Last week’s round -up;
14-18 December 2020

The Ph. Eur. Commission’s 168th session

The 168th session of the Ph. Eur. Commission was held between the 24th and 25th November 2020, during which the Commission adopted 114 texts for publication in Ph. Eur. Supplement 10.6, including 101 revised texts and 13 new texts. The new texts include several individual monographs and the following general chapters: Particulate contamination: sub-visible particles in non-injectable liquid preparations (2.9.53), Balances for analytical purposes (2.1.7), N-Nitrosamines in active substances (2.5.42) and Contaminant pyrrolizidine alkaloids (2.8.26).

Ph. Eur. Supplement 10.4 – Updates to CEP Applications

Ph. Eur. Supplement 10.4 is now available and CEP holders are invited to update their applications according to the revised monographs that will be implemented on the 1st April 2021. More information and instructions may be found at the following link:

New & Updated Guidance available from UK MHRA

The UK MHRA has issued some new guidance regarding what clinical trial Sponsors need to do to supply investigational medicinal products (IMPs) from Great Britain to Northern Ireland from 1 January 2021, and some updated guidance regarding the supply of authorised medicines to Northern Ireland during the period 1 January – 31 December 2021. They have also issued some new/updated guidance on how to register medical devices for the markets in Great Britain and Northern Ireland from 1 January 2021. Further information is available at

New policy for dissolution and disintegration testing in Ph. Eur. monographs

A new policy for dissolution and disintegration testing in Ph. Eur. monographs has been adopted by the Ph. Eur. Commission. A dissolution or disintegration test will be included in each medicinal product monograph on an immediate-release solid dosage form. Details of the scope of such a test and the conditions for its use in an MA application will be included in the General Notices (Ph. Eur. Chapter 1), which will be published in Supplement 10.6.

The revised General Chapter states that when a dissolution test is described in an individual monograph on a medicinal product, the applicant may either select the monograph dissolution test or develop an in-house dissolution test as the product-specific dissolution test. In either case, the applicant should also demonstrate the suitability of the selected test to the competent authority. Also, when tested, the medicinal product should comply with the monograph dissolution test, unless otherwise justified by the applicant.

UK Public Assessment Report for the Pfizer/BioNTech COVID-19 vaccine added to MHRA website

UK MHRA has added the Public Assessment Report for the Pfizer/BioNTech COVID-19 vaccine (BNT162b2) to their website. Please use the link below to access the PAR for this vaccine, as well as the Information for Healthcare Professionals (Summary of Product Characteristics), the Information for UK Recipients (Patient Information Leaflet), and the Conditions of Authorisation under Regulation 174 of the UK Human Medicine Regulations 2012 (as amended).

EMA issues update to the guideline on Quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells, which becomes effective from 1st June 2021.

The original guideline was developed way back in 2010-2011, before the first gene therapy medicinal product based on genetically modified cells was authorised. Thus this revision reflects the significant experience gained since then. Novel technologies that were not even on the horizon in 2010 are now commonplace: including CAR-T cells, induced pluripotent stem cells and genome editing. Therefore, this revision incorporates guidance on genetically modified cells developed using these novel technologies. The updated guidance and the original guidance can be found under this link (more…)

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.

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’.

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: 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.

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:

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. 


Last week’s round-up;
20-24 July 2020

MHRA News: Medical Device “Certificates of Compliance” / “Attestation of Conformity” have no legal standing under MDR

Certificates of compliance or Attestation of Conformity documents have no legal standing under the UK Medical Device Regulations 2002 (UK MDR). They are not evidence that the manufacturer of the device has met the requirements of the UK MDR, nor are they CE Certificates. The certification body may have issued these following a review of the technical documentation for the medical device. However, this is not a regulatory requirement and so the certificate issued has no regulatory validity. Evidence of registration and declaration of conformity are documents of regulatory validity and may be requested from the manufacturer or the EU Authorised Representative.

New EMA guideline on Water quality for pharmaceutical use

The EMA has issued a new guideline on the quality of water for pharmaceutical use that will replace its current guidance and position statement on water quality when it takes effect in February 2021. The new guideline applies to the manufacture of active substances and drug products for both human and veterinary use, ATMPs and where relevant, to IMPs, and should be consulted for new marketing authorization applications and variations to existing authorizations.

Recommendations are provided with respect to the minimum acceptable quality of water for different uses and applications, including the manufacture of sterile and nonsterile medicinal products, active substances and water used for cleaning and rinsing equipment and containers/closures for pharmaceutical products. This new guideline should be read in conjunction with EMA’s 2017 Questions and answers on production of water for injections by non-distillation methods – reverse osmosis and biofilms and control strategies document.

EC has issued an updated draft Q&A on the Clinical Trials Regulation (CTR)

EC has issued an updated draft Q&A on the Clinical Trials Regulation (CTR). Updates to this draft document are as follows:


There are various modifications to section 7 on safety reporting and it includes a new question 7.19 which clarifies how RSI for the development of biosimilar drug products should be written.

MHRA to return to on-site GxP Inspections

MHRA is currently making careful preparations for a safe return to normal UK on-site inspection scheduling. During the last few weeks they have been engaging with industry trade associations and the NHS to discuss the practical arrangements that may be required to facilitate on-site inspection starting in September and scaling up to a full programme from October 2020. The conduct of the inspections will vary according to the requirements of each GxP area and may include a hybrid model of on- and off-site activities that support a single inspection cycle.Further information will be made available later in the summer. Details of the announcement can be found here:

Pharmeuropa 32.3 Public Consultation

Pharmeuropa 32.3 is now available for public consultation and includes 48 new and revised draft texts. A list of the draft texts is available for perusal at the link below, and it includes draft monographs on Raman spectroscopy, Extractable elements in plastic materials for pharmaceutical use and Cyclo-olefin polymers. These draft monographs are not currently considered official standards, however, once they are adopted by the Ph. Eur. Commission they will become applicable and the legally binding standards for the products concerned in all Ph. Eur. member states. Users should submit their comments by the 30th September 2020.

EMA sets up infrastructure for real-world monitoring of COVID-19 treatments and vaccines

EMA has set up an infrastructure to support the monitoring of COVID-19 treatments and vaccines when used in day-to-day clinical practice. This is underpinned by three contracts for observational research that EMA has signed with academic and private partners, to be ready to effectively monitor vaccines performance in the real world, and to support the safe and effective use of both vaccines and medicines.The latest contract was finalised in mid-July with Utrecht University and the University Medical Center Utrecht as coordinators of the CONSIGN project (‘COVID-19 infectiOn aNd medicineS In preGNancy’).

This project will collect data on the impact of COVID-19 in pregnancy. In June, EMA contracted the company IQVIA with a project to build a framework for the conduct of multicentre cohort studies on the use of medicines in COVID-19 patients. In May, EMA commissioned the ACCESS project (‘vACcine Covid-19 monitoring readinESS’) for preparatory research into data sources and methods that can be used to monitor the safety, effectiveness and coverage of COVID-19 vaccines in clinical practice, once authorised.Full discussion on the supportive infrastructure and other aligned collaborations, can be found here:

Quality Risk Management – Transportation Risks

Quality Risk Management (QRM) in transportation tends to be a significant weakness for many wholesalers, according to the MHRA inspectorate. A new blog post by the department details one practical approach for ensuring good transportation QRM, based on the theory within ICH Q9. It covers risk assessment, control, communication within and outside the organisation, and periodic review. Common weaknesses seen by inspectors are also listed, such as QRM not being understood by managers or being used as an excuse to avoid developing appropriate mitigation:

Medical Device Coordination Group (MDCG) issues a template for Clinical Evaluation Assessment Reports

MDCG has issued a new template for clinical evaluation assessment reports, which will be used by NBs to clearly document the conclusions of its assessment of the clinical evidence presented by the manufacturer in the clinical evaluation report (CER) and related clinical evaluation that was conducted. This is a core requirement of the Medical Device Regulation (EU) 2017/745 (MDR). As part of the assessments performed NBs will assess the suitability of using data from claimed equivalent devices, clearly document its conclusions on the claimed equivalence, and on the relevance and adequacy of the data for demonstrating conformity.

The NB will verify that the clinical evidence and the clinical evaluation are adequate and shall verify the conclusions drawn by the manufacturer on the conformity with the relevant general safety and performance requirements. Finally the NB will consider the clinical evaluation and the benefit-risk determination, and whether specific milestones need to be defined to allow the notified body to review updates to the clinical evidence that result from post-market surveillance and PMCF data. The document in full can be found here:

Public consultation extension of Ph. Eur. nitrosamine analysis chapter

Following the closure of the public consultation for the new Ph. Eur. general chapter on the analysis of N-nitrosamine impurities in active substances (2.4.36), the EDQM is now accepting comments from stakeholders who were not able to take part in the consultation due to restrictions brought on by the COVID-19 pandemic. The general chapter proposes three procedures relying on GC-MS, LC-MS/MS and GC-MS/MS analytical techniques, which cover seven N-nitrosamine impurities. The stakeholders concerned are required to contact their respective national pharmacopoeia authority (NPA) or the EDQM as soon as possible in order to announce their intent to comment. Comments will be received until the 31st August 2020.


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.

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

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.

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:

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.

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:

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: 


Ongoing Clinical trials during COVID-19: Common issues and EU regulatory expectations

Due to the success of our recent webinar, we shall be running it again. We hope you can join us!

Will you be joining us at our complimentary webinar?

Join us on Thursday 18th June for a complimentary webinar presented by Real Regulatory team members Tessa Fiorini Cohen and Louise Spencer. The webinar will focus on the impact of COVID-19 on ongoing clinical trials within the EU and related regulatory expectations. Risk assessment and regulatory reporting requirements will also be tackled through specific examples encountered by RRL.

Register here:

Presenters : Tessa Fiorini-Cohen and Louise Spencer

Last week’s round-up;
08 – 12 June 2020


Disinfectant residues can pose various risks to a cleanroom environment, and there is renewed focus on best practice related to their prevention and removal. Current industry thinking is that any residual chemical is a potential contaminant to a process and possibly to product, and regulators are showing increased concern over residual disinfectants. This article gives an overview on why these residues matter, their main sources, and how to assess related risks. It also explains ways to tackle these residues, including through a routine residue removal program, instituting “low-residue” disinfectant formulations, and focusing on operator training to control application:


The EMA’s SME office has just issued their annual report for 2019. It makes for interesting reading. Some of the highlights include the highest ever number of registered SMEs with 12% created over the last 3 years. Product pipelines include 27% Orphan Medicines, 10% advanced therapies, 12% paediatric medicines and 25% generic medicines. Noteworthy too is the number of positive PRIME eligibility recommendations of 7 out of 16.

The report in full can be found here:


The EMA has just issued new guidance on remote GCP inspections during the COVID19 pandemic. The inspection team, in agreement with the CHMP requesting the inspection, should make a case-by case decision on whether a remote inspection is considered appropriate and feasible. It too is assumed that Sponsors, CROs and service providers (e.g. medical imaging, central laboratories) have at their disposal advanced technologies, electronic systems and virtual working environments which facilitate remote staff or company locations worldwide to communicate systematically. These technologies may allow the necessary access for inspectors to the relevant systems (e.g. electronic trial master file (eTMF)) remotely and enable appropriate communication settings during inspection. The guidance covers initiation, preparation (setting, team location, technical requirements, agenda), conduct and reporting process.

The full document is available here:


The EMA has published a new ‘Clinical pharmacology and pharmacokinetics Q&A’ regarding biowaivers (Q&A 6.4) in fixed combination oral solid dosage forms. The EMA Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1) allows for a biowaiver in multiple strength applications of fixed combinations as long as the applicant can demonstrate quantitative proportionality between the strengths. However, deviations from the quantitatively proportional composition are still considered acceptable under certain conditions. This extremely useful new Q&A provides clarification on these conditions and it also includes various examples.

Further information is available here:


EMA has just issued a neat 1-page leaflet describing their preparedness to support the development and marketing authorisation of safe, effective and high-quality therapeutics and vaccines against COVID-19. The Agency has put in place rapid review procedures related to COVID-19 to deliver assessments of high-quality applications from sponsors in the shortest possible timeframes.

The leaflet can be found here:


This morning I was reading a very interesting commentary on the EMA Regulatory Science strategy to 2025 published on the Nature site.  The article spoke to the core recommendations that stakeholders deem the most significant to advance evidence generation for medicines, including fostering innovation in clinical trials, reinforcing patient relevance in evidence generation, use of high quality real-world data in decision making, developing the regulatory framework for emerging data sources and contributing to HTAs’ preparedness and downstream decision-making for innovative medicines.

The article in full can be found


As of June 1st 2020, two new Pharmaceutical Inspection Co-Operation Scheme (PIC/S) guidance documents have entered into force: Questions and Answers on Implementation of Risk-based Prevention of Cross-contamination in Production and ‘Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities’, and an aide-memoire on health-based exposure limit (HBEL) assessments. The Q&A guidance on cross-contamination fully mirrors the EMA’s guideline of the same name except for an additional references section that points to other PIC/S guidelines. Whereas the HBEL guidance document “describes an approach to assessing HBEL that can be conducted by inspectors without specialised toxicology knowledge”.

Further information about these new guidance document may be found here:

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; 11 – 15 May 2020


The GCP IWP has published its meeting dates and a list of its priorities for 2020. The priorities of the group will continue with an EU focus and maintaining international relationships. However, of particular interest is the upcoming work to create and finalise a series of Q&As on the following noteworthy topics Q&A on inspectors’ access to patients’ medical records/data when the access of EEA inspectors to medical information is not clearly stated in the Informed Consent Form (ICF). Q&A on sponsor oversight of activities subcontracted to third parties. Q&A on expectations for provision of written information to clinical trial subjects in relation to new information requiring re-consent. Q&A on confidentiality undertaking of EU/EEA inspectors.

The full entirety of the work plan can be found under this link:


The EMA’s Dasatinib product-specific bioequivalence guidance is currently under revision. A revised draft guideline has been released for public consultation and comments will be received until 31st August 2020. The current adopted guidance concerns bioequivalence testing requirements for Dasatinib 20, 50, 70, 80, 100 and 140 mg film-coated tablets. The draft revised document also includes requirements for Dasatinib 10 mg/ml suspension and the additional requirement for a fed study for both dosage forms.


CMDh has updated the following guidance: – RMS validation checklist for human medicinal products in DCP – Data requested for New Applications in the MRP/DCP which are not stated in the current EU legislation and/or in Volume 2B, Presentation and format of the dossier Common Technical Document (CTD) and/or in the EEA approved Guidelines/Recommendation papers – Data requested for Variations and/or Renewal Applications in the MRP/DCP which are not stated in the current EU legislation and/or in Volume 2B, Presentation and format of the dossier Common Technical Document (CTD) and/or in the EEA approved Guidelines/ Recommendation papers – CMDh Best Practice Guide on the use of the electronic Common Technical Document (eCTD) in the Mutual Recognition and Decentralised Procedures – CMDh Questions & Answers on implementation of outcome of Art. 31 referral on angiotensin-II-receptor antagonists (sartans) containing a tetrazole group – Practical guidance for procedures related to Brexit for medicinal products for human use approved via MRP/DCP.

The updated documents (most with tracked changes) may be viewed here:


The MHRA has recently adopted a flexible and pragmatic approach to regulatory requirements for medical device clinical investigations during the COVID-19 pandemic. This is documented in Guidance “Medical devices clinical investigations (CIs) during the coronavirus (COVID-19) outbreak”. The updated guidance, which now includes a new section relating to COVID 19, details regulatory flexibilities introduced for ongoing and new submissions for CIs.

There is an expedited process in place for CIs directly relating to COVID-19. However, it states that if MHRA is unable to reach a decision by the new internal deadline, the 60-day assessment period still applies, and the applicant cannot start the study until they have received a final decision from the MHRA or until 60-days after the notification. The update also states that the MHRA is working on a process for studies where there is both a medicine and a medical device to allow for a single application via the Clinical Trials Unit to ensure a smooth and fast assessment of both elements.

The guidance document which can be accessed via this link: 


The EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended the precautionary suspension of all ranitidine medicines in the EU due to the presence of low levels of the potentially carcinogenic impurity, N-nitrosodimethylamine (NDMA).

Many European national authorities had already recalled ranitidine medicines as a precautionary measure during the EMA’s review. There is some evidence which shows that NDMA may form from the degradation of ranitidine itself over the course of its shelf-life, however, it is still unclear whether the impurity can also be formed from ranitidine inside the human body.

The CHMP recommendation will be forwarded to the European Commission, which will issue a final legally binding decision applicable in all EU Member States.


The 166th European Pharmacopoeia (Ph.Eur.) Commission session was still held electronically despite the restrictions and lockdowns brought on by the COVID-19 pandemic. During the Ph.Eur. Commission session, 91 texts, including 11 new texts, were adopted and will be published in the Ph. Eur. Supplement 10.4 and effective from 1st April 2021.

The new texts include general chapter 5.28 on Multivariate Statistical Process Control and monographs for Regorafenib Tablets, Riociguat Tablets, Rivaroxaban Tablets and Sorafenib Tablets. A list of the adopted texts will soon be available on the EDQM website. Monographs for sartan drug substances have also been revised to add a requirement for risk assessment of the manufacturing process and to replace interim limits for NDMA and NDEA with a 0.03 ppm limit. The next Ph. Eur. Commission session is due to take place on 23rd June 2020.

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; 27 April 2020 – 1 May 2020


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EMA has issued updated instructions on how to amend the name and/or address details of a Sponsor of an Orphan Drug Designation. This does not require a new legal act, provided that the sponsor remains the same person or legal entity. Sponsors need to use EMA’s IRIS platform to submit post-designation activities. EMA will not be able to process any submissions outside of IRIS. A change in the name and/or address can be requested only after a designation has been granted by the European Commission. Full details of the guidance can be found


Guidance is now available to assist stakeholders in implementing the MDR Clinical Investigation and Clinical Evaluation requirements. The Medical Device Coordination Working Group (MDCG) developed the following guidance documents which were published on the website of the European Commission (EC) on the 23rd April:

The documents provide much needed clarification on MDR requirements pertaining to clinical data and demonstration of equivalence. The documents can be accessed via the following link


The European Commission (EC) has issued guidance to ensure that clinical trials can continue during the COVID-19 pandemic. The aim is to mitigate the disruption of clinical research without compromising on quality and safety. With more than 200 coronavirus clinical trials now registered in the EudraCT database, the guidance offers recommendations for simple and flexible measures. Key recommendations of the guidance cover, distribution of medicines to patients, remote source data verification, and communications with authorities. For the latter, the guidance clarifies the classification and notification of these actions. The measures will be used exclusively during the coronavirus pandemic, and will be revoked once the current health crisis in the EU/EEA has been surpassed.


In response to Covid-19 the European Commission (EC) adopted a proposal on the 3rd April to postpone by one year the application of the Medical Devices Regulation (MDR). The European Parliament adopted the proposal on the 17th April, followed quickly by adoption of the Council on 22 April. The EC has announced that the amending Regulation 2020/561 was published in the Official Journal on the 24th April and has entered into force on its date of publication. This means that the date of application of the MDR will become 26 May 2021 instead of 26 May 2020 and that the Medical Devices Directives will be repealed one year later on the new date of application of the MDR. EC announcement can be viewed via link here