Questions & Answers Archives - European Industrial Pharmacists Group (EIPG)

Approval of the Data Governance Act, and EMA’s consultation on the protection of personal data in the CTIS


by Giuliana Miglierini The Data Governance Act (DGA) was approved and adopted in May 2022 by the European Council, following the positive position of the EU Parliament; the new legislation will entry into force after being signed by the presidents Read more

The transition towards EMA's new Digital Application Dataset Integration (DADI) user interface


by Giuliana Miglierini The Digital Application Dataset Integration (DADI) network project is aimed to replace the current PDF-based electronic applications forms (eAFs) used for regulatory submissions with new web-forms accessible through the DADI user interface. The European Medicines Agency (EMA) has Read more

IVD regulation in force: new MDCG guidelines and criticalities for innovation in diagnostics


by Giuliana Miglierini The new regulation on in vitro diagnostic medical devices (IVDR, Regulation (EU) 2017/746) entered into force on 26 May 2022. The new rules define a completely renewed framework for the development, validation and use of these important Read more

Revision of the CDMh’s Q&As document on nitrosamine impurities

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by Giuliana Miglierini

The review process of medicinal products started in 2018 to assess the presence of nitrosamine impurities is still ongoing. The Coordination Group for Mutual Recognition and Decentralised Procedure (CMDh) last updated in December2021 its Questions & Answers document (Q&A) proving guidance on how to approach the revision procedure.

The US’s Food and Drug Administration (FDA) also updated its guidance on how to minimise the risks related to nitrosamine through formulation design changes. We summarise the latest news of the topic of nitrosamine impurities.

The CMDh’s update of the Q&A document

The CMDh Questions & Answers document (CMDh/400/2019, Rev.5) specifically refers to the implementation of the outcome of Art. 31 referral on angiotensin-II-receptor antagonists (sartans) containing a tetrazole group. According to the indications released in November 2020 by EMA’s human medicines committee (CHMP), these outcomes should now be aligned with those issued for other classes of medicines. This provision impacted on the allowed limits for nitrosamines, which are now applied to the finished products instead than to the active ingredient. The limits are determined on the basis of internationally agreed standards (ICH M7(R1)).

Companies are called to implement an appropriate control strategy to prevent or limit the presence of nitrosamine impurities as much as possible and to improve their manufacturing processes where necessary. A risk assessment should be run to evaluate the possible presence of N-nitrosamines in medicinal products, and tests carried out if appropriate.

Four different conditions (A-D) are set for the marketing authorisation (MA) of tetrazole sartans, with specific dates to be met for their fulfilment by marketing authorisation holders (MAHs). Revision 5 of the Q&As document specifically addresses conditions B and D.

Condition B asks the MAH to submit a step 2 response in the general “call for review”. To lift the condition on the risk assessment for the finished product, and provided no nitrosamine was detected in step 2 or levels are below 10% of acceptable intake (AI), submission of the step 2 response must now be followed by the submission of the outcome of the risk assessment. To this instance, the relevant template “Step 2 – No nitrosamine detected response template” should be used to fill a type IA C.I.11.a variation.

A further amendment to Condition B refers to nitrosamines being detected in step 2 above 10% AI. In this case, a variation application should be submitted as appropriate to support changes to the manufacturing process and the possible introduction of a limit in the specification of the finished product.

Condition D now specifies that it applies only to N-nitrosodimethylamine (NDMA) and N nitrosodiethylamine (NDEA) impurities. Thus, to lift the condition on the change of the finished product specification, and if the MAH wants to apply for omission from the specification, supporting data and risk assessments should be submitted via a type IB C.I.11.z variation referring only to these two impurities. Should any other nitrosamine impurity be potentially present, data should be submitted under separate variation (also grouping them together). Conditions A and C remain unchanged. The former refers to the three different possibilities for lifting the condition on the risk assessment for the active substance and with specific reference to the manufacturing process used to prepare it, the second to lifting the condition on the control strategy.

The guidance from the FDA

The US regulatory agency Food and Drug Administration (FDA) released in February 2021 the first revision of the “Guidance for Industry Control of Nitrosamine Impurities in Human Drugs”, establishing a three-step process to demonstrate the fulfilment of requirements.

The guideline widely discusses the structure of nitrosamine impurities and the possible root causes for their presence in medicinal products. While not binding for manufacturers, recommendations contained in the document should be applied in order to evaluate the risk level for the contamination of both active ingredients and finished products. This exercise should be run on the basis of a prioritisation taking into consideration the maximum daily dose, the duration of treatment, the therapeutic indication, and the number of patients treated.

The FDA provides also the acceptable intake limits for a set of different nitrosamine impurities (NDMA, NDEA, NMBA, NMPA, NIPEA, and NDIPA); the approach outlined in ICH M7(R1) should be used to determine the risk associated with other types of nitrosamines.

Manufacturers do not need to submit the results of the risk assessment to the FDA, the relevant documentation has to be made available just upon specific request.

The second step refers to products showing a risk for the presence of nitrosamine impurities. In this case, highly sensitive confirmatory testing is needed to confirm the presence of the impurities.

The implementation of all changes to the manufacturing process for the API or final product have then to be submitted to the FDA in the form of drug master file amendments and changes to approved applications.

The Agency also provides specific guidance for API manufacturers to optimise the route of manufacturing in order to prevent the possible formation of nitrosamine impurities. API manufacturers should participate to the risk assessment run by the MAH; this last exercise should include the evaluation of any pathway (including degradation) that may introduce nitrosamines during drug product manufacture or storage.

Additional points to be considered

A Communication issued in November 2021 by the FDA specifies the terms for the recommended completion dates of the above mentioned three steps and adds some additional points to be considered in the evaluations. MAHs should have already completed by 31st March 2021 all risk assessments, while there is time up to 1st October 2023 for confirmatory testing and reporting changes. According to the FDA, the time left is enough to include in the development of the mitigation strategies also new considerations on how formulation design may prove useful to control nitrosamine levels in drug products.

More in particular, manufacturers are asked to evaluate the presence of nitrosamine drug substance-related impurities (NDSRIs), that may be produced if nitrite impurities are present in excipients (at parts-per-million amounts) or may be generated during manufacturing or shelf-life storage. Should NDSRIs be present, FDA recommends the mitigation strategy should include a supplier qualification program that takes into account potential nitrite impurities across excipient suppliers and excipient lots.

Formulation design is another possible approach to solve the issue. This may use, for example, common antioxidants – such as ascorbic acid (vitamin C) or alpha-tocopherol (vitamin E) – that according to the scientific literature inhibit the formation of nitrosamines in vivo. The kinetic of the reaction leading to the formation of nitrosamine impurities may be also addressed by using a neutral or basic pH for formulation, to avoid acidic conditions which favours the side reaction.

Formulation changes may be submitted to the FDA through supplements or amendments to the applications, also following a preliminary meeting with the Agency to better discuss the approach to be used. Should this be the case, applicants or manufacturers are asked to prepare a comprehensive meeting package with the appropriate regulatory and scientific data on the selected approach to be submitted to the FDA in advance of the meeting.


EMA’s OMS has turned mandatory for centrally authorised products

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by Giuliana Miglierini

Since November 1st, 2021, the use of the Organisation Management Service (OMS) became mandatory for all Centrally Authorised Products (CAPs). The European Medicines Agency (EMA) has published a Questions & Answers document to better explain the new procedures, that will impact the source of data to be used to exactly identify the organisations filing CAP procedures with EMA.

The progression in the implementation of the new provisions

The use of the OMS system is now compulsory for all organisations filing CAP submissions, with the final goal to improve the interoperability of data and the overall efficiency of the regulatory process. Should applicants lack to use OMS data, the relevant applications will be filtered out of the EMA’a validation procedure and sent back to the applicant for remedial action.

The OMS data management service was launched in 2015, and applied to electronic application forms (eAFs) since 2017, and then to many other types of procedures. The availability of OMS data may prove critical to allow the smooth implementation, in early 2022, of the new Clinical Trial Information System (CTIS) and of the Clinical Trial application procedure; during the next year, EMA plans to integrate the OMS also with the Union Product Database (UPD), Variation applications (via DADI project) and Manufacturing/Importers Authorisations (MIAs), Good Manufacturing Practice (GMP) inspections and Wholesale distribution authorisations (via EudraGMDP).

Validated OMS data also need to be used with reference to the “applicant” and “contact person affiliated organisation” sections of pre-submission applications. With the new eAF release (eAF V.1.25.0.0) for Medical Devices, the compulsory use of OMS data will also refer to the “Device Manufacturer”, “Notified Body” and “Companion diagnostic” sections.

Remediation in case of lack to use OMS data includes the insertion of all relevant information in the OMS database before updating and re-submitting the application form. Should applicants not provide sufficient responses, the application may be completely or partially invalidated.

Discussions are undergoing to further extend the use of OMS data also to National Procedures (NP); according to EMA, this may be turn inevitable in the next couple of years, as current eAF forms will be progressively replaced by web-based application forms (through the DADI project), being the latter the same for centrally and nationally authorised products by design.

Any question on the use of the OMS can be sent to EMA’s e-mail addresses specified in the Q&As document.

What is new for applicants

The use of OMS master data (the so-called “OMS Dictionary”) is now mandatory for both Human and Veterinary centralised procedures, namely those making use of eAFs (initial marketing authorization applications, variations applications, and renewals) and well as other procedures (see the Q&A document for more detail). The name and contact details of the contact person are not OMS data, and do not need to be registered with the system; historical organisational data do not have to be registered as well.

To manage a CAP procedure, applicants now need to first register their organisation data with the OMS, or request the update of data already registered by submitting a “Change Request” before filing of the regulatory application.

All requests will be assessed by EMA OMS Data stewards, that will also update data in the systems if the requirements are met. This validation step is fundamental to avoid duplication of data, as all information is checked against the same reference sources (i.e. national business registry, DUNS and/or GMP/MIA certificates) and standardised according to the OMS rules agreed with the Network. The Service Level Agreement provide for EMA to process 75% of OMS requests within five working days and 90% within ten working days. Changes will become visible in the eAF the day after they had been processed, and only upon active refresh of the relevant lists.

The business process which makes use of OMS data is usually responsible to submit such a request, but it can arise also form other parties. More specifically, EMA advises the user who needs to use the data should take the lead in updating it. This may prove relevant, for example, to ensure all manufacturer organisations are included in the OMS Dictionary as needed.

EMA warns applicants to consider the turnaround time for processing the OMS change request when planning to submit applications: even if the application forms will not immediately change and everything may appear as usual, the background process has been now modified and may need additional activities to validate the change requests.

Changes in the eAF templates are planned to remove the free text fields for CAP applications, but until the new models will be available, the free text field for “organisations” should not be used. Planned availability and entry into force of the new versions are December 2021 for Human procedures (v1.26.0.0) and January 28th, 2022 for Veterinary procedures (in line with the veterinary regulation).

How to access the OMS

EMA’s data management system refers to four different domains of data, including the substance, the product, the organisation and referential (SPOR) master data in pharmaceutical regulatory processes.

The SPOR portal provides access to the respective four specific areas of service (e.g. SMS for substances, PMS for products, OMS for organisations and RMS for referential). SPOR is the mechanism used by EMA to implement the ISO IDMP standards, as required by articles 25 and 26 of the Commission Implementing Regulation (EU) No. 520/2012. Organisation master data, even if not covered by ISO IDMP, have been considered by EMA, National Competent Authorities and Industry in Europe to be essential in order to make the master data operating model work.

Applicants need to create an EMA account with SPOR user roles to conduct additional tasks, such as requesting changes to data, translating data or managing user preferences. Already granted credentials to access other active accounts for any EMA-hosted website or online application can also be used. OMS data can now no longer be captured in other EMA databases.

OMS master data include the organisation name and address, labelled by mean of unique identities (ID) (i.e. ‘Organisation_ID’ and ‘Location_ID’). Different categories of organisations are possible (i.e. ‘Industry’, ‘Regulatory Authority’ or ‘Educational Institution’), and of different size (i.e. ‘Micro’, ‘Small’, or ‘Medium’). The role played by a certain organisation is context-specific and cannot be defined within the OMS.