Review of Developments in GMP and the Regulation of Medicines March 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 MHRA, EU and Australian regulatory authorities. Unusually, there were no items of note from the US FDA this month although there have been verbal/ media reports of it making a conditional approval of the J&J single dose Coronovirus vaccine – another giant step in the potential to control this pandemic.
The topics covered in this edition of the “Update” include:
MHRA
GPvP -latest inspection metrics
Adapting COVID-19 vaccines to SARS-CoV-2 variants: guidance for vaccine manufacturers
Type-1A and IB variations: Q&As
Nitrosamine impurities
CHMP early contact with patient/ consumer organisations
Accelerated assessment
Joint Audit Programme
TGA invited to participate on European committees on COVID-19 vaccines and therapeutics
The TGA's risk management approach V 5.0
International cooperation to align approaches for regulation of COVID-19 vaccines and medicines
EMA starts rolling review of Novavax’s COVID-19 vaccine (NVX-CoV2373)
EMA starts rolling review of CureVac’s COVID-19 vaccine (CVnCoV)
Clarification on Sputnik V vaccine in the EU approval process
Australian TGA provisionally approves AstraZeneca's COVID-19 vaccine
Precautionary marketing suspension of thalassaemia medicine Zynteglo
EMA issues advice on use of REGN-COV2 antibody combination (casirivimab / imdevimab)
Rapid implementation of the revised sartan monographs on 1 April 2021
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
GPvP -latest inspection metrics
The MHRA GPvP inspectorate recently published their latest inspection metrics for the period from April 2019 to March 2020.
This report contains data relating to all 22 inspections conducted during the period 01 April 2019 to 31 March 2020. Information on the types of inspection, inspection findings and the amount of time spent on inspection have been examined, including analysis of specific technical topics where the highest number of findings were found.
Europe
EMA
Adapting COVID-19 vaccines to SARS-CoV-2 variants: guidance for vaccine manufacturers
EMA has issued guidance outlining the requirements for manufacturers planning to modify their COVID-19 vaccines to address variants.
Viruses typically mutate and several variant strains of SARS-CoV-2 have already been identified worldwide. The three authorised vaccines provide protection against the variants that are currently prevalent across Europe. However, it appears that with continued mutations and new variants emerging, authorised vaccines may need to be adapted, in time to ensure continued protection. Initial data indicates that some of these variants may have an impact on the level of protection provided by COVID-19 vaccines against infection and disease.
Therefore, it is an urgent public health priority to define an expedited regulatory process for the adaptation of vaccines to protect against current or future variants.
EMA’s CHMP has adopted a reflection paper which details the laboratory (non-clinical), clinical, quality and manufacturing data needed to support the approval of such ‘variant’ vaccines. The assumption behind the CHMP’s guidance is that a new variant vaccine would largely rely on the same technology and platform as the ‘parent’ vaccine - a vaccine already approved in the EU for the prevention of COVID-19. The difference would be in the specific structure (antigen) selected to trigger the immune response in the body.
Type-1A and IB variations: Q&As
This page lists Q&As that marketing-authorisation holders (MAHs) may have on type-1A and IB variations. It provides an overview of the EMA's position on issues that are typically addressed in discussions or meetings with MAHs in the post-authorisation phase. Revised topics are marked 'New' or 'Rev.' upon publication.
Nitrosamine impurities
EMA has updated its guidance on this ongoing topic.
CHMP early contact with patient / consumer organisations
Patients and their representative are currently involved at various timepoints during the medicines’ lifecycle, including CHMP evaluations. However, requests for patient input generally come at a later stage of the evaluation, often once major objections have been identified (e.g. expert meeting, oral explanation). Experience shows that late input may lead to missed opportunities to properly incorporate patient perspectives into the assessment process.
To enhance the way CHMP currently interacts with patient groups during the assessment of new medicines, it is proposed to reach out to relevant patient/consumer organisations at the start of the evaluation of new Marketing Authorisation Applications (MAAs) so that patients can share their experience and concerns about their condition(s) and key aspects that are important for them in order for this to be taken into account in a timely manner during the assessment process. A pilot is proposed to define how this could occur to maximal effect.
Accelerated assessment
EMA has updated these pages on its website. Evaluating a marketing-authorisation application under the centralised procedure can take up to 210 days, not counting clock stops when applicants have to provide additional information. On request, the CHMP can reduce the timeframe to 150 days if the applicant provides sufficient justification for an accelerated assessment.
Joint Audit Programme
The Joint Audit Programme (JAP) forms an essential part of the quality system adopted by good manufacturing practice (GMP) inspectorates in the European Economic Area (EEA), aiming to ensure consistency of GMP standards and a harmonised approach throughout Europe.
Joint audits are expected to lead to an improvement of the assessed authorities and enable national auditors to transfer experiences gained during the audits to their national inspectorates. These joint visits establish and maintain mutual confidence among European inspectors. Possible exposure of weaknesses and deficiencies allows the authorities to improve their quality system.
The JAP also contributes to the training of inspectors.
A new document “Audit checklist – interpretation guide” has been added (Published Feb 16 2021, though dated 1 Sep 2020) to the programme.
EDQM
Rapid implementation of the revised sartan monographs on 1 April 2021
The five monographs on sartans with a tetrazole ring, namely Valsartan (2423), Losartan potassium (2232), Irbesartan (2465), Candesartan cilexetil (2573) and Olmesartan medoxomil (2600) have been revised to align them with the latest regulatory recommendations issued by the CHMP that were published on 13 November 2020 on the EMA’s website. The revision concerns a rewording of the “Production” section and deletion of the N-nitrosamines test section. These revised monographs were not published in Pharmeuropa for public enquiry as the changes made are in line with the CHMP recommendations. In addition, to ensure that the implementation date for the Ph. Eur. requirements is aligned with regulatory decisions as much as possible, the Ph. Eur. Commission has decided to publish the monographs under the rapid-revision procedure. The implementation date for the five revised monographs has therefore been set as 1 April 2021. The PDF versions of these monographs can be downloaded from the EDQM website and contain a production statement to the effect “As N-nitrosamines are classified as probable human carcinogens, their presence in XXX YYY should be avoided or limited as much as possible. For this reason, manufacturers of XXX YYY for human use are expected to perform an assessment of the risk of N-nitrosamine formation and contamination during their manufacturing process; if this assessment identifies a potential risk, the manufacturing process should be modified to minimise contamination and a control strategy implemented to detect and control N-nitrosamine impurities in XXX YYY. The general chapter 2.5.42. N-Nitrosamines in active substances is available to assist manufacturers.”
International
Australia
TGA invited to participate on European committees on COVID-19 vaccines and therapeutics
Australia, through the TGA, is one of only five non-European Union regulators formally invited to participate by the European Medicines Agency (EMA) on the evaluation of vaccines and therapeutics to combat COVID-19. Senior medical officers at the TGA contribute to meetings of the EMA pandemic task force, as well as its human medicines committee, as active participants in the consideration of applications for vaccines and medicines for the treatment of COVID-19 infection. This will greatly assist TGA in understanding the medical and scientific considerations made in the review of these products by the EMA and other major global regulators. TGA will continue to make fully independent 'sovereign' decisions on whether or not particular products should be approved in Australia, the appropriate patient group for treatment with the product and any conditions to be applied to product registration.
The TGA's risk management approach V 5.0
This guidance outlines the broad approach adopted by the TGA to identify and manage risk associated with therapeutic goods.
International Coalition of Medicines Regulatory Authorities (ICMRA)
International cooperation to align approaches for regulation of COVID-19 vaccines and medicines
Regulators around the globe are committed to aligning their regulatory requirements and addressing knowledge gaps to facilitate the development, authorisation and monitoring of safe, effective and high-quality vaccines and medicines against COVID-19. This was highlighted in a series of regulatory workshops, convened under the umbrella of the (ICMRA) in the first weeks of 2021, which focused on three areas: responding to emerging COVID-19 virus variants, addressing knowledge gaps regarding COVID-19 vaccines and treatments in pregnant and breastfeeding women, and strengthening collaboration on safety monitoring of vaccines.
Products
EMA starts rolling review of Novavax’s COVID-19 vaccine (NVX-CoV2373)
EMA’s human medicines committee (CHMP) has started a rolling review of NVX-CoV2373, a COVID 19 vaccine being developed by Novavax CZ AS (a subsidiary of Novavax, Inc.).
The CHMP’s decision to start the rolling review is based on preliminary results from laboratory studies (non-clinical data) and early clinical studies in adults. These studies suggest that the vaccine triggers the production of antibodies and immune cells that target SARS-CoV-2, the virus that causes COVID 19.
The company is currently conducting trials in people to assess its safety, immunogenicity (how well it triggers a response against the virus) and its effectiveness against COVID-19. EMA will evaluate data from these and other clinical trials as they become available.
The rolling review will continue until enough evidence is available for a formal marketing authorisation application.
EMA starts rolling review of CureVac’s COVID-19 vaccine (CVnCoV)
EMA’s CHMP has started a rolling review of CVnCoV, a COVID 19 vaccine being developed by CureVac AG.
The CHMP’s decision to start the rolling review is based on preliminary results from laboratory studies (non-clinical data) and early clinical studies in adults. These studies suggest that the vaccine triggers the production of antibodies and immune cells that target SARS-CoV-2, the virus that causes COVID 19.
The company is currently conducting trials in people to assess the vaccine’s safety, immunogenicity (how well it triggers a response against the virus) and effectiveness against COVID-19. EMA will evaluate data from these and other clinical trials as they become available.
The rolling review will continue until enough evidence is available for a formal marketing authorisation application.
Clarification on Sputnik V vaccine in the EU approval process
EMA has to date not received an application for a rolling review or a marketing authorisation for the vaccine developed by the Gamaleya National Centre of Epidemiology and Microbiology in Russia, the Sputnik V vaccine (Gam-COVID-Vac), despite reports stating the opposite.
The developers have received scientific advice from EMA providing them with the latest regulatory and scientific guidance for the development of their vaccine.
EMA is in dialogue and collaborating with the company to define the next steps. The developers have expressed their interest that the vaccine be considered for a rolling review.
Australian TGA provisionally approves AstraZeneca's COVID-19 vaccine
TGA has granted provisional approval to AstraZeneca Pty Ltd, making it the second COVID-19 vaccine to receive regulatory approval in Australia.
COVID-19 Vaccine AstraZeneca is provisionally approved and included in the Australian Register of Therapeutic Goods (ARTG) for the active immunisation of individuals 18 years and older for the prevention of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2. The use of this vaccine should be in accordance with official recommendations and given in two separate doses. "TGA's regulatory approval allows the second dose to be administered from 4 to 12 weeks after the first. The Australian Technical Advisory Group on Immunisation has recommended that the interval between first and second dose is 12 weeks. However, if this interval is not possible, for example because of imminent travel, cancer chemotherapy, major elective surgery, a minimum interval of 4 weeks between doses can be used.
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 AstraZeneca to continue providing information to the TGA on longer term efficacy and safety from ongoing clinical trials and post-market assessment.
Precautionary marketing suspension of thalassaemia medicine Zynteglo
The company that markets the gene therapy medicine Zynteglo for treating the rare blood condition beta thalassaemia has suspended sales pending investigation of a safety concern.
The company, bluebird bio, notified EMA that a related medicine it was developing, which uses the same technology as Zynteglo, may have been associated with a case of cancer. Although no cases of cancer have been reported with Zynteglo itself, the company suspended marketing of Zynteglo until the possibility that the same risk might apply to the licensed medicine has been investigated.
Zynteglo was granted conditional marketing authorisation on 29 May 2019. Currently it is only marketed in Germany, and because of limited availability and the rarity of the condition it is intended to treat, only a very small number of patients have received or would have been eligible to receive treatment. However, if treated patients do have any concerns, they should contact the specialist supervising their Zynteglo treatment.
EMA will communicate further once additional information becomes available.
EMA issues advice on use of REGN-COV2 antibody combination (casirivimab / imdevimab)
Casirivimab and imdevimab have been designed to attach to the spike protein of SARS-CoV-2 at two different sites. When the active substances are attached to the spike protein, the virus is unable to enter the body’s cells.
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.