Review of Developments in GMP and the Regulation of Medicines October 2023
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.
The topics covered in this edition of the “Update” include:
UK MHRA
Guidance published on the new international regulatory recognition routes for medicines approvals
The Northern Ireland MHRA Authorised Route (NIMAR) – update
UK-wide licensing for human medicines
MHRA Corporate Plan 2023 to 2026
Berkshire couple receive prison sentence for illegal possession and supply of £1.6m of unlicensed medicines
EU
20 years EU/US collaboration on medicines regulation
Frequently asked questions about parallel distribution
Accelerating Clinical Trials in the EU (ACT EU) – New video released
Q&A for biological medicinal products
Guideline on quality data requirements for applications for biological veterinary medicinal products intended for limited markets.
Concept paper on the revision of the Guideline on user safety of topically administered veterinary medicinal products
Update to Appendix 1 of Q&A on nitrosamine impurities in human medicinal products
Updated pre-authorisation procedural advice for users of the centralised procedure
Certification monthly report (CEPs)
CEP 2.0: Changes from September 2023 to information published in Certification Online and Knowledge databases
CEP 2.0 – Certificates of suitability: electronic signature features
Validating analytical procedures for determining nitrosamines in pharmaceuticals: European OMCLs participate in collaborative study with international regulatory agencies
Reference standards
USA
Wholesale distributor verification requirement for saleable returned drug product and dispenser verification requirements when investigating a suspect or illegitimate product
Human Prescription Drug and Biological Products--Labeling for Dosing Based on Weight or Body Surface Area for Ready-to-Use Containers--“Dose Banding”
Post-Warning Letter Meetings Under GDUFA
Labeling for Biosimilar and Interchangeable Biosimilar Products
Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act (Rev. 1)
Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications
Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products
Products
Topiramate - new measures to avoid exposure in pregnancy
MHRA approves Pfizer/BioNTech’s adapted COVID-19 vaccine (Comirnaty) that targets Omicron XBB.1.5
Australia - Changes to choline salicylate access
EMA recommends non-renewal of authorisation of Duchenne muscular dystrophy medicine Translarna
EMA recommends non-renewal of authorisation of multiple myeloma medicine Blenrep
Australian prescribers advised not to start new patients on Ozempic
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
UK
MHRA
Guidance published on the new international regulatory recognition routes for medicines approvals
At the time of the UK’s exit from the European Union, the MHRA introduced temporary routes to market for European approved products in Great Britain, known as EU ‘reliance’ routes, to ensure that patients could continue to have timely access to new treatments. These temporary routes will end on 31 December 2023.The MHRA is currently running a public consultation on their closure that will close on 27 September 2023.
Guidance on the new scheme to replace the current EC Decision Reliance Procedure (ECDRP) on 1 January 2024, informs the sector on how they can use the scheme to apply for a medicine licence in the UK, following approval by trusted regulatory partners in Australia, Canada, the European Union, Japan, Switzerland, Singapore, and the United States.
The Northern Ireland MHRA Authorised Route (NIMAR) – update
NIMAR guidance provides for key stakeholders in the medicines supply chain to facilitate their use of the NIMAR regulatory route for the continued supply of GB licensed medicines to Northern Ireland. The latest update (29 September 2023) covers the information added about transitional arrangements for licences associated with the implementation of the Windsor Framework and links to relevant guidance.
UK-wide licensing for human medicines
This guidance is designed to provide information on the implementation of changes to the licensing of medicines for human use in the UK following the agreement of the Windsor Framework.
The Windsor Framework will be implemented from 1 January 2025
After the implementation of the Windsor Framework, the Medicines and Healthcare products Regulatory Agency (MHRA) will license all medicines across the whole of the UK.
MHRA Corporate Plan 2023 to 2026
Contents include the priority actions and activities which the agency will take forward to ensure delivery of the statutory role and functions of the agency.
This update to the corporate plan (7 Sept 2023) covers the MHRA Business Plan for 2023-24
Berkshire couple receive prison sentence for illegal possession and supply of £1.6m of unlicensed medicines
The MHRA were notified in 2020 of seizures of parcels containing unlicensed medicines, following an investigation of suspicious parcel activity by the Royal Mail Group (RMG).
The MHRA’s Criminal Enforcement Unit launched an investigation and, supported by local police, arrested the couple at their home in Maidenhead, where they were found to be in possession of over 1.3m pills of 65 different brands of medicines used for a range of conditions including sexual dysfunction, infertility, obesity, alcohol and opioid dependence, narcolepsy/ADHD, breast cancer and HIV. The medicines were estimated to be worth £1.6m on the illegal market.
They were each sentenced to eight months imprisonment suspended for 18 months and 150 hours unpaid work for possession and intent to supply medicinal products contrary to the Human Medicines Regulations 2012.
[Is a suspended sentence really enough?? MBH]
Europe
European Health Union
20 years EU/US collaboration on medicines regulation
A useful schematic diagram has been published showing the various stages of this cooperation
Frequently asked questions about parallel distribution
Revisions have been made to questions 4 & 5 in the section regarding Safety updates/bulk changes/annual update. Q4 relates to ‘how to submit a bulk change’ & Q5 to ‘What is an annual update.
Accelerating Clinical Trials in the EU (ACT EU) – New video released
Interested readers may wish to watch this short explanatory video to see how EMA believe that ACT-EU is transforming the way that clinical trials are initiated, designed and run.
Q&A for biological medicinal products
This Q&A page is developed and maintained by the CHMP Biologics Working Party (BWP) and provides agreed positions by the Biologics Working Party position on issues that can be subject to different interpretation or require clarification, typically arising from discussions or correspondence during assessment procedures of biological human medicinal products.
In order to obtain information on a topic, please click on the topics/questions. Please note that this page has been produced to provide transparency and additional information, and should be read in conjunction with the European Pharmacopoeia, CHMP guidelines on quality and other guidance documents.
Guideline on quality data requirements for applications for biological veterinary medicinal products intended for limited markets.
The general aim of this guidance is to define acceptable data requirements for the demonstration of the quality of biological veterinary medicinal products, including immunological veterinary medicinal (IVMPs) products classified as limited markets in line with Article 4(29) of Regulation (EU) 2019/6.
Concept paper on the revision of the Guideline on user safety of topically administered veterinary medicinal products (EMA/CVMP/SWP/721059/2014
The Guideline on user safety of topically administered veterinary medicinal products was published in May 2018. This guideline was written to provide specific guidance and advice on how user risk assessments should be conducted for topically administered products. The guideline is to be used in conjunction with the ‘Guideline on user safety for pharmaceutical veterinary medicinal products’ (EMA/CVMP/543/03-Rev.1). The Guideline is planned to be revised in relation to the possible inclusion of reference to current EU-standards in the assessment of dermal absorption, and to updated OECD ‘Guidance notes on dermal absorption’ No. 156. The revision could also include developments on the toxicological reference values, defaults and exposure calculations (e.g. absorption factors, appropriateness of the default values and of the wipe test) and risk mitigation measures.
The consultation period ends 30 Nov 2023
Update to Appendix 1 of Q&A on nitrosamine impurities in human medicinal products
Ema has published this updated table as of 28 Sept 2023.
Updated pre-authorisation procedural advice for users of the centralised procedure
The latest revision, in Sept 2023, concerns Section 1.11:- “In which exceptional cases would combination packs be acceptable in the centralised procedure, and where can I submit my request for consideration?”
[Note that there were also a number of revisions / new sections made / added in July 2023. Well worth a check through to see that you are fully up to date on these very important requirements. – It’s a big 147 page document. MBH]
The European Directorate for the Quality of Medicines & HealthCare (EDQM)
Certification monthly report (CEPs)
This report covers Certificates of Suitability activity through to the end of August 2023. During August 3 CEPs were Suspended by EDQM due to GMP non-compliance
• CEP 1996-106 Calcium glycerophosphate.
• CEP 1999-164 Ferrous gluconate hydrate.
• CEP 2012-221 Zinc gluconate.
The report covers new CEPs granted, revisions approved, suspended, withdrawn and expired CEPs, timelines for treatment of applications and the inspection programme.
Results are displayed for the year to date as well as for August only.
CEP 2.0: Changes from September 2023 to information published in Certification Online and Knowledge databases
The tabulated data will now include additional columns showing SPOR ORG and LOC-ID information for the holder where this is available, as well as the renewal date for the CEP (where not yet renewed) and the closure date of the last procedure. Users will also be able to view and print a tabulated history of a selected CEP that provides information on the revision type, and on the outcome and closure date of completed procedures.
These changes are intended to increase transparency and encourage communication between CEP holders and the users of CEPs.
CEP 2.0 – Certificates of suitability: electronic signature features
On 1 September 2023, the EDQM implemented electronic signatures for CEPs and some other documents as part of the CEP 2.0 project. A document explaining the features of electronic signatures is now available on the EDQM website:
Validating analytical procedures for determining nitrosamines in pharmaceuticals: European OMCLs participate in collaborative study with international regulatory agencies
This inter-laboratory study responded to a need for more in-depth knowledge on the overall performance of mass spectrometry (MS)-based analytical procedures for nitrosamine analysis. To assess the measurement variation across different analytical procedures, the six participating laboratories used their own analytical methods to determine the amounts of small-molecule nitrosamines (NDBA, NDEA, NDIPA, NDMA, NEIPA and NMBA*) in a set of identical samples (valsartan and losartan drug substances and products).
Most laboratories used MS detection following gas or liquid chromatographic separation (GC-MS or LC-MS), but these techniques – routinely used in the analysis of pharmaceutical substances – were not necessarily designed to determine trace-level nitrosamines, and therefore required sound validation.
The results demonstrated that accurate and precise quantitation of trace-level nitrosamines can be achieved using different analytical procedures. The study also provided insight into the performance characteristics of MS-based analytical procedures in terms of accuracy, repeatability and reproducibility.
Reference standards
2 new Ph. Eur. reference standards and 16 replacement batches released in August 2023
United States of America
Wholesale distributor verification requirement for saleable returned drug product and dispenser verification requirements when investigating a suspect or illegitimate product
This revised guidance explains that FDA intends to extend for an additional year (from November 27, 2023, to November 27, 2024), the enforcement policies described in the guidance and published in the Federal Register on October 23, 2020. The 2020 Compliance Policies relate to provisions in the Federal Food, Drug, and Cosmetic Act (FD&C Act), as added by the Drug Supply Chain Security Act (DSCSA), requiring wholesale distributors to verify the product identifier prior to further distributing saleable returned product and requiring dispensers to verify the product identifier for suspect or illegitimate product in the dispenser’s possession or control.
[It seems to me that there is lots of heel dragging going on with this topic MBH]
Human Prescription Drug and Biological Products--Labeling for Dosing Based on Weight or Body Surface Area for Ready-to-Use Containers--“Dose Banding”
This guidance provides recommendations for incorporating dose banding information into the labeling of an injectable drug product that is seeking approval through a new drug application submitted under section 505(b) of the FD&C Act (21 U.S.C. 355(b)), a biologics license application submitted under section 351(a) of the PHS Act (42 U.S.C. 262(a)), or a supplement to one of these approved applications. The recommendations and examples in this guidance are relevant to situations in which an applicant (1) proposes to develop ready-to-use containers with a range of different strengths for an injectable drug product and (2) seeks to incorporate dose banding information into the prescribing information based on dosing information of a previously approved drug product that is based on weight or body surface area (BSA).
Post-Warning Letter Meetings Under GDUFA
This guidance provides information on the implementation of the Post-Warning Letter Meeting process for certain facilities, a program enhancement agreed upon by the Agency and industry as part of the negotiations relating to the reauthorization of the Generic Drug User Fee Amendments (GDUFA).
A Post-Warning Letter Meeting is a meeting with FDA regarding the facility’s remediation of deficiencies identified in a warning letter.
This guidance specifically describes the process in the GDUFA III commitment letter for how an eligible facility may request a Post-Warning Letter Meeting with FDA regarding the facility’s ongoing remediation efforts to CGMP deficiencies described in a warning letter, how to prepare and submit a complete meeting request package, and how FDA intends to conduct the Post-Warning Letter Meeting.
Labeling for Biosimilar and Interchangeable Biosimilar Products
This guidance is intended to help applicants develop draft labeling for proposed biosimilar and interchangeable biosimilar products for submission in an application.
The recommendations for biosimilar and interchangeable biosimilar product labeling in this guidance pertain only to the Prescribing Information, except for certain recommendations in section V, FDA-Approved Patient Labeling of Biosimilar and Interchangeable Biosimilar Products, pertaining to FDA-approved patient labeling (e.g., Patient Information, Medication Guide, Instructions for Use).
Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act (Revision 1)
This draft guidance document provides answers to common questions from prospective applicants and other interested parties regarding the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). The question and answer (Q&A) format is intended to inform prospective applicants and facilitate the development of proposed biosimilar products and proposed interchangeable products, as well as describe FDA’s interpretation of certain statutory requirements added by the BPCI Act.
Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications
The purpose of this guidance is to provide information to applicants on how FDA intends to use alternative tools to assess manufacturing facilities identified in a marketing application. FDA agreed to issue guidance on the use of alternative tools to assess manufacturing facilities named in pending applications and to incorporate best practices from the use of such tools during the Coronavirus Disease 2019 (COVID-19) pandemic.
Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products
This draft guidance provides recommendations to industry on formal meetings between the FDA and sponsors or applicants relating to the development and review of drug or biological drug products regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).
Each year, FDA review staff participate in many meetings with requesters who seek advice relating to the development and review of investigational new drugs and biologics, and drug or biological product marketing applications. Because these meetings often represent critical points in the drug and biological product development, it is important that there are efficient, consistent procedures for the timely and effective conduct of such meetings. The good meeting management practices in this guidance are intended to provide consistent procedures that will promote well-managed meetings and to ensure that such meetings are scheduled within a reasonable time, conducted efficiently, and documented appropriately.
Products
Topiramate - new measures to avoid exposure in pregnancy
EMA’s safety committee (PRAC) recommends new measures to avoid exposure of children to topiramate-containing medicines in the womb, because the medicine may increase the risk of neurodevelopmental problems after exposure during pregnancy. Topiramate is already known to cause serious birth defects when used during pregnancy.
MHRA approves Pfizer/BioNTech’s adapted COVID-19 vaccine (Comirnaty) that targets Omicron XBB.1.5
Approval has been granted by the MHRA for an adapted Pfizer/BioNTech COVID-19 vaccine that targets the Omicron XBB 1.5 subvariant, after it was found to meet the UK regulator’s standards of safety, quality and effectiveness.
The vaccine has been approved for use in individuals from 6 months of age
This new line extension granted by the MHRA is valid in Great Britain only and was approved via the European Commission Decision Reliance Route.
Australia - Changes to choline salicylate access
Choline salicylate is an ingredient in a number of products for teething and the relief of pain, inflammation and discomfort associated with new dentures or braces and mouth ulcers and sores.
From 1 October 2023, products containing choline salicylate for oromucosal (mouth) use will only be available for purchase at pharmacies.
In making this decision, the risks associated with prolonged use and overuse of choline salicylate, especially in children, were considered. The Therapeutic Guidelines in Australia do not recommend teething gels (irrespective of choline salicylate content) because of the lack of evidence of efficacy and the potential for harm.
EMA recommends non-renewal of authorisation of Duchenne muscular dystrophy medicine Translarna
EMA’s human medicines committee (CHMP) has recommended not renewing the marketing authorisation for Translarna (ataluren), a medicine for treating patients with Duchenne muscular dystrophy whose disease is caused by a type of genetic defect called a ‘nonsense mutation’ in the dystrophin gene and who are able to walk.
The recommendation follows the full re-evaluation of the benefits and risks of the medicine during the renewal of its marketing authorisation, including results of a new study which failed to confirm Translarna's effectiveness.
Because Translarna was meant to address an unmet medical need for a serious disease, it received a conditional marketing authorisation in July 2014.The CHMP considered that the data now available on Translarna are comprehensive. The committee concluded that Translarna’s benefit-risk balance is negative and therefore recommended not renewing the marketing authorisation in the EU. EMA will now send the CHMP opinion to the European Commission, which will issue a final legally binding decision applicable in all EU Member States.
[An example of risk management in practice involving early access to a medicine meant to address an unmet medical need. MBH]
EMA recommends non-renewal of authorisation of multiple myeloma medicine Blenrep
EMA’s CHMP has recommended not renewing the conditional marketing authorisation for Blenrep (belantamab mafodotin), a medicine used to treat multiple myeloma (a cancer of the bone marrow).This recommendation follows a review of available data by the CHMP as part of the renewal of Blenrep’s marketing authorisation In its review, the CHMP considered that results from a new study (DREAMM-3) did not confirm the effectiveness of Blenrep as agreed when conditional marketing authorisation was granted.
However, on 21 September, the company that markets Blenrep asked for re-examination of the CHMP opinion. Upon receipt of the grounds of the request, the CHMP will re-examine its recommendation and issue a final recommendation. Once this re-examination is finalised EMA will send the CHMP final opinion to the European Commission, which will issue a final legally binding decision applicable in all EU Member States.
[Another example of risk management in practice involving early access to a medicine meant to address an unmet medical need. In this case the review is ongoing as the company has challenged the CHMP recommendation MBH]
Australian prescribers advised not to start new patients on Ozempic
The pharmaceutical company that supplies Ozempic, Novo Nordisk, has recently advised the Australian TGA and the Ozempic Medicine Shortage Action Group that supply will be limited for the rest of 2023 and throughout 2024.
Novo Nordisk advised that demand had accelerated in recent months, particularly for the low-dose (0.25/0.5 mg) version. This additional demand is caused mainly by a rapid increase in prescribing for off-label use (prescriptions for conditions other than those approved by the TGA). Ozempic’s TGA-approved ‘indication’ (reason for use) is for the management of type 2 diabetes not adequately managed by other medications, in conjunction with diet and exercise. If you are prescribed Ozempic for another reason, your doctor may decide to switch you to a different medicine.
The advice to prescribers is:
do not initiate new patients on Ozempic unless there are no suitable alternatives or there is a compelling clinical reason to do so
for patients who are already prescribed Ozempic, consider if they can be changed to an alternative (by consulting appropriate prescribing guidelines) as continuous supply cannot be guaranteed
supplies should be conserved for patients who are stabilised on Ozempic who have no other treatment options
it is not known when the medicine will be available in sufficient quantities to meet the ongoing high demand.
[indications are, that in multiple markets, the product is increasingly being prescribed off label (outside of its approved license) for weight loss. This in turn inhibits access by patients to the medicine for its licensed purpose.
Dramatically increasing supply of a medicine over a short period of time is usually no easy task for a manufacturer. In reflection it makes one realize what a brilliant job both regulators and industry did and continue to do, on vaccines during the COVID 19 pandemic. 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.
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