Review of Developments in GMP and the Regulation of Medicines February 2023
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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, US, PIC/S ICMRA and Australian regulatory authorities.
The topics covered in this edition of the “Update” include:
Medicines and Healthcare Regulatory Authority (MHRA)
First-of-its-kind framework to make it easier to manufacture innovative medicines at the point of care
Increased UK assessment capacity for in-vitro diagnostic devices
Status update: Implementation of the Clinical Trials Regulation
CTIS newsflash – 6 January 2023
EMA update on shortages of antibiotics in the EU
ICH guideline Q13 on continuous manufacturing of drug substances and drug products - Scientific guideline
Post-authorisation procedural advice for users of the centralised procedure
List of centrally authorised products requiring a notification of a change for update of annexes
Regulatory expectations and GMP certificates during COVID-19 pandemic (updated)
GMP & GDP Q&A
ICH guideline M10 on bioanalytical method validation and study sample analysis – Q&A.
Big Data Steering Group (BDSG): 2022 report
SME Office newsletter
Human Medicines Highlights – Issue 165
New WHO certificate template – compilation of changes
Information note on the format and validity features of electronic certificates for medicines issued by the EMA
European Paediatric Formulary: Simple syrup (preservative-free) monograph published
Implementation of the European Pharmacopoeia Supplement 11.2 – Notification for CEP holders
CEP holders invited to comment on draft monographs published in Pharmeuropa 35.1
Outcome of the 174th session of the European Pharmacopoeia Commission
Ph. Eur. Commission adopts revised general monographs 2034 and 2619 after inclusion of new paragraph on control of N-nitrosamines
Management of EDQM CEP documents: EDQM introduces a consultation phase
Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection
Content and Format of the Dosage and Administration Section of Labeling for Human Prescription Drug and Biological Products
Mpox: Development of Drugs and Biological Products
M13A Bioequivalence for Immediate-Release Solid Oral Dosage Forms
Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products
Australia
Therapeutic Goods Administration(TGA)
Antibiotics shortage in Australia
Nitrosamine Impurities in medicines
UK MHRA Good Manufacturing and Distribution Practice (GMDP)
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
First-of-its-kind framework to make it easier to manufacture innovative medicines at the point of care
The UK will be the first country to introduce a tailored framework for the regulation of innovative products manufactured at the point where a patient receives care. This will mean that new medicines with very short shelf lives and highly personalised medicines can more easily be made in or near a hospital setting or ambulance and can get to the patients who need them much more quickly.
In order to implement this framework, new legislation is being developed to amend the UK’s Human Medicines and Clinical Trials legislation and will be brought to Parliament later this year. The MHRA will also begin to develop guidance, in conjunction with stakeholders, to accompany the new framework, which will be issued in due course.
[A highly innovative move from MHRA – a new frontier for modern medicines manufacture bringing about significant patient benefit and almost certainly a new set of GMP challenges for both industry/practitioner and regulator, involving an emergent pharmaceutical manufacturing and supply sector beyond the current ‘standard model’ of factory—based manufacture.
Local supply of the finished product, will force manufacture to be in very close proximity to the patient and also mean that they will need to be manufactured at a large number of sites, i.e. scale out rather than scale up.
Additionally there is likely be no time at the end of manufacture for Quality Control testing and Qualified Person certification prior to supply. – watch this space MBH]
Increased UK assessment capacity for in-vitro diagnostic devices
MHRA has confirmed that UL International UK Ltd is now designated to assess most in-vitro diagnostic (IVD) devices, increasing the UK’s capacity to process conformity assessments and ensure safe and effective IVDs reach the UK public.
UL International UK Limited have had their current designation as an approved body extended to include almost all Part IV In-vitro Diagnostics Medical Devices, adding to the capacity already provided for these types of products by BSI Assurance UK Ltd and SGS United Kingdom Ltd.
Europe
European Medicines Agency (EMA)
Status update: Implementation of the Clinical Trials Regulation
On 31 January 2023, the clinical trial information system (CTIS) became the single-entry point for sponsors and regulators of clinical trials for the submission and assessment of clinical trial data which includes a public searchable database for healthcare professionals, patients, and the public.
On 31 January 2023, the use of CTIS became mandatory. CTIS is the information system supporting the implementation of the Clinical Trials Regulation, which changes the way that applications for authorisation of clinical trials in the EU are submitted, how the clinical trials are authorised and supervised.
The provisions of the Clinical Trial Regulation bring extensive changes in practices by all stakeholders and require effective change management.
Some users have experienced problems with the system. EMA is working closely with Member States, the European Commission, and stakeholders to improve the CTIS user experience for core CTIS processes by the time the use of the system becomes mandatory for all new applications. The Agency has invested additional resources to achieve this goal.
Training material is available to help sponsors submit information on their clinical trials data, including their applications for authorisation of a clinical trial; the material is updated regularly to reflect information needs. EMA is also running regular training webinars with sponsors to explain the system and listen to and address concerns.
CTIS newsflash – 6 January 2023
With the aim to enhance communication with the CTIS user community, as of December 2022 EMA has reinstated the regular CTIS newsflash, providing key updates on CTIS and links to useful reference materials. A status update on the implementation of the Clinical Trials Regulation is also available on the CTIS public portal.
The next CTIS newsflash will be circulated on 13 January 2023.
Key Updates
A CTIS “Hotfix” went live on 22 December 2022 and on 5 January 2023 with the following improvements:-
Documents will no longer be inadvertently removed from the original clinical trial application when deleted in a copied clinical trial application.
Sponsor will be able to submit a response to a RFI with a change application without documents being lost in part I.
EMA update on shortages of antibiotics in the EU
EMA's Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG) met to discuss the progress made and to agree on the next steps in the coordinated response to the ongoing shortages of antibiotic medicines containing amoxicillin (alone and in combination with clavulanic acid) in the EU.
The MSSG is made up of representatives from EMA, the European Commission and the Heads of Medicines Agencies (HMA).
A recent surge in respiratory infections has driven an increase in demand for amoxicillin which combined with other issues including manufacturing delays and production capacity challenges led to shortages affecting the majority of Member States. The MSSG and its SPOC working party have been closely monitoring the situation since November 2022 and have been engaging with key players in the supply chain of amoxicillin to take forward possible mitigating measures. The MSSG noted some progress since the start of the monitoring and mitigation efforts:
a positive trend has been observed in a number of Member States
EU regulators have met with the main parties involved in the supply chain of amoxicillin to provide regulatory support so as to increase production capacity and reviewed the possibility to increase supply to fulfil the Member States’ immediate needs.
Many national competent authorities have managed to mitigate certain shortages.
EU Member States expect the peak in infections to begin to subside soon, which is expected to lower the currently increased demand for antibiotics.
ICH guideline Q13 on continuous manufacturing of drug substances and drug products - Scientific guideline
EMA has published this guideline which 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.
This guideline applies to CM of drug substances and drug products for chemical entities and therapeutic proteins. The principles described in this guideline may also apply to other biological/biotechnological entities.
It is applicable to CM for new products (e.g., new drugs, generic drugs, biosimilars) and the conversion of batch manufacturing to CM for existing products.
Post-authorisation procedural advice for users of the centralised procedure
As of 21 Dec 2022 EMA has published Rev 101 of this document. Revised sections are:- 3.7/3.8/4.5/15.8/23.4/23.9/23.11/24,7
List of centrally authorised products requiring a notification of a change for update of annexes
Parallel distributors are only required to inform the EMA of changes to the labelling or leaflet related to any update of the annexes of marketing authorisation once a year in their annual update application, except in cases related to safety or quality issues. The following table lists the centrally authorised products for which the EMA requires notifications of safety update before implementation.
Regulatory expectations and GMP certificates during COVID-19 pandemic (updated)
In this context, for sites in and outside the European Economic Area (EEA), GMP certificates and time-limited manufacturing and import authorisations are automatically extended until the end of 2023.
GMP & GDP Q&A
Two new Q&A have been added to the GDP section as of Jan 2023. Both concern Broker / Broker activities.
See
ICH guideline M10 on bioanalytical method validation and study sample analysis – Q&A.
In response to questions posted to ICH M10 comment period, a number of Q&As have been devised to provide clarity around some of the bioanalytical issues covered in the Guideline.
This Q&A document is intended to provide additional clarification and to promote convergence and improve harmonization of the bioanalytical method validation and study sample analysis.
The scope and organization of this Q&A document follow that of ICH M10.
Big Data Steering Group (BDSG): 2022 report
This report provides a summary of the key activities and achievements of the BDSG in 2022.
In 2022 the BDSG met 10 times virtually. Step by step, progress is made in line with the agreed workplan on enabling the use and establishing the value of the Big Data in the development, authorisation and supervision of medicines in Europe.
Informed by feedback from experts and stakeholders, the third workplan covering 2023 to 2025 was adopted by the BDSG in 2022.
SME Office newsletter
Issue 57 of this newsletter for small and medium sized entities was published in January 2022
Human Medicines Highlights – Issue 165
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.
Information is selected based on recommendations from consulted patients, consumers and healthcare professionals, and does not necessarily cover all relevant information published by the Agency
New WHO certificate template – compilation of changes
From 16th January 2023 EMA is implementing the new WHO certificate template under the World Health Organization certification scheme for electronic certificates of medicinal products.
Please note that any request received on or after 16th January 2023 will be implemented in accordance with the new template and issuing certificates based on the old template for the requests received as of the mentioned date will no longer be possible
Information note on the format and validity features of electronic certificates for medicines issued by the EMA
The aim of this “Questions and Answers” document is to provide guidance on the format of the electronic certificates issued by EMA, the safety features supporting their authenticity and integrity as well as the Agency ́s measures to support the regulatory authorities of importing countries for confirming their validity, in case of any doubt.
European Directorate for the Quality of Medicines and Healthcare (EDQM)
European Paediatric Formulary: Simple syrup (preservative-free) monograph published
EDQM has added a new monograph, Simple syrup (preservative-free), to the European Paediatric Formulary. The monograph was published in Issue 4 of Pharmeuropa PaedForm in January 2022, approved by the European Pharmacopoeia Commission at its 174th session in November 2022 and recently adopted by the European Committee on Pharmaceuticals and Pharmaceutical Care (CD-P-PH). Widely used in Europe, simple syrup is also used as the vehicle for some of the first PaedForm monographs.
A review of simple syrups used in Europe indicated that the concentrations prepared ranged from 63% to 66%. The 64% concentration was selected here because it was most commonly used.
Owing to national variations in conditions for the control, storage and labelling of simple syrups, the statement “National requirements may differ” has exceptionally been added to the “Storage” section of the monograph.
Implementation of the European Pharmacopoeia Supplement 11.2 – Notification for CEP holders
Supplement 11.2 of the European Pharmacopoeia (Ph. Eur.) is now available. Holders of Certificates of suitability to the monographs of the Ph. Eur. (CEPs) are invited to update their applications according to the revised monographs that will be implemented on 1 July 2023
CEP holders invited to comment on draft monographs published in Pharmeuropa 35.1
Holders of Certificates of suitability to the monographs of the European Pharmacopoeia (CEPs) are requested to consult the list of substances for which draft revised monographs of the Ph. Eur. have been published in Pharmeuropa 35.1.
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 2023.
Outcome of the 174th session of the European Pharmacopoeia Commission
The European Pharmacopoeia Commission (EPC) held its 174th session on 22 and 23 November 2022. The 85 texts adopted by the Commission at this session will be published in European Pharmacopoeia (Ph. Eur.) Supplement 11.3 (July 2023), with an implementation date of 1 January 2024.
These 85 texts included 13 new monographs and 1 new general chapter
Ph. Eur. Commission adopts revised general monographs 2034 and 2619 after inclusion of new paragraph on control of N-nitrosamines
The European Pharmacopoeia (Ph. Eur.) Commission adopted the revised general monographs Substances for pharmaceutical use (2034) and Pharmaceutical preparations (2619), which now include a paragraph explaining the Ph. Eur. approach to N-nitrosamine impurities. This approach was defined based on the comments received during the last round of public consultation in Pharmeuropa together with recent feedback from Heads of Medicines Agency and the EMA groups and from the national competent authorities of non-EU Ph. Eur. member states.
The following paragraph has been added to 2034 under “Production”:
“N-Nitrosamines. As many N-nitrosamines are classified as probable human carcinogens, manufacturers of active substances for human use are expected to evaluate the potential risk of N-nitrosamine formation and contamination occurring throughout their manufacturing process and during storage. If the risk is confirmed, manufacturers should mitigate as much as possible the presence of N-nitrosamines – for example by modifying the manufacturing process – and a control strategy should be implemented to detect and control these impurities. General chapter 2.5.42 N-Nitrosamines in active substances is available to assist manufacturers.”
A similar paragraph has been added to the same section in 2619.
Management of EDQM CEP documents: EDQM introduces a consultation phase
The EDQM has updated its policy for the elaboration of documents related to the Certification of Suitability (CEP) procedure. A major change compared to the current practice is the introduction of a consultation phase (public or targeted) with stakeholders for certain documents in order to ensure transparency of the process, to inform them of upcoming proposed/potential changes and to give them the opportunity to provide input or comments.
United States of America
The US Food and Drug Administration (USFDA)
Circumstances that constitute delaying, denying, limiting, or refusing a drug or device inspection
The FDA Reauthorization Act of 2017 (FDARA) amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) so that, as is the case with a drug, a device is deemed to be adulterated if the owner, operator, or agent of the factory, warehouse, or establishment at which the device is manufactured, processed, packed, or held delays, denies, or limits an FDA inspection. This draft guidance describes, for both drugs and now devices, the types of behaviors (actions, inactions, and circumstances) that the FDA considers to constitute delaying, denying, or limiting inspection, or refusing to permit entry or inspection. Once finalized, this draft guidance is intended to supersede the October 2014 FDA final guidance for industry
FDA is particularly interested in comments on the inclusion of devices to the October 2014 guidance.
Content and format of the dosage and administration section of labeling for human prescription drug and biological products
This guidance is intended to assist applicants in developing the dosage and administration section of labeling. The purpose of this guidance is to assist applicants in ensuring that the dosage and administration section contains the dosage- and administration-related information needed for safe and effective use of a drug and that the information is clear, concise, and presented in a manner that is pertinent and understandable to health care practitioners. FDA is withdrawing the previous guidance for industry entitled “Dosage and Administration Section of Labeling for Human Prescription Drug and Biological Products--Content and Format” issued on March 29, 2010, and issuing this draft guidance.
Mpox: development of drugs and biological products
FDA is issuing this guidance to support sponsors in their development of drugs for mpox. This guidance provides nonclinical, virology, and clinical considerations for mpox drug development programs, with a focus on recommendations to support initiation of clinical trials. Preventive vaccines are not addressed in this guidance. Development of preventative vaccines raise different and additional considerations, including those pertaining to subject selection, safety monitoring, and effectiveness evaluation. Monkeypox virus is in the Orthopoxvirus genus of the Poxviridae family and is biologically similar to variola virus (the causative agent of smallpox). Although FDA has approved drugs for the treatment of smallpox under regulations commonly referred to as the Animal Rule, this pathway is not applicable to drugs for mpox because researchers can design and implement clinical trials for mpox that are both ethical and feasible.
M13A bioequivalence for immediate-release solid oral dosage forms
This ICH guideline has now been published by FDA as a draft guideline and is intended to provide recommendations on conducting bioequivalence (BE) studies during both development and post approval phases for orally administered immediate-release (IR) solid oral dosage forms designed to deliver drugs to the systemic circulation, such as tablets, capsules, and granules/powders for oral suspension.
Considerations for the design and conduct of externally controlled trials for drug and biological products
This guidance provides recommendations to sponsors and investigators considering the use of externally controlled clinical trials to provide evidence of the safety and effectiveness of a drug product. In an externally controlled trial, outcomes in participants receiving the test treatment according to a protocol are compared to outcomes in a group of people external to the trial who had not received the same treatment. The external control arm can be a group of people, treated or untreated, from an earlier time (historical control), or it can be a group of people, treated or untreated, during the same time period (concurrent control) but in another setting.
[This item has been published by FDA under the category Real World Data/Real World Evidence (RWD/RWE) – MBH]
International
International
Australia
Therapeutic Goods Administration(TGA)
Antibiotics shortage in Australia
There are current shortages of some antibiotics in Australia, including amoxicillin, cefalexin and metronidazole. TGA is facilitating supply of alternative medicines as a priority.
Most of the shortages are caused by manufacturing issues or an unexpected increase in demand. Many of these medicines have alternatives available.
Nitrosamine Impurities in medicines
TGA has published updated information on nitrosamine impurities, on the TGA response and requirements for medicine sponsors and manufacturers.
Conferences
UK MHRA Good Manufacturing and Distribution Practice (GMDP)
In person tickets have now sold out for GMDP but you can still register to join virtually. The Symposia’s will provide the latest information and guidance on changing legislation and increasing complexity in the manufacturing and distribution chain.
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.
