Last week’s round-up; 22 – 26 June 2020

Mutual Recognition of European/US GMP Inspections

Earlier this month, the European Commission, EMA and the FDA held their 2020 bilateral regulatory dialogue meeting. Various topics were discussed including the mutual recognition of GMP inspections. In July 2019, the authorities fully implemented the MRA for certain human medicines, and in this month’s meeting the next milestones in this regard were tackled. These milestones include the expansion of the MRA to veterinary medicines and the inclusion of vaccines and plasma-derived products by July 2022 is under consideration.

EC: European Reference Networks (ERN) ecosystem to horizon 2030

In 2 virtual meetings organized on 17 and 18 June, the Coordinators and the Board of Member States shared information on initiatives put in place during the pandemic to support patients affected by rare diseases and to draw lessons for a potential second wave. They discussed the questions related to the on-going enlargement process of the ERNs through the recent inclusion of Affiliated partners and the forthcoming new members in 2021. They also spoke to the implications in terms of financing, use of the virtual consultation platform CPMS and integration of the ERNs within national systems. The discussions on the current system, then kick-started a brainstorming concerning a more long term vision of the whole ERN ecosystem by horizon 2030, that will continue for discussion in future meetings.

The entire press release can be found here:

EMA nominates Emer Cooke as new EMA Executive Director

At an extraordinary virtual session on 25 June, the Board of the EMA selected Emer Cooke from a shortlist of candidates created by the European Commission.Ms Cooke will now be invited to give a statement to the European Parliament’s Committee on Environment, Public Health and Food Safety (ENVI) on 13 July 2020. The appointment of the new Executive Director will be made after that meeting. Emer Cooke, an Irish national, is currently the Director of the Regulation and Prequalification Department at the World Health Organization (WHO) in Geneva.

Further details of the press release can be found here:

EMA Press Release:  Data requirements for phase 3 COVID-19 trials

Convergence on key aspects of phase 3 CT designs will help developers to generate robust evidence on potential COVID-19 vaccines and to consistently meet the needs of global regulators. This should expedite and streamline development and authorisation of vaccines against COVID-19. On 22 June in a workshop organised by EMA and FDA under the umbrella of ICMRA, global regulators focused on non-clinical and clinical data from early phase studies that are needed before proceeding with advanced (phase 3) trials, further details can be found here:

Nitrosamines and other unexpected impurities: lessons learnt

The European Commission, the EMA, national competent authorities in the EEA and the EDQM have issued recommendations that draw on lessons learnt from the presence of nitrosamines in sartan medicines, which are widely used to control blood pressure. With these recommendations, European regulators aim to clarify the roles and responsibilities of pharmaceutical companies and to amend the guidance on the control of impurities and GMP. The management of detected impurities, communication with patients and healthcare professionals, and international cooperation are also included in the recommendations. The European Network hopes that this guidance will help regulators and companies prevent and mitigate the risks of nitrosamines and other unexpected impurities in the future.

FDA, EC and EMA intensify collaboration

The EC, EMA and FDA have further intensified their collaboration through regular interactions, notably under the umbrella of the International Coalition of Medicines Regulatory Authorities (ICMRA). Topics discussed in the June meeting include; sharing experience and challenges on development of Covid19 vaccines, co-operation on therapies for ultrarare diseases, real world evidence, GMP mutual recognition agreements, orphan and pediatric medicines.

The full press release can be found here:

Free EMA SAWP protocol assistance for Academia

Free EMA SAWP protocol assistance for Academia Applicants from the academic sector can receive free protocol assistance for developing orphan medicines, as of 19 June 2020.   EMA offers this incentive to further encourage the development of medicines for rare diseases. The fee waiver for academia is available to: public or private highereducation establishments awarding academic degrees; public or private non-profit research organisation whose primary mission is to pursue research; international European interest organisations (as defined in Regulation (EU) No1290/2013).  Firstly, the applicant must be established in the EEA.  Secondly, the applicant must neither be financed nor managed by private for-profit organisations in the pharmaceutical sector, nor have concluded any agreement with any pharmaceutical companies about sponsorship or participation in the research project in question.

Full details of the scheme can be found here:

EMA SAWP meeting dates for 2021

EMA has issued dates for the 2021 SAWP meetings and deadlines for submission of scientific advice, protocol assistance, qualification of biomarkers and parallel consultation requests. Full details can be found under this link:

EC requests expression of interest in a consultation on voluntary sharing of market launch intentions

The EC has invited stakeholders to comment on a pilot project which will request prospective MAHs to declare their market launch intentions on a voluntary and confidential basis. The pilot aims to raise awareness of the limited roll-out of CP medicines in some EU Member States, and to improve regulators’ understanding of the reasons behind delayed market launch. The focus of the pilot will be on orphan medicines and medicines to treat cancer with the deadline for comments on 22 July 2020.

As link to the EC site can be found here:

Ph. Eur. Revised Raman Spectroscopy Chapter Public Consultation

The Ph. Eur. is seeking feedback on the revised draft chapter 2.2.48 on Raman Spectroscopy. Recent technological developments in Raman spectrometry have prompted several updates as well as the addition of new sections to the chapter: • Update of the section on response-intensity scale. • A new section on spectral resolution using calcium carbonate. • Procedures for the comparison of spectra have been included. The draft chapter is published in Pharmeuropa 32.3 and is open for public consultation between July and September 2020. Users who wish to submit comments but are unable to do so by the end of the consultation period due to COVID-19, are encouraged to contact their National Pharmacopoeia Authority in Ph. Eur. member states or the EDQM Helpdesk.

EC proposes relaxing GMO regulations for COVID-19 vaccines

The European Commission (EC) has proposed changes to the EU regulation of genetically modified organisms (GMOs), which would relax the requirements for the development of COVID-19 vaccines. The proposed changes would allow the clinical trials of GMO-containing candidate vaccines and COVID-19 treatments to start within the shortest possible timelines. The EC still plans to include an environmental risk assessment as part of the marketing authorization procedure for any products that fall under the proposed relaxed GMO regulations. These proposed regulations would also allow the distribution of medicinal products containing GMOs under a compassionate use exemption of Regulation (EC) No 726/2004. The EC has also indicated that this proposed regulation is temporary and is applicable only for the duration of the pandemic:

EMA: Updated procedural advice for orphan medicinal product designation

The EMA updated its procedural advice for orphan medicinal product designations on 15th June 2020. Applicants are now required to provide a description of the mechanism of action of their medicine in lay language in a maximum of 100 words. The text should describe as simply as possible the clinically relevant principle mechanism of action, in relation to the condition applied for. If orphan status is granted the text provided will be included in the public summary of the orphan designation published on the EMA website. The preferred format of the document is word format which should be submitted via IRIS with the other required documents listed in section 3.2 of the procedural advice.

Brexit:  Joint letter on the need for a Mutual Recognition Agreement (MRA) between the EU and UK

Six organisations from biopharma industry, including EFPIA and EUCOPE, have urged the EU to separate talks about post-Brexit regulatory cooperation from broader political negotiations. The plea is made amid fears the collapse of free trade talks will force a hard split between the UK and EU regulatory regimes. Particularly in current environment they stress it is crucial to ensure as much cooperation as possible with regard to regulatory processes and the import and export of medicines and medical supplies across UK/EU borders, in order to minimise delays in products reaching patients.

The letter in full can be found here: 

International Coalition of Medicines Regulatory Authorities (ICMRA) issues statements on vaccines to the public and HCPs

ICMRA has issued statements on vaccine confidence for the general public and on vaccine safety and effectiveness for HCPs. They explain the robust scientific and independent processes that medicines regulators worldwide follow, that ensure only vaccines that conform to the highest standards of safety and effectiveness can reach and remain on the market.

Full details of the statements in 7 languages can be found under this link:

Last week’s round-up; 01 -05 June 2020


We are delighted to have Michael Edwards join the team at Real Regulatory as a Senior Regulatory Consultant. Michael has worked in regulatory affairs since 2000, having held positions in the UK medicines competent authority, a couple of CRO/consultancies, a couple of small/medium pharmaceutical companies, and as an independent consultant, as well as taking some time out during that time to do post-graduate research and complete a PhD investigating the vascular bioactivity in vitro of the phenolic phytochemicals anthocyanins, and their in vivo degradation products or metabolites, in the Department of Nutrition at Norwich Medical School. His first degree was BSc Pharmacology with Toxicology (First) at King’s College London, including a year-long industrial placement in a large pharmaceutical company research centre. His regulatory experience includes clinical phase through post-marketing authorisation, national and European procedures. Michael will be a valuable asset to our company and to our clients.


At a recent virtual meeting of the ICH Assembly, the ICH has announced that Turkey’s Medicines and Medical Devices Agency (TITCK) is now one of its regulatory members and that Lebanon’s Ministry of Public Health (MOPH) is now a new observer. During the meeting, the Council also announced that the following guidelines have reached Step 4 in the ICH process: M8 electronic Common Technical Document (eCTD) v4.0 guideline; S11 Nonclinical Safety Testing in Support of Development of Paediatric Pharmaceuticals guideline; and S5(R3) Guideline on Revision of S5 Guideline on Detection of Toxicity to Reproduction for Human Pharmaceuticals. The Council has also announced that the Q3C(R8) guideline on residual solvents, which is currently under revision to include the permitted daily exposures for three new impurities, has reached Step 2 of the ICH process, and that the 4Q(R1) Common Technical Document (CTD) guideline will be revised.

Further updates given by the ICH during the Assembly may be found at the following link:


Joint procedural information is available from EMA and the FDA for medicine developers planning to submit a PIP to EMA and an iPSP, to the FDA, respectively, for a COVID-19 vaccine or treatment, the document can be found under this link

The joint document aims to make it easier for developers to submit paediatric development plans simultaneously to the regulators, to help speed up the development and approval of COVID-19 treatments and vaccines. Both agencies are encouraging medicine developers to submit PIPs and iPSPs early.


The FDA has just released 26 new and 43 revised draft product-specific guidances on the development of generic drugs. The documents are intended to clarify the FDA’s recommendations on demonstrating bioequivalence of generics to the corresponding reference products. The new drafts include recommendations to support ANDAs for generic versions of the acute myeloid leukemia drug gilteritinib, the PARP inhibitor talazoparib, the HIV-1 treatment dolutegravir/lamivudine, fish oil triglycerides, subcutaneous buprenorphine and extended-release metformin. The updated guidance documents include altered recommendations for generic versions of type 2 diabetes drugs dapagliflozin, dapagliflozin and saxagliptin, the renal failure treatment ferric citrate and transdermal buprenorphine.


The European Commission’s updated ‘Annex to the European Commission guideline on Excipients in the labelling and package leaflet of medicinal products for human use’ is effective from 22 November 2019. The guidance describes the information that should be available in the package leaflet on excipients that are known to have a recognised action or effect. In order to ensure compliance with the new guidance, marketing authorisation holders are required to submit a type IB variation within three years from the publication of the revised Annex. HPRA has pointed out that applicants should also be aware that some of the updates included in the Annex were also published in the previous version of the document, therefore, applicants are requested to submit the relevant variations by 9/10/2020.


New measures for all UK arrivals have been announced, including a 14 days’ self-isolation for anyone entering the UK, apart from a “short” list of exemptions. At moment of writing, these measures are due to come into effect on 8 June, although this could change given the backlash from the UK travel industry. The “short list of exemptions” is not really all that short, and amongst the many listed are including the following of note to the pharmaceuticals and clinical trials sectors: qualified persons and responsible persons for human medicines, clinical trials and pharmacovigilance quality assurance inspectors for human medicines sponsors and essential persons needed for clinical trials or studies The new measures can be found at:

The list of exemptions can be found at:


Horseshoe crabs’ blood has long been used in the pharmaceutical industry to detect the presence of bacterial endotoxins, causing concern amongst animal rights groups who are pushing for the use of synthetic alternatives. The USP Microbiology Expert Committee had proposed the inclusion of synthetic recombinant factors in ‘Chapter 85 Bacterial Endotoxins’. Based on public comments received, this will not happen. Instead, a new general chapter will be drafted, to provide guidance on the qualification of alternative tests by demonstrating comparability: <1085.1> Use of Recombinant Reagents in the Bacterial Endotoxins Test – Photometric and Fluorometric Methods Using Recombinantly Derived Reagents The proposed new general chapter should be available for public consultation by November 2020. More information may be found at the following link:

This matches the approach taken by Ph. Eur. in 2016 when ‘Chapter 5.1.10 Guidelines for Using the Test for Bacterial Endotoxins’ was updated. Ph. Eur. is further ahead as it has already published a new section ‘2.6.32 Test for bacterial endotoxins using recombinant factor C’ in supplement 10.3, effective from 1 January 2021.


The European Medicines Agency (EMA), European Commission and Heads of Medicines Agencies have updated their ‘Questions and answers on regulatory expectations for medicinal products for human use during the covid-19 pandemic’. The guidance document now includes a new section on temporary flexibilities for good manufacturing practice (GMP) and good distribution practice (GDP) that pharmaceutical companies may employ during the pandemic to ensure an adequate supply of medicines used to treat COVID-19 patients. A new section on the suspension of on-site inspections of plasma collection centres has also been included. Temporary flexibilities related to the duties of the responsible person (RP), the use of new equipment or newly authorized storage and distribution sites, and deviations from normal practice are also discussed in the document. Further information is available at the following link:

Last week’s round-up; 4 – 8 May 2020


EMA has published an overview of how the Agency will accelerate its regulatory procedures so that marketing authorisations of safe, effective and high-quality COVID-19 related medicines can be granted as soon as possible. The rapid procedures described in the inventory can accelerate every step of a medicine’s regulatory pathway and the Agency is fully mobilised to deliver these fast-track assessments in the shortest possible timeframes while ensuring robust scientific opinions are reached. The text of the press release can be found under


In particular, EMA will review applications for a PIP, deferrals or waivers for treatments and vaccines for COVID-19 in an expedited manner, in order to speed up an approval. The compliance check can also be expedited, if needed. For these products,

      1. No pre-specified PIP submission deadlines;
      2. Review of a PIP is reduced to a minimum of 20 days;
      3. EMA decision following a review is reduced to 2 days;
      4. Compliance check can be reduced to 4 days.


There is also a possibility for the developer to provide a focused scientific documentation, to be agreed on a case-by-case basis. Full details can be found under this link


EMA’s Scientific Advice Working Party (SAWP) has updated meeting dates in September 2020. The full tabulations under link include deadlines for submissions for scientific advice, protocol assistance, qualification of biomarkers and parallel consultation EMA/EUnetHTA requests.


An updated draft of the impurities guideline for residual solvents, ICH Q3C (R8), has been published. ICH Q3C recommends acceptable amounts for residual solvents in pharmaceuticals, and this draft only contains information on three additional solvents: 2-methyltetrahydrofuran, cyclopentyl methyl ether, and tertiary-butyl alcohol.

The Permitted Daily Exposure (PDE) for each has been set at 50mg/day, 15mg/day and 35mg/day respectively. The document is open for consultation until 30 July 2020. Once agreed upon, this data will be integrated into a complete ICH Q3C (R8) guideline document:


The EMA has released a new Clinical pharmacology and pharmacokinetics Question & Answer. The new Q&A (4.12) clarifies the EMA’s position on the demonstration of bioequivalence for the anticoagulant drug dabigatran etexilate. The following clarifications are provided:

        • A bioavailability study under fed conditions may not replace the comparative bioavailability study with proton pump inhibitors.
        • Dissolution tests at various pHs may not replace the comparative bioavailability study with proton pump inhibitors.
        • Demonstration that the effect of proton pump inhibitor on the bioavailability of dabigatran is equal or less than for the innovator product, is not sufficient.


Bioequivalence should also be demonstrated in the presence of proton pump inhibitors. Further details are available here:


A promising new model of the gastrointestinal tract could speed up drug development. Created by MIT engineers, the model tests how well drugs are absorbed in the small intestine and should help oral drug formulation. The model uses pig intestinal tissue, and more closely replicates the human intestine than the currently used approach of testing these formulations in human colorectal cancer cells.

The system can be used to test up to 10,000 samples per day and its results have been found to be 90% accurate, through tests carried out using 60 drugs already approved by the FDA. In contrast, tests using colorectal cancer cells have a near 50% percent accuracy:


The FDA has released draft guidance explaining how combination product developers can demonstrate that their emergency-use injectors will reliably deliver drugs as intended in a life-threatening emergency. The draft guidance specifically applies to emergency-use injectors that are prefilled or co-packaged with emergency drugs or biologics. The document expands on FDA’s ‘Technical Considerations for Pen, Jet, and Related Injectors for Use with Drugs and Biological Products’ guidance that was released in 2013.

The “FDA recommends that emergency-use injectors include design control specifications for successful injection reliability of 99.999% with a 95% level of confidence”, which ensures that the emergency-use injector performance is as safe and reliable as possible as well as feasible. The guidance also provides a model for establishing reliability and recommendations for completing a reliability report to submit premarket submissions for these products.


The European Commission has released some new questions and answers on regulatory expectations for medicinal products for human use during the COVID-19 pandemic. The document includes the following guidance (questions 2.2 – 2.4) on the manufacturing and importation of finished products and active pharmaceutical ingredients:


The EC has released the above guidance in order to prevent disruptions in the availability of medicines during the pandemic.

Last weeks round-up; 6 – 10 January 2020


CMDh has amended the Q&A on the impact of EU-USA Mutual Recognition Agreement on marketing authorisation applications and relevant variations. In particular, Q1 has been changed in relation to the documentation to be submitted in EU as proof of GMP compliance for US manufacturing sites that have been previously inspected by US FDA. Further information can be found under this link


On the 17th of December, the EMA announced the launch of a pilot programme which would see cooperation between European and International partners of the EMA in the inspection of sterile medical device manufacturers. This programme would improve oversight of manufacturers as well as reduce the likelihood of duplicate of inspections. For further information, please see the following link:


Europe as a Centre for Regulatory Excellence – The journey

Chair: Lorraine Nolan, Chief Executive, HPRA, Ireland


Lorraine Nolan welcomed attendees to Dublin and introduced the session, asking attendees to answer a few questions using the mobile app, to show the demographics of the attendees (e.g., which area of regulatory affairs they work in and how many years of regulatory experience they have) and what the attendees saw as key developments going forward (real world evidence(RWE) and artificial intelligence (AI) were the top answers).

Pär Tellner gave the industry view regarding whether Europe is a centre for regulatory excellence. On the positive side, the EU review procedure is predictable with clear timelines; the EU Centralised Procedure (CP) system of having both a rapporteur and a co-rapporteur ensures continuity; the EU system is an example and inspiration for other regions, e.g., Eurasian Economic Union; and the EMA’s coordination role for joint HTA/regulator scientific advice (SA), Priority Medicines (PRIME) scheme and Regulatory Science Strategy to 2025 are great examples of regulatory excellence. However, there are also areas with potential for improvement: EU approval times are generally longer than for US and Japan; the perception amongst EFPIA companies is that the US FDA is more open to accepting data from complex clinical trials (CTs) and RWE (although no evidence that this is in fact true); there is insufficient consistency at all levels of the network, e.g., paediatrics; EMA SA timelines are too long at 4-6 months; and processes for drug-device combinations and biomarker validation need to be optimized. The risk is that new active substance submissions will be submitted first in US, Japan and China, with European submission only later in a second wave.

Representing the EMA, Anthony Humphries asked how can the EMA be future-proofed, and what should the agency be doing in the next 5 years? The EMA holds technology platform meetings with companies to find out what new technologies they are developing. EMA is trying to: foster innovation in CTs, e.g., methodological complexity, multiplicity and digital therapeutics; promote use of high quality real world data (RWD) with involvement of patients across the product life-cycle; encourage health technology assessment (HTA) preparedness for faster patient access; keep abreast of medical innovations in diagnosis, e.g., genomics and AI. The goal is to provide an environment that fosters innovation, not to set up hurdles, in order to ensure availability of safe and effective medicines.

Greet Musch provided a national competent authority (NCA) view, discussing the Heads of Medicines Agencies (HMA)-EMA regulatory framework common strategy, which focuses on four areas. First, innovation, which requires the medicines agencies to reach out to the medical technology sectors to develop a more holistic view of the different regulatory initiatives, e.g., interplays of CT Regulation with IVD Regulation; seek out critical expertise and focus on innovative CT designs. Second, availability/accessibility of medicines, which requires reaching out to HTA bodies, payers, health care providers and patient both from an early stage and during the product life-cycle; and enhancing international alignment. Third, use of data analytics and AI in decision making, with use of RWD/RWE and digitalization of CT and manufacturing processes. Fourth, sustainability and operational excellence of the regulatory network, with a leaner iterative process to enhance return on investment with innovation committees linking together existing groups, e.g., SAWP-CTFG-EUNetHTA, CTFG-PDCO; and development of NCAs as centres of excellence.

Florian Schmidt presented the European Commission view, admitting that there are challenges for the system now with new political leadership due in November 2019.  However, divergences are being addressed with medical devices being considered now also under the same DG with medicines and setting the dual priorities of supply of affordable medicines whilst still supporting innovation to keep the EU at the forefront of development.  Innovation is of no help if it doesn’t reach the patient, so access and availability are focus areas. The recent nitrosamines issue has raised the question of whether the EU quality system is strong enough, with more global diversity in supply introducing more risk. With the rise in ATMPs, drug/device combinations, use of AI in CTs and post-market, is the EU regulatory system still fit for purpose? These changes in paradigm must affect the regulatory framework.

During the panel discussion, the following key points emerged for future action to keep Europe a centre of regulatory excellence: