley Park Manchester UK on 1-2 April 2020. There will also be an evening discussion forum on the latest revision of Annex 1


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.