Last week’s round -up;
10-21 January 2022

Ph. Eur. Supplement 10.8 Implementation – Notification for CEP holders

Supplement 10.8 of the Ph. Eur. is now available and CEP Holders are invited to update their applications according to the revised monographs that will be implemented on the 1st July 2022. 16 revised Ph. Eur. monographs are now available including texts for ‘Calcium gluconate for injection’ and ‘Cholecalciferol concentrate (powder form)’. The article linked below provides a full list of the revised monographs as well as instructions for CEP holders and a description of information that should be submitted to the EDQM depending on the classification of the updates made to the monograph.

https://bit.ly/RealCMC-3tK6ad0

Manufacturers object to provisions in FDA’s microbiological quality guidance

An industry trade group and several manufacturers are calling for revisions to the FDA’s draft guidance on microbiological quality considerations for non-sterile drugs (NSDs). The draft guidance was designed to help manufacturers control microbiological contamination of their NSDs and stems from the Agency’s concerns over a high number of adverse events and recalls associated with contaminated products, including Burkholderia cepacia complex (BCC) in non-sterile water-based drug products. According to one manufacturer, one of the main issues with the guidance is a recommendation for the periodical identification of microorganisms in manufacturing facilities, which would be a “significant new requirement” that is not necessary for NSDs and which would be unsustainable. Another stakeholder has said that the new provision calling for manufacturers to test potential objectionable organisms for each nonsterile product, is not practical. Another issue brought up by the industry is that the draft FDA guideline is not aligned with the ICH Q7 guideline on APIs as the former calls for microbiological testing of components such as APIs and excipients, while the Q7 guidance does not. Further comments from stakeholders may be found in the RAPS article below.

https://bit.ly/RealCMC-3txYMl3

Revised ICH Q9 guideline to improve risk assessments

The ICH has issued a revised ICH Q9(R1) guideline that aims to address the shortcomings of the current guideline by providing “more scientific and robust applications of quality risk management principles” leading to “fewer quality defects and recalls” and reduced costs for the pharmaceutical industry.

The revised Q9 guideline is intended to address four shortcomings of the current version:

· High levels of subjectivity in risk assessments and in QRM outputs

· Failure to adequately manage supply chain and product availability risks

· Lack of understanding as to what constitutes formality in QRM work

· Lack of clarity on risk-based decision making The revision includes new text which acknowledges that some degree of subjectivity in QRM is unavoidable while offering methods to reduce or control subjectivity.

The document also includes a new section on formality in quality risk management and contains new text on the role of QRM in addressing product availability risks. The revised guideline is open for public consultation until the 15th March 2022.

https://bit.ly/RealCMC-34Ncoym

Phthalates

Phthalates are commonly used as softeners to make plastics more flexible and durable. They can also be found in adhesives, sealants, paints, rubber materials, wires and cables, flooring, packaging, food contact materials, medical devices and sports equipment. Several ortho-phthalates may have endocrine effects and may affect the sexual development of boys which can lead to infertility in adults. Some phthalates are also harmful to the environment. From the 7th July 2020 the use of phthalates has been restricted in the EU/EEA. These restrictions are estimated to save approximately 2000 boys per year from impaired fertility. The Candidate List of substances of very high concern (SVHC) contains several ortho-phthalates. Manufacturers and importers must notify the ECHA if their products contain a substance on the list within six months after inclusion of the substance in the list. 14 phthalates are also on the REACH Authorisation List. Use of substances on the list will be prohibited after a given date unless the EC authorises the company to continue its use. Prior to applying for authorization, companies also need to demonstrate that the use of the substance is controlled, that there are no suitable alternatives and that the benefits of continued use exceed the risks.

https://bit.ly/RealCMC-3A0iOFP

FDA: Risk of benzene contamination in certain drugs

The FDA has alerted drug manufacturers to the risk of benzene contamination in certain drugs and is currently evaluating the root cause of contamination. Benzene is a known human carcinogen that causes leukaemia and other blood disorders. In pharmaceuticals, inactive ingredients such as carbomers (thickening agents), isobutane (a spray propellant), or other drug components made from hydrocarbons may be potential sources of benzene. The Agency is advising manufacturers to conduct risk assessments to evaluate the possible presence of benzene in their drug products and components, with a special focus on ingredients that are hydrocarbons or are manufactured with benzene or other hydrocarbons. According to ICH Q3C, benzene is classified as a Class I solvent and should not be used in the manufacture of drug substances, excipients, or drug products because of its unacceptable toxicity. However, the guidance does allow for limited cases where the presence of benzene may be tolerated up to a level of 2 ppm, unless otherwise justified. The article linked below provides information on how manufacturers should contact the FDA if benzene is detected in their drug products (including products that are already in distribution). It also contains information that the Agency may request during follow up.

https://bit.ly/RealCMC-3K8p435

 

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Last weeks’ round -up;
31 May – 11 June 2021

Draft revised Ph. Eur. General Chapter 2.8.2 on Foreign Matter

A draft revised general chapter on Foreign Matter (with tracked changes) has been published in Pharmeuropa 33.3 and is available for comment until the 30th September 2021. Requirements for other foreign elements like moulds, insects and other animal contamination have been further specified in the revised chapter which may be viewed at the following link: http://bit.ly/RealCMC-357VGXl

Comments concerning revised texts published in Supplement 10.6

The EDQM has released information regarding the technical modifications that have been made to revised Ph. Eur. texts adopted by the European Pharmacopoeia Commission at the November session and published in Supplement 10.6. Modified texts are indicated by horizontal or vertical lines in the margin of 10.6. The details given in the article linked below complete this information but are not necessarily exhaustive. The details concerned may also be consulted in the Knowledge Database under View History.

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

UK-Canada mutual recognition of GMP certificates and batch testing continues

The MHRA has confirmed that Canada and the UK will continue to recognise Certificates of Good Manufacturing Practice (GMP) Compliance 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, following entry into force on 1 April 2021 of the comprehensive UK-Canada Trade Continuity Agreement (TCA) entered into force on 1 April 2021. For further details and a link to the TCA itself, please see the MHRA page at the following link: https://lnkd.in/eWZcrhS

New Ph. Eur. general chapter on cell-based assay for potency determination of TNF-alpha antagonists

A new draft general chapter on cell-based assay for potency determination of TNF-alpha antagonists (2.7.26) has been published in Pharmeuropa 33.2 and is open for public consultation until 30th June 2021. This new general chapter is the first in a series of three planned new “horizontal standards” for therapeutic monoclonal antibodies (mAbs). It covers the execution of four specific cell-based assay procedures and provides considerations on data analysis, system suitability, assay acceptance criteria and results evaluation, as well as best practices for the adjustment of assay conditions, addressing certain critical aspects. http://bit.ly/RealCMC-3yWvInr

Revised Ph. Eur. General Chapter on Particulate Contamination: Sub-visible Particles

A revised general chapter 2.9.19. Particulate Contamination: Sub-visible Particles has been published in Pharmeuropa 33.2. This revised chapter is the result of discussions held between the Japanese Pharmacopoeia and the United States Pharmacopoeia within the Pharmacopoeial Discussion Group (PDG). The revised chapter includes a harmonised procedure for each of the analytical procedures described and includes the following changes: the light obscuration particle count test allows the use of sample volumes less than 5 mL depending on the instrument capability, the microscopic particle count test no longer requires at least 10 units to be combined for small volume preparations, and a combination of fewer units for this test is permitted depending on instrument capability and sample properties. The chapter is open for public consultation until 30th June 2021.

http://bit.ly/RealCMC-3c8AMv8

 

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Last week’s round-up; 18 – 22 May 2020

EMA UPDATES – CENTRALISED PROCEDURE

The EMA has released several updates to its pre-authorisation and post-authorisation procedural advice for users of the centralised procedure. Some of the updates include:

 

The EMA now aims to respond to queries within 10 days instead of 5. Other changes as can be seen in the tracked documents linked here: https://lnkd.in/dpW7TF7

ICH PLOTS CLOSER COLLABORATION WITH PIC/S

The International Council for Harmonisation (ICH) Management Committee and Assembly has indicated that it intends to collaborate more closely with the Pharmaceutical Inspection Co-Operation Scheme (PIC/S) and that new topics and reflection papers are currently under development.

ICH Management Committee has proposed that the PIC/S would be involved in ICH guideline work relevant to regulatory assessor [MG1] and inspector disciplines, during the public consultation following Step 2b. Additionally as an ICH Observer, the PIC/S may also request to be part of Plenary Working Parties which would allow its involvement prior to Step 1.

A revised draft reflection paper on model-informed drug development and an update on a draft reflection paper on patient-focused drug development are also in the pipeline. The Biotechnology Innovation Organization has also proposed to develop a reflection paper on gene therapy harmonization. https://bit.ly/RealCMC-3eagyQe

PH. EUR. 2.4.35 EXTRACTABLE ELEMENTS IN PLASTIC MATERIALS FOR PHARMACEUTICAL USE

Pharmeuropa has released new supporting information on the new draft Ph. Eur. Chapter 2.4.35 ‘Extractable elements in plastic materials for pharmaceutical use’, which is open for consultation until the end of June 2020. The document proposes that the long‑established individual tests for specific elements are maintained in the Ph. Eur. general chapters on plastic materials, since the quality of plastic materials influences that of the containers manufactured from them.

In future, cross‑reference to this new general chapter will also be made in each existing Ph. Eur. text on plastic materials. The supporting information also indicates that all the existing Ph. Eur. general chapters on plastic materials should be revised to delete the heavy metals test and to perform the tests on target elements according to the new general chapter. https://bit.ly/RealCMC-3bUORJM

MHRA GUIDANCE- EFFECTIVE FIELD SAFETY NOTICES (FSNS) FOR MANUFACTURERS OF MEDICAL DEVICES

“Field Safety Notices (FSNs) are a key part of the medical device vigilance system. Manufacturers are required to inform users about corrective actions involving their device as soon as possible using a Field Safety Notice (FSN). Published on the 20th May by the MHRA to advise manufacturers on how to write clear FSNs to maximise response rates the guidance provides supplementary information to MEDDEV 2.12/1 rev 8 (how to write and distribute effective FSNs) and covers such topics as good traceability, content, effective targeting of FSNs and Field Safety Corrective Action (FSCA) strategy. Manufacturers are advised to read the document via the following link: https://bit.ly/36hrYiH.

2nd DIA – EUCOPE WORKSHOP ON ATMPs INNOVATIVE GENE AND CELL THERAPIES

We’re proud to have our Real expert, Dorothée Fouchier, attending the virtual 2nd Joint DIA-EUCOPE Workshop on ATMPs, Innovative Gene and Cell Therapies, next week alongside our industry peers to discuss the challenges, opportunities and political implications of advanced therapies. If you’re also attending, get in touch! To arrange a meeting visit: https://lnkd.in/dc_SDsr

FEE REDUCTIONS FOR GMP INSPECTIONS

The European Medicines Agency (EMA) has reduced the fee for on-site GMP inspections by 100%. This fee reduction is only applicable in cases where the GMP compliance of a manufacturing site with restricted access due to the COVID-19 pandemic, could not be confirmed via a distant assessment and an on-site inspection is, therefore, required. Fees for Plasma Master Files inspections will also be similarly reduced.

The EMA has also advised that during this initiative, remuneration to national competent authorities (NCA) will not be reduced, if the NCA provides a comprehensive inspection report for the distant assessment and a subsequent independent report for the on-site inspection. Further information is available here: https://bit.ly/RealCMC-2XbhKMr

EMAS INNOVATION TASK FORCE (ITF) NEW BRIEFING MEETING REQUEST FORM

The scope of EMAs ITF covers regulatory, technical and scientific issues arising from innovative medicines development, new technologies and borderline products. The objective of the interactions with the ITF is to facilitate informal exchange of information and guidance during the product development process. Interactions take the form of informal brainstorming discussions are led by experts from the Agency network, working parties and committees. These meetings are free of charge and 1.5 hours long. ITF has just issued a new briefing meeting request form in order to standardise company initial dialogue. The form can be found here: https://lnkd.in/dTK2axt

MHRA INSPECTORATE: HOW TO MANAGE TEMPORARY GDP PROCESS CHANGES AND RISKS THROUGH THE COVID-19 PANDEMIC

The MHRA inspectorate posted ‘How to manage temporary GDP process changes and risks through the COVID-19 pandemic’ on their blog on the 13th May to advise companies on how to manage changes to GDP processes to address exceptional circumstances that have arisen due to Covid-19. Such changes should be documented either as deviations, change controls or similar and incorporate quality risk management principles. Changes may be documented either as single reports or an over-arching one specific to COVID-19. The post has a link to GDP flexibilities introduced by the MHRA to assist with distribution of medicines during COVID-19 pandemic documented in ‘Guidance Exceptional GDP flexibilities for medicines during COVID-19’. The GDP flexibilities introduced cover Supply Chain, Transportation, RP, Facilities & Equipment and Reporting.

Companies applying these flexibilities need to report to Covid19.GMDP@ mhra.gov.uk as outlined in the guidance, however you only need to report once for each flexibility and reports don’t require approval to implement. The post can be accessed via this link: https://bit.ly/2LIjR5g

GETTING YOUR 505(b)(2) PRODUCT APPROVED IN EUROPE

The 505(b)(2) route to marketing authorisation in the United States has become very popular. Companies owning a product registered (or eligible to be registered) via this pathway might also wish to submit their product in Europe. Real Regulatory can help companies navigate the significant complexities involved in choosing an appropriate legal basis for submission, setting regulatory strategy and dealing with scientific advice and marketing authorisation procedures.

Read the linked article for an overview of the intricacies and the ways in which we can assist. https://lnkd.in/dzjU_Jj

NEW VERSION OF MHRA APPLICATION FOR ‘SPECIALS’ LICENCE

The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has released a new version of its ‘Application for new Manufacturer’s “Specials” Licence (MS) (Human Use).

To access the new version of the application form please see the following link: https://bit.ly/RealCMC-2ThytN4

Last weeks round-up; 20 – 24 January 2020

NEW REAL REPORT: EUROPEAN REGULATORY LANDSCAPE 2020

2020 will see changes to all regulatory landscapes including Clinical Trials, Medical Devices and Chemistry and Manufacturing Controls changes, with the hopes of implementing a robust and effective regulatory network. The focus is on the New Medical Device Directive and the Clinical Trial Regulations which are designed to keep current with technological and medical advances and help ensure safe and effective medicines and medical devices are delivered to patients. For more information, please see the following link: https://lnkd.in/dcf–H6

EMA AND HMA PROPOSES TEN RECOMMENDATION TO UNLOCK THE POTENTIAL OF BIG DATA FOR PUBLIC HEALTH IN THE EU

The joint Big Data Task Force of EMA and the Heads of Medicines Agencies (HMA) proposes ten priority actions for the European medicines regulatory network to evolve its approach to data use and evidence generation, in order to make best use of big data to support innovation and public health, in a report published 20th Jan 2020. Further details and a pdf of the report can be found here; https://lnkd.in/dB2Czi9

EMA REFLECTION PAPER ON GOOD MANUFACTURING PRACTICE (GMP) AND MARKETING AUTHORISATION HOLDERS (MAHS)

In general, the responsibilities for MAHs relate to outsourcing and technical agreements, 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. Further specific details can be found under the link below; https://lnkd.in/dGJb34u

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