Guidance Archives - European Industrial Pharmacists Group (EIPG)

PIC/S Annual Report 2021


by Giuliana Miglierini The Annual Report of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) resumes the many activities and results achieved in 2021, despite the ongoing pandemic that required remote coordination and on-line virtual meetings. To this regard, a written procedure Read more

Joint implementation plan for the IVDR regulation


by Giuliana Miglierini Regulation (EU) 2017/746 (IVDR), establishing the new legislative framework for in vitro diagnostic medical devices (IVDs), will entry into force on 26 May 2022. The Medical Device Coordination Group (MDCG) has published an updated version of the Read more

Key issues in technical due diligences


by Giuliana Miglierini Financial due diligence is a central theme when discussing mergers and acquisitions (M&A). Not less important for the determination of the fair value of the deal and the actual possibility to integrate the businesses are technical due Read more

Joint implementation plan for the IVDR regulation

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by Giuliana Miglierini

Regulation (EU) 2017/746 (IVDR), establishing the new legislative framework for in vitro diagnostic medical devices (IVDs), will entry into force on 26 May 2022. The Medical Device Coordination Group (MDCG) has published an updated version of the Joint implementation and preparedness plan, discussing the priority actions to be implemented and monitored at the level of member states, Commission and MDCG.

The implementation of the IVDR is highly complex, as it requires a strict coordination between all the different stakeholders, including manufacturers, notified bodies, authorised representatives and laboratories. The IVD regulation has introduced a completely new device classification system for in vitro diagnostics, as well as a greater involvement of notified bodies in conformity assessment and new regulatory structures such as the EU reference laboratories and expert panels.

The Joint implementation plan is aimed to support the harmonised implementation of the new framework, a process led by the Commission and where member states are called to ensure the new provisions are effectively applied and enforced at national level.

Ongoing actions and future goals

As of January 2022, six notified bodies were already designated and the examination of other applications is undergoing. The Unique Device Identifier system that will support the punctual tracing of the devices has also been set up, while the Eudamed database is still under development. From the regulatory perspective, a number of new common specifications are being drafted; some guidance documents are already available while others are under development.

To smooth the impact of the transition and to prevent disruption in the supply of essential IVDs, Regulation (EU) 2022/112 has established the calendar for the transition of different classes of devices, i.e. 26 May 2025 for IVDs that fall in class D under the IVDR, 2026 for class C, 2027 for class B and A sterile.

The Joint implementation plan identifies two sets of priorities to be tackled by the stakeholders, on the basis of public health’s goals, patient safety and transparency. Set A includes essential actions to enable IVDs to maintain access to the market. Set B includes the development of other new pieces of legislation and guidance documents needed to better support the transition and the designation of EU reference laboratories for high-risk IVDs.

Set A, essential actions

Contingency planning and monitoring are the first priority to be met under Set A essential actions, in order to anticipate possible risks of IVDs’ shortages arising from the transition to the new framework. The MDCG will closely follow this process to monitor its progress and identify systemic risks and mitigation actions, with a particular attention to the availability of particularly critical IVDs.

Regular updates are also expected from the industry and notified bodies to inform member states and the Commission about the need of specific actions. This type of activity would also support the identification of barriers that could result in shortages of devices, e.g. with reference to the designation of notified bodies or the certification process. Stakeholders are also requested to be ready to manage some uncertainty in areas where guidance is still not available, thus requiring the provision of sound justifications to maintain critical IVDs on the market.

The second highest priority is the availability of a sufficient number of notified bodies to support the expected very high volume of applications for the certification of medium and high-risk IVDs. The plan indicates the need to make available national experts for the joint assessment of notified bodies. Member states should also address the need to improve the notified body capacity, discussing this issue within the MDCG and its specialised working groups as well as with the Commission. According to the Joint plan, the percentage of IVDs requiring certification under the new IVDR will rise up to 80-90%, from approx. 10% devices requiring involvement of a notified body under Directive 98/79/EC.

To facilitate this part of the transition, Regulation (EU) 2022/112 establishes that certificates issued under the Directive 98/79/EC are valid, under certain conditions, until May 2025. Renewals of existing certificates by a set of nineteen notified bodies designated under the current Directive is possibile, if necessary, up to 26 May 2022.

The plan also takes into consideration the possible occurrence of new Covid-19 restrictions, that may highly impact the work of the notified bodies (for example, due to the need to run first-time audits of many manufacturers). The Commission and the MDCG are thus called to consider how notified bodies can perform conformity assessment activities in such circumstances.

Set B, high priority actions

Actions included in set B are not essential for manufacturers to market their IVDs, but their implementation would support a smoother transition.

The EU reference laboratories are a new type of independent scientific body designated by the Commission to carry out additional tests on the performance and compliance with any common specifications of class D devices, before placing them on the market. If the Commission would not designate a EU reference laboratory for a particular device in class D, those requirements are not applicable. According to the Joint plan, a call for application to member states and the Joint Research Centre shall be issued by the Commission to nominate candidate laboratories. New implanting acts on tasks and criteria and on fees to be levied by the EU reference laboratories are also expected.

According to the IVDR, the adoption of common specifications (CS) is optional; nevertheless, the Joint plan indicates the intention of the Commission to propose some sets of common specifi cations and reach an agreement on the text that should enter the first adoption round. This should also lead to the adoption of the first implementing act containing the common specifications. This round should include common specifications relative to Kidd and Duffy blood grouping, Chagas and syphilis, and cytomegalovirus/Epstein-Barr virus devices, for which the drafting process is at an advanced phase.

New common specifications should be targeted to class D devices and will be developed by the IVD sub-group of the MDCG. Already existing CS under the old Directive should be transposed without major modifications.

A new implementing act on the MDR/IVDR standardisation request should be adopted by the Commission and accepted by relevant bodies (CEN/Cenelec). The Commission should also adopt the implementing acts on the publication in the Official Journal of references of harmonised European standards in support of the IVDR requirements.

Set B of actions include also the drafting and endorsement of a guidance on notified body designation codes, as well as of guidance on batch testing for notified bodies. New guidance may be also developed on significant changes and on appropriate surveillance, as referred to in Article 110(3) of IVDR. The MDCG should also complete the issuing of a new guidance on clinical evidence for IVDs, which is part of the documents needed to support the evaluation of the devices’ performances and the work of expert panels.

To this instance, the plan also indicates the need for a clarification on what constitutes a “type of device” and on the process to be followed by notified bodies in context of views of the expert panel. A template for summary of safety and performance should be also released, together with a template for the application/notification of performance studies. The issuing of an IVDR-specific guidance on harmonised administrative practices and alternative technical solutions until Eudamed is fully functional is also planned.

The joint plan also includes sections on actions required in the field of companion diagnostics, legacy devices and in-house devices.


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.