Review of Developments in GMP and the Regulation of Medicines August 2021
Click below to download file.
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, ICH, ICMRA, USA and UK regulatory authorities.
The topics covered in this edition of the “Update” include:
MHRA
MHRA puts delivering for patients at the heart of its Delivery Plan 2021-2023
Combined review to facilitate speedier set up for clinical research trials
Reflection paper on GMP and Marketing Authorisation Holders
Nitrosamine impurities Update (Champix)
Updated Q&A on the review of medicines for which studies have been conducted at Texas-based Cetero Research facility.
Human medicines highlights
SME Newsletter #53
Guideline on quality documentation for medicinal products when used with a medical device
Guideline on manufacture of the veterinary finished dosage form
Draft EU Common Standard for electronic product information for human medicines (ePI)
Revised general chapter 5.21 Chemometric methods
Concept paper on the development of a guideline on determination of the need for an MRL evaluation for biological substances
Suspension of the monograph on Gonadotrophin, equine serum, for veterinary use
New monograph on a single-source anti-TNF-alpha monoclonal antibody released for public consultation in Pharmeuropa
Field Alert Report Submission: Q&A
Assessment of adhesion for topical and transdermal systems submitted in new drug applications
Australia TGA
Nicotine vaping products and vaping devices
Australian regulatory guidelines for sunscreens (ARGS)
International Coalition of Medicines Regulatory Authorities (ICMRA)
Working towards alignment on development and authorisation of second-generation COVID-19 vaccines
ICH
ICH guideline Q13 on continuous manufacturing of drug substances and drug products-Step 2b
COVID-19 vaccine safety updates
EMA starts rolling review of COVID-19 vaccine Vidprevtyn
Increased manufacturing capacity for COVID-19 Vaccine Janssen
Increased manufacturing capacity and supply for Spikevax
Spikevax approved for children aged 12 to 17
EMA finds no evidence linking viral vector in Zynteglo to blood cancer
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
MHRA puts delivering for patients at the heart of its Delivery Plan 2021-2023
A new and ambitious Delivery Plan centred on putting patients first, has been published by the MHRA.
“Putting patients first: A new era for our agency”, ensures the agency keeps a constant focus on delivering meaningful outcomes for patients, protecting public health through excellence in regulation and science and becoming a truly world-leading, enabling regulator.
Priorities include delivering the recommendations set out in the Independent Medicines and Medical Devices Safety Review by ensuring patients are listened to and engaged with more systematically.
Another key challenge will be the strengthening of international regulatory relationships and enhancing partnerships with the wider health system now that the UK has left the EU; the agency will need to work quickly to evolve regulatory frameworks, so they remain fit for purpose in an era of fast-paced, cutting edge scientific developments.
The plan sets out 14 objectives grouped into 6 central themes:
Scientific innovation
Healthcare access
Patient safety
Dynamic organisation
Collaborative partnerships
Financial sustainability
Combined review to facilitate speedier set up for clinical research trials
MHRA is playing a pivotal role helping to ensure that the UK remains one of the best places in the world to deliver safe, cutting-edge research. Part of this work is the combined review, which will provide a more streamlined and efficient service for research applicants. From January 2022, all new Clinical Trials of Investigational Medicinal Products (CTIMPs) in the UK will be subject to a combined review from the MHRA and the UK Research Ethics Services, in collaboration with the Health Research Authority (HRA), facilitating rapid start up and benefitting patients sooner.
Applicants need only make a single application for both Clinical Trial Authorisation and Research Ethics Committee (REC) opinion and approval is delivered together. A number of sponsors have already used this new process with some reporting a 30 per cent improvement in overall trial set up times.
This work is part of the transformation of the Integrated Research Application System (IRAS) being led by the Health Research Authority in collaboration with MHRA, the devolved administrations, the National Institute for Health Research (NIHR) and other research partners. It will create a world-class hub for health and social care research in the UK, with smooth and intuitive access to research approval, study management, best practice guidance and lay-friendly information about the results of research.
Europe
EMA
Reflection paper on GMP and Marketing Authorisation Holders
This Reflection Paper is focussed on the GMP-related responsibilities that apply to Marketing Authorisation Holder (MAH) companies. While it is recognised that many MAH companies are not directly engaged in the manufacture of medicinal products themselves, the current European Commission (EC) Guide to GMP (hereafter referred to as the ‘GMP Guide’) refers, in several places, to MAHs and their responsibilities in relation to GMP. In general, these responsibilities range from responsibilities that relate to outsourcing and technical agreements, to ones that require the MAH to perform certain specific tasks (e.g. evaluating the results of product quality reviews, agreeing irradiation cycles with manufacturers, etc.). These responsibilities are spread over the various chapters and annexes of the GMP Guide, and are quite numerous. This Reflection Paper seeks to provide clarity as to what the various responsibilities are and what they mean for MAHs at a practical level. In addition to the MAH responsibilities in the GMP Guide, this paper also addresses the various legislative provisions (i.e. in European Directives, Regulations and in other guidelines) which relate to GMP and which concern MAHs. It is acknowledged that many MAHs are part of large and complex global organisations which operate shared Pharmaceutical Quality Systems. While tasks pertaining to the MAH responsibilities outlined in this paper may be delegated to other groups or entities within the global organisation, the actual responsibilities of the MAH may not be delegated. It is recognised that, while MAHs have a significant role in facilitating GMP and MA compliance, their responsibilities in this area can, in some cases, be difficult to comprehend when reading the GMP Guide or the applicable legislation. Notwithstanding this, such responsibilities are there and may be inferred. This Reflection Paper seeks to provide clarity on these.
[A 29 page document which requires careful reading and comprehensive understanding. QPs would be well advised to ensure that MAH holders are briefed, fully aware of and in compliance with their GMP requirements. MBH]
Nitrosamine impurities Update (Champix)
EMA and the national competent authorities are investigating the presence of a nitrosamine impurity, N nitroso-varenicline, in Champix (varenicline), a smoking cessation medicine. As a precaution while investigations are ongoing, the MA holder has paused distribution and is recalling several batches of the medicine containing the impurity at levels above the company’s acceptable limit.
Updated Q&A on the review of medicines for which studies have been conducted at Texas-based Cetero Research facility.
EMA has recently released this updated Q&A
Human Medicines highlights
This newsletter is addressed primarily to organisations representing patients, consumers and healthcare professionals. It provides a summary of key information relating to medicines for human use published during the previous month by the European Medicines Agency.
SME Newsletter #53
EMA has published this issue of the Quarterly newsletter for micro, small and medium-sized enterprises (SMEs) d. It provides key facts and figures of companies registered as SMEs with EMA and services provided.
Guideline on quality documentation for medicinal products when used with a medical device
This guideline describes the information that should be presented in the Quality part of a marketing authorisation dossier for a medicinal product when it is used with a medical device, or device part, and submitted in accordance with Directive 2001/83/EC and/or Regulation (EC) 726/2004. This guideline focuses on product-specific quality aspects of a medical device, or device part, that may have an impact on the quality, safety and/or efficacy (and hence overall benefit/risk determination) of a medicinal product.
Increasingly, medicinal products are developed for use with a medical device, or device part; this ranges from a simple prefilled syringe to more advanced autoinjectors to medical devices used as sensors embedded in tablets. Given the wide range of medical devices, or device parts, that may be used with a medicinal product and continuous technological developments, the information provided in submissions has been found to be inconsistent and often incomplete. It is therefore appropriate within the scope of this guideline to provide guidance to quality assessors and the applicant/MAH of a medicinal product on the type of information that should be provided in a submission. This guideline considers three different, yet common, configurations of medicinal products used with medical devices, and describes the information that should be submitted to a Competent Authority (CA) for each of these configurations.
Guideline on manufacture of the veterinary finished dosage form
This guideline replaces the veterinary note for guidance on the manufacture of the finished dosage form (EMEA/CVMP/126/95). The note for guidance has been updated to reflect the requirements as laid down in the current legislation (Regulation (EU) 2019/6 and its Annex II amended by Commission Delegated Regulation (EU) 2021/805 (ref. 1, ref. 2 respectively)). It also addresses current manufacturing practices in terms of complex supply chains and worldwide manufacture. In addition, applicants for EU marketing authorisations (MAs) of veterinary medicinal products may voluntarily choose to follow enhanced concepts in the manufacturing process of the final dosage forms as outlined in the ICH guidelines Q8, Q9 and Q10 (formally applicable to medicinal products for human use). The revised guideline takes this option into account although it is highlighted that the traditional approach is still acceptable. This guideline does not introduce new requirements for authorised medicinal products for veterinary use. However as stated in Article 58 of Regulation (EU) 2019/6, after a marketing authorisation has been approved, the authorisation holder should, in respect of the methods of manufacture and control, take account of scientific and technical progress and introduce any changes that may be required to enable the medicinal product to be manufactured and controlled by means of generally accepted scientific methods. The objective of this guideline on the manufacture of the finished dosage form is to provide clarification on the type and level of information that should be included in the Part 2 (CTD Module 3) of the marketing authorisation application (MAA) dossier with respect to the manufacturing process description. This description should include information about critical steps and intermediates and provide a link between the pharmaceutical development, the proposed control strategy and process validation. The guideline also addresses aspects related to outsourcing and new manufacturing practices such as complex manufacturing chains or issues with prolonged holding times and transportation conditions. Detailed information about requirements of any sterilisation process is provided in a separate guideline.
The guideline is effective from 28 Jan 2022
Draft EU Common Standard for electronic product information for human medicines (ePI)
ePI is authorised, statutory product information for EU medicines (the summary of product characteristics [SmPC, intended for healthcare professionals], labelling [outer and inner packaging information] and package leaflet [PL, for patients / consumers]) in a semi-structured format created using the EU Common Standard. ePI is adapted for electronic handling and allows dissemination via the web, e-platforms and print.
EDQM
Revised general chapter 5.21 Chemometric methods
The revised general chapter Chemometric methods applied to analytical data (5.21) has been published in this quarter’s issue of Pharmeuropa (33.3), the European Pharmacopoeia (Ph. Eur.) online forum, for comment.
This general chapter, published for information, is an introduction to the use of chemometrics and data science techniques. The objective is to provide indications on good practice and requirements for the processing of analytical data.
This general chapter was first published in 2015 (Supplement 8.7) and continuous evolution in data science techniques since then has prompted its revision. Indeed, data analysis is an extremely dynamic field which has led to numerous changes in the way algorithms are referenced and applied.
In view of the latest developments, numerous sections of the chapter have been completely rewritten or updated and new sections/sub-sections have been introduced.
The deadline for comments is 30 September 2021.
Concept paper on the development of a guideline on determination of the need for an MRL evaluation for biological substances
This (veterinary) concept paper addresses the need for a guideline on determination of the need for a Minimum Residual Level (MRL) evaluation for biological substances, when it is intended that those substances are included in products for use in food-producing species. According to Annex I Section I.7 of Commission Regulation (EU) 2018/782, the European Medicines Agency (‘Agency’) is requested to publish guidance in order to determine whether there is the need for an MRL evaluation for these substances. Biological substances for which it is concluded that an MRL evaluation is not required shall be published by the Agency in a list of such substances. As immunologicals are exempted from the need for MRL assessment according to Article 1 point 2 (a) of Regulation (EC) No 470/2009, this guidance concerns ‘biologicals, other than immunologicals’ only. The standard assessment approaches currently used for MRL and consumer safety assessment do not always adequately match assessment requirements for biological substances and may need to be adapted. This concept paper describes and discusses the basis for new guidance in this area.
Comments should be submitted by Sept 30 2021.
Suspension of the monograph on Gonadotrophin, equine serum, for veterinary use
The estimation of the potency of preparations covered by the Gonadotrophin, equine serum, for veterinary use (0719) monograph relies on comparative analyses performed with the WHO International Standard (IS) for equine serum gonadotrophin.
The stocks of the IS for equine serum gonadotrophin are exhausted and the material is no longer available from the producer (NIBSC). Consequently, the Gonadotrophin, equine serum, for veterinary use (0719) monograph can no longer be applied.
Therefore, , the European Pharmacopoeia Commission decided to suspend the Gonadotrophin, equine serum, for veterinary use (0719) monograph. This means that as of Supplement 10.8, the monograph in question will no longer be part of the Ph. Eur. but will nonetheless remain on the Ph. Eur. work programme until a final decision can be made concerning its fate.
New monograph on a single-source anti-TNF-alpha monoclonal antibody released for public consultation in Pharmeuropa
A new draft monograph, Golimumab concentrated solution (3103), has been published in this quarter’s issue of Pharmeuropa (33.3), the European Pharmacopoeia (Ph. Eur.) online forum for comment. All interested parties are invited to review the draft monograph and submit their comments on its technical content. In addition, the Ph. Eur. sees this new monograph as an opportunity to reiterate the approach taken for the development of individual monographs for monoclonal antibodies. The deadline for comments is 30 September 2021.
United States of America
The US Food and Drug Administration (USFDA)
Field Alert Report Submission: Q&A
This guidance provides FDA’s current thinking regarding the requirements for submission of field alert reports (FARs) by applicants of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) and outlines FDA’s recommendations for FAR submissions to help improve their consistency and relevancy. The guidance also addresses certain frequently asked questions.
The FAR regulations found in 21 CFR 314.81(b)(1) establish an early warning system to help FDA fulfil its responsibility to protect patient health. Under these regulations, NDA and ANDA applicants must submit certain information to FDA about distributed drug products. Specifically, the regulations state that an NDA or ANDA applicant must submit a FAR to FDA within 3 working days of receiving certain kinds of information for distributed drug product(s):
[See Q&A 2 - In my experience of auditing / consulting, I have on occasion found that compliance particularly within the 3 day timescales can prove problematical where the manufacturing company and the NDA holder are different and based in different locations/ countries (whether same parent company / contract manufacturer). The NDA holder usually has very good oversight / control over the manufacturer making a timely submission but the manufacturer can sometimes find itself not so well placed to ensure that the NDA holder subsequently submits within the required timelines to FDA. This can prove problematical in subsequent FDA inspections of the manufacturer. It can also cause friction between the manufacturer and the NDA holder .MBH]
Assessment of adhesion for topical and transdermal systems submitted in new drug applications
This draft guidance provides recommendations for clinical trials designed to assess the adhesion performance of transdermal and topical delivery systems (collectively ref erred to as TDS). Adhesion performance is defined in this guidance as whether the TDS fully adheres to the subject in the applied location for the duration of use of the TDS. Adhesion performance can affect both safety and effectiveness of TDS products because adhesion failures can result in reduced effectiveness caused by suboptimal dosing or potentially increased exposure when a new TDS needs to be applied sooner than the scheduled dose. Additionally, partial or full detachment of a TDS from a patient’s skin may result in unintentional exposure of the active pharmaceutical ingredient to a partner, child, or other individual, potentially exposing them to the drug’s toxicity. Adhesion performance may also inform the Dosage and Administration section of labeling.
The recommendations in this guidance relate to studies to be submitted in support of a new drug application (NDA) or supplemental new drug application (sNDA) for human prescription and nonprescription drug products under Section 505 of the Federal Food, Drug, and Cosmetic Act 31 (21 U.S.C. § 355) and 21 CFR Part 314. Because biological products are often more complex and of a higher molecular weight, it is likely that these products would not be absorbed across the skin, requiring a different approach for administration, so they are outside the scope of this guidance.
International
Australia TGA
Nicotine vaping products and vaping devices
TGA has issued v1.2 of Guidance for the Therapeutic Goods (Standard for Nicotine Vaping Products) (TGO 110) Order 2021 and related matters
Nicotine vaping products are finished products that contain nicotine (in base and/or salt form(s)) in solution that are intended to be vaporised and inhaled using a vaping device (e.g. an e- cigarette or other electronic nicotine delivery system). These products include nicotine vape liquids, e-liquids and e-juices and nicotine in disposable e-cigarettes. ‘Heat-not-burn’ and other tobacco products are not nicotine vaping products and are not covered by this guidance. There are currently no nicotine vaping products registered in the Australian Register of Therapeutic Goods (ARTG). Consumers can legally access ‘unapproved’ nicotine vaping products (i.e. products that are not registered in the ARTG) with a valid prescription via established access pathways; namely, the Authorised Prescriber Scheme (APS), the Special Access Scheme – Category B (SAS), the Personal Importation Scheme or as part of a clinical trial. Domestic access may be subject to state and territory requirements. The TGA does not assess the safety, quality and efficacy of ‘unapproved’ nicotine vaping products nor of Export Only products listed on the ARTG (together, unregistered nicotine vaping products). There are many nicotine replacement therapies (e.g. nicotine patches, gum, lozenges, mouth sprays and inhalators) in the ARTG that have been assessed by the TGA for safety, quality and efficacy. The purpose of this guidance is to help health practitioners, consumers, importers and other sponsors, wholesalers and manufacturers to understand the minimum safety and quality requirements for unregistered nicotine vaping products and TGA’s role in regulating vaping devices.
Australian regulatory guidelines for sunscreens (ARGS)
The ARGS; describe the regulatory requirements and standards for sunscreens (and their ingredients) regulated as therapeutic goods in Australia by the TGA under the Therapeutic Goods Act 1989 as at the date of publication.
For the purpose of these Guidelines, sunscreens that are regulated as therapeutic goods under the Act are referred to as 'therapeutic sunscreens'. Unless excluded, therapeutic sunscreens include:
Primary sunscreens: Products that are used primarily for protection from UV radiation.
Some secondary sunscreens: Products with a primary purpose other than sun protection, but which also contain sun screening agents.
Many secondary sunscreen products, such as cosmetic sunscreens, are not considered to be therapeutic goods and are 'excluded' from therapeutic goods legislation.
ICMRA
Working towards alignment on development and authorisation of second-generation COVID-19 vaccines
Regulatory convergence is critical for expediting and streamlining global development and authorisation of new or modified COVID-19 vaccines to address emerging coronavirus variants.
The virtual workshop took place on 24 June 2021. It built on the experience and knowledge gained from the first workshop on COVID-19 vaccine development and virus variants held in February 2021, which underlined the need for robust data that would help to swiftly approve updated versions of available vaccines against the emerging strains. The second workshop brought together delegates from more than 20 countries, representing 30 medicines regulatory authorities globally and the World Health Organization to exchange information about the global efforts towards developing modified and new vaccines against current and emerging variants.
The meeting was co-chaired by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) and the UK’s Medicines and Healthcare products Regulatory Agency (MHRA).
ICH guideline Q13 on continuous manufacturing of drug substances and drug products-Step 2b
This draft guideline describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing (CM). Building on existing ICH Quality guidelines, this guideline provides clarification on CM concepts, describes scientific approaches, and presents regulatory considerations specific to CM of drug substances and drug products. CM involves the continuous feeding of input materials into, the transformation of in-process materials within, and the concomitant removal of output materials from a manufacturing process. While this description may apply to an individual unit operation (e.g., tableting, perfusion bioreactors), this guideline focuses on the integrated aspects of a CM system in which two, or more unit operations are directly connected. In this context, any changes made in a unit operation of CM may have a direct and often immediate impact on downstream and upstream (e.g., via a feedback control) unit operations.
Fundamental aspects of CM that are generally not specific to technology, dosage form, or molecule type are described within the main body of this guideline. Annexes are provided to augment the main guideline by providing illustrative examples and considerations specific to certain modalities (e.g., chemical entities, therapeutic proteins), technologies, and production methods (e.g., integration of drug substance and drug product manufacturing). The examples and approaches described in these annexes are not exhaustive, and alternative approaches can be used.
The draft guideline is open for public comment until 20 Dec 2021.
Products
COVID-19 vaccine safety updates
For each of the following vaccines The product information will be updated, and each of the vaccines remain effective in preventing COVID-19.
-SPIKEVAXModerna Biotech Spain, S.L
Inflammation of the heart muscle (myocarditis) or membrane (pericarditis) may occur in a small number of people after vaccination with Spikevax.
-COVID-19 VACCINE JANSSEN Janssen-Cilag International NV
People who have previously had capillary leak syndrome must not receive COVID-19 Vaccine Janssen. Capillary leak syndrome may also occur as a side effect of COVID-19 Vaccine Janssen.
Additionally Guillain-Barré syndrome (GBS) will be listed as a very rare side effect of COVID-19 Vaccine a warning will be included in the product information to raise awareness among healthcare professionals and people taking the vaccine.
-VAXZEVRIA AstraZeneca AB
Vaccinated persons need to seek immediate medical attention if they develop weakness and paralysis in the extremities, possibly progressing to the chest and face, after vaccination with Vaxzevria, as these could be signs of Guillain-Barré syndrome.
-COMIRNATY BioNTech Manufacturing GmbH
Inflammation of the heart muscle (myocarditis) or membrane (pericarditis) may occur in a small number of people after vaccination with Comirnaty.
EMA starts rolling review of COVID-19 vaccine Vidprevtyn
EMA’s human medicines committee (CHMP) has started a rolling review of Vidprevtyn, a COVID-19 vaccine developed by Sanofi Pasteur. Vidprevtyn is expected to prepare the body to defend itself against infection with SARS-CoV-2. It is a protein-based vaccine that contains a laboratory-grown version of the spike protein found on the surface of SARS-CoV-2. It also contains an ‘adjuvant, a substance to help strengthen the immune responses to the vaccine.
Increased manufacturing capacity for COVID-19 Vaccine Janssen
EMA’s CHMP has approved a scale-up of the active substance manufacturing process at Janssen Biologics B.V. The plant, which is located in Leiden, the Netherlands, produces all active substance for the manufacture of the EU supply of COVID-19 Vaccine Janssen, the COVID-19 vaccine developed by Janssen-Cilag International NV.
The approved modifications to the Janssen Biologics B.V. facility include a newly constructed building, new equipment and the introduction of additional process optimizations.
This recommendation does not require a European Commission and the new building can become operational immediately.
Increased manufacturing capacity and supply for Spikevax
EMA's CHMP has approved a scale-up of the active substance production process at Moderna's COVID-19 vaccine manufacturing sites in the United States (US).
This recommendation is expected to have significant impact on the supply of Spikevax, the COVID-19 vaccine developed by Moderna, in the European Union. It is estimated that in the third quarter of 2021, the US supply chain will provide 40 million doses of vaccine for the European market.
EMA's decision reaffirms that the two recently approved US facilities, ModernaTX, Inc. in Norwood, Massachusetts and Lonza Biologics, Inc. in Portsmouth, New Hampshire, are capable of consistently manufacturing high-quality active substance and will enable Moderna to increase production capacity at these sites.
Spikevax approved for children aged 12 to 17
CHMP has recommended granting an extension of indication for the COVID-19 vaccine Spikevax to include use in children aged 12 to 17 years. The vaccine is already authorised for use in people aged 18 and above.
The use of the Spikevax vaccine in children from 12 to 17 years of age will be the same as in people aged 18 and above.
EMA finds no evidence linking viral vector in Zynteglo to blood cancer
EMA’s safety committee (PRAC) has concluded that there is no evidence Zynteglo causes a blood cancer known as acute myeloid leukaemia (AML).
Zynteglo, a gene therapy for the blood disorder beta thalassaemia, uses a viral vector (or modified virus) to deliver a working gene into the patient’s blood cells.
The PRAC reviewed two cases of AML in patients treated with an investigational medicine, bb1111, in a clinical trial for sickle cell disease. Although there have been no reports of AML with Zynteglo, both medicines use the same viral vector and there was a concern that the vector may be implicated in the development of the cancer (insertional oncogenesis).
The review found that the viral vector was unlikely to be the cause. In one of the patients, the viral vector was not present in the cancer cells, and in the other patient it was present at a site (VAMP4) that does not appear to be involved in cancer development.
After examining all the evidence, the PRAC concluded that more plausible explanations for the AML cases included the conditioning treatment the patients received to clear out bone marrow cells and the higher risk of blood cancer in people with sickle cell 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 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.
Comments