Last week’s round -up;
18-22 January 2021

Canada-UK Trade Continuity Agreement

As of the 1st January 2021, the Canada-EU Comprehensive Economic and Trade Agreement (CETA) no longer applies to the United Kingdom. However, Canada and the UK have agreed on an interim Canada-United Kingdom Trade Continuity Agreement (Canada-UK TCA) until a comprehensive free trade agreement is in place. Until the agreement officially enters into force, Health Canada, the MHRA and the VMD have agreed on an interim arrangement for continued cooperation on the application of the CETA Protocol on pharmaceuticals in order to avoid any disruption in trade. Canada and the UK will continue to recognise GMP certificates issued by each country’s regulatory agencies and to accept batch testing certificates held by a manufacturer without re-control of that batch at import.

http://bit.ly/RealCMC-3iA6x2i

Brexit Trade Deal

The Brexit trade deal contains certain provisions concerning the pharmaceutical and biotech industries that allow for smoother trade between the UK and EU. However, since the two parties now function as separate legal and regulatory jurisdictions, pharma and biotech companies will face additional barriers that did not exist prior to Brexit. The deal does ensure some intellectual property protections and commits the two parties to adhere to international standards. It also allows for mutual recognition of inspections and GMP documents between the UK and EU member states, with some conditions. The agreement allows the EU and UK regulators to request official GMP documents from each other, committing to provide requested documents within 30 calendar days. The agreement also reserves the rights of each party to conduct inspections of facilities that have been certified compliant by the other party. However, the other party must be notified prior to the inspection to allow for its participation during the inspection.

More information with regards to how the Brexit trade deal affects the pharmaceutical and medical device industries is available at the following RAPs article: http://bit.ly/RealCMC-2XSIdzk

 

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Last week’s round -up;
07-11 December 2020

Brexit – Article 41 of the Withdrawal Agreement

The EC and EMA have published a notice to stakeholders titled ‘Withdrawal of the United Kingdom and EU Rules for Medicinal Products for Human Use and Veterinary Medicinal Products’ (Rev 3, dated 13 March 2020). Article 41 of this agreement indicates that medicines, which are certified by a Qualified Person and have been released in the United Kingdom for sale or supply before 11 pm on 31 December, can be supplied to the Irish market after the transition period ends. The receiving site in Ireland must ensure that certain requirements, described in the following article, are met: https://bit.ly/RealCMC-39ZZkGt

New Ph. Eur. general chapter for the analysis of N-nitrosamine impurities

The Ph. Eur. Commission has adopted a new general chapter on the analysis of N-nitrosamine impurities in active substances (2.5.42). The general chapter covers the different needs of control laboratories as it proposes three procedures which rely on different instruments (GC-MS, LC-MS/MS and GC-MS/MS). The chapter focuses mainly on the analysis of N-nitrosamine impurities in angiotensin-II-receptor antagonists (sartans) containing a tetrazole group, including valsartan, losartan potassium, candesartan cilexetil, irbesartan and olmesartan medoxomil. However, the procedures may also be applied to other substances or to medicinal products following demonstration of suitability for the intended purpose with additional validation.

https://bit.ly/RealCMC-3n6sfwa

Joint published EMA and HMA strategy sets direction for EMA and EU medicines regulatory agencies to 2025

The European Medicines agency and Heads of Medicines Agencies, have published their joint strategy for the next 5 years. It lists 6 areas of priority, availability and accessibility of medicines; data analytics, digital tools and digital transformation; innovation; antimicrobial resistance and other emerging health threats; supply chain challenges; and finally the sustainability of the network and operational excellence. Emer Cooke, EMA’s Executive Director commented that “The COVID-19 pandemic has highlighted the pivotal role of medicine regulation for the protection of public health,” and “This strategy ensures that we join forces across the EU to effect tangible improvements for citizens.”

Full details of the news item and a link to the strategy document can be found here: https://lnkd.in/eK-_MQq

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Last week’s round -up;
30 November – 04 December 2020

Revised Palbociclib and Abiraterone product-specific bioequivalence guidance

The EMA has issued the following product-specific bioequivalence guidance: • A draft bioequivalence guidance for Palbociclib 75 mg, 100 mg and 125 mg hard capsules and 75 mg, 100 mg and 125 mg film-coated tablets. This guidance is open for public consultation until the 28th February 2021. • A newly adopted bioequivalence guidance for Abiraterone tablets 250 mg and 500 mg.

https://bit.ly/2UVpfae

Comments concerning revised texts published in Supplement 10.5

The EDQM has published the technical modifications that have been made to revised texts adopted by the European Pharmacopoeia Commission at the June 2020 session and published in Supplement 10.5. The details may also be consulted in the Knowledge database under ‘View history’.

https://bit.ly/RealCMC-2JGPzlk

UK medicines regulator gives approval for first UK COVID-19 vaccine

The first COVID-19 vaccine for the UK, developed by Pfizer/BioNTech, has today been given approval for use following a thorough review carried out by the Medicines and Healthcare products Regulatory Agency (MHRA). A copy of the press release is at the link: https://lnkd.in/dvDb4FR The BBC was reporting this morning that the UK is the first country worldwide to authorise a COVID-19 vaccine for a mass-vaccination programme.

https://lnkd.in/epySwje

Specific permits required to order Residual solvent solution class 1 CRS COVID-19 vaccine

As of the 1st January 2021, specific permits will be required to order R0250000 – Residual solvent solution class 1 CRS. This reference standard contains two controlled substances, carbon tetrachloride and 1,1,1–trichloroethane, which are ozone-depleting substances and, thus, prohibited in the EU except under certain conditions for laboratory and analytical uses. Users that require delivery within the EU, must provide a valid LabODS number to the EDQM when ordering the Ph. Eur. RS R0250000 reference standard, while any orders for delivery outside the EU are subject to licensing requirements.

Further information may be obtained from: https://bit.ly/RealCMC-3fVJT3i

Updated Brexit post transition guidance

The MHRA has updated its guidance on the location and other authorised personnel requirements for the post transition period. Guidance on centrally authorised MAs, mutual recognition and decentralised MAs, existing UK national MAs, GB MAs, named distributor, manufacturing sites, quality control and QPs was updated. The MHRA has also published a new section on the definition of products placed on to the GB market.

https://bit.ly/RealCMC-33rtSNg. 

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Last week’s round-up;
07 – 11 September 2020

Qualification of Balances – EDQM Guidance

The EDQM has revised its “Qualification of Balances” guideline. The document is the 8th Annex to the OMCL Network Guideline “Qualification of Equipment”, and it has entered into force as of September 2020. The 8th Annex should be used in conjunction with the core guideline “Qualification of Equipment” when planning, performing and documenting the qualification process of balances. The core document contains the general introduction and Levels I and II of qualification pertaining to all types of instruments, while the 8th Annex contains a general introduction and requirements for balances (electronic – digital) used in official medicines control laboratories for physicochemical and biological tests. The revised guideline covers ultra-micro balances, micro balances, semi-micro balances, analytical balances, precision balances and technical balances.

http://bit.ly/RealCMC-3ix12As

Comparator products in studies supporting UK MAAs from 01-Jan-21

According to new guidance published on 1 September 2020, the UK MHRA will allow the use of comparator products sourced from outside Great Britain for studies supporting abridged MAAs (but not biosimilars), to avoid unnecessary repetition of bioequivalence and therapeutic equivalence studies. All EEA countries, Switzerland, USA, Canada, Australia and Japan are acceptable source countries. An applicant choosing this option must demonstrate that the non-GB comparator product is representative of the GB reference product. The nature of the analytical bridging data to be provided is described in considerable detail in the guideline. Minor differences between the comparator product and the GB reference product can be accepted, e.g. colour.

http://bit.ly/RealCMC-33a9nUq

EMA Workshop on the draft guideline on registry based studies

EMA has published an agenda for their upcoming workshop on the draft guideline on registry based studies. The key objectives of the workshop are

1. To respond to key questions and requests for clarification,

2. To present stakeholders’ perspectives on the usefulness of the Guideline for registry-based studies, and

3. To present recent experience on methodological aspects of registry-based studies.

The workshop takes place on 19th October on a virtual basis, further details can be found under this link: https://lnkd.in/ebhsM-y

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Last week’s round-up;
31 August – 04 September 2020

FDA issues nitrosamine detection and prevention guidance

The US FDA has implemented new nitrosamine guidance with immediate effect. The document details the necessary steps that should be taken to detect and prevent the introduction of potentially carcinogenic nitrosamine impurities into finished drug products and active pharmaceutical ingredients (APIs). The guidance describes circumstances that can lead to the introduction of nitrosamine impurities in medicines and APIs. This includes the potential roles of tertiary and quaternary amines used as reagents during the manufacturing process and which may be a potential source of nitrosamines, as well as amide solvents that can be a source of secondary amines. The guidance also covers circumstances in vendor-sourced materials where recovered solvents, catalysts and reagents may be a source of nitrosamine contamination. Risk assessment processes are also laid out in the guideline.

Further information on the new FDA guidelines may be viewed at the following link: http://bit.ly/RealCMC-3bpTOvz

Public Consultation on the CEP of the future

The EDQM has launched a project to design the Certificate of Suitability (CEP) of the future. The content and layout of the current CEP have not changed significantly since the original CEP was created in 1992. The aim of the project is “to develop a “new-look” CEP that will better fit the emerging needs of stakeholders and offer both enhanced user-friendliness and greater transparency of the information conveyed without, however, increasing the administrative regulatory burden related to their revision”. Therefore, the EDQM is requesting general feedback on the content, layout, format and use of the CEP from stakeholders in the pharmaceutical industry and from National Competent Authorities around the world. Stakeholders may submit their comments in the form of an online survey until 31st December 2020. A “read only” version of the survey is also available in order to allow users to prepare their answers in advance: https://bit.ly/RealCMC-3jFpaBi

MHRA publishes New Rules to apply from January 2021

MHRA has published Guidance for industry and organisations to follow from 1 January 2021 following the transition period when UK fully exits the EU. The guidance covers the requirements for Clinical Trials, Devices, Licensing, Importing and Exporting, IT systems, Pharmacovigilance and Paediatrics.

The link to the guidance can be found here:  https://lnkd.in/e7mstgx

New FDA product-specific guidance

The US FDA has published 19 new and 17 revised product-specific guidances, which clarify the agency’s expectations for demonstrating equivalence between generic and reference drugs, in an effort to promote generic competition. The new draft product-specific guidances include recommendations for generic versions of the breast cancer drug alpelisib, generic esketamine which is a nasal spray for treating major depression and larotrectinib, which is used to treat solid tumors with neurotrophic receptor tyrosine kinase gene fusions. The following product-specific guidance documents were revised: generics of the blood clot drug rivaroxaban and several HIV treatments, including dolutegravir, and the combination products abacavir/dolutegravir/lamivudine and dolutegravir/rilpivirine: https://bit.ly/RealCMC-2EKeLFD

ENPR-EMA: Preparedness of medicines’ clinical trials in paediatrics

Enpr-EMA issues recommendations on preparedness, for sponsors, principal investigators and triallists involved in paediatric clinical trials. They have defined ‘Preparedhttp://bit.ly/RRL-2DziLrQness’ as the structured assessment of contributing factors that enable the smooth conduct of CTs in a timely manner. The recommendations cover data and information collection, contributor involvement (such as CT sites, expert groups , patients and families, and regulators), following a structured approach, and approaches for preparing plans and studies.

A link to the full document can be found here:  https://lnkd.in/fSahvZK

EMA Consultation issued: QT/QTc Q&A

EMA has issued a consultation on the ICH Guideline E14/S7B Implementation working group document: Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential Questions and Answers. The document comprises proposed revisions to sections 5.1 and 6.1 of the current Q&As for ICH E14. Other sections are not proposed for revision. At Step 4, the revised sections 5.1 and 6.1 will be integrated with the other current Q&As for ICH E14. The consultation also includes new Q&As for ICH S7B.

A link to the consultation can be found here: http://bit.ly/RRL-2DziLrQ

FDA addresses nitrosamines in TB drugs

Following the discovery of elevated levels of nitrosamine impurities in two tuberculosis drugs, rifampin and rifapentine, the FDA has clarified how it will address the presence of these potentially carcinogenic impurities. Elevated levels of the nitrosamine 1-methyl-4-nitrosopiperazine (MNP) were found in rifampin and high levels of 1-cyclopentyl-4-nitrosopiperazine (CPNP) were found in rifapentine. The Agency has taken a risk-benefit approach to the issue and has said that “to mitigate or avoid shortages and to help ensure patients have access to these necessary medicines, FDA will not object to certain manufacturers temporarily distributing” rifampin and rifapentine containing nitrosamines above the acceptable intake limits “until they can reduce or eliminate the impurities”. Manufacturers should however ensure that levels of the MNP and CPNP in these antibiotics are below 5 ppm and 14 ppm respectively. In cases where nitrosamine levels are found to be above these limits, the manufacturer is required to contact the Center for Drug Evaluation and Research’s Drug Shortage Staff who will determine whether the products should be released for distribution. http://bit.ly/RealCMC-31FOLUA

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Last week’s round-up;
13-17 July 2020

New EMA opinion on nitrosamines

The CHMP has finalised its opinion on the presences of nitrosamines in human medicines, which is available on the EMA’s nitrosamine impurities website. The opinion requires pharmaceutical companies to take measures in order to limit as much as possible the presence of nitrosamines in their drug products and to ensure that the levels of these impurities do not exceed set limits. Such measures include the implementation of appropriate control strategies to prevent or limit the presence of nitrosamines as well as the improvement of manufacturing processes, where necessary. Companies will also be required to carry out the necessary risk assessments and evaluation and conduct appropriate tests if the risk of nitrosamine contamination is identified.

https://bit.ly/RealCMC-2ZzN0au

EU Notified Bodies designated under the EU MDR (2017/745)

There are currently 15 Notified Bodies(NB) designated under MDR with GMED France being the latest NB to be designated and also the first NB to receive designation in France. A full list of NB’s currently designated are listed below and on the Nando Database linked here https://bit.ly/39aaypy.

Manufacturers don’t know for certain if and when their NB will be designated and are advised to regularly check the Nando database to see status of NBs designate.

      1. BSI (Netherlands) – 2797 (MDR scope)
      2. BSI (UK) – 0086 (MDR scope)
      3. CE Certiso (Hungary) – 2409 (MDR scope)
      4. DARE!!! Services (Netherlands) – 1912 (MDR scope)
      5. DEKRA Certification (Germany) – 0124 (MDR scope)
      6. DEKRA Certification (Netherlands) – 0344 (MDR scope)
      7. DNV GL Presafe (Norway) – 2460 (MDR scope)
      8. GMED (France) – 0459 (MDR scope)
      9. IMQ (Italy) – 0051 (MDR scope)
      10. Intertek IMNB (Sweden) – 2862 (MDR scope)
      11. MDC Medical Device Certification (Germany) – 0483 (MDR scope)
      12. MEDCERT (Germany) – 0482 (MDR scope)
      13. NSAI (Ireland) – 0050 – (MDR scope)
      14. TÜV Rheinland LGA (Germany) – 0197 (MDR scope)
      15. TÜV SÜD (Germany) – 0123 (MDR scope)

CMDh updates

The CMDh has revised the following documents (available with tracked changes): • Flow chart of the Decentralised Procedure. • CMDh Best Practice Guide on the processing of renewals in the Mutual Recognition and Decentralised Procedures. • CMDh Best Practice Guide on Multilingual Packaging. CMDh has also published its Procedural guidance during Covid-19 pandemic, which includes a new template for notification of implementation of a change under a previously agreed ECMP.

https://bit.ly/RealCMC-2DHSfw8

MHRA COVID-19 Flexibilities

MHRA is offering to provide temporary inspection flexibility for manufacturers of human plasma-derived medicines, in exceptional circumstances. For 3rd country plasma collection sites that have been previously inspected by MHRA, they will implement a control measure in line with EMA recommendations and a Statement of Next Inspection (SONI) will be issued. For 3rd country sites that have not been previously inspected, MHRA gives 2 separate options depending on whether a partent company has been previously inspected or not. Full details of the guidance and all the MHRA COVID-19 Flexibilities can be found here: https://lnkd.in/dduB8EB

EDQM evaluation of impurity found in paracetamol API

The EDQM is actively working with a pharmaceutical company and other stakeholders to evaluate the detection of 4-chloroaniline, a carcinogenic impurity found in the active substance paracetamol that is manufactured by the company. The company concerned holds a Certificate of Suitability (CEP) for this active substance. The evaluation is underway to better understand the potential impact of this impurity as well as the extent of the issue.

https://bit.ly/RealCMC-3h9usnx

Brexit:  Joint technical notice by the European Commission, EMA and HMA

EC, EMA and HMA have announced that, since ‘The Withdrawal Agreement’ provides for a transition period end 31st Dec 2020 and no extension was requested as of 1st July 2020, there is no possibility of further extension beyond that date. Sponsors of EU CTs are reminded of the legal situation applicable after the end of the transition. Two specified areas that must be implemented prior to end of transition period are as follows; EU based QP will be required for IMP release and the sponsor or legal representative for the trial must be established within the EU. Further discussion can be found here: https://lnkd.in/dd2XgPt

New metformin recalls

Following last month’s voluntary recall of extended-release (ER) metformin by five pharmaceutical companies from the US market, the FDA has announced that another two manufacturers have issued further recalls of ER-metformin due to the presence of elevated levels of the potential carcinogen NDMA. Six pharmaceutical companies have been affected by the voluntary recalls. The FDA has also published a paper on the investigations carried out to study the initial discrepancies between FDA testing and testing by a private laboratory. The private laboratory, which had filed a Citizen Petition, reported higher NDMA levels in more metformin products than the FDA test results. On investigation, the cause of the discrepancy was found to be the presence of another chemical, N,N-dimethylformamide (DMF), that interfered with NDMA mass spectrometry measurements in the analytical methods used by the FDA. Further information on the latest ER-metformin recalls may be found here: https://bit.ly/RealCMC-3fogQ7n 

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Last weeks round-up; 2 – 6 December 2019

EMA GUIDANCE ON NITROSAMINE ASSESSMENTS

CMDh has issued an update to the practical guidance on Nitrosamine assessments. It is confirmed that MAHs can combine several MAs in one template of the risk assessment step 1 outcome, where the outcome is the same. However, national requirements too as mentioned later in the guidance needs to be considered. The national requirements may not necessarily be overruled by the general possibility given by CMDh. The full guidance document can be found under this link https://lnkd.in/dBHf63p EMA

HMA/EMA BIG DATA TASK FORCE REPORTS

Massive amounts of data are generated on a daily basis that could potentially be harnessed to support medicines regulation. The EMA and HMA have established a joint task force to investigate the potential role of ‘big data’ in the context of medicines development and regulation in the EU. A series of Subgroup reports were issued on 27th Nov 2019, links to the different subgroup reports can be found here https://lnkd.in/dU6Kwu2. Topics include, Clinical Trial and Imaging, Genomics, Genetics Transcriptomics and Epigenetics, Observational Data and Bioanalytical Omics.

NEW CMDH BEST PRACTICE GUIDE ON MULTILINGUAL PACKAGING

A new CMDh Best Practice Guide on Multilingual Packaging was published this month, November 2019.  Multilingual packaging relates to the use of two or more languages on the immediate and /or outer packaging and/or package leaflet of a medicinal product. The published guidance is aimed to assist applicants in creating multilingual packages which are recognised for their importance in maintaining products in EU markets. To view the guidance in full, please see: http://bit.ly/37QiHOI

SECOND CORRIGENDUM OF MDR (EU) 2017/745 CONCERNING CLASS I MEDICAL DEVICES

The council of the European Union published the second corrigendum to the EU Medical Devices Regulation (MDR) on the 25th November. The most significant changes relate to Class I medical devices which are sterile, include a measuring function, or are reusable surgical instruments. The corrigendum will mean that manufacturers would have an additional 4 years up to 26th May 2024 to comply with the new regulations in full. The changes proposed in the second corrigendum must be formally adopted by the European Parliament to take effect. MDR Corrigendum 13081/19 is linked here https://bit.ly/381YEgB with the English version starting on page 43 of the document.

BREXIT MEDICINES SHORTAGES

EMA has just updated its Q&A document (Link – https://lnkd.in/dg7PUay ) on the work being done to avoid medicines shortages following the UKs exit from EU. Medicines agencies will make information on Medicines procedures available via usual means, therefore, there is also a link therein to where details of medicines subject to ongoing shortages in EU countries can be found.

Last weeks round-up; 14 – 18 October 2019

EVALUATION OF THE EU BLOOD, TISSUE AND CELLS LEGISLATION

On 11 October 2019, the European Commission published its evaluation of the EU blood, tissues and cells legislation. An executive summary is also available. This was the first evaluation of the legislation since the adoption of the basic Acts in 2002 (blood) and 2004 (tissues and cells). Further information and a link to the evaluation can be found under this link https://lnkd.in/ds48XHY. The results of the evaluation will be disseminated at a Conference in Brussels on 28 October 2019.

EMA: UPDATED VERSIONS OF eAFs NOW AVAILABLE

EMA has just issued version 1.23.1.3 of the 4 electronic Application Forms (eAF), which are now available on the eAF website, along with new release notes and a release milestone plan. This release is a bug fix release to correct a number of issues which affect the forms. The bug fix release does not affect the Data Exchange Standard (DES). Applicants are reminded that the version of the form should not be changed during an ongoing procedure. https://lnkd.in/de7AFKu

PAEDIATRIC COMMITTEE (PDCO) MEETING MINUTES

An overview of Pedmed-NL (the former Dutch Medicines for Children Research Network) was presented. The network has been involved in the development of the Dutch Paediatric Formulary (kinderformularium), the establishment of European Paediatric Translational Research Infrastructure (EPTRI) and Paediatric Clinical Research Infrastructure (PEDCRIN) as well as in the planning of clinical trials, mainly via Connect4Children (C4C). The network was relaunched in 2018 as PedmedNL with main goal to facilitate and support the conduct of C4C proof of viability studies (by 2023). The main goal beyond 2023 is to create a sustainable network for research in children. The minutes can be found under; https://lnkd.in/dpNCPqQ

UK WITHDRAWAL FROM EU: EMA RELOCATION TO AMSTERDAM

EMA has recently reported a further 6% reduction in workforce as a result of relocating to Amsterdam. As a result EMA is reviewing its organisational structure and looking to set up task forces that will focus on key priorities for the European medicines regulatory network further details can be found here: https://lnkd.in/dx49VpY

EMA ADVISES COMPANIES ON STEPS TO TAKE TO AVOID NITROSAMINES IN HUMAN MEDICINES *UPDATE*

As previously advised, EMA has requested all EU marketing authorisation holders of medicinal products containing chemically synthesised APIs to review their medicines within the next 6 months for the presence of nitrosamines. Real Regulatory has both the expertise and resource to support this review process. For more information on the EMA recommendation, including a Q&A quide: https://lnkd.in/erne7TZ

EMA PRIME ELIGIBILITY REQUESTS

EMA has just published its deadlines and timetable for PRIME Eligibility request assessments for 2020. Further details can be found here; https://lnkd.in/d7Z8x6J

 

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