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


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Vol27.4C Dec 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 UK, EU, US, PIC/S ICMRA and Australian regulatory authorities.


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



Medicines and Healthcare Regulatory Authority (MHRA)

  • Return to International GMP Inspections

  • Horizon Scanning Case Study: Developing standards for Adeno-associated virus gene therapies


  • DARWIN EU® welcomes first data partners

  • New Quality Innovation Expert Group (QIG) supports medicine innovation

  • Sales of antibiotics for animal use have almost halved between 2011-2021

  • Concept Paper on the revision of EU-PIC/S GMP Annex 11 (Computerised Systems)

  • Reflection paper on the application of Article 40(5) of Regulation (EU) 2019/6 for certain categories of variations

  • Reference standards

  • Agreement expanding the scope of co-operation in the field of substances of human origin


  • Compounding Certain Beta-Lactam products in shortage under section 503a of the federal FD&C act

  • Cross Labeling Oncology Drugs in Combination Regimens

  • Sameness Evaluations in an ANDA — Active Ingredients

  • Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin



Australia


Therapeutic Goods Association (TGA)

  • Standard for serialisation and data matrix codes commences 1 January 2023

The International Coalition of Medicines Regulatory Authorities (ICMRA)

  • Best practices to fight antimicrobial resistance

The Pharmaceutical Inspection Co-operation Scheme (PIC/S)

  • Concept Paper on the revision of EU-PIC/S GMP Annex 11 (Computerised Systems)


  • 2nd Pfizer/BioNTech bivalent COVID-19 booster vaccine approved by UK medicines regulator


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


UK


MHRA

Return to International GMP Inspections

International travel is now becoming easier to organise and less likely to suffer unexpected disruption, although we take nothing for granted. Since April 2022, GMP Inspectors have been taking part in a pilot programme to evaluate a potential return to international onsite GMP inspections. Considerations include whether the risk to inspectors is acceptable, and whether we can make efficient use of our inspectors’ time.

MHRA are pleased to announce that the pilot was successful, and it is now resuming its programme of international onsite GMP inspections.

There will still be restrictions on the countries that MHRA are able to travel to, particularly those that still have a requirement for international travellers to quarantine on arrival, so that we can make the most efficient use of limited inspection time.

We will be adopting a risk-based approach, prioritising inspections with the greatest impact on UK public health and patient safety. MHRA will do this in conjunction with its product licence assessors and using existing risk-based inspection (RBI) tools. Whilst implementing this return to international inspections, MHRA asks that sites do not contact them asking to arrange a routine inspection or to enquire about when they can expect their inspection to be; MHRA will make contact when we are able to arrange each inspection.

Horizon Scanning Case Study: Developing standards for Adeno-associated virus gene therapies

Horizon scanning at the MHRA leads to external funding being secured, helping our scientists work in a new area of standardisation that will support developers and manufacturers of AAV gene therapies. Horizon scanning identified a need for standardisation of AAV products to support developers and manufacturers of these therapies, and to enable patients to access these innovative products but to also ensure they are regulated appropriately and are safe and effective. Together with colleagues at the UK Cell & Gene Therapy Catapult CGTC, MHRA secured funding from the Regulators Pioneer Fund (RPF).

The CGTC produced and purified a batch of AAV2 material using their new state of the art bioreactors and facilities at Braintree.

The materials are now being evaluated by multiple external collaborators, from industrial stakeholders to academic laboratories, and its ‘fitness for use’ as a reference material is being assessed.



Europe


European Medicines Agency (EMA)

DARWIN EU® welcomes first data partners

EMA has selected the first set of data partners data partners to collaborate with DARWIN EU®, the Data Analysis and Real-World Interrogation Network. The data available to these partners will be used for studies to generate real-world evidence that will support scientific evaluations and regulatory decision making. Real-world evidence refers to information derived from analysis of real-world data, which is routinely collected data about a patient’s health status or delivery of healthcare from a variety of sources other than traditional clinical trials.

The selected partners include both public and private institutions. The common feature is that they all have access to real-world healthcare data from one or more sources such as hospitals, primary care, health insurance, biobanks, or disease-specific patient registries. The data partners will provide the DARWIN EU® Coordination Centre with results of analyses of these data.

With the onboarding of data partners, EMA has initiated the launch of the first three studies to be provided by DARWIN EU®. One study will focus on the epidemiology of rare blood cancers to inform on their prevalence in Europe. The second study is on drug use of valproate and the third one is looking at the use of antibiotics to inform future work on anti-microbial resistance.

New Quality Innovation Expert Group (QIG) supports medicine innovation

EMA has established a Quality Innovation Expert Group (QIG) to support innovative approaches for the development, manufacture, and quality control of medicines for the benefit of patients in the European Union (EU). These include, but are not limited to, new technologies, digitalisation, novel materials and novel devices, in line with the priorities highlighted in EMA’s Regulatory Science Strategy to 2025.

The role of the QIG is to ensure that the European medicines regulatory network keeps pace with innovation, identifies and addresses gaps in the regulatory framework and increases predictability for developers of innovative technologies. The group will also be a forum for exchange and interaction within the EU regulatory network, as well as between EU regulators and stakeholders such as academia and industry. Considering that development and manufacturing of medicines is global in nature, the QIG also aims to establish close collaboration with international partners to facilitate global regulatory convergence.

Sales of antibiotics for animal use have almost halved between 2011-2021

EMA’s annual report on the European surveillance of veterinary antimicrobial consumption (ESVAC) shows that, since 2011, European countries have substantially reduced sales of veterinary antibiotics in animals. According to data from 25 countries that continuously provided input for the full 2011-2021 period, overall sales of veterinary antibiotics decreased by 47% in this interval, reaching the lowest value ever reported.

Sales of antibiotic classes considered critically important in human also decreased noticeably between 2011 and 2021 and accounted for only 5.5% of total sales in 2021. Sales of third and fourth generation cephalosporins dropped by 38%, polymyxins by 80%, fluoroquinolones by 14% and sales of other quinolones dropped by 83%. These antibiotics should be used prudently and responsibly to preserve their effectiveness and mitigate the potential risk to public health, as indicated in the Antimicrobial Ad Hoc Expert Group (AMEG) categorisation.

“The positive results reflect the efforts of veterinarians, farmers and pharmaceutical industry to reduce the use of antibiotics to prevent antimicrobial resistance. It also shows that European Union (EU) policy initiatives and national campaigns promoting prudent use of antibiotics in animals are having a positive impact,” said Ivo Claassen, Head of EMA’s Veterinary Medicines Division.

Concept Paper on the revision of EU-PIC/S GMP Annex 11 (Computerised Systems)

See the entry in the international section of this Update report under PIC/S.

Reflection paper on the application of Article 40(5) of Regulation (EU) 2019/6 for certain categories of variations

Recital 33 of Regulation (EU) 2019/61 reasons that “Tests, pre-clinical studies and clinical trials represent a major investment for companies...” which “should be protected in order to stimulate research and innovation...” and “similar protection of investments should be applied to studies supporting a new pharmaceutical form, administration route or dosage that reduces the antimicrobial or antiparasitic resistance or improves the benefit-risk balance”. For variations involving a change to the pharmaceutical form, administration route or dosage, Article 40(5) of Regulation (EU) 2019/6, building on this high-level objective, envisages four years of protection of technical documentation to the results of the concerned pre-clinical studies or clinical trials assessed to have demonstrated:-

a) a reduction in the antimicrobial or antiparasitic resistance, or

b) an improvement of the benefit-risk balance of the veterinary medicinal product (VMP).

Whereas Article 40(5) provides the abovementioned high-level criteria (a) and (b), it will be necessary to elaborate more detailed scientific criteria to ensure a clear and consistent interpretation.

This reflection paper aims to provide an overview of the CVMP’s considerations to date, taking into account the comments received during the public consultation of the concept paper preceding this reflection paper (20 July to 21 September 2020), as well as during a workshop with stakeholders held by the EMA on 15 October 2020. Closing date for comments is 28 Feb 2023.


EDQM

Reference standards

EDQM has announced the release of 7 new and 14 replacement batches of Ph. Eur. reference standards. It also announces immediate and or future removal of several other reference standards.

Agreement expanding the scope of co-operation in the field of substances of human origin

The Council of Europe (EDQM) and the European Union (EU), through the European Commission, have concluded a new contribution agreement, with equal financing, which will run until 2024. This agreement further enhances their already well-established co-operation in the field of substances of human origin (SoHO).

SoHO, such as blood, organs, tissues and cells, are used in essential therapies that save lives and improve the quality of life of millions of Europeans every year.

The agreement will contribute to providing all Council of Europe member states, including the EU 27, with a coherent European regulatory SoHO framework and to supporting professionals of the sector in implementing this framework and in strengthening their SoHO systems.


United States of America


The US Food and Drug Administration (USFDA)

Compounding Certain Beta-Lactam products in shortage under section 503a of the federal FD&C act

This guidance describes the Food and Drug Administration’s FDA regulation and enforcement priorities regarding preparation of beta-lactam oral antibiotic suspension products that appear on FDA’s drug shortage list by a licensed pharmacist in a State-licensed pharmacy or Federal facility. There is currently an acute shortage of amoxicillin oral antibiotic powder for suspension. Amoxicillin oral antibiotic powder for suspension products currently appear on FDA’s drug shortage list. Amoxicillin is widely used for the treatment of bacterial upper and lower respiratory infections in the pediatric population, among other uses. As a result of this shortage, there is an urgent need to increase the supply of these beta-lactam oral suspension products. FDA has received a number of reports related to increased demand for amoxicillin oral antibiotic suspension products in particular. FDA has also received requests for clarification about preparation of compounded versions of those products from FDA-approved tablets and capsules.

This guidance is being implemented without prior public comment because FDA has determined that prior public participation for this guidance is not feasible or appropriate. This guidance document is being implemented immediately because of the public health need for amoxicillin oral antibiotic suspension products, but it remains subject to comment in accordance with the Agency’s good guidance practices.

[‘Interesting’ risk based decision making by the FDA- but make sure you read the whole document MBH]

Cross Labeling Oncology Drugs in Combination Regimens

Drug approvals in oncology often build on treatment effects by adding drugs to current regimens or by combining investigational drug products in a combination regimen, creating new regimens with greater efficacy.

The purpose of this guidance is to describe the Food and Drug Administration’s (FDA’s) current recommendations about including relevant information in labeling for oncology drugs approved for use in a combination regimen, including important considerations for cross labeling of these drugs.

Applicants proposing cross labeling for oncology drug combination regimens should contact the review division for information on cross labeling of their individual products.

This guidance also does not address circumstances in which a drug product and a biological product packaged separately constitute a cross-labeled combination product as defined in 21 CFR 3.2(e).

Sameness Evaluations in an ANDA — Active Ingredients

This draft guidance is intended to assist applicants preparing an abbreviated new drug application (ANDA) by providing recommendations on demonstrating sameness between the active ingredient in a proposed generic drug product and its reference listed drug (RLD)

Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin

This guideline concerns the testing and evaluation of the viral safety of biotechnology products, and it outlines what data should be submitted in marketing application and registration packages for those products. Biotechnology products include biotherapeutics and certain biological products derived from cell cultures initiated from characterised cell banks of human or animal origin (e.g., mammalian, avian, insect). In this document, the term “virus” excludes non-conventional transmissible agents like those associated with mammalian prions (e.g., bovine spongiform encephalopathy, scrapie). Applicants are encouraged to discuss bovine spongiform encephalopathy-associated issues with the appropriate regulatory authorities.


International


Australia


Therapeutic Goods Association (TGA)

Standard for serialisation and data matrix codes commences 1 January 2023

If you include data matrix codes or serialisation on your medicines, you need to be ready for the requirements set out in TGO 106.

TGO 106 was introduced in 2021 to give clarity for adopters of serialisation and data matrix codes on medicines supplied in Australia.

TGO 106 aligns with global standards to give consistency for sponsors and manufacturers operating in multiple jurisdictions and to allow international interoperability. Both the standard and guidance were developed with stakeholder input and incorporated feedback received during consultation.

The International Coalition of Medicines Regulatory Authorities (ICMRA)

Best practices to fight antimicrobial resistance

The ICMRA highlights successful regulatory and non-regulatory interventions used in different countries to address the growing public health problem of antimicrobial resistance (AMR) in a new report.

AMR threatens our ability to effectively treat infections because of an ever-increasing range of bacteria and other microorganisms that have adapted to become resistant to available treatments.

Tackling AMR is one of ICMRA’s strategic priorities. ICMRA recognises that AMR is a complex, multifaceted problem and calls for better coordination across all sectors, including public health, animal health and the environment, through a ‘One Health’ approach. A concerted and collaborative effort is essential to address this threat to global health, economies and security effectively.

The report presents case studies on best practices from different countries that were developed in line with the ‘One Health’ approach.

The Pharmaceutical Inspection Co-operation Scheme (PIC/S)

Concept Paper on the revision of EU-PIC/S GMP Annex 11 (Computerised Systems)

A dedicated European Medicines Agency (EMA) Drafting Group, in which PIC/S is represented by Ib Alstrup (Denmark / DKMA), who is also the Chair of the PIC/S Working Group on the revision of PI 011 (PIC/S Recommendation on Computerised Systems), has developed a concept paper on the revision of Annex 11 (computerised systems) of the EU-PIC/S GMP Guide.

This concept paper is submitted to a joint PIC/S-EMA public consultation from 16 November 2022 until 16 January 2023 and can be downloaded on the PIC/S website.

The current version was issued in 2011 and since then, there has been extensive progress in the use of new technologies.

The current Annex 11 does not give sufficient guidance within a number of areas already covered, and other areas, which are becoming increasingly important to GMP, are not covered at all. The revised text will expand the guidance given in the document and embrace the application of new technologies which have gained momentum since the release of the existing version.

If possible, the revised document will include guidelines for acceptance of AI/ML algorithms used in critical GMP applications. This is an area where regulatory guidance is highly needed as this is not covered by any existing regulatory guidance in the pharmaceutical industry and as pharma companies are already implementing such algorithms.


Products


2nd Pfizer/BioNTech bivalent COVID-19 booster vaccine approved by UK medicines regulator

Approval has today been granted by the MHRA for a Pfizer/BioNTech ‘bivalent’ Covid vaccine that targets both the original strain of SARS-CoV-2 and the Omicron BA.4 and BA.5 sub-variants. The updated booster vaccine is the second bivalent vaccine from Pfizer/BioNTech to receive MHRA approval.

The vaccine has been approved for use as a booster dose in individuals aged 12 years and above. In each dose of the booster vaccine, half of the vaccine (15 micrograms) targets the original virus strain and the other half (15 micrograms) targets Omicron (BA.4-5).



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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