Guidance Archives - European Industrial Pharmacists Group (EIPG)

Generative AI in drug development


by Giuliana Miglierini Generative AI is perhaps the more advanced form of artificial intelligence available today, as it is able to create new contents (texts, images, audio, video, objects, etc) based on data used to train it. Applications of generative Read more

PGEU annual medicine shortages report


by Giuliana Miglierini The situation of medicine shortages is getting worse, with many countries which in 2023 experienced more issues than the previous years, according to the PGEU annual report on medicine shortages. Community pharmacists are on the front line Read more

EMA’s pilot scheme for academic and non-profit development of ATMPs


by Giuliana Miglierini Advanced therapy medicinal products (ATMPs) are often developed by academic and non-profit organisations, because of their high level expertise in the biotechnological techniques that underpin many new therapeutic approaches. On the other hand, these organisations often lack Read more

EMA’s recommendations to prevent medicines shortages

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By Giuliana Miglierini

Continuity of medicinal product supply is still representing a key issue for European countries. The HMA/EMA Task Force on the Availability of Authorised Medicines for Human and Veterinary Use has published a new guidance document in the form of recommendations for the industry on best practices to be adopted to prevent shortages of human medicines.

The recommendations are targeted at marketing authorisation holders (MAHs), wholesalers, distributors and manufacturers. The specific role of each actor is detailed, and highlights are provided on how to optimally approach the prevention and mitigation of shortages. The document refers to the harmonised definition of shortage agreed by EMA and HMA, i.e. “A shortage of a medicinal product for human or veterinary use occurs when supply does not meet demand at a national level“.

Different players for different roles

The pharmaceutical supply chain is characterised by many different actors, each of which plays a specific role in the development, manufacturing and distribution of medicinal products.

Marketing authorisation holders are the ultimate responsible for the monitoring of all activities needed to timely produce and distribute their products. This means MAHs should oversight the entire supply chain, from suppliers of active ingredients (APIs) to end users, in order to continually align demand with supply, evaluate the actual impact of a shortage, and establish the more suitable prevention or mitigation strategies. According to the guidance, reference should be made to the “ISPE Drug shortages prevention plan – Holistic view from root cause to prevention” in order to build a suitable quality culture integrated into product lifecycle; compliance to ICH Q10 is also recommended.

Manufacturers include both APIs suppliers and producers of the medicinal product, which should possess a in depth knowledge of their processes and issues that may impact on product availability. This is even more true for contract manufacturing organisations (CMOs), as a problem with their manufacturing capacity may impact many different customers. Wholesale distributors have general visibility of stock levels and product flow and can identify early signals of a potential medicine shortage. They are subject to national laws as for their obligations to ensure continuity of supply to patients.

As for institutions, national competent authorities (NCAs) are responsible for the coordination of the response to a shortage by means of regulatory tools and strategies. Existing regulatory flexibility can be used, while NCAs cannot intervene in pricing, sourcing, and clinical practice. NCAs are also responsible to communicate actual shortages from their websites.

EMA’s responsibilities relate to shortages of centrally authorised products and coordination of the EU response to supply issues due to major events or public health emergencies. The Agency is also responsible for the publication of a public catalogue for shortages assessed by the CHMP and/or PRAC committees, and for the publication of information on critical shortages monitored at EU level.

National health service providers are responsible for the setting up of policy and operational aspects needed to guarantee the timely access to medicines (i.e. reimbursement schemes, purchasing arrangements, clinical guidelines, etc.). In case of a shortage, they are called to indicate available alternatives, and to issue specific clinical guidance for healthcare professionals if needed.

The overall sustainability and accountability of health systems is the major goal for national Ministries of Health, to be tackled by mean of legislative initiatives. End users include healthcare professionals responsible for appropriate prescribing and for the identification of available alternatives in the case of a shortage affecting their patients. Timely information to patients, in particular for specific diseases, may be provided by patients representative groups, which may also collect feedback on the impact of shortages for patients.

Ten recommendations to prevent shortages

The guidance highlights the importance to notify as soon as possible to NCAs any potential or actual shortage, in order to timely face the increased demand for alternative product suppliers. To this instance, MAHs and wholesalers are in the best position to monitor available stocks and report at early stages about possible issues.

An improved transparency would be needed as for the provided shortage information, to avoid patients’ concerns and the consequent risk of stockpiling and to avoid duplication of efforts. To this instance, MAHs are called to provide all available information requested by the notification form, including also multi-country information (e.g. related to API suppliers).

MAHs should also have a shortage prevention plan in place, addressing the entire life cycle of the specific product from sourcing of raw materials to manufacturing capacity and distribution. Wholesale distributors are also called to develop similar plans focusing on their specific role. Prevention plans should include an analysis of vulnerabilities and risks of interruption of supply, the assessment of the robustness of the supply chain arrangements and controls as well as of the need of revalidation, and the availability of a medicine shortage risk register to identify products of clinical importance by therapeutic use and availability of alternatives.

MAHs and wholesalers should also have a shortage management plan to be activated in case of issues with the availability of a certain product. To this instance, the capacity of available alternative manufacturing sites is critical, including CMOs which should always be kept timely informed by MAHs. A possible approach suggested by the guidance sees the development of a dashboard to continuously monitor signals for potential supply disruption. Procedures to identify true shortage points would also be needed to overcome the current limitation of the automated order systems.

The punctual implementation of Pharmaceutical Quality System according to ICH Q10 and ICH Q12 is also deemed fundamental to prevent any delay related to regulatory procedures that may impact on product availability. Product quality reviews (PQRs) are suggested as a possible tool to capture appropriate data and trends for continuous improvement.

The overall resilience of the supply chain should be supported by the justification of the adoption of the just-in-time supply model, particularly when limited alternatives are available. MAHs and wholesalers should guarantee the availability of suitable contingency stocks to face any unexpected delay.

Sub-optimal communication among different stakeholders should be also addressed by means of an improved cooperation, including a two-way communication system extending also to potential or actual shortages. Critical points of attention are identified in the intra-company communication between different departments, those between local MAH representatives and manufacturer, and the availability of information on stock levels to entities entitled to supply medicines to the public via ordering portals. Specific criteria for communication, together with the description of key processes and supply chain maps should be developed by each stakeholder.

Stockpiling is another critical practice to be avoided in order to ensure the fair and timely distribution of medicines. To this instance, healthcare professionals are called not to order or dispense more stock than normal in case of shortage, while MAH stock allocation practices between different countries should also take into account the clinical need of patients, and not just economic factors. Parallel trade should be also avoided as far as possible. NCAs should duly justify any decision to limit this practice, while companies should seek advice from their relevant authorities of the exporting country in case of critical shortages.


EDQM introduces a consultation phase in the management of CEP documents

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by Giuliana Miglierini

The new process implemented by the European Directorate for the Quality of Medicines and HealthCare (EDQM) for the elaboration of documents related to the Certification of Suitability  (CEP) procedure includes a newly inserted consultation phase. This new step, which may be public  or targeted to specific groups of stakeholders, aims to increase the transparency of the  elaboration process and offers stakeholders the possibility to forward comments to the draft documents  in order to optimise them.

Transparency and efficiency are also the main goals inspiring the overall new elaboration process, which covers the entire pathway of CEP documents, from development, through consultation,  up to final adoption, publication and implementation.

A dedicated page on the EDQMs’s website will host the documents open to consultation, together with the respective instructions for the stakeholders wishing to submit comments. Announcements  on new documents available for consultation will be made on EDQM Certification webpages.  The CEP Steering Committee will be responsible for the elaboration process for CEP documents, in compliance with the EDQM document CEP Terms of Reference and Rules of Procedure (PA/PH/CEP (01) 1).

The elaboration process will cover both public documents (the main part), as well as those the CEP Steering Committee would indicate as restricted for use by the bodies involved in the CEP  procedure. The new process does not cover the Resolution on the Certification procedure, which falls under another specific process established by the Council of Europe.

A guidance to understand the new process

The management of CEP guidelines and operational documents for the CEP procedure has been described in a specific guidance issued in November 2022 by the EDQM’s Certification of Substances Department.

The guidance covers a broad range of documents participating from different perspectives to the CEP procedure. The elaboration of the different types of documents may slightly differ from one another, with possible exemptions from some steps, for example in the case of minor revisions (which in any case always have to be full justified and documented). All CEP documents will be drafted in English; the guidance provides indication of the format to be used to establish the unique reference code for governance documents and technical guidelines (PA/PH/CEP (XX)  YY), as well as for the revision number (ZR) where needed.

 The EDQM specifies that the implementation date of the newly approved CEP documents will be such to allow interested parties to have enough time to comply with the new or revised requirements.

Governance documents define procedural aspects for the practical implementation of the CEP procedure. The initial draft will be prepared by the EDQM and reviewed and agreed upon by the CEP Steering Committee before entering the consultation phase. Comments collected will serve as the basis to consolidate the final version of the document. A second round of consultation may be needed in case of critical comments preventing finalisation. The adoption of the final document falls under the responsibility of the CEP Steering Committee, which may also indicate the need to improve and re-submit the draft before adoption. Once the final version of the document is available, its publication on the EDQM’s website and implementation will close the process.

Technical guidelines inform about the requirements applicants should fulfil for the submission or evaluation of CEP applications. Their drafting may be initiated also by members of the relevant Technical Advisory Board (TAB), in addition to the EDQM. The TAB is also called to review and agree upon the draft document before the assessment and approval by the CEP Steering Committee and the following consultation phase can take place. The same applies to the consolidation of comments and finalisation of the document, that has to be approved by the relevant TAB. In this case too, a second round of consultation is possible should criticalities arise during the first one, followed by adoption by the CEP Steering Committee (and a possible second round of updating and approval by the TAB, if needed), and publication and implementation.

The management of specific aspects of the procedure can be supported by the issuing of administrative or operational documents. These documents fall under the responsibility of the EDQM, that may consult the CEP Steering Committee of other parties where necessary.

The consultation phase

A specific chapter of the EDQM’s guidance describes the newly inserted consultation phase, those details (type of process and duration) will be decided on a case-by-case basis by the CEP Steering Committee.

In the case of a public consultation, the draft document will be made available at the dedicated page of the EDQM website. The draft may also be sent to identified relevant stakeholder organisations, to ensure a better awareness of the ongoing process.

Targeted consultations aim to obtain feedback from selected stakeholders on specific areas of intervention. In such instances, the forwarding of the draft document will be restricted only to identified interested parties, including regulators and relevant industrial associations or other organisations.

According to the type of document and/or the topic under consultation, the consultation phase may vary in duration. To this instance, the guidance indicates a possible range between 3 weeks and 3 months, with the effective duration to be communicated as a part of the call for consultation.  A template will also be available to submit comments, which should be always justified and contain concrete proposals for action to tackle the issue under consideration. All comments and justifications received will be transmitted to the groups in charge of approving and adopting the documents.

At the end of the elaboration process, the final approved versions of CEP documents will be published on the EDQM’s website.   


MDCG, a position paper on the capacity of notified bodies

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by Giuliana Miglierini

The lack of a suitable capacity of notified bodies (NBs) is one of the main issues still pending after the entry into force of the new Medical Device Regulation (MDR) (EU) 2017/745 and In Vitro Diagnostic Regulation (IVDR) (EU) 2017/746. The Medical Devices Coordination Group (MDCG) discussed some suggestions on how to address the problem within a position paper published in August 2022.

Even if the document does not represent an official guideline, it describes some critical points to be considered by manufacturers and notified bodies in order to face the great challenge of the re-certification of medical devices and in vitro diagnostics according to the new rules. Should this not occur in time, many products may exit the market at the end of the transition period, potentially leading to a supply crisis greatly impacting on the health of patients and the normal functioning of healthcare institutions.

The MDCG position paper answers the request of EU Health ministers advanced during the EPSCO Council meeting on 14 June 2022 to figure out some immediate measures to face the problem. The final goal of the document is to improve the efficiency in the application of the current regulatory framework, with no reduction of requirements to be fulfilled by manufacturers. Waivers from applicable conformity assessments procedures should be considered only in relation to an interest of public health, patient’s safety, or health.

The position paper consists of nineteen points addressing the issue under its different perspectives, the first eleven of which refer to the increase of notified bodies’ capacity. The MDCG calls on all stakeholders to collaborate in order to smoothly implement the suggested actions, a process that will be monitored by the MDCG itself.

How to increase the capacity of NBs

Hybrid audits should be the elective tool notified bodies may use where appropriate to timely and efficiently run conformity assessment. Duplication of activities should be also avoided. To this instance, the suggestion is to “develop a framework for leveraging evidence, or components thereof, from previous assessments” run according to previous Directives. A pre-condition to activate this possibility is that the previous assessment has been judged “valid and properly substantiated also with regard to the MDR/IVDR requirements and the device” by a duly qualified notified body personnel.

A flexible approach may also apply to the combination of audits for legacy devices and actions needed to guarantee their ‘appropriate surveillance’. Combined audits may be used particularly for legacy devices whose application for MDR/IVDR certification is under review by a NB, thus moving the focus more towards the assessment of compliance with the new rules. To this instance, the MDCG also announced the intention to produce a specific guidance on ‘appropriate surveillanceunder Article 110(3) IVDR and to update MDCG 2022-4.

Already existing guidance may also be reviewed to reduce the administrative burden for NBs, and remove limitations related to the scope of documentation not required by MDR/IVDR.

A fundamental piece of the new European infrastructure for medical devices and IVDs is represented by the centralised Eudamed database, which should be timely fed by NBs with all relevant information using machine-to-machine procedures. Double registrations should be avoided as much as possible.

New notified bodies are essential in order to increase capacity. To this instance, the MDCG suggests supporting training, coaching and internship activities for their personnel. The rationalisation of internal administrative procedures is also deemed important.

Time for re-assessment of NBs is undergoing a review by the European Commission, which is expected to result in the publication of new Delegated Acts. The proposal is to move from the current first re-assessment at three years after notification (and then every 4th year) to up to five years after notification, on the basis of a flexible approach. There are currently ten re-assessments planned in 2022, twelve in 2023 and 11 in 2024. According to the MDCG, the new timeframe for re-assessment would allow national designating authorities to free resources to assess new NBs, while existing ones could process higher numbers of first MDR/ IVDR certifications.

Assessment, designation and notification of conformity assessment bodies (including the European Commission) are also called to reduce their timeframes and improve the efficiency of their processes, keeping unaltered the requirements to be met. The possibility to add specific codes to the designation of NBs shall be also explored by the MDCG. The Group is also committed to prioritise some ongoing actions which may impact on NB’s capacity (i.e. revision of section III.6. of MDCG 2019-6 revision 3).

MDCG’s guidance documents should be seen as an aid “to apply the legal requirements in a harmonised way, providing possible solutions endorsed by the MDCG”. Nevertheless, demonstration of the compliance to requirements should always benefit of a certain flexibility. A reasonable time should also be granted to integrate the new guidance in the relevant systems and/ or to apply them, suggests the MDCG.

Suggestions for the manufacturers

Under the perspective of manufacturers of MDs and IVDs, costs to access NBs may play an important role, especially for small-and-medium companies (SMEs). The MDCG position paper recalls NBs to the obligation to make their standard fees publicly available, possibly in a way that might be easily compared. Specific access schemes should be also in place to make available some capacity to SMEs and other first-time applicants for conformity assessment.

Manufacturers should also refer to notice MDCG 2022-11 to ensure timely compliance with MDR requirements. IVDs should not left behind, even if this category of products benefits of one more year for the transition to new rules compered to medical devices.

Structured dialogue is the suggested tool to improve the collaboration between manufacturers and notified bodies along the entire process of conformity assessment aimed at regulatory procedures, should this approach turn to be useful in order to improve the overall efficiency and predictability.

A timely communication to manufacturers by mean of webinars, workshops, targeted feedback and informative sessions is also deemed important in order to allow for a better preparedness, with a particular attention to SMEs and first-time applicants. The MDCG also suggest NBs to develop common guidelines for manufacturers to assist them in the application phase, containing explicative examples of typical non-conformities and details on he preparation and content of technical documentation. National authorities and industry associations are called as well to contribute to the dissemination of relevant information across their stakeholders.

Specific guidance should be issued by the MDCG to support a simpler conformity assessment of some aspects of legacy and orphan devices denoted by a demonstrable track record of safety. The development of a specific definition of “orphan devices” is also planned.

An improved dialogue between NBs and medicines authorities, and cases where expedited review would be possible is also supported in order to speed up consultations on medical devices incorporating an ancillary medicinal substance and companion diagnostics.



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.