Last week’s round -up;
06 -13 November 2020

New EMA product-specific bioequivalence guidance

The EMA has released the following updated product-specific bioequivalence guidance: • A new draft guidance for Acenocoumarol 1 mg and 4 mg tablets. This draft guidance is open for public consultation until the 28th February 2021. • Revised guidance for Dasatinib 20, 50, 70, 80, 100 & 140 mg film-coated tablets and 10 mg/ml suspension, which comes into effect on the 1st May 2021. This product-specific bioequivalence guidance was updated to include the additional requirement for a fed study and the requirements for the suspension.

Pharmeuropa 32.4 – Revised draft monographs for substances with a CEP

Twelve revised Ph. Eur. monographs for substances with a CEP have been published in Pharmeuropa 32.4. CEP holders are requested to consult the list of draft monographs and submit their comments on these draft monographs by the 31st December 2020. Users are also encouraged to review the draft monographs to ensure that their drug substances still comply with the revised drafts.

A list of the revised draft monographs may be viewed at 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;
03-07 August 2020

Common excipients more active than thought

Common ‘inactive’ excipients may be more active than currently thought. Using a combination of computer modelling and lab testing, researchers investigated 639 excipients in the FDA’s Inactive Ingredient Database, screening them against thousands of potential human targets. Overall, 38 excipients were identified as having 134 activities against 44 physiologically relevant targets. Half of these activities were more potent than the on-target activity of some small-molecule drugs. In further testing, seven of these excipients were orally dosed in rats and systemic exposure was assessed. Two of these – cetylpyridinium chloride and thimerosal – reached sufficient concentrations to theoretically modulate their target:

CMDh meeting report – July 2020

A report from the CMDh meeting held in July 2020 has been published. Some of the topics covered during the meeting include: • Brexit • EMA review of dexamethasone for treating COVID-19 • Update on nitrosamines in medicines and medicines containing metformin • Recommendations on common regulatory approaches for allergen products • Update of the RMS Day 70 and Day 120 overview assessment report templates and new RMS similarity assessment report template • Update of examples for acceptable and not acceptable groupings for MRP/DCP products • Questions and Answers on QP declaration • An overview of new applications, variations and renewals related to MRP/DCP that were submitted or finalised during June 2020.

The full CMDh report may be viewed at the following link:

EC releases checklists for reusable and re-sterilisable Medical Devices

The EC released the Compliance and Enforcement Group (COEN) document COEN Working Group -2014 V1.0 on the 28th July 2020. The document includes checklists “Instruction for Use (IFU)” based on EN ISO 17664 & checklist “Assessment of the Validation” based on EN ISO 14937 in Annex 1 and Annex 2 of the document respectively. Checklist “Instruction for Use (IFU)” provides a quick and reliable way to assess IFU in view of making an informed decision on using or purchasing a specific re-sterilisable medical device (RMD). Checklist “Assessment of the Validation” of RMD’s is primarily for manufacturers of Class I devices and allows them to see the criteria adopted by CA for the assessment of validation.

The checklists can be accessed via this link:

Ph. Eur. Supplement 10.3 – CEP Updates

Ph.Eur. Supplement 10.3 is available and includes a list of substances covered by a CEP and for which a revised monograph will be implemented on the 1st January 2021. CEP holders are invited to update their applications according to the revised monographs. Further information and the list of substances with a revised monograph may be viewed at the following link:

Recommendations on common regulatory approaches for allergen products

The CMDh has issued guidance for harmonising regulation of medicinal allergen products across the EU, as they are currently authorised and distributed on different legal bases across member states.

Butylparaben to be phased out

Butylparaben, a chemical used in pharmaceuticals, cosmetics and personal care products, has been added to the Candidate List of substances of very high concern (SVHCs) and will gradually be phased out due to its endocrine-disrupting properties. The Candidate List includes substances of very high concern that may have serious effects on our health or environment, and which will eventually be phased out. Companies that have a substance on the list may have certain legal obligations to fulfil. As of January 2021, companies are obliged to notify products containing SVHCs to the European Chemicals Agency’s (ECHA) upcoming SCIP database on substances of concern in articles and products.


Last week’s round-up;
27 -31 July 2020

Country-specific requirements update for MRP/DCP variations and/or renewals

The CMDh has revised its “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” document. Croatia has now been removed from the list, which indicates that Croatia does not have any country-specific requirements for Variations and/or Renewal Applications related to the MRP/DCP.

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Revision of Ph.Eur.  Sieve Test

A revised Ph. Eur. Chapter 2.9.12 Sieve Test has been published in Pharmeuropa 32.4. The chapter was revised in response to comments received to a previous proposed revision of the chapter that was released in Pharmeuropa 20.4 and 22.4. The chapter was previously revised to adapt it to the newer harmonized general chapter 2.9.35 Powder fineness, which provides a classification of powders according to their degree of fineness.

EDQM Clarification on revision of CEP applications

The EDQM has issued some clarifications on the revised ‘Guideline on requirements for revision/renewal of certificates of suitability to the European Pharmacopoeia Monographs’, which was introduced in January 2019. In the announcement the EDQM provides clarifications on several situations involving the revision/renewals of CEPs, including:

· When a new substantially different route of synthesis is introduced.

· Where different grades of material with different specifications are involved.

· Misclassification of minor/major revisions by CEP holders.

EMA requirements for the qualification and validation of computerised systems for CT data.

EMA published a notice for clinical trial sponsors to highlight the requirements for the qualification and validation of computerised systems used for managing clinical trial data. This is based on inspection findings and based on the implications on the integrity, reliability, robustness and acceptability of data in future MAAs.

EMA has also updated associated questions 8 and 9 on their Q&A, which can be found here:

CMDh Q&A – QP Declaration Update

The CMDh has revised its QP Declaration Q&A guidance. The document includes an update to guidance on QP declaration requirements in situations where a CEP or ASMF has two manufacturing sites but the MAH just wishes to approve one of the sites.

The updated document with tracked changes may be viewed at the following link: