Review of Developments in GMP and the Regulation of Medicines April 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 and Australian regulatory authorities. Once again this month COVID 19 and also nitrosamine issues dominate the news.
The topics covered in this edition of the “Update” include:
MHRA
Inspectors grounded - a year of innovation
Webinar on “Approaches for CEPs and the Ph. Eur. strategy with regard to nitrosamine control: current guidance and practical implementation”
Nitrosamine Implementation Oversight Group (NIOG) - meeting with pharmaceutical industry
How CEP holders can avoid the rejection of notifications
European Pharmacopoeia (Ph. Eur.) reference standards
Revision of CEPs referring to one of the “sartan” monographs following their rapid implementation
Q&A to Stakeholders on the implementation of the Protocol on Ireland/Northern Ireland
Pilot project ‘Market Launch Intentions of Centrally Authorised Products’ Practical Q&As
Sartans (article 31 referral) CHMP Assessment.
Brexit Update
Classification of changes: Q&A
EMA Management Board
Labelling flexibilities for COVID-19 therapeutics
Compliance Group Mandate- Joint Audit Programme for EEA GMP Inspectorates
The US Food and Drug Administration (USFDA)
COVID-19 Container Closure System and Component Changes: Glass Vials and Stoppers
Proposal for clarifying regulatory requirements for residual claims for disinfectants
TGA adopts Access Consortium guidance for fast-tracking authorisations of modified COVID-19 vaccines for variants
New standard for serialisation and data matrix codes on medicines
4th COVID-19 Vaccine authorised in EU
Advice on use of regdanvimab for treating COVID-19
Reply to open letter concerning Covid 9 vaccines
TGA Virtual GMP Forum 2021
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
Inspectors grounded - a year of innovation
In this blog MHRA notes that the start of lockdown this time last year meant a complete change to the way of working for the inspectorate, with the potential to impact dramatically on its ability to maintain regulatory oversight of public health.
Since the start of lockdown, MHRA has now carried out over 750 inspections conducted remotely across the Good Practice Standards (GxPs), a huge achievement given both the pandemic restrictions and also juggling with caring and childcare responsibilities, both on the part of the inspectors and those which MHRA inspects. The inspectorate has maintained an international perspective on remote inspections, sharing experiences through the International Coalition of Medicines Regulatory Authorities (ICMRA) and Pharmaceutical Inspection Co-operation Scheme (PIC/S), including training other regulators in MHRA approaches.
One of the unexpected outcomes of remote inspections, is that they actually take longer to perform than the on-site model due to the limitations (even with technology) of not having that real time presence of questions raised and answered or being able to ‘dig around’ to see what the compliance level of a facility is really like. [industry has been aware of this ever since the Japanese inspectorate started remote Pre Approval inspection several years ago MBH]
Europe
EDQM
Webinar on “Approaches for CEPs and the Ph. Eur. strategy with regard to nitrosamine control: current guidance and practical implementation”
In this webinar, the EDQM will provide users and stakeholders with an update and detailed overview of the approaches for CEPs and the Ph. Eur. strategy with regard to controlling these impurities. There will be a presentation on the recently revised Ph. Eur. monographs for the five sartans with a tetrazole ring, to explain the changes made with a view to helping users in appropriately applying the texts.
The speakers will share the EDQM’s expectations with regard to carrying out a risk assessment and identifying appropriate control strategies, as well as the data that should be provided in CEP applications to meet the requirements.
The webinar was held on 7 April 2021
Nitrosamine Implementation Oversight Group (NIOG) - meeting with pharmaceutical industry
The Nitrosamine Implementation Oversight Group (NIOG) was set up to oversee the harmonised implementation of the Article 5(3) CHMP opinion on nitrosamines in human medicinal products.
The NIOG will be the main interface between regulators and industry to agree on topics requiring further scientific discussion.
The first meeting of the NIOG with industry stakeholders was held on 31 March 2021. Attendance is by invitation only. The aim is to explain the NIOG's mandate and operating methods, and to future interactions with industry on specific nitrosamine-related topics.
How CEP holders can avoid the rejection of notifications
In order to facilitate the acceptance of proposed changes in a timely manner, CEP holders are reminded that the (EDQM Guideline on requirements for revision/renewal of Certificates of Suitability to the European Pharmacopoeia Monographs (PA/PH/CEP (04) 2, 7R corr) lists different notifications and associated conditions, and that any change not classified as a notification or a major change should be classified as a minor change by default (with the exception of editorial changes for which specific guidance is given in the policy document). If the change cannot be classified by the document and specifically as a notification, a minor revision (by default) should be submitted. Any submission of a notification which includes changes not classifiable as a notification will be rejected and the changes will then need to be resubmitted using the correct classification.
European Pharmacopoeia (Ph. Eur.) reference standards
7 new reference standards and 30 replacement batches were released in February 2021.
Revision of CEPs referring to one of the “sartan” monographs following their rapid implementation
Given the changes in these monographs, it is considered that the currently valid CEPs referring to these monographs are already in conformity with the requirements of the monographs and therefore remain valid (i.e. there is no need to demonstrate conformity to the monographs). CEP holders of these concerned substances will therefore not be contacted by the Certification Department, as is the usual procedure following the introduction of a revised monograph.
However, on the basis of the production statements included in the monographs, CEP holders may decide to revise their control strategy for nitrosamine impurities, in which case a request for a minor revision should be made according to the EDQM Guideline on requirements for revision/renewal of Certificates of Suitability to the European Pharmacopoeia monographs
CEP holders are reminded of the need to elaborate the revised control strategy following the guidance in ICH M7 and to clearly demonstrate, in the request for revision, how the new strategy is in accordance with these requirements.
EMA
Q&A to Stakeholders on the implementation of the Protocol on Ireland/Northern Ireland
Revision 3 of this Q&A has been published. The revision specifically updates the response to question 14.3 in light of the Trade & Cooperation Agreement between the EU and UK (in particular, its Annex on Medicinal Products). In addition, a reminder under question 2.1 is added to consider also the guidance in question 2.2.
Pilot project ‘Market Launch Intentions of Centrally Authorised Products’ Practical Q&As
From 25 March 2021, marketing authorisation applicants for orphan medicines and medicines to treat cancer will be invited to take part in a pilot project by declaring their market launch intentions on a voluntary and confidential basis.
The pilot aims to help regulators understand why delays may occur in the marketing of certain medicines in EU Member States after they receive a marketing authorisation.
EMA will invite marketing authorisation applicants to share this information via an online survey at the time of validation or when they receive the CHMP opinion.
They will be also asked to provide feedback on challenges and limiting factors they face in ensuring the availability of their medicines in the EU.
The pilot project will run for 18 months, until August 2022.
Sartans (article 31 referral) CHMP Assessment.
CHMP has, on March 2 2021 published this report (dated 12 Nov 2020),
Brexit Update
The EMA has formally updated its Brexit Guidance to companies to include that the EU-UK Trade & Cooperation Agreement concluded between the EU and the UK provisionally applies since 1 January 2021, pending the completion of ratification procedures. It notes that the agreement contains a specific annex on medicinal products
('Annex TBT 2'), which covers the recognition of GMP inspection outcomes carried out by EU and UK authorities.
Also, in terms of International collaboration on GMP inspections the EU and UK recognise the outcomes of GMP inspections carried out by the other party in their territories and may also recognise the outcomes of inspections carried out in other third countries.
Classification of changes: Q&A
EMA has updated these pages
EMA Management Board
Highlights of March 2021 meeting have been published and cover:-
Update on COVID-19
Monitoring of EMA’s independence policies11th annual report:
MUMS/limited markets scheme for veterinary medicines
EU IT systems required by the Clinical Trial Regulation
Big Data Steering Group: 2020 report
Revision of EMA’s anti-fraud strategy
Labelling flexibilities for COVID-19 therapeutics
The Q&A on labelling flexibilities for COVID-19 vaccines provides various exemptions to vaccine developers in order to facilitate their rapid deployment at large scale during the pandemic. These flexibilities are exceptional and may not be appropriate or necessary for all other products with a COVID-19 claim. To avoid any misuse, the full application of these flexibilities will not be automatic. On the other hand, it is necessary to adopt a pragmatic and balanced approach for future requests from therapeutics’ developers with similar arguments (as for COVID-19 vaccines), i.e. the need for immediate availability; to this end it is also important to consider and manage in the most efficient way the administrative and logistical impact of such requests to National Competent Authorities (NCAs) and EMA, but also to Health Care Professionals (HCPs) and patients. Therefore, a series of qualification criteria have been set up to filter requests for labelling flexibility for COVID-19 therapeutics with the aim to determine the applicability of already established exemptions for COVID-19 vaccines.
Heads of Medicines agencies(HMA)
Compliance Group Mandate- Joint Audit Programme for EEA GMP Inspectorates
Revision #2 of this document has been published.
The role of the Compliance Group in the Joint Audit Programme (JAP) of EEA GMP Inspectorates is to oversee the audit programme, plan the audits, review the outcome and coordinate follow up of any corrective and preventive actions, in liaison with the concerned audit team. The Compliance Group will report to the GMDP Inspectors Working Group (GMDP IWG) and prepare up on request reports to the HMA.
United States of America
The US Food and Drug Administration (USFDA)
COVID-19 Container Closure System and Component Changes: Glass Vials and Stoppers
Many FDA-regulated human drugs (finished pharmaceuticals and biological products) related to, and products being developed for, the treatment and prevention of COVID-19 use glass vials and stoppers as their primary Container Closure System (CCS). The supply of CCS components for FDA-regulated products generally may become constrained as manufacturers respond to the public health emergency related to COVID-19. As a result, manufacturers of FDA-regulated products may need to update their approved applications to make changes to CCS components to meet current product demand or increase supply resilience. In response to this public health emergency, FDA will consider risk-based approaches to facilitate implementation of chemistry, manufacturing, and controls (CMC) changes to a CCS in an effort to mitigate the disruptive effect of the COVID-19 pandemic. These measures may include, but may not be limited to, recommendations for adjustments to submission content and reduction in reporting categories for CMC changes.
International
Australia
Proposal for clarifying regulatory requirements for residual claims for disinfectants
TGA has received a number of enquiries relating to residual activity claims for disinfectants, including whether statements can be made for disinfectants such as ‘residual activity for up to 30 days’, and what testing methods should be used to provide evidence for these claims. As a result it has put forward a proposal document asking for feedback on the following:-.
A definition of residual activity of a disinfectant product
Testing standards for residual activity claims
Acceptance criteria for residual activity claims
Whether there should be a limit on the period over which residual activity is claimed
Whether residual activity claims should be restricted to general bacteria only and other specific organisms
Whether residual activity claims should be disallowed.
The consultation was only open from March 1 – 26 2021
TGA adopts Access Consortium guidance for fast-tracking authorisations of modified COVID-19 vaccines for variants
TGA has adopted guidance developed by the Access Consortium - a coalition of regulatory authorities from Australia, Canada, Singapore, Switzerland and the United Kingdom. The guidance lays out what information the medicines regulators would need in order to approve any modifications to authorised COVID-19 vaccines, should virus mutations make them less effective at preventing the disease.
According to the guidance, vaccine manufacturers would need to provide robust evidence that the modified vaccine produces an immune response, but time-consuming clinical studies that do not add to the regulatory understanding of a vaccine's safety, quality or efficacy are unlikely to be needed.
[Readers may also be interested to read the TGA’s very pragmatic & risk based update statement regarding the TGA’s position on the Oxford AstraZeneca covid 19 vaccine in response to reports of blood clots in vaccinated individuals outside of Australia MBH].
New standard for serialisation and data matrix codes on medicines
TGA has introduced a new standard TGO106 for serialisation of medicines and use of data matrix codes. TGO 106 commences on 1 January 2023 and provides clarity for adopters of serialisation and data matrix codes on medicines supplied in Australia.
The standard aligns with global standards to provide consistency for sponsors and manufacturers operating in multiple jurisdictions and to ensure global interoperability.
TGO 106 does not mandate the use of data matrix codes or serialisation of medicines but sets out requirements if medicine sponsors choose to do either of these.
Medicines released from supply from 1 January 2023 must comply with the requirements of TGO 106 if they:
Are serialised
nclude a data matrix that encodes the Global Trade Item Number (GTIN)
Products
4th COVID-19 Vaccine authorised in EU
COVID-19 Vaccine Janssen is now authorised across the EU to prevent COVID-19 in people from 18 years of age. This follows the granting of a conditional marketing authorisation by the European Commission on 11 March 2021.
Advice on use of regdanvimab for treating COVID-19
EMA’s human medicines committee (CHMP) has completed its review on the use of the monoclonal antibody regdanvimab (also known as CT-P59) to treat patients with COVID-19. This review was undertaken to provide a harmonised scientific opinion at EU level to support national decision-making on the possible use of the antibody prior to marketing authorisation. The Agency concluded that regdanvimab can be used for the treatment of confirmed COVID-19 in adult patients who do not require supplemental oxygen therapy and who are at high risk of progressing to severe COVID-19.
The medicine is given by infusion (drip) into a vein
Reply to open letter concerning Covid 9 vaccines
EMA has published a reply (with redactions concerning source of the open letter and signature of responder) – which takes the form of a Q&A – to this open letter.
Conferences
TGA Virtual GMP Forum 2021
The Therapeutic Goods Administration (TGA), has announced its third GMP forum, which will be held over three (3) half days on Wednesday, 12 May - Friday, 14 May 2021.
This will be a virtual event due to the ongoing impact of the COVID-19 pandemic. It will be free to attend.
This Forum will be of interest to industry personnel involved in the quality assurance, regulation, risk assessment and good manufacturing practice of medicines and biological products.
[A chance to tap into TGA thoughts on GMP and it’s free – if perhaps a little inconvenient time wise. TGA in my experience is a great regulator so don’t look a gift horse in the mouth. MBH]
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.