February 2023
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in February 2023 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

Reporting organic impurity content

For impurities <1.0%, report results to two decimal places (e.g. 0.06%, 0.13%).  For impurities ≥1.0%, report results to one decimal place (e.g. 1.3%). All impurities above the reporting threshold should be summed and reported as total impurities. When comparing to a reporting, identification or qualification threshold, the result should first be rounded to the same decimal place as the threshold. Thresholds have to be exceeded to apply.

 

Ph. Eur. status in Europe

As the official pharmacopoeia in the European Economic Area (complemented by national pharmacopoeias where relevant), the Ph. Eur. helps define the requirements to obtain a marketing authorisation. The quality standards it contains are legally binding. However, appropriately validated, alternative test methods (though not specifications) can be submitted for approval by competent authorities during MA application procedures.

 

Ph. Eur. status in Britain

Many people think that the Ph. Eur. is a publication of the EU. It is not! It is published by the Council of Europe, an organisation completely distinct from the EU. The United Kingdom remains a member of the Council of Europe and party to the Convention on the Elaboration of a European Pharmacopoeia irrespective of Brexit. Therefore, the Ph. Eur. remains legally binding in the UK.

 

Checking CEPs

Upon receipt of a certificate of suitability, check that it is complete i.e. all pages are present and all Annexes attached. Check the EDQM Knowledge Database to ensure that the CEP is current and valid. Before submitting the CEP to a competent authority, make sure that the Declaration of Access has been completed by the CEP holder, authorising you to use the document.

 

 

 

February 2023
Real Regulatory Tips and Insights

Please find below a roundup of our weekly Regulatory Tips and Insights from our Regulatory experts on our Real Regulatory LinkedIn page. The tips we published in February 2023 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

Digital Application Dataset Integration (DADI) project – web-based variation form for human medicinal products launching in October 2022

The European Medicines Agency will launch the electronic application form (eAF) variations web form in October 2022 – this will be the first release of a web-based variation form for human medicinal products, and will be limited to centrally authorised products at go-live. A subsequent release of the form in March 2023 will cover all types of European variations procedures. Further details are available on the eSubmissions website: https://esubmission.ema.europa.eu/cessp/cessp.htm

 

eTMF Quality Control and Audit Preparation Advice

Don’t wait for notification of Health Authority Audit to begin considering Sponsor Functional QC (SFQC) Checks on your eTMF! Real Regulatory specialises in performing SFQC checks on eTMF. Inadequate or incomplete filing of eTMF documentation can be a cause of major findings in an audit but is easily allayed by consistent and pre-emptive SFQCs.

 

Industry Single Point of Contact (i-SPOC) Registration Required

MAHs should register their Industry Single Point of Contact (i-SPOC) on the EMA IRIS platform by 2 September 2022. The i-SPOC will inform and facilitate rapid communication with EMA about the supply and availability of critical medicines identified in the context of ‘public health emergency’ or a ‘major event’. Registration in IRIS is a two-step process and MAHs should allow 5-10 working days for the process to be completed. EMA has updated the IRIS user guide and published a video demo to support companies with registration. https://www.ema.europa.eu/en/human-regulatory/post-authorisation/availability-medicines#industry-contact-points-for-supply-and-availability-of-critical-medicines-(new)-section https://www.ema.europa.eu/documents/other/iris-guide-applicants-how-create-submit-scientific-applications-industry-individual-applicants_en.pdf

 

 

 

January 2023
Real Regulatory Tips and Insights

Please find below a roundup of our weekly Regulatory Tips and Insights from our Regulatory experts on our Real Regulatory LinkedIn page. The tips we published in January 2023 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

Importing investigational medicinal products (IMPs) into Great Britain from an approved country – end of transition period

Remember that the holder of an MA, as the person or entity responsible for placing a product on the market, bears the legal responsibility for that product and this cannot be delegated. Where activities such as manufacture are conducted by third parties, an MAH must ensure that they have - and can demonstrate - adequate oversight of these activities.

 

IRIS-Scientific Advice

From October 2020 it has been mandatory to use the IRIS platform when applying to the EMA for scientific advice. Applicants should be aware that, where they wish to apply for follow-up scientific advice and the original advice was given to a different organisation, that organisation needs to transfer the original procedure to the applicant. This is accomplished within IRIS using the process type ‘Transfer of Scientific Advice’; procedures occurring prior to October 2020 should be available for selection within IRIS.

 

Transferring a Research Product Identifier (RPI) in IRIS

For certain types of scientific procedures in the EMA’s IRIS portal, you first need to create an RPI for your research product. Remember that, if the product is subsequently transferred to a new sponsor/owner, you will also need to transfer the RPI to this organisation if they need to create new procedures based on the RPI – for example initial scientific advice or a new orphan designation. Full details are available in the IRIS guide to registration, available at: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/iris-guide-registration-rpis_en.pdf.

 

 

January 2023
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in January 2023 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

Reporting impurities

ny impurities present above the reporting threshold should be reported individually. Reporting a ‘maximum observed impurity’ provides very little information on the analyte’s impurity profile, especially when trying to observe trends during stability studies. For in-house evaluation, it is preferable to individually report all impurities at or above the LOQ.

 

Dissolution profiling of biobatches

Study the dissolution profiles of your bioequivalence study batches in as many media using as many different test parameters as possible. Characterisation of biobatch dissolution will form the basis for your dissolution specifications throughout your product’s lifecycle. The more information you collect, the more thankful you’ll be years down the line.

 

Specifications in the Dossier

 

Specifications presented in a marketing authorisation application should be numbered and dated. Many assessors will insist on this, and it is good practice in any case, for traceability. It is advisable to create an SOP laying out the numbering system and linking back to in-house specifications.

 

Polymorphism

For polymorphic drug substances, you need to demonstrate that: 1. The same form of the drug substance is consistently synthesized and does not change during the retest period. 2. Conversion to a different form does not occur during finished product manufacture and shelf-life. If conversion does occur, you will have to show that product performance, safety and efficacy are not affected.

 

 

 

December 2022
Real Regulatory Tips and Insights

Please find below a roundup of our weekly Regulatory Tips and Insights from our Regulatory experts on our Real Regulatory LinkedIn page. The tips we published in December 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

MA Holder & Delegated Activities

Remember that the holder of an MA, as the person or entity responsible for placing a product on the market, bears the legal responsibility for that product and this cannot be delegated. Where activities such as manufacture are conducted by third parties, an MAH must ensure that they have - and can demonstrate - adequate oversight of these activities.

 

Questions & Commitments from Prior Submissions

For amendments to CTAs and variations to MAs, it’s always worth checking prior submissions for questions or commitments relevant to the current submission. For example, an updated investigator's brochure should always incorporate any comments made by authorities on the previous version, or the comments may be raised as questions or findings on the updated version.

 

EMA QRD Guidance Documents

If you are preparing documents using the EMA QRD templates, remember that there are reference documents available concerning formatting conventions, use of abbreviations, past QRD recommendations etc. These can be found on the EMA website at: https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/product-information/product-information-reference-documents-guidelines

 

EMA Christmas Closure

EMA Christmas Closure The EMA will close for Christmas from 23rd Dec 2022 – 3rd Jan 2023

 

 

 

December 2022
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in December 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

SOPs in the Dossier

Resist the temptation to include SOPs in an IMPD or Module 3. SOPs invariably contain excess information that is not relevant to a regulatory application. Instead, get an experienced regulatory technical writer to pare down your manufacturing and analytical procedures to the essentials for presentation in the dossier.

 

Mass Balance

Take a long, hard look at your stability results. Is any reduction in assay accompanied by a corresponding increase in degradation products? If not, you have a mass imbalance which you should investigate thoroughly. Mass imbalances are normally due to analytical deficiencies but can happen for other reasons e.g. API sublimation.

 

Reviewing an IMPD or Module 3

When preparing to submit a clinical trial or marketing authorisation application, get one experienced reviewer to read the IMPD or Module 3 from cover to cover. In our experience, he or she will uncover a surprising amount of inconsistencies that reviewers of individual sections will not catch.

 

 

November 2022
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in November 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

Updating a QOS

It is good practice to keep your Quality Overall Summary fully updated at all times, even if not strictly required by competent authorities. When done properly, the QOS focuses on the salient points of Module 3 and can be used to quickly familiarise staff, QPs and consultants with a product (as well as to refresh one’s memory!)

Compatibility

Section 3.2.P.2.6 of the CTD is only applicable if reconstitution diluents or dosage devices are required to administer the product. Information on the compatibility of the drug product with any diluents or devices (e.g. precipitation, sorption, stability) should be provided. Compatibility with excipients and the container closure system is tackled elsewhere.

Reduced testing of starting materials

Reduced or skip-lot testing of starting materials (APIs, excipients and packaging materials) is fully covered by EU GMP and is not product-specific. Therefore, in the relevant specifications in the MA application you should not include any reference at all to reduced testing on receipt by the finished product manufacturer. CMC assessors will object if you do.

Finished product assay limits

Finished product assay limits at release of ±5% are acceptable in the EU without further justification. Wider limits (even if based on pharmacopoeial monographs) have to be soundly justified based on production variability, the analytical test procedure, stability data and other relevant considerations. This differs from the North American norm, where assay limits at release are typically ±10%.

Ingredients in the eAF

When preparing to submit a European MAA, make sure that the dropdown lists in the eAF include all the ingredients your formulation contains. If not, you will need to get in touch with EMA in advance to get the ingredient included in the lists. So don’t leave it till the last minute.

November 2022
Real Regulatory Tips and Insights

Please find below a roundup of our weekly Regulatory Tips and Insights from our Regulatory experts on our Real Regulatory LinkedIn page. The tips we published in November 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

Clinical study reports and the ICH template

When preparing a clinical study report, it’s always worth remembering that the ICH E3 structure and content guideline is guidance and not a template, as noted in Q1 of the E3 question and answer document (available at https://database.ich.org/sites/default/files/E3_Q%26As_R1_Q%26As.pdf). ICH E3 is not an absolute set of requirements and flexibility may be needed depending on the nature of each particular study.

EMA guidance on CSR signatures and appendices

Two useful guidance documents for CSRs are available on the EMA website, which cover inclusion of appendices to CSRs in MAAs (https://www.ema.europa.eu/en/documents/scientific-guideline/note-guidance-inclusion-appendices-clinical-study-reports-marketing-authorisation-applications_en.pdf), and designating the coordinating investigator signature of CSRs (https://www.ema.europa.eu/en/documents/scientific-guideline/note-guidance-coordinating-investigator-signature-clinical-study-reports_en.pdf).

Clinical Trial Comparators

Do you have comparator drugs in your EU clinical trial? Keep section D of your initial Clinical Trial Application form as open as possible. If your protocol allows, it is possible to identify comparators via active substance or INN, and not specify the manufacturer or marketing authorization holder on the form. Maintaining this flexibility may allow you to change supply during the trial, without needing to submit an amendment to authorities.

Clinical Trials: Planning for EU sites

If you are planning to run a clinical trial in the EU, check the Clinical Trials Facilitation Group website (https://www.hma.eu/ctfg.html) "key documents list" for the latest guidance. The CTFG guidance is not included in EudraLex Volume 10, but does include important EU guidance on, eg, clinical trials safety, contraception recommendations, and trial management during the COVID-19 pandemic, amongst others.

 

 

Otober 2022
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in October 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

Acceptance Criteria for Microbiological Quality

Ph. Eur. and USP acceptance criteria for microbiological quality are interpreted as follows: - 101 CFU: maximum acceptable count is 20 not 10 - 102 CFU: maximum acceptable count is 200 not 100 and so on. This seems counterintuitive, but the leeway is meant to allow for the poor accuracy and precision of microbiological enumeration.

EPCRS

When a European Pharmacopoeia Chemical Reference Substance is available, European competent authorites will generally expect it to be used as the primary standard for the in-house qualification of secondary (working) standards. Other sources of primary standards are considered less authoritative in the region.

Structuring Module 3

A well-structured dossier is so much easier to evaluate. If you wish to facilitate review, list tests in the same order throughout the dossier: in the specifications table, when describing analytical procedures, when justifying specifcations, on COAs, and in the batch analyses and stability tables.

 

 

October 2022
Real Regulatory Tips and Insights

Please find below a roundup of our weekly Regulatory Tips and Insights from our Regulatory experts on our Real Regulatory LinkedIn page. The tips we published in October 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

Clinical Trials: Substantial Amendments

If there is no change in the substantial amendment that affects the EudraCT (Annex 1) Form other than the Protocol version number and date, then you should not include an updated EudraCT Form in the submission package.

eVariation eApplication Forms

When applying for a grouping of variations, particularly large groupings, ensure that all the required types of application are selected in Section 1 of the eAF before proceeding to choose the types of changes required in Section 3. Any changes (both the addition and deletion of variation types) made to Section 1 will automatically result in the loss of all changes selected and details entered in Section 3, and Section 3 will need to be completed again from scratch.

Clinical studies and sponsor responsibilities

For a sponsor of a clinical study, it must be remembered that the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor, even if some or all of the tasks associated with conducting the study are outsourced to third parties. Sponsor oversight of a study is a key element of the sponsor’s responsibilities under ICH E6(R2) (available at https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf)

Submission of renewals to HPRA

Based on the most recent update of the HPRA Guide to Renewal of Marketing Authorisations: - Products authorised under Directive 2001/83/EC may follow a shortened renewal procedure, i.e. a 30-day timetable under certain circumstances. The applicant should submit a cover letter and an application form (without annexes) with a declaration that full documentation will be available for submission upon request. Changes to MA particulars will not be accepted during the shortened renewal procedure. - It is no longer necessary to submit product information at the end of the renewal procedure unless minor editorial changes are being introduced. In these cases revised product information should be submitted as the agreed national text

 

 

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