Review of Developments in GMP and the Regulation of Medicines September 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 Australian, EU, UK and USA regulatory authorities.
The topics covered in this edition of the “Update” include:
Medicines and Healthcare Regulatory Authority (MHRA)
First bivalent COVID-19 booster vaccine approved by UK medicines regulator
MHRA and CAP take action against illegal ‘hayfever jab’ adverts online
Innovation, Quality & Transparency – a Compliance Team 1 Perspective. (Blog)
Annex 1 Manufacture of Sterile Medicinal Products
EMA’s Emergency Task Force advises on intradermal use of Imvanex / Jynneos against monkeypox
Overview of comments received on ICH guideline Q14 on analytical procedure development
ICH Q2(R2) Validation of analytical procedures – overview of comments
SME office newsletter
Accelerating Clinical Trials in the EU
Nitrosamines – Deadline extension for all CEP holders to complete step 3 Revision to the CEP
European Pharmacopoeia 11th edition
Ph. Eur. survey for the availability of alternative plasticisers to DEHP in containers for aqueous solutions for intravenous infusion in authorised medicinal products
Q14 Analytical Procedure Development
Q2(R2) Validation of Analytical Procedures
Australia
Therapeutic Goods Administration (TGA)
TGA business plan 2022-23
TGA participates in global operation tackling illicit and counterfeit therapeutic goods
Moderna bivalent COVID-19 vaccine for use as a booster dose in adults
FDA works to avoid shortage of sitagliptin following detection of nitrosamine impurity
EMA starts review of conditional marketing authorisation application for Skycovion COVID-19 vaccine
PHSS Annual conference
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
First bivalent COVID-19 booster vaccine approved by UK medicines regulator
An updated version of the COVID-19 vaccine made by Moderna that targets two coronavirus variants (known as a “bivalent” vaccine) has been approved for adult booster doses by the MHRA after it was found to meet the UK regulator’s standards of safety, quality and effectiveness. In each dose of the booster vaccine, ‘Spikevax bivalent Original/Omicron’, half of the vaccine (25 micrograms) targets the original virus strain from 2020 and the other half (25 micrograms) targets Omicron.
MHRA and CAP take action against illegal ‘hayfever jab’ adverts online
A joint enforcement notice warns all organisations offering Kenalog as a hayfever treatment to stop advertising it in any of their social media or website advertising.
Kenalog is a prescription-only medicine (POM), which must not be directly or indirectly advertised to the public. Kenalog is not licensed for the treatment of hayfever in the UK, although it is offered by some beauty and aesthetics clinics, under the personal responsibility of an individual prescriber, and advertised widely on social media. As of 29 August 2022. the Committees of Advertising Practice (CAP)’s compliance team will remove non-compliant ads using targeted software and those who continue to promote it may be referred to the MHRA for further enforcement action.
Kenalog is the brand name for triamcinolone acetonide and is a steroid injection that is licensed as a medicine for a number of conditions, though not for the treatment of hayfever.
Innovation, Quality & Transparency – a Compliance Team 1 Perspective (Blog)
There has been much discussion of late between regulators and industry on how we can ensure that patients and the public get new medicines as quickly as possible - all the way from development to regulatory approval - while still ensuring they are safe, effective and of the required quality.
There has also been a focus on innovation, and where the traditional ‘Quality’ activities and professionals fit within this space. This conversation has been ongoing within the MHRA following recent global conferences focused on the clinical / GCP side of things.
This blog relays some of MHRA’s reflections. Future updates to the Medicines for Human Use (Clinical Trials) Regulations and looks to push risk adaptation into the forefront of planning and managing clinical trials. We are in the early stages of seeing this type of activity, but from the MHRA perspective - quality input built into these risk assessments and transparent release of this detail to regulators is exactly what is required to support innovation. As trial designs become more complex and we see an increasing level of decentralised ways-of-working, issues are bound to occur – we should embrace these setbacks and learn from them for the good of public health. Innovation will never come without some risks; the challenge is to ensure those risks are managed and mitigated to ensure they do not become too large or irreversible where this is possible; but where it is not then we need to be looking for where issues may arise and be ready to act.
Europe
European Commission (EC)
Annex 1 Manufacture of Sterile Medicinal Products
The European Commission has, as of 25 Aug published this critically important Annexe of the EU GMP in Eudralex Vol 4 as part of The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use.
The deadlines for coming into use are:-
25 August 2023 : one year from the date of publication in Eudralex Volume 4
and
25 August 2024 : two years from the date of publication in Eudralex Volume 4 for point 8.123
[It has been a very long time in the drafting and review process. It is a big -58- page- document. All companies and regulators will need to fully verse themselves with its content and ensure that their operations and those of any contact manufacturers of product being supplied into the EU are in compliance by the required dates. MBH]
European Medicines Agency (EMA)
EMA’s Emergency Task Force advises on intradermal use of Imvanex / Jynneos against monkeypox
EMA’s Emergency Task Force (ETF) has reviewed data on the monkeypox vaccine Imvanex used as an intradermal injection (given just below the top layer of the skin).
The vaccine is only authorised for subcutaneous injection (injection under the skin). However, when given intradermally, a smaller dose of the vaccine can be used. Given the currently limited supply of the vaccine, this means that more people can be vaccinated.
The ETF noted that there is no information available on the maximum number of 0.1 ml doses that can be withdrawn from the authorised presentation (0.5 ml suspension) and recommended using low-dead volume syringes to optimise the number of doses that can be extracted.
National authorities may decide as a temporary measure to use Imvanex as an intradermal injection at a lower dose to protect at-risk individuals during the current monkeypox outbreak while supply of the vaccine remains limited.
[Another good example of risk-based decision making by EU regulators MBH]
Overview of comments received on ICH guideline Q14 on analytical procedure development
EMA has recently published this overview. The comments (54 pages) will be sent to the ICH Q14 Expert Working Group (EWG) for consideration in the context of Step 3 of the ICH process.
ICH Q2(R2) Validation of analytical procedures – overview of comments
EMA has also recently published this overview. The comments (72 pages) will be sent to the ICH Q14 Expert Working Group (EWG) for consideration in the context of Step 3 of the ICH process.
SME office newsletter
Issue #56 has been published.
Accelerating Clinical Trials in the EU
The European Commission (EC), the heads of Medicines Agencies (HMA) and the EMA have published the 2022-2026 workplan of the initiative Accelerating Clinical Trials in the EU (ACT EU).
ACT EU launched in January 2022, seeks to transform how Clinical Trials are initiated, designed and run. The aim is to further develop the EU as a focal point for clinical research, promote the development of high-quality, safe and effective medicines, and to better integrate clinical research in the European health system. ACT EU will strengthen the European environment for Clinical Trials, whilst maintaining the high level of protection of trial participants, data robustness and transparency that EU citizens expect.
The workplan lays out deliverables and timelines. In 2023, they include:
Large, multinational Clinical Trials: establishing a support process specifically aimed at academic sponsors in order to make the EU a more attractive region to conduct clinical research
Implementation of the CTR: a particular focus on Clinical Trial Information System and CTR training activities and trouble-shooting any issues encountered by Clinical Trials sponsors
Multi-stakeholder platform: will be established in 2023 to facilitate the evolution of the Clinical Trials environment through regular dialogue between all stakeholders, including patients, healthcare professionals and academia, to find practical solutions to enable and drive change
Modernisation of good clinical practice: ACT EU will support not only the adoption but also the implementation of revised EU guidelines in technology and Clinical Trials design
Facilitation of innovative Clinical Trials methods: the initiative will issue guidance on decentralised Clinical Trials by the end of 2022 and publish a methodology roadmap to identify and prioritise key advances in Clinical Trial methods.
EuropeanDirectorate for the Quality of Medicines and Healthcare (EDQM)
Nitrosamines – Deadline extension for all CEP holders to complete step 3 Revision to the CEP
The European medicines regulatory network has agreed to extend the deadline for submissions related to Step 3: variation to the marketing authorisation until 1 October 2023. This extension is intended to allow companies time to perform a thorough investigation and establish any required risk-mitigating actions. The deadline for Step 2: confirmatory testing remains unchanged: 26 September 2022.
A similar approach is being adopted for Certificates of suitability (CEPs) and therefore the previously announced deadline to submit any required revisions as part of step 3 is now also extended until 1 October 2023. Nevertheless, CEP holders are encouraged to submit their requests for revision as soon as investigations are concluded and therefore in advance of the above deadline.
European Pharmacopoeia 11th edition
EDQM)1 is pleased to announce the release of the print version of the 11th Edition of the European Pharmacopoeia (Ph. Eur.). This latest edition contains numerous revised and new texts, reflecting the latest scientific and technological progress and regulatory developments in the quality control and safety of medicinal products and their constituents. The launch of this new edition will be marked by a three-day international conference from 19-21 September.
With a total of 2 469 monographs, 386 general texts and more than 2 800 descriptions of reagents, the 11th Edition offers new additions such as general chapter 2.7.26. Cell-based assay for potency determination of TNF-alpha antagonists, the landmark first ‘horizontal’ or ‘performance-based’ standard for monoclonal antibodies that was elaborated in response to stakeholder demand, and 5.26. Implementation of pharmacopoeial procedures, a general text providing more detailed practical information on one of the key processes underpinning the correct use and application of Ph. Eur. texts. This Edition also includes the long-awaited final revised version of the harmonised general chapter 2.2.46. Chromatographic separation techniques.
Ph. Eur. survey for the availability of alternative plasticisers to DEHP in containers for aqueous solutions for intravenous infusion in authorised medicinal products
Due to a change in the REACH Regulation ((EC) N° 1907/2006) introduced in November 2021, the experts of the Ph. Eur. have been considering replacing the plasticiser DEHP (bis(2-ethylhexyl)phthalate), described as plastic additive 01 in Ph. Eur. general chapter 3.1.14.
To help with this reflexion, the experts of the Ph. Eur. would like to gather information from manufacturers on the availability on the market and use for medicinal products of containers for aqueous solutions for intravenous infusion that include alternative plasticisers to DEHP in their composition.
United States of America
The US Food and Drug Administration (USFDA)
Q14 Analytical Procedure Development
This draft guideline describes science and risk-based approaches for developing and maintaining analytical procedures suitable for the assessment of the quality of drug substances and drug products. The systematic approach suggested in ICH Q8 Pharmaceutical Development together with principles of ICH Q9 Quality Risk Management can also be applied to the development and lifecycle management of analytical procedures. When developing an analytical procedure, a minimal (also known as traditional) approach or elements of an enhanced approach can be applied. Furthermore, the guideline describes considerations for the development of multivariate analytical procedures and for real time release testing (RTRT). This guideline is intended to complement ICH Q2 Validation of Analytical Procedures.
Q2(R2) Validation of Analytical Procedures
This draft guideline presents a discussion of elements for consideration during the validation of analytical procedures included as part of registration applications submitted within the ICH member regulatory authorities. Q2(R2) provides guidance and recommendations on how to derive and evaluate the various validation tests for each analytical procedure. This guideline serves as a collection of terms, and their definitions. These terms and definitions are meant to bridge the differences that often exist between various compendia and documents of the ICH member regulatory agencies.
International
Australia
Therapeutic Goods Administration (TGA)
TGA business plan 2022-23
The TGA Business Plan sets out its product regulation, stakeholder engagement, regulatory compliance and innovation agenda for 2022-23 and lists the activities it will undertake to achieve these objectives. The Plan supplements the Department of Health and Aged Care's Portfolio Budget Statements and Corporate Plan.
TGA participates in global operation tackling illicit and counterfeit therapeutic goods
Locally, the TGA worked with enforcement agencies to assess a large number of consignments containing therapeutic products detected by the Australian Border Force entering the country.
This work enabled the seizure of over 860,000 units of unlawfully imported products, of which around 7% were counterfeit. The estimated combined value is over AU$2 million. This represents a significant disruption of dangerous medicines from entering our community.
This operation serves as a reminder that therapeutic goods must be entered in the Australian Register of Therapeutic Goods before they can be lawfully imported, advertised and/or supplied in Australia unless an exemption applies. Unregistered medicines and medical devices are often not assessed for quality, safety or efficacy and could be counterfeit, posing a risk to consumers.
Those considering importing unregistered therapeutic goods into Australia should heed the warning that they risk financial penalties, seizure and loss of goods, and other legal action as appropriate.
Moderna bivalent COVID-19 vaccine for use as a booster dose in adults
On 29 August, the TGA provisionally approved Moderna's bivalent COVID-19 vaccine, elasomeran/imelasomeran (SPIKEVAX Bivalent Original/Omicron) for use as a booster dose in adults 18 years and over.
This is the first bivalent COVID-19 vaccine approved for use in Australia.
Products
FDA works to avoid shortage of sitagliptin following detection of nitrosamine impurity
FDA recently became aware of a nitrosamine impurity, Nitroso-STG-19 (known as NTTP), in certain samples of sitagliptin, a medicine used to treat type 2 diabetes mellitus. To avoid a shortage and help ensure patients have access to an adequate supply of the medicine, FDA will not object to the temporary distribution of sitagliptin containing NTTP above the acceptable intake limit of 37 ng per day, and up to 246.7 ng per day. The manufacturer of a marketed product that contains sitagliptin should contact the Center for Drug Evaluation and Research’s (CDER) drug shortages staff when its testing shows levels of NTTP that exceed 37 ng per day. FDA will determine on a case-by-case basis whether those drugs should be released for distribution.
[An example of FDA using Quality Risk Management. – Product not meeting certain requirements but risk of drug shortage considered to be greater that risk to patient if the product is used as is. MBH]
EMA starts review of conditional marketing authorisation application for Skycovion COVID-19 vaccine
Skycovion (by SK Chemicals GmbH) has small particles known as nanoparticles containing parts of the spike protein found on the surface of SARS-CoV-2. When a person is given the vaccine, their immune system is expected to identify the nanoparticles containing parts of the spike protein as foreign and produce natural defences - antibodies and T cells - against them. If, later on, the vaccinated person comes into contact with SARS-CoV-2, the immune system will recognise the spike protein on the virus and be prepared to attack it.
The vaccine also contains an adjuvant, a substance to help strengthen the immune response to the vaccine.
Quinapril
The Australian Therapeutic Goods Administration (TGA) is investigating potential contamination of quinapril medicines with very low levels of the nitrosamine impurity N-nitroso-quinapril and in quinapril medicines with hydrochlorothiazide.
Quinapril, marketed in Australia under multiple trade names, is an angiotensin converting enzyme (ACE) inhibitor prescription medicine used to treat high blood pressure.
The TGA has been advised that very low levels of the N-nitroso-quinapril have been detected in Australian quinapril products including when quinapril has been combined with hydrochlorothiazide. This issue also affects quinapril products and quinapril with hydrochlorothiazide supplied internationally.
Conferences
PHSS Annual conference
This year’s conference will address the key challenges in manufacturing and aseptic processing of Biological and Advanced Medicinal Therapeutic products (ATMPs), considering the impact of Covid, supply chain, knowledge/skills gap and need for more rigorous risk and hazard assessments.
As part of the PHSS 40th anniversary celebrations, a panel discussion will be held to explore the paradigm shift and how things have changed in the industry over the past 40 years. Prepare to be surprised by the challenges that faced the industry then and now!
[No doubt there will also be some discussion relating to the recently release Annex 1 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.