Review of Developments in GMP and the Regulation of Medicines Feb 2021
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INTRODUCTION
This is a particularly momentous period where we note the approval several more COVID 19 vaccines in various markets (a tremendous achievement in what is a record time). There will be many logistics challenges to ensure a smooth roll out and supply of the vaccines but the pharma industry, academia and the regulatory bodies involved have done a fantastic job so far in such a short timescale.
The topics covered in this edition of the “Update” include:
MHRA
Guidance for industry and organisations to follow from 1 January 2021.
Exporting active substances manufactured in Great Britain for use in EEA and Northern Ireland
Blog - Pharmacovigilance requirements for UK authorised products
Ranitidine-containing medicinal products
Application of the EU pharmaceutical acquis in markets historically dependent on medicines supply from Great Britain
New status of NIBSC (UK) as observer within OCABR network post-Brexit
Implementation of the European Pharmacopoeia Supplement 10.5 – Notification for CEP holders
CEP holders invited to comment on draft monographs published in Pharmeuropa 33.1
New Ph Eur Technical Guide for the elaboration of monographs on medicinal products containing chemically defined active substances.
Transparency: exceptional measures for COVID-19 medicines
Extra dose from vials of Comirnaty COVID-19 vaccine
Cyberattack on EMA - updates
Medicines for use outside the European Union
Overview of comments received on ICH guideline Q3D(R2) on elemental impurities
SME Office Newsletter
Implementation of the new Veterinary Medicines Regulation
COVID-19: Potency assay considerations for monoclonal antibodies and other therapeutic proteins targeting SARS-CoV-2 infectivity.
Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19)
Moderna vaccine becomes third COVID-19 vaccine approved by UK regulator
EMA recommends COVID-19 Vaccine Moderna for authorisation in the EU
EMA recommends COVID-19 Vaccine AstraZeneca for authorisation in the EU
EMA Clarification of Comirnaty dosage
Australia provisionally approves Pfizer COVID-19 vaccine
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
Guidance for industry and organisations to follow from 1 January 2021.
This guidance should be followed from 1 January 2021. It replaces previously published guidance on what to do from the end of the transition period.
Exporting active substances manufactured in Great Britain for use in EEA and Northern Ireland
This guidance which was updated 12 Jan 2021 describes how the ‘Written Confirmation’ process operates for active substances manufactured in Great Britain (England, Wales and Scotland).
Blog - Pharmacovigilance requirements for UK authorised products
A new post, “Pharmacovigilance requirements for UK authorised products has just been published on the MHRA Inspectorate blog. The pharmacovigilance requirements for UK authorised products are discussed in a webinar recording, which took place on 13 January 2020. This webinar was part of a series of Brexit and post-transition guidance webinars.
Europe
EC
Ranitidine-containing medicinal products (revised decision 5 Jan 2021)
Following a re-examination of CHMP’s April 2020 opinion, which was requested by one of the companies marketing ranitidine medicines. There is some evidence that NDMA may form from the degradation of ranitidine itself with increasing levels seen over its shelf life. It is not clear if NDMA can also be formed from ranitidine inside the body. Some studies suggest that it can, while others do not. Given the uncertainties, the CHMP has recommended in April 2020 a precautionary suspension of these medicines in the EU. Following the re-examination, the CHMP maintained the conditions for lifting the suspension of the medicines, including requirements for companies to provide more data on the possible formation of NDMA from ranitidine inside the body. The formation of NDMA in the body is expected to be very low following a single low dose of ranitidine given by injection or infusion (drip). Therefore, the CHMP slightly amended the conditions for lifting the suspension for those ranitidine medicines that are given by injection or infusion as a single, low dose.
Application of the EU pharmaceutical acquis in markets historically dependent on medicines supply from Great Britain
The European Commission has issued a notice to stakeholders on application of the EU pharmaceutical acquis in markets historically dependent on medicines supply from Great Britain
Some markets which have historically relied on supply of medicinal products from or through Great Britain (Cyprus, Ireland, Malta and Northern Ireland) may still need some additional time to adapt supply chains and take account of the end of the transition period. Against that background, it is crucial that the Union’s pharmaceutical acquis is implemented and enforced in a manner that both prevents shortages of medicines and ensures the high level of public health protection foreseen by Union law. The Commission has identified the following challenges (described below) as the principal difficulties for the abovementioned markets which are historically dependent on medicines supply from or through Great Britain in complying with the Union’s pharmaceutical acquis:
1. Lack of operators holding a manufacturing authorisation necessary for imports of medicinal products from third countries;
2. Difficulties to carry out quality control testing (‘batch testing’);
3. Difficulties to comply with the provisions of Directive 2001/83/EC and Delegated Regulation (EU) 2016/161 with respect to the placement and verification of the unique identifier.
Recognising these challenges, and taking into consideration the exceptional circumstances of the COVID-19 pandemic, the Commission takes note of the request, from both private and public stakeholders in the Union and the United Kingdom, for more time in the transition towards full compliance with the Union’s pharmaceutical acquis.
EDQM
New status of NIBSC (UK) as observer within OCABR network post-Brexit
The Official Control Authority Batch Release (OACBR) Network for human vaccines and medicinal products derived from human blood and plasma and the National Institute of Biological Standards and Control (NIBSC, United Kingdom) have signed a memorandum of understanding (MOU) to renew, post-Brexit, the exchange and collaboration on common activities related to batch release of human vaccines and medicinal products derived from human blood and plasma. The MOU enters into force on 21 January 2021. It makes NIBSC an observer to the OCABR Network for human biologicals and reinstates the sharing of information related to batch release activity in this field.
Mutual recognition of certificates is not within the scope of this MOU, however. Mutual recognition of OCABR, as defined in European Union legislation, would require a formal agreement between the EU and the UK that included also OCABR. The network looks forward to continuing a fruitful exchange with the United Kingdom OMCL in this new framework.
[Note the clear requirement for a formal agreement between the EU and the UK that included also OCABR before mutual recognition of certificates can be included in the new arrangements post Jan 2021MBH].
Implementation of the European Pharmacopoeia Supplement 10.5 – Notification for CEP holders
Supplement 10.5 of the European Pharmacopoeia (Ph. Eur) is now available. CEP holders are invited to update their applications according to the revised monographs that will be implemented on 1 July 2021.
It is the responsibility of the manufacturer to comply with the current version of a Ph. Eur. monograph, and therefore to update the specification when a revised monograph is issued. In addition, the EDQM ensures that CEPs refer to the most recent version of a Ph. Eur. monograph at any time.
The need to submit information to the EDQM following a revised monograph depends on the changes made to the monograph. Updates to the monographs are classified by the EDQM into two categories, labelled “Case A” and “Case B”, and this influences the information required.
CEP holders invited to comment on draft monographs published in Pharmeuropa 33.1
CEP holders are requested to consult the list of substances for which draft revised monographs of the European Pharmacopoeia (Ph. Eur.) have been published in Pharmeuropa 33.1. Although these draft monographs are published for public consultation only at this stage and are therefore not official standards, they will, once adopted by the European Pharmacopoeia Commission, become legally binding standards for the substances concerned. It is therefore extremely important that manufacturers and users of the substances provide feedback on these draft monographs before the commenting deadline, i.e. before 31 March 2021. Comments made after adoption of a monograph and/or the publication in the Ph.Eur. will not be considered and manufacturers and users of substances concerned may find themselves in a position where their substance does not comply with the relevant Ph.Eur. monograph, which is a legal standard in Europe.
New PhEur Technical Guide for the elaboration of monographs on medicinal products containing chemically defined active substances
This document provides clear guidance for those involved in drafting medicinal product monographs and is also a means of communicating the principles for the elaboration of monographs to users of the Ph.Eur.
A monograph on a medicinal product is drafted with the same overall structure as a monograph on a chemically defined substance and the latest versions of both the Technical guide for the elaboration of monographs (2015) and the Style guide of the European Pharmacopoeia (2017) apply.
This new guide develops the specific points that are relevant to medicinal products containing chemically defined active substances and which are not presented in the above-mentioned overarching guides. In particular, it includes a section on the Ph.Eur’s newly agreed dissolution and disintegration testing policy for medicinal products
EMA
Transparency: exceptional measures for COVID-19 medicines
During the COVID-19 pandemic, the EMA is implementing exceptional measures to maximise the transparency of its regulatory activities on treatments and vaccines for COVID-19 that are approved or are under evaluation.
EMA is achieving this by shortening its standard publishing timeframes and publishing information it does not normally publish for other medicines.
These measures aim to address the high interest for information and to support global research on COVID-19 medicines. They are in addition to the information EMA normally publishes on human medicines.
EMA may increase transparency of other regulatory procedures.
Extra dose from vials of Comirnaty COVID-19 vaccine
EMA’s human medicines committee (CHMP) has recommended updating the product information for Comirnaty to clarify that each vial contains 6 doses of the vaccine.
In order to extract six doses from a single vial, low dead-volume syringes and/or needles should be used. The low dead-volume syringe and needle combination should have a dead volume of no more than 35 microliters. If standard syringes and needles are used, there may not be enough of the vaccine to extract a sixth dose from a vial.
This in effect will achieve a 20% increase in the number of patients able to be treated from each multidose vial (6 patients instead of 5 per vial). In terms of the increase in the possible number of patients vaccinated during the mass vaccination programmes across the EU the numbers involved are significant.
[This is an unusual initiative, but if it can be realistically achieved it could be a good example of Risk Based decision taking by the EU regulator and a very positive initiative for those extra patients who would be protected MBH]
Cyberattack on EMA - updates
The ongoing investigation of the cyberattack on EMA revealed that some of the unlawfully accessed documents related to COVID-19 medicines and vaccines have been leaked on the internet.
This included internal/confidential email correspondence dating from November, relating to evaluation processes for COVID-19 vaccines. Some of the correspondence has been manipulated by the perpetrators prior to publication in a way which could undermine trust in vaccines.
EMA is in constant dialogue with the EC, and other regulators across the network and internationally. Authorisations are granted when the evidence shows convincingly that the benefits of vaccination are greater than any risks of the vaccine. Full details of the scientific assessments are publicly available in the European Public Assessment Reports (EPAR) on EMA’s website.
The Agency continues to fully support the criminal investigation into the data breach. Necessary action is being taken by the law enforcement authorities.
Medicines for use outside the European Union
The EMA, in cooperation with the World Health Organization (WHO), can provide scientific opinions on high priority human medicines, including vaccines, that are intended for markets outside of the European Union (EU).
The aim is to facilitate patient access to essential medicines in low- and middle-income countries, including new or improved therapies for unmet medical needs, which are intended to prevent or treat diseases of major public health interest.
The procedure combines EMA's scientific review capabilities with the local epidemiology and disease expertise of WHO and national regulators in the target countries, to provide a unique development and assessment pathway. It is targeted both at innovative and new developments of already authorised medicines.
EMA's Committee for Medicinal Products for Human Use (CHMP) assesses medicines and vaccines under this procedure to the same rigorous standards as medicines intended for use in Europe.
Following the evaluation, EMA publishes its scientific opinion of the benefit-risk balance of the product, which aims to facilitate prequalification of the medicine by WHO and registration in the target countries.
The procedure is called EU-Medicines for all or 'EU-M4all'. It was previously known as the Article 58 procedure, as the legal basis is Article 58 of Regulation (EC) No 726/2004. It has been in place since 2004.
Overview of comments received on ICH guideline Q3D(R2) on elemental impurities
These comments will be sent to the ICH Q3D(R2) Maintenance Expert Working group (EWG) for consideration in the context of Step 3 of the ICH process
SME Office Newsletter
This Newsletter provides Information for Small and medium sized Entities (SMEs) on the EU regulatory environment for medicines.
Issues covered include:-
15-year anniversary of SME Regulation
UK withdrawal from the EU
COVID-19
Pharmaceutical strategy for Europe
EMA network strategy to 2025
Big data
IRIS
Paediatric medicines
Clinical Trial Regulation
Nitrosamine impurities
Veterinary products
Scientific guidelines for human medicines
Regulatory guidance
Pharmacovigilance
Events of interest
Implementation of the new Veterinary Medicines Regulation
A new draft document ‘Implementing the Union Product Database’ is available for public consultation.
It contains guidance for marketing authorisation holders and national competent authorities on the submission of data on veterinary medicines to the Union Product Database(UPD) using standardised data formats and terminologies throughout the EU.
The different chapters of the guide explain the timelines, requirements, process, technical specification, data elements and associated business rules for submitting these data.
The UPD will draw on the four Substances and products data management services (SPOR) data management services for the centralised management of master data in the EU.
Stakeholders should send their comments by 21 March 2021
United States of America
The US Food and Drug Administration (USFDA)
COVID-19: Potency assay considerations for monoclonal antibodies and other therapeutic proteins targeting SARS-CoV-2 infectivity.
Due to the current public health emergency, FDA is issuing this final guidance to assist sponsors in the development of monoclonal antibodies (mAbs) and other therapeutic proteins for use as COVID-19 therapeutics. A critical quality control measure for these products is the development and implementation of a potency assay(s) adequate to ensure that each lot is consistently produced with the potency necessary to achieve clinical efficacy and that such potency is maintained over the shelf life of the product. Typically, FDA engages with sponsors regarding their development of appropriate potency assays over the course of drug development; these interactions usually happen over a span of years. However, given the compressed development timelines associated with therapeutics intended to treat COVID-19, FDA is issuing this guidance to provide more detailed recommendations to drug developers with the goal of facilitating more complete submissions. FDA is committed to supporting all scientifically sound approaches to attenuating the clinical effect of COVID-19 and to doing so in a timely and efficient manner commensurate with the urgent clinical need. This guidance applies only to mAbs and other therapeutic proteins designed to bind to viral receptors on host cells, inhibit viral entry, and/or elicit Fc-mediated effector function. Vaccines, hyperimmune globulins, gene therapies, cell therapies, and convalescent plasma are not within the scope of this guidance. The guidance describes how potency assay methods required for release and stability testing can be shown to assess comprehensively known or potential mechanism(s) of action of the product. Such methods should also be sufficiently sensitive to demonstrate lot-to-lot consistency. In addition to release and stability methods, additional methods that demonstrate the biological function(s) of the product may be needed for characterization and comparability studies. The guidance describes methods that applicants should use to ensure the potency of mAbs and other therapeutic proteins proposed for use as anti-infective agents for COVID-19.
Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19)
This guidance is intended to alert pharmaceutical manufacturers and pharmacists in State-licensed pharmacies or Federal facilities who engage in drug compounding to the potential public health hazard of alcohol (ethyl alcohol or ethanol) or isopropyl alcohol contaminated with or substituted with methanol. FDA is aware of reports of fatal methanol poisoning of consumers who ingested alcohol-based hand sanitizers that were manufactured with methanol or methanol-contaminated ethanol. FDA has also received numerous reports of dermal toxicity associated with such products. This guidance was developed by the FDA’s Center for Drug Evaluation and Research (CDER), in cooperation with the Center for Biologics Evaluation and Research (CBER)and the Center for Veterinary Medicine (CVM). For the purposes of this guidance, references to “manufacturers” include registered outsourcing facilities because outsourcing facilities are subject to current good manufacturing practice (CGMP) requirements.
FDA also is concerned that other drug products containing ethanol or isopropyl alcohol (pharmaceutical alcohol), which are widely used active ingredients in a variety of drug products, could be similarly vulnerable to methanol contamination. For example, certain inhalation products, mouthwashes, cough and cold products, and many topical drug products include pharmaceutical alcohol. As the COVID-19 pandemic has increased the demand for hand sanitizer products, the demand for pharmaceutical alcohol as the active ingredient of those products has also increased. In the past, increased stress on supply chains has made ingredients more vulnerable to economically motivated adulteration. For these reasons, the policy outlined in this guidance applies to pharmaceutical alcohol used as an active or inactive ingredient in a drug regardless of whether the drug product is a hand sanitizer. This policy will help pharmaceutical manufacturers and pharmacists who engage in drug compounding avoid using pharmaceutical alcohol contaminated with or substituted with methanol in drug products.
Products
Moderna vaccine becomes third COVID-19 vaccine approved by UK regulator
The vaccine has been approved after meeting the required safety, quality and effectiveness standards.
EMA recommends COVID-19 Vaccine Moderna for authorisation in the EU
EMA has recommended granting a conditional marketing authorisation for COVID-19 vaccine Moderna to prevent Coronovirus disease (COVID-19) in people from 18 years of age. This is the second COVID-19 vaccine that EMA has recommended for authorisation.
EMA’s CHMP has thoroughly assessed the data on the quality, safety and efficacy of the vaccine and recommended by consensus a formal conditional marketing authorisation be granted by the European Commission. This will assure EU citizens that the vaccine meets EU standards and puts in place the safeguards, controls and obligations to underpin EU-wide vaccination campaigns.
EMA recommends COVID-19 Vaccine AstraZeneca for authorisation in the EU
EMA has recommended granting a conditional marketing authorisation for COVID-19 Vaccine AstraZeneca to prevent coronavirus disease 2019 (COVID-19) in people from 18 years of age. This is the third COVID-19 vaccine that EMA has recommended for authorisation.
There are not yet enough results in older participants (over 55 years old) to provide a figure for how well the vaccine will work in this group. However, protection is expected, given that an immune response is seen in this age group and based on experience with other vaccines; as there is reliable information on safety in this population, EMA’s scientific experts considered that the vaccine can be used in older adults. More information is expected from ongoing studies, which include a higher proportion of elderly participants.
EMA Clarification of Comirnaty dosage interval
EMA’s human medicines committee (CHMP) has updated the product information for the COVID-19 vaccine Comirnaty to clarify its position on the interval between the first and second dose.
The product information (section 4.2 and package leaflet) now recommends the administration of the second dose 3 weeks after the first dose. Previously, the product information stated that the interval should be “at least 21 days”.
The product information (section 5.1) already states that the participants whose data was used to calculate efficacy received their second dose within 19 to 42 days after their first dose. A sentence has been added with the information that 93.1% of these participants received the second dose 19 to 23 days after the first dose.
There are currently no clinical data on the efficacy of the vaccine when administered beyond intervals used in the clinical trial.
TGA provisionally approves Pfizer COVID-19 vaccine
TGA has granted provisional approval to Pfizer Australia Pty Ltd for its COVID-19 vaccine Comirnaty, making it the first COVID-19 vaccine to receive regulatory approval in Australia. Provisional approval of this vaccine is valid for two years and means it can now be legally supplied in Australia.
The approval is subject to certain strict conditions, such as the requirement for Pfizer to continue providing information to the TGA on longer term efficacy and safety from ongoing clinical trials and post-market assessment. COMIRNATY has been shown to prevent COVID-19 however, it is not yet known whether it prevents transmission or asymptomatic disease.
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 hyperlinks 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.