Last week’s round -up;
16 -20 November 2020

Impact of GMP Annex 1 on Isolator Design and Cleaning

PharmTech has published an article on the impact of the EU good manufacturing practice (GMP) Annex 1 “Manufacture of Sterile Medicinal Products” guidance on aseptic operation and cleaning in the pharmaceutical industry. The article focuses on barrier systems including restricted access barrier systems (RABS) and isolators, and includes information on isolator design and cleaning validation.

Erratum concerning the Danaparoid sodium (2090) revised monograph

The EDQM has released an Erratum for the English version of the Danaparoid sodium (2090) revised monograph that was published in Ph. Eur. Supplement 10.3 with an implementation date of 1st January 2021. The Erratum concerns the erroneous deletion of the time from the addition of the chromogenic substrate after which the first measurement of the absorbance in the anti-factor IIa activity test is to be performed. The corrected text of the English version of the monograph will be included in the print version of Ph. Eur. Supplement 10.5, however, the online and downloadable versions of the monograph have been corrected:

Nitrosamines recommendations alignment for sartans

The CHMP has aligned the recommendations for limiting nitrosamine impurities in sartan medicines with the recent recommendations for other classes of medicines. The limits for nitrosamine levels will now apply to the finished product, rather than to the active substance as in the previous recommendations. The limits are based on internationally agreed standards (ICH M7(R1)) and should ensure that the excess risk of cancer from these impurities in sartan medicines is below 1 in 100,000 for people taking the medicine for lifelong treatment. The newly aligned recommendations also require that companies have appropriate control strategies in place to prevent or limit the presence of nitrosamines as much as possible, improve their manufacturing processes when necessary, and conduct risk assessments for possible nitrosamine contamination in their medicines.

The Role of Integrity Testing in Laboratory Sterility Filtration

Sterility filtration is essential in research and pharmaceutical laboratories as many processes demand that the filtrate is free of biological contaminants to prevent downstream contamination, equipment failure and human health risks. Therefore, validation of the sterility performance of filters is required. Several factors may affect the performance of sterility filters, such as the handling of filters, particle load, pressure and temperature fluctuations, and chemical exposure. Integrity tests are used by manufacturers and users to confirm the structural soundness and performance of a sterility filter before and after use. The following PharmTech article reviews destructive and non-destructive integrity tests which are commonly used to validate sterility filter performance. The article delves into the different testing methodologies and why these are critical to ensure filter performance and reduce laboratory risks:


Last week’s round-up;
21 – 25 September 2020

Revision of ICH guideline Q3D on elemental impurities

Proposed changes to ICH Q3D have been issued by the EMA for consultation. The deadline for comments is 18 December 2020. The changes are as follows: • Raised PDEs for gold (all routes), silver (parenteral) and nickel (inhalation). • Corrected monographs for gold and silver. • New Appendix 5 on limits for elemental impurities by the cutaneous and transcutaneous route (previously the guideline covered only the oral, parenteral and inhalation routes)

EU suspension of ranitidine medicines confirmed

In April 2020, EMA recommended that all ranitidine medicines in the EU should be suspended due to the presence of low levels of the nitrosamine impurity NDMA, pending further investigation. The EMA has now re-examined its recommendation upon request from one of the companies marketing ranitidine in the EU. The recommendation holds, because the possibility of NDMA forming from ranitidine itself during the shelf-life of the product or inside the body is still being studied.

Ph. Eur. Parenteral Preparations Monograph Revision

The Ph. Eur. Commission has adopted the revised version of the dosage form monograph on Parenteral Preparations. The revised chapter describes the mandatory quality requirements for many pharmaceutical products in Europe and will be published in Supplement 10.5 of the Ph. Eur. on the 1st January 2021 and implemented by the 1st July 2021. Tests on particulate contamination for both visible and sub-visible particles are now described in the test section as release criteria. The tests apply to all liquid parenteral preparations intended for injection or infusion (including solutions, suspensions, emulsions or gels). A reference to general chapter 5.17.2 has also been included for additional guidance, and the test for visible particles has been included in the production section to ensure that parenteral preparations are kept free from visible particles during manufacture.

Other updates to the text have also been made and are described in the following article:

EMA Launches IRIS for use for scientific advice processes

IRIS is the European Medicines Agency’s (EMA) secure online platform where you can carry out certain regulatory procedures with EMA. To date this has been used for Orphan Designations, Parallel Distribution notifications, Innovation Task Force applications and to request a Research Product Identifier (RPI) for a new medicinal product. From 19 October 2020, EMA will require scientific advice applicants to use the IRIS platform to manage scientific advice processes with EMA. The procedures concerned are: Human domain: Initial and Follow-up Scientific Advice, Initial and Follow-up Protocol Assistance, Initial and Follow-up Qualification Procedure AND Veterinary domain: Initial and Follow-up Scientific AdviceFurther information on the IRIS platform and guides to registration can be found here:


Last week’s round-up;
14 – 18 September 2020

Investigations in the GMDP environment

The MHRA Inspectorate has released a blog post on the most common issues related to investigations in the GMP and GDP environment that are encountered during inspections. The aim of the article is to help pharmaceutical manufacturers and wholesalers improve the outcome of their investigations, and it is applicable to deviations, customer complaints and other Pharmaceutical Quality System (PQS) activities. Several issues that may be encountered during investigations are covered, as well as the relevant implications on CAPA systems, risk assessments, patient safety and root cause analysis.

EMA:  Clinical Data Publication temporarily suspended – except for COVID-19 related products

EMA suspended all new activities related to the publication of clinical data on 1st Aug 2018. This was done as a result of the implementation of the third phase of EMA’s business continuity plan during the relocation of its offices from London to Amsterdam. However, the agency has just clarified that the suspension of clinical data publication does not apply to COVID-19 related products, in line with EMA’s exceptional transparency measures for treatments and vaccines for COVID-19. Pharmaceutical companies should contact EMA as soon as possible concerning publication of clinical data if they plan to submit an application for a COVID-19 related product.

Further details can be found under this link:

EC:  Proposed European agency for biomedical advanced research and development

The EC President Ursula von der Leyen yesterday (16th Sept 2020) gave her state of the union address, in which she called for lessons to be learned from the current pandemic. She asserted that Europe must build a stronger European health union, with a future-proof and properly funded EU4Health programme, a reinforced European Medicines Agency (EMA) and a strengthened European Centre for Disease Prevention and Control (ECDC). The President also pledged to build a European agency for biomedical advanced research and development to enhance Europe’s capacity to respond to cross-border threats and called for a debate on new competences for the EU in the field of health, as part of the forthcoming Conference on the Future of Europe.

Full details of the address can be found under this link

USP General Chapter <1469> Nitrosamines – Public consultation

A new USP general chapter <1469> Nitrosamines has been proposed. The aim of this standard is to ensure the appropriate control of potentially carcinogenic nitrosamine impurities, eliminating or reducing their presence in drug products and drug substances. This USP chapter also covers potential sources of nitrosamines, risk assessments, nitrosamine limits, testing and analytical procedures, test method performance characteristics of nitrosamine methods and USP reference standards. The chapter has been published in draft form in Pharmacopoeial Forum 46(5) and is open for public consultation until the 30th November 2020.

Biotherapeutics Ph. Eur. Monographs Updates

The EDQM has updated its Ph. Eur. monograph portfolio on Biotherapeutics. Several monographs are under revision and the EDQM intends to emphasise “greater flexibility as a means of better addressing the structural complexity and naturally occurring heterogeneity of these substances, and the potential diversity of the preparation resulting from different manufacturing processes”. Several individual Ph. Eur. monographs are also under revision including Erythropoietin concentrated solution, Follitropin, Follitropin concentrated solution, Human coagulation factor VIII rDNA, Somatropin concentrated solution, Somatropin, Somatropin for injection and Somatropin solution for injection. The Ph. Eur. Biotherapeutics portfolio also includes a list of new monographs that are currently in preparation. Since the portfolio was published, the revised version of Erythropoietin concentrated solution (1316) monograph has been adopted. The updates include several changes which bring about a significant improvement in the analytical performance of the monograph, while also providing the sought-after flexibility. The updates to the monograph are discussed in the following link:


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

FDA issues nitrosamine detection and prevention guidance

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

Further information on the new FDA guidelines may be viewed at the following link:

Public Consultation on the CEP of the future

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

MHRA publishes New Rules to apply from January 2021

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

The link to the guidance can be found here:

New FDA product-specific guidance

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

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

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

A link to the full document can be found here:

EMA Consultation issued: QT/QTc Q&A

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

A link to the consultation can be found here:

FDA addresses nitrosamines in TB drugs

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


Last week’s round-up;
24 – 28 August 2020

Aseptic Processing Practices: Reviewing Three Decades of Change

Thought-provoking article by Agalloco, Akers and Madsen highlighting challenges that are emerging for 2020 and beyond for aseptic processing and arguing that it is time to revise the pharmaceutical industry’s expectations and approaches to validation. In the authors’ own words, “Technologies in use and on the horizon could change aseptic processing in ways that seemed inconceivable years ago but approaches to aseptic process validation still need to move beyond their 1970s roots.”

EMA’s Lapatinib product-specific bioequivalence guidance

The EMA has released a 2nd draft of its product specific guidance on the demonstration of the bioequivalence of lapatinib 250 mg film-coated tablets. The guidance was extensively revised following the first public consultation. Stakeholders may submit their comments on the revised draft guidance by the 30th October 2020.

EMA interactive guidance on IRIS access

The EMA has released an interactive presentation on how to register for their IRIS system, which gives a step by step guide to gaining access, and also information on some submission-specific requirements.

MHRA reflection on cross-contamination control

The MHRA has shared its reflections on some of the common factors in critical deficiencies found in control strategies for cross contamination between products in shared facilities. The Agency’s expectations are focussed mainly on sites handling products with lower level Health Based Exposure Levels (HBELs), those with products around the red area of the continuum seen in the PIC/S Q&A document. The MHRA has highlighted the following aspects that companies are required to address:

• HBELs should be completed by experienced professional toxicologists for all products

• The HBEL value and hazard knowledge should be used to set the context and the reference for conducting Quality Risk Management development of Organisational and Technical controls

• Companies may rely solely on visual inspection for cleanliness at changeover between products following cleaning validation, only when there is clear and safe evidence that residues can be consistently and readily seen at the acceptance criteria level

Further details on the MHRA’s expectations may be viewed at the following link:

Nitrosamines risk assessment: update for CEP holders

The EDQM has decided not to extend the deadline of 31st July 2020 for CEP holders to submit step 1 of the nitrosamine risk assessment for their APIs. The Directorate has said that “risk assessments for the presence of nitrosamines in active substances should be available early enough to allow MAHs to collect the relevant data for their medicinal products. In addition, most CEP holders have already completed this step.” CEP holders who have yet to submit their risk assessment and need support are required to contact the EDQM as soon as possible and should propose a justifiable timeline. As of 1st October 2020 applicants and CEP holders are also required to include a risk assessment regarding the potential formation of nitrosamines in any new CEP application, sister file or renewal application, and also in any revision where a risk of nitrosamine formation may be introduced. Applicants are advised to include the risk assessment in the CEP submission, even in cases where a risk is not identified.


Last week’s round-up;
10 -14 August 2020

Evaluation of the medicines for rare diseases and children legislation

On 11 August 2020, the EC published an evaluation of the EU orphan and pediatric regulations, adopted in 2000 and 2006, respectively. Following an evaluation comprising several steps, the regulations were analysed according to five criteria: effectiveness, efficiency, relevance, coherence; and EU added value. It was concluded that the regulations met their main objectives of increasing the number of products for patients with rare and paediatric diseases in the EU. Conversely, however, issues were recognised including: · Products may not be equally accessible across the EU or affordable to national health systems; · Circumstances may have changed since the regulations were introduced; · The regulations do not have instruments to counteract observed clustering of products leaving areas of unmet need, or to direct development to areas most relevant to children; · The concept of prevalence as a tool to receive orphan designation and the length of the 10-year market exclusivity period may need to be re-examined. Looking forward, it was noted that some of the issues identified are closely linked to and will be tackled by the Pharmaceutical Strategy for Europe.

EMA addresses risk evaluation, mitigation for nitrosamines

The EMA has updated its Q&A document on nitrosamine impurity testing for marketing authorisation holders. MAHs need to perform a risk evaluation to determine whether chemically synthesized active pharmaceutical ingredients are at risk of containing nitrosamines by 31 March 2021 (extended deadline). This same requirement has now been extended to biologicals, with a deadline of 1 July 2021. Biologicals considered particularly at risk include those containing chemically synthesized fragments, those where nitrosating reagents are added, and those packaged in nitrocellulose blister packs. The document includes further deadlines for confirmatory testing where applicable, as well as related variation submission requirements. It also delineates specific requirements for analytical methods to be used in testing, mitigation measures when nitrosamines are detected, and daily acceptable limits for various nitrosamines.

Tackling serious impurities

Discovery of N-nitrosamines in a variety of medicines over the last two years could have a much wider impact on pharmaceutical manufacturers and regulators than previously expected. The underlying issue in all N-nitrosamine contamination cases was inadequate control of impurities, and so European Union regulators want manufacturers and national regulators to take more effective action in tackling all potentially carcinogenic impurities in APIs and finished products. This decision arises from results published by a ‘lessons learnt’ group within the EU medicines licensing network. The group has proposed a variety of guidance reviews, including those relating to marketing authorization holders, finished product and API manufacturers, active substance master file and CEP holders. Updates to ICH M7 and the EU’s good manufacturing practice guidance have also been proposed.

GMP inspectorate audits, Brexit stockpiling, and MHRA’s Covid-19 divergences

The EMA’s Mutual Recognition partners can now take part in audits of the GMP inspectorates of national authorities. MRA partners could previously participate in audits as observers and, from now on, will also be able to participate as co-auditors if they express an interest in doing so. However, MRA partners still won’t be able to serve as lead auditor, as this role is reserved for European groups. In other regulatory news, the UK government has asked industry to stockpile medicines ahead of the next Brexit deadline at the end of the year. The MHRA has also highlighted nine areas where its COVID-19 flexibilities diverge from EU policies. The list includes MHRA’s positions on qualified person declarations, the 30-day limit for type 1B variation replies, leaflet mock-ups and over-labelling.

Endotoxin levels in investigational cancer treatments

The US FDA has released new draft guidance on setting limits for endotoxins during the clinical trial process for parenteral oncology drugs intended for serious and life-threatening cancers. This new document provides risk-based guidance on endotoxin limits for investigational therapies that are used in early clinical trials in conjunction with other approved treatments or with other investigational medicines. Patients’ possible exposure to endotoxin levels exceeding USP recommendations may be considered an acceptable risk under appropriate circumstances.


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: 


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; 25 – 29 May 2020


The US FDA has found the carcinogenic nitrosamine impurity NDMA in several batches of extended-release (ER) formulations of metformin, which is used to treat patients with type 2 diabetes. The impurity was found to be above the acceptable limit in these products.

The agency has, therefore, called upon the five pharmaceutical companies involved to voluntarily recall these ER metformin products. Other metformin manufacturers which supply a large portion of the US market have not been affected by the recall. However, the FDA is collaborating closely with manufacturers to ensure appropriate testing for NDMA levels in these products. The agency is also conducting assessments to determine whether any shortages in metformin may arise due to the recalls, and it intends to help prevent or reduce the impact of any such shortages.


The EMA has issued a Q&A document (June 2020) highlighting some key points for successful qualification of digital technology-based methodologies used in medicines development, for example as part of the conduct of a clinical trial. The Q&A reflects the EMA’s current experience, and notes that if a digital technology is used in the context of product development, evaluation or monitoring, and could impact the benefit-risk assessment, then relevant aspects will be discussed at product assessment (such as reliability versus established data capture methods), and so qualification should be considered during development. Examples are given of technologies falling within the scope of the qualification programme, and the process for requesting advice or an opinion is outlined. The Q&A ends with five overarching guiding principles for a qualification submission, and in particular the importance of early and focused interactions with the agency.

The document is available here:


MHRA “Guidance Good clinical practice for clinical trials” gives guidance on how to show MHRA you’re meeting GCP standards and what to expect from an inspection. MHRA requests pre-inspection documentation information in the form of a GCP inspection dossier & a clinical trials spreadsheet within 30 days of notification of an inspection. The GCP dossier clinical trials spreadsheet which is used to prepare the GCP dossier and is part of the requested pre-inspection documentation was updated on the 22nd May 2020.

The updated GCP inspection dossier clinical trial spreadsheet can be viewed via this link


What are the key pharmacokinetic considerations in the assessment of biosimilarity?

The EMA has updated question 7.1 of its Clinical Pharmacology and Pharmacokinetics Q&A, which tackles the above issue. The related response clarifies the differences between requirements for biosimilar products and small molecule generics. It provides further detail on the following issues that need to be considered in assessment of biosimilarity: linear clearance, nonlinear clearance, anti-drug antibodies, batch selection and protein content correction, study population, dose level, sampling times, and statistical comparison:


Mexico has been welcomed as an observer state by the European Pharmacopoeia Commission.

Mexican authorities can now participate in the scientific work of the European Pharmacopoeia Commission and other activities of the European Directorate for the Quality of Medicines (EDQM). This brings the European Pharmacopoeia’s total observer countries to 30, together with the 39 European countries and European Union as signatory parties:


The WHO has released a new digital version of its Model list of Essential Medicines (EML).

This WHO reference tool is currently used by over 150 countries to compile their national essential medicines lists to ensure that these essential medicines are always available in their health care system in the appropriate dosage forms and quality, and at affordable prices.

Users will now be able to freely access the EML online database on smartphones and computers. The system also allows users to create their own customized lists by exporting the list (or part thereof) into an Excel or Word version.