The ICMRA collaborative hybrid inspection pilot (CHIP)

January 22, 2024

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by Giuliana Miglierini

Hybrid inspections emerged during the pandemic as a new way to approach the assessment of pharmaceutical plants and productions by regulators. More in particular, under this approach regulatory authorities from different geographical areas join efforts to reach a shared regulatory decision based on results of either on-site or remote inspections (see here more information on EMA’s website).

Hybrid inspections are the focus of a pilot project launched by the International Coalition of Medicines Regulatory Agencies (ICMRA), following a workshop held in July 2023 and organised in collaboration with the International Federation of Pharmaceutical Manufacturers and Traders (IFPMA).

Among the main objectives of the collaborative hybrid inspection pilot (CHIP) is the assessment of existing technologies and virtual inspection methods in supporting a stronger collaboration among regulators. The development of a global Pharmaceutical Quality Knowledge Management System (PQ KMS) would be one of the main consequences of such collaboration. The CHIP pilot is now open to new applications from the pharmaceutical industry. More information is available on ICRMA website, together with the summary report of the PQ KMS workshop and related documentation. We summarise the main features of the pilot.

The CHIP pilot on hybrid inspections

The methodology used to run the CHIP pilot, together with inspection expectations to be met by the industrial partners, are described in the dedicated page of the ICMRA website. The implementation plan is available at this link.

The first phase of the pilot ran in 2023 and included the collaborative assessments of post-approval changes as a useful tool to improve cross-regional access to critical medicines. This part of the project led, in May 2023, the European Medicines Agency (EMA) and the US Food and Drug Administration to approve on the same day, without any delay between the two areas, the addition of three new manufacturing sites in the supply chain of a treatment for a rare type of cancer. The Japanese regulator PDMA also participated to the project as observer.

The new phase of the project will involve other regulators and will focus on the collaboration between regulatory authorities (RAs) and industry to implement and promote innovative regulatory approaches and technologies.

In hybrid inspections, only one leading RA is present on-site with its inspectors (the local RA, whenever feasible), while the other regulators participate from remote to follow the on-site inspection team procedures. The new approach is expected to reduce efforts, cost and time for both regulators and inspected pharmaceutical companies, as a single inspection will allow multiple authorities to agree on a site’s compliance. Marketing authorisation holders (MAHs) may also experience a smoother submission process, as they would possibly receive a single list of information requests, comments, and questions from multiple regulatory authorities. The pilot is also expected to lead to the definition of a suitable approach to handle post-authorisation inspections (routine inspection).

Preparing for the hybrid inspection

Hybrid inspections start with pre-inspections activities, to be launched 30-60 days prior to the actual inspection. The main goal of the pre-inspection is to ensure the target facility has all the needed resources to host, support and accommodate the hybrid inspection.

In this phase, the on-site lead inspectorate is called to liaise with the site to arrange for all the organisational and logistical aspects, as well as networking with all the other participating RAs to plan the activities to be observed during the inspection. The anticipated agenda and length of the hybrid inspection should be determined in advance by participating RAs and shared with the company by the lead inspectorate. Hybrid inspections should be no longer than normal on-site inspections.

The planned scope of the inspection has also to be agreed upon during pre-inspection, and it should be the same for each participating RA. To this instance, the leading on-site inspectorate is in charge of obtaining from the company all the requested information, on the basis of accepted global standards (i.e., Site Master File based on PIC/S). The inspected facility is entitled to receive details of the closing meeting between RAs prior to the conduct of the inspection.

As for the number of participants in the inspection (including investigators and coordinator roles), it should reflect realistic staffing levels for long-term implementation. The planning phase should also be comprehensive of the establishment of a communication channel (including testing the stability of the connection) between RAs and the facility, and a second one for RAs to communicate between the on-site and remote teams.

A coordinating officer, assigned by the lead inspectorate team, should oversee the logistics for the remote team, and a facilitator from the company should also be identified to manage the remote team’s requests and upload all the documentation. This last one should be shared using the appropriate exchange platforms, as specified by each authority, and agreed during the pre-inspection phase.

The actual hybrid inspection

The opening meeting is the first act of the hybrid inspection, during which all participants (both on-site and remote) introduce themselves and define the lead inspector in charge of the coordination of all activities. The coordinating officer is also nominated in the opening meeting, and the inspection team schedule is presented to the facility’s key personnel. The hosting site can introduce the facility, including the Quality management system and production schedule.

The possibility to run a virtual tour for remote RAs of the areas and activities to be inspected has to be assessed and agreed on during the pre-inspection phase. Should this not be possible due for example to difficulties with the Internet connection, remote RAs may rely on the observations made by the on-site team, which will inspect the plant according to the defined scope of the inspection, with reference to critical manufacturing activities.

Inspectors may start their tour of the plant following the same logical flow of the process they are assessing, from inwards warehouses to production areas, QC areas and outwards warehouses. Some breakout rooms may be created along this flux in order to allow inspectors to check the relevant documentation and run interviews with personnel. To this instance, the remote team should request in advance documents through the coordinating officer, and possibly access them off-line during the inspection should different time zones apply. Questions to be proposed during the interviews should also be provided in advance by the remote team to the lead inspector or through the coordinating officer.

The results of the activities performed during the inspection is discussed by RAs at the end of each-day, in order to plan the activities for the following day; the lead inspector shall then communicate them to the facility.

Closure of the inspection

The closing meeting is the final act of the inspection, during which the lead inspector should report on the observed GMP deficiencies. In case of a different perception of a certain issue by different RAs, they should try to reach a common position on its significance during a pre-meeting. Any difference in GMP deficiencies or outcomes should be illustrated to the company by the lead inspector during the closing meeting.

This should also be the place to discuss post-inspection activities and their timelines, that should be aligned between the different participating RAs. Collaboration between regulators should also extend to the coordinated assessment of the documentation on corrective and preventive actions (CAPAs) submitted by the manufacturer.

The first Union list of critical medicines

December 21, 2023

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by Giuliana Miglierini

The first version of the Union list of critical medicines was published on 12 December 2023 by the European Commission, the European Medicines Agency (EMA) and the Heads of medicines Agencies (HMA).

The initiative is part of the actions planned according to the Pharmaceutical Strategy and the Communication on addressing medicine shortages in the EU. A Q&As documentwas also published to illustrate the main features of the list, together with the methodology to identify critical medicinesto be included in the list (see the dedicated webpage of EMA’s website). The first version of the Union list of critical medicines is comprehensive of approx. 200 active substances, selected starting from a pool of more than 600 referred to in the national lists of critical medicines of Finland, France, Germany, Portugal, Spain, and Sweden. These six countries were chosen as their lists were based on criteria aligned with those agreed for the Union list. The process also comprised consultations of key stakeholders, including patients and healthcare professionals’ organisations and industry associations.

The list will be updated annually, and further references will be added in 2024. The final list will also include the separate assessment of the vulnerability of the supply chains to be run by the European Commission.

The Union list will not replace existing national lists of critical medicines, that will continue to support national policy decisions. EU member states may also use the Union list to create their own national lists, if not yet available.

“Ensuring an uninterrupted supply of critical medicines is essential for a strong European Health Union. With the publication of the first Union list of critical medicines today, we are delivering on our promise to accelerate work in this area and to take every possible measure to avert the risk of shortages for our citizens”, said Stella Kyriakides, Commissioner for Health and Food Safety.

A list to prevent shortages

The Union list of critical medicines represents a warning about the importance of avoiding shortages for specific medicines, as they would highly impact both patients and healthcare systems. No immediate effect is expected on shortages, but the risk might decrease in the longer term.

The Union list specifies human medicines (both innovators and generics, vaccines, and medicines for rare diseases) those continued supply is considered a priority in the EU. It will be used by the EU Commission, EMA and HMA for the definition of proactive measures to strengthen the supply chain and minimise the risk of supply disruptions (see more on EMA’s webpage on Availability of critical medicines).

The Union list of critical medicines will also serve as the basis for the Commission to run the analysis of vulnerabilities, followed by recommendation of suitable measures in consultation with the Critical Medicines Alliance (we wrote about this part 1 and part 2). The Commission may issue recommendations for companies to diversify suppliers or increase production within the EU. Incentives to invest may also be used to favour the resilience of European manufacturing. As for procurement, strong contractual obligations for delivery may apply.

Medicines included in the Union list will also be prioritised for actions by the European medicines regulatory network, in charge of monitoring their availability and implementing measures to minimise the risk of supply disruptions. To this instance, existing processes and structures will be used as defined in the mandate of EMA’s Medicine Shortages Single Point of Contact (SPOC) Working Party and EMA’s Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG).

No additional obligations have been introduced by now for marketing authorisation holders and national competent authorities. This will be a topic of discussions during the final phase of negotiations on the proposed revision of the EU pharmaceutical legislation.

The methodology to select critical medicines

The therapeutic indication and the availability of alternative medicines are the two main criteria for the insertion of a certain medicinal product in the Union list of critical medicines. Additionally, it has to be classified as critical in at least one-third (33%) of EU/EEA (European Eco-nomic Area) member states.

National lists of critical medicines may differ from one another, reflecting differences of the internal evaluation criteria used to assess criticality. For example, some products are marketed just in some countries, or alternatives are available in some countries and not in others. Furthermore, the Union list is still incomplete, as some important medicines have not yet been assessed at the central level. The Union list does not include as well products mentioned in the WHO list of essential medicines. Orphan medicines are included in the Union list if they meet the above-mentioned assessment criteria.

The document on methodology further clarifies the governance of the process and the matrix for identifying medicines to be included in the Union list of critical medicines. The methodology was created starting in 2021 (European Commission Structured Dialogue initiative), finalised by the HMA/EMA Task Force on the availability of authorised medicines for human and veterinary use (HMA/EMA TF-AAM), and finally adopted in June 2023.

The medicinal product criticality is evaluated on the basis of a risk assessment. As for therapeutic indications (criterion 1), all authorised medicines in a member state should be classified, irrespective of their marketing status. Criterion 2 refers to the availability of alternatives, and only authorised medicines marketed in the respective member state should be classified.

A low, medium or high-risk level is assigned for each of the two above-mentioned criteria, thus resulting in a risk matrix. The exercise allows to assign the medicine in one of the following categories: critical medicines, medicines at risk, other medicines.

Medicines considered at high risk with respect to their therapeutic indication refers to products those use may have very serious implications for the health of individual patients or public health (general life-threatening acute conditions, specific life-threatening acute conditions, or irreversibly progressive conditions). Evaluation parameters include the fact the disease is potentially fatal, irreversibly progressive or, if left untreated, will pose an immediate threat to the patients. Furthermore, the treatment must be administered immediately or within regular dosing intervals, and the product has to be part of a national disease control program.

Appropriate alternatives are identified according to the fact they are authorised for the same therapeutic indication and are available on the market in the respective member state. Furthermore, alternative treatment has to be clinically possible, without negative impact on the patient’s health and providing the same quality of care standard. As for criterion 2, high risk cri-tical medicines refer to products for which no appropriate alternative is available, or only one appropriate alternative (product) on ATC level 4 or 5 (same active substance or alternative is within the same ATC level 4 group or in another ATC level 4 group) is available.

Public consultation for the review of HERA

We inform all interested EIPG’s members that the public consultation for the review of the Health Emergency Preparedness and Response Authority (HERA) is open until 19 February 2024 and it can be accessed through the dedicated webpage of the EU Commission website.

The consultations aim to assess how HERA’s mandate and tools contributed to achieve EU’s political objectives, and how the Authority complements the work of other EU bodies and responds to the current health challenges.

Swissmedic’s technical interpretation of Annex 1

December 15, 2023

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by Giuliana Miglierini

New insights on the interpretation of the new Annex 1 to Good manufacturing practices (GMPs) comes from the Swiss regulatory authority Swissmedic, that at the end of October 2023 published the first revision of its Q&As document (you can find it on the Swissmedicines Inspectorate webpage)

The technical interpretation refers to the revised Annex 1 to the PIC/S GMP Guide (PE 009), adopted on 9 September 2022 and entered into force on 25 August 2023 (with the exception of point 8.123 on lyophilisation, which will enter into force on 25 August 2024). The Q&As follow the same scheme and chapters of Annex 1.

Scope and Premises

According to Swissmedic, for certain types of advanced medicinal products (e.g. ATMPs or allogenic and autologous cell therapy products) specific considerations are required with respect to the fact they cannot be terminally sterilised or filtered. The unsterile patient material should also be considered. Requirements of Annex 2A, paragraph 5.29(b) should be followed for aseptic processing, that should be maintained from the time of procurement of cells through manufacturing and administration back into the patient.

Exceptions to the application of Annex 1 need to be always justified: the Contamination Control Strategy (CCS) is the appropriate tool to detail all risk analysis performed on the basis of the specific manufacturing processes under consideration.

As for the Premises, segregated unidirectional flow airlocks for material and personnel for grade A and B cleanrooms are expected in the case of new facilities. Temporary separation of the flows in the airlocks is the minimum requirement for existing facilities, together with a detailed risk analysis to assess the need for additional technical or organisational measures.

The transfer of materials in and out of a critical grade A cleanroom should be based on the careful definition of the technical and procedural measures associated with it. For example, prior introduction of materials in an isolator followed by decontamination is considered possible only for small batches and for materials resistant to VHP treatment. In all other cases, materials have to be sterilised before entering the already sterile isolator. The transfer process is also subject to a risk analysis to be included in the CCS, as well as to measures to control the maintenance of the integrity and functionality of the systems (also with respect to aseptic process simulation, APS).

Swissmedic specifies that the cleanroom sequence for the transfer of materials via airlocks or passthrough hatches is expected to be fulfilled for zones A and B. In the case of the passage from grade A to C, qualification is needed to prove adequacy of the established systems and procedures. The corresponding risk analysis has to be included in the CCS.

Updating equipment to reach full compliance with the new Annex 1 may require high investments. According to the Q&As, older barrier technologies should be subject to an in-depth internal evaluation to assess the need for new technical measures. The document underlines that starting from 25 August 2023 all barrier technologies not compliant with the new Annex 1 are considered deficient, thus companies should start projects to evaluate the upgrading of background cleanrooms and to define CAPA plans and interim measures to reduce risks.

The risk assessment should also include the evaluation of all automated functionalities and processes associated with the use of the isolator and the activities taking place in it. To this instance, Swissmedic highlights that robotic systems may help improving the reproducibility of operations and minimising both errors and manual interventions. Automatic processes are also expected for the decontamination of isolators, while for RABS manual processes might be used, provided they are designed to ensure reproducibility and are subject to validation and regular monitoring. The absence of negative effects on the medicinal product associated to the cleaning or biodecontamination substances used should also be validated.

As for barrier technology systems with unidirectional air flow, air velocity must be defined so that uniform airflow conditions prevail at the working positions where high-risk operations take place. Alternative air speed ranges or measurements at different heights in the system have to be scientifically justified in the CCS.

Utilities and Personnel

The section on Utilities offers additional guidance on systems used for water generation, that should be designed to allow for routine sanitisation and/or disinfection. Procedures are needed to define regular preventive maintenance of the reverse osmosis system, including the regular change of membranes. A suitable sampling schedule should be in place to regularly check water quality. More stringent controls are needed for the sampling of water-for-injection distribution systems, including daily microbial and bacterial endotoxin testing. The monitoring of the process gas should be performed as close as possible before the sterilisation filter.

Adequate training and qualification of all people working in grade A and B areas, including aseptic gowning and aseptic behaviors, is essential. According to Annex 1, this should include an annual successful APS. Swissmedic adds that, even if not explicitly required, practical process simulations, including manual interventions, should be carried out under the supervision of qualified trainers/QA; the company can choose if to integrate these process simulations into the APS.

Production and specific technologies

As for lyophilisation, initial loading patterns must be always validated, and revalidated annually. The Q&As specify cases where revalidation can be skipped, adding that a theoretical reference load is not acceptable. Revalidation has also to include temperature mapping for moist heat sterilisation systems.

Should a closed system be opened, this should be followed by cleaning (if required) and a validated sterilisation process. Alternatively, the system can be opened in a decontaminated isolator; a class A cleanroom with a class B background might be considered only for exceptional cases.

Non-aseptic connections can be carried out for coupling closed systems, provided a validated sterilisation cycle (SIP) occurs prior to use. Sterile aseptic connectors can be used if the supplier was checked and validated; data from the supplier can be used to file the relevant documentation, but handling of these parts has to be included in the APS.

Swissmedic also underlines that piercing a septum with a needle is to be regarded as a breach of the sterile barrier, and thus avoided for ascetic steps. Should this not be possible, temporary measures should be undertaken to prevent contamination.

Tube welding has also to be qualified and validated, and included in the APS if it is part of the aseptic filling process. The advice is to use more reliable systems, to avoid risks of undetected integrity deficiencies.

Critical single use systems (SUS) should always be tested for integrity by the end user on site before they are used in production. In case of difficult to test, small single use systems, the decision not to test their integrity must be justified in the CCS, as well as the decision to make use of test results provided by suppliers. To this instance, Swissmedic underlines that the comprehensive assessment (including quality system, etc.) should cover the SUS manufacturer/ s, as well as any subcontractors involved in critical services or processes.

Furthermore, the intended use of a SUS in the specific manufacturing process represents the basis for setting the respective acceptance criteria. The Q&As also detail the modalities for the visual inspection of SUSs and the possible acceptance of validation data provided by their suppliers.

As for extractables, the end user is expected to assess the data provided by the suppliers in order to define the need for additional evaluation or leachable studies. A redundant filtration step through a sterile sterilising grade filter, to be included as close to the point of fill as possible, is also encouraged, and its absence has to be justified. A risk analysis is required to justify the choice not to include pre-use/post-sterilisation integrity testing (PUPSIT) of sterilising grade filters used in aseptically processes.

Environmental and process monitoring

According to ICH Q9 (R1), the frequency of the risk review should be based on the level of risk determined for the specific process under consideration, as well as on the level of uncertainty of previous assessments. The recommendation of Swissmedic for new plants is to review the risk assessment after the first year of operations, so to take into due consideration the acquired experience. The document also suggests cases where more stringent action limits may be needed, and the type of statistics to be used to establish alert levels.

The use of rapid microbiological methods (RMM) requires validation and demonstration of equivalence with more traditional approaches. Details on the frequency of the interventions and their inclusion in the APS are also discussed, as well as the container/closure configuration and the distinction between liquid filling and lyophilisation.

The APS of campaign manufacturing represents a complex case for Swissmedic, for which the start-of-campaign (including aseptic assemblies if the case) and end-of-campaign studies should be both conducted. The Q&As also confirm that any contaminated unit with a contamination > 0 CFU results in a failed APS and requires the activation of the consequent actions. Production should resume only after completion of a successful revalidation.

Quality control

A university degree or an equivalent diploma in the field of microbiology (or other natural sciences, or medicine) together with a good understanding of the manufacturing processes under consideration are required for the person in charge of supporting the design of manufacturing activities and environmental monitoring.

As for raw materials, the need for microbiological testing should be evaluated taking into consideration their nature and respective use in the process. All specifications should be discussed and justified in the CCS.

Swissmedic also confirms that the bioburden has to be tested on each batch of raw material as incoming control as well as on the compounding solution in which it is formulated before sterile filtration. In the case of products with short shelf life, should an out-of-specification (OOS) event appear after release of the batch, a procedure is needed to inform doctors, patients, and health authorities, and to assess the connected risks and define remediation actions.

The current status of the transition to the MDR and IVDR regulations

December 8, 2023

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by Giuliana Miglierini

As the term to apply for the certification of medical devices and in vitro diagnostics according to regulation 607/2023 approaches (24 May 2024), new data have been published by the European Commission on the current status of the procedures. The critical goal for all the stakeholders involved in reaching compliance with the new rules in time is to avoid the risk of seeing many products excluded from the market.

The last release of the Notified Bodies Survey on certifications and applications run under the DG SANTE’ Framework contract reports data from notified bodies (NBs) designated under MDR/ IVDR until 30 June 2023.

The Medical Devices Coordination Group (MDCG) also updated its position paper “Notice to manufacturers and notified bodies to ensure timely compliance with MDR and IVDR requirements”.

The Notified Bodies Survey on certifications and applications

The Notified Bodies Survey was launched by the European Commission in December 2022 and will close in December 2025. All the 39 notified bodies included in its last release responded to the survey. The majority of them (29) are designated only under the MDR, 9 both under the MDR and IVDR and just 1 only under the IVDR.

Data for medical devices show that there are currently 22.793 total valid certificates referred to Directive 93/42/EEC (MDD) or Directive 90/385/EEC (AIMDD, on active implantable devices). The great majority of them (17.045) will expire during 2024. As for 30 June 2023, there were 13.177 applications filed to comply to the new MDR (+22% compared to October 2022), and 3.899 issued certificates (+32%).

The great part of both applications and certificates refer to devices that need to meet requirements listed in Annex IX (classes I&III and II). Many of the applications and certificates refer to the Quality Management System (QMS, 9.071 and 2.682 respectively), while product ap-plications and certificates were respectively 4.106 and 1.217. A small part of the applications (388) refers to devices incorporating a medicinal substance, thus requiring the activation of the consultation procedure with pharma regulatory authorities (57 issued certificates). The survey also indicates it takes a mean of one to three months to reach signature of the written agreement for applications filed for changes of already MDR issued certificates.

The main reasons for the refusal of the certification include the fact the application is outside the scope of the NB’s designation (47%) or is incomplete (27%). To this instance, the percentage of submissions with a completeness rate > 50% is still low (21% in June 2023, vs 31% in October 2022). The survey also indicates it takes a longer time to obtain MDR QMS + product certificates (13-18 months for 40% of NBs), compared to just the QMS certificate (6-12 months for 45% of NBs).

As for products with no intended medical purpose that fall under the scope of the MDR, the collected data show an increase of the requests to sign a written agreement for a conformity assessment procedure of an Annex XVI product. This trend is expected to continue further in 2024, as well as the estimated transit of MDD certificates for Annex XVI products to the MDR without maintaining the medical purpose for the covered devices.

As for certification applications in accordance with Annex VII section 4.3 of MDR (Application review and contract), the survey reports a total of 15.530 applications and 9.422 signed written agreements (+28% vs the results of the survey closed on 31 March 2023).

The situation for vitro diagnostics

The survey run in October 2022 showed a total of 1.551 valid IVDD certificates. In this case too, the great part of certificates will expire in 2024 (482) and 2025 (866).

The trend of applications and certificates is similar to that of medical devices, with a total of 1.155 applications received as for June 2023 (+22% compared to March 2023) and 500 granted certificates (+51%). Again, the great majority refers to products following Annex IX requirements.

As for class D devices (i.e. IVDs aimed to detect or exposed to transmissible agents which are life-threatening or have a high risk of propagation), the survey reports a total of 231 applications received by June 2023, and 62 certificates. Incomplete applications are again the main reason for refusal of certification. Times required to reach certification are also similar to those seen for medical devices.

MDCG’s amendments to the Notice to NBs and manufacturers

Revision 1 of the MDCG position paper 2022-11 is focused on the new section which calls notified bodies to streamline the certification process, and on the revision of the one referred to manufacturers to submit applications without delay.

The MDCG’s document adds further details to the above seen data from the survey. According to the Coordination Group, the actions taken to facilitate the transition and improve NBs’ capacity (MDCG 2022-14, e.g. use of hybrid audits, deferral of re-assessment of notified bodies, etc.) are showing good results.

Despite the increased number of notified bodies designated under the MDR and the IVDR (40 and 12, respectively), the MDCG highlights that data from the survey indicates limited progress for both the applications and certifications. “This shows that manufacturers tend to transfer at different times devices to be included in the same certificate. Whilst this approach is understandable, it might create issues in planning and in the capacity of notified bodies”, wrote the Coordination Group, also underlining the more worrisome situation for IVDs.

On this basis, the MDCG calls the manufacturers “to make the best possible use of the additional time provided by the amendments of the MDR and IVDR by submitting applications for conformity assessment in good time”.

The position paper also comments on the need to file complete and high-quality applications, so to avoid undue delays in the certification process, possibly before the end of 2023 as strongly recommended by notified bodies.

Manufacturers are also expected to regularly provide data on their devices, to increase transparency, improve the exchange of information on specific medical devices and support institutions and Member States in preparing for changes to product ranges.

As for notified bodies, the MDCG asks them to make the certification process more efficient, transparent, and predictable. Streamlined procedures should be the main objective, together with the need to operate in accordance with consistent, fair, and reasonable terms and conditions.

The position paper highlights the importance for notified bodies to provide regulatory guidance and technical information to manufacturers on how to apply for the conformity assessment procedure, so to avoid any issue and delay with the application and certification process.

The MDCG also recalls the importance to support small and medium size companies, and to organise structured dialogues with manufacturers as a part of the normal pre-application and conformity assessment activities. Notified bodies are also expected to regularly provide data on the progress made as for certification, capacity, and timelines for conformity assessment. To this instance, the tool suggested by the position paper would see the activation of a publicly available, common website.

EMA’s reflection paper on AI in the pharmaceutical lifecycle

September 22, 2023

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by Giuliana Miglierini

The rapidly evolving role of artificial intelligence (AI) and its possible application in the pharmaceutical field led the European Medicines Agency (EMA) to publish a draft Reflection paper on the use of AI along the entire lifecycle of both human and veterinary medicines.

The Reflection paper summarises the current view on the possible use of AI and machine leaning (ML) technologies and is open to public consultation until 31 December 2023. Comments, together with the outcomes of the joint HMA/EMA workshop to be held on 20-21 November 2023, will support its finalisation, as well as the possible development of new guidance. The initiative aims to identify the aspects of AI/ML use that would fall within the remit of EMA or of the single National Competent Authorities (NCAs) in charge of the dossiers’ assessment.

The document is part of the effort to improve the European Medicines Regulatory Network’s capability in data-driven regulation set forth by the joint HMA-EMA Big Data Steering Group (BDSG), and it has been developed in coordination with EMA’s CHMP and CVMP committees.

“The use of artificial intelligence is rapidly developing in society and as regulators we see more and more applications in the field of medicines. AI brings exciting opportunities to generate new insights and improve processes. To embrace them fully, we will need to be prepared for the regulatory challenges presented by this quickly evolving ecosystem” said Jesper Kjær, Director of the Data Analytics Centre at the Danish Medicines Agency and co-chair of the BDSG.

“With this paper, we are opening a dialogue with developers, academics, and other regulators, to discuss ways forward, ensuring that the full potential of these innovations can be realised for the benefit of patients’ and animal health” added Peter Arlett, EMA’s Head of Data Analytics and Methods, co-chair of the BDSG.

The main contents of the Reflection paper

The Reflection paper addresses the use of AI/ML with a dedicated chapter for each one of the steps, part of the overall lifecycle of a medicinal product. The interactions with regulators are then explored, as well as the different technical aspects to be taken into consideration. The final chapters discuss the governance of AI/ML applications, the integrity, and ethical aspects to be considered and how to address data protection.

The increasing use of AI technologies is based on the wide availability of big amounts of data produced and captured in electronic format on a routine basis. This data can be analysed by machine learning algorithms to inform the training of other systems able to analyse data and take actions with some degree of autonomy in order to achieve specific goals. These latter systems are the truly intended AI algorithms, those use is under discussion also in the field of regulatory decision making.

The Reflection paper recalls how the diffusion of these new technologies carries with it also some new risks, due to the “exceptionally great numbers of trainable parameters arranged in non-transparent model architectures”. Measures should thus be taken to ensure the safety of patients and the integrity of data, as well as to avoid the integration of bias into AI/ML applications.

The contents of the Reflection paper may also refer to combinations between a medicinal pro-duct and AI/ML-including medical device, as in such occurrence EMA is involved in the assessment of the characteristics of the device.

In general terms, existing guidelines, best practices, and recommendations relative to model in-formed drug development and biostatistics also apply to AI/ML; the adjacent methodology guidelines which may be relevant to this instance are listed in the document. The Reflection paper warns readers about the differences between the human and veterinary regulatory domains, suggesting that another reflection document specific for veterinary may be developed in future.

A risk-based approach

The usual risk-based approach typical of pharmaceutical development should be used to identify risks throughout the entire AI/ML tool lifecycle, including regulatory impact. According to the Reflection paper, the level of risk may depend also on the context of use and the degree of influence the AI technology exerts.

Developers should always seek early regulatory interaction and scientific advice, especially in cases where the AI/ML system may impact on the benefit-risk ratio of the medicinal product un-der development. To this instance, the EMA Innovation Task Force (ITF) is responsible for pro-viding early interaction on experimental technology, while scientific advice and qualification of novel methodologies in medicines development is provided by the Scientific Advice Working Parties (SAWP) of the CHMP for human medicines and of the CVMP for the veterinary ones.

As for all other steps of pharmaceutical lifecycle, the final responsibility for the suitability and use made of AI/ML algorithms, as well as their compliance to ethical, technical, scientific, and regulatory standards (GxP standards) and to current EMA scientific guidelines falls under the Marketing Authorisation Holders (MAHs) or applicants.

According to the Reflection paper, risks referred to in the discovery step may be limited, but they may impact the final evidence presented for regulatory review, thus principles for non-clinical development should be followed. This second step may include, for example, AI/ML modelling approaches according to the 3R principles. Regulators would expect to receive Standard Operating Procedures (SOPs) for AI/ML applications in preclinical studies; advisory documents on Application of GLP Principles to Computerised Systems and GLP Data Integrity should be also considered where appropriate. A pre-specified analysis plan would be needed for preclinical data potentially relevant for the assessment of the benefit-risk balance.

In the field of clinical trials, ICH E6 and VICH GL9 on human and veterinary GCPs should also be applied to the use of AI/ML. In particular, regulators expect the full model architecture and description of the data processing pipeline would be made fully available for comprehensive assessment should a model be generated for clinical trial purposes, as they would be considered parts of the clinical trial data or trial protocol dossier.

From precision medicine to pharmacovigilance

Particular considerations may be needed for applications of AI/ML in precision medicine, to individualise treatment according to the patient’s characteristics. AI/ML application supporting indication or posology decisions should be referenced in the Summary of product characteristics and their assessment falls under medicines regulation, representing a high-risk use both from the patient and regulatory perspectives. Close human supervision is also expected for AI applications used to draft or translate product information documents.

Many are the possible applications of AI/ML in the manufacturing of medicinal products, where they should follow the usual quality risk management principles (ICH Q8, Q9 and Q10) to guarantee safety, quality, and data integrity. New recommendations are also expected from EMA.

In the post-authorisation phase, AI/ML tools can effectively support efficacy and safety studies and post-marketing surveillance studies for veterinary medicines, as well as pharmacovigilance activities. Good pharmacovigilance practices should always be respected, and the used model should be validated, monitored and documented under the responsibility of the MAH. For conditional marketing authorisations, AI/ML applications should be discussed within a regulatory procedure unless details are agreed already at time of authorisation.

EMA’s reflection paper on single-arm clinical trials

July 14, 2023

by Giuliana Miglierini

Single-arm clinical trials (SATs) are often the preferred study design in cases where target populations are very small, and it turns thus impossible to run a standard randomised clinical trial comprehensive of two patients’ arms. In single-arm trials, all recruited patients receive the experimental treatment, without the presence of a control arm. This means the observed effects of the investigational treatment are the sole source of evidence, without possibility to compare them with another available treatment or a placebo.

Rare diseases, including some rare cancers, are typically addressed by single-arm clinical trials. The so gained evidence is often submitted to regulatory authorities as pivotal evidence to demonstrate efficacy in a marketing authorisation application (MAAs). In order to improve single-arm study design and robustness of the collected data, the European Medicines Agency has published a Reflection paper, which is open to consultation until 30 September 2023. Comments will support the drafting of the final guideline, to be published in 2024.

The reflection paper represents the first guidance document produced at the international level to address issues and challenges typical of single-arm clinical trials. The document has been adopted by EMA’s CHMP committee with contributions from the CAT committee, the Methodology Working Party and the Oncology Working Party.

A choice that needs to be always justified

The choice to use SAT to produce the pivotal evidence to be submitted to regulatory authorities has to be always justified by sponsors, as it greatly deviates from the standard approach of double arms randomised clinical trials. The reflection paper suggests always seeking prior scientific advice to verify the acceptability of this type of study design with respect to the specific development programme.

EMA’s document focuses on the assessment of the efficacy of the treatment under study, but similar considerations are valid also to support the assessment of its safety; it can be applied also to SATs not intended to provide pivotal evidence. Trials in which only experimental arms are randomised, but without formal comparisons between the arms (i.e., platform trials) are also considered as SATs.

The direct consequence of the lack of randomisation is that SATs do not support a causal interpretation of the observed effect of the treatment. External data thus need to be used to estimate the average outcome for patients not being treated with the experimental drug.

The choice of the endpoints

The reflection paper addresses different items which should be considered in the planning and execution of a single-arm clinical trial, starting from the choice if the endpoints for the assessment of causal interpretation. According to ICH Q9, this should reflect the variable capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial.

The selection of the primary endpoint should take into consideration its validity, reliability and feasibility, as well was its ability to isolate the treatment effects. This is particularly critical, as SATs cannot exclude biases in the interpretation of results, and thus may lead to uncertainties in their effective acceptability. The reflection paper indicates the need to always discuss on clinical bases the possibility to accept a specific endpoint in a therapeutic area or in order to establish a clinically relevant treatment effect. Examples of some more common endpoints are also provided.

These include time-to-event endpoints (i.e., time to death, progression-free survival, etc.), which are considered not suited to be used in SATs as individual outcomes cannot often be attributed to the treatment. The determination of “time 0”, i.e., the starting point of being at risk for a specific endpoint, is also challenging, as well as the impact of the course of the disease on the selected endpoint.

Continuous endpoints measure changes the patient experience during the trial in comparison to baseline values. This type of endpoint may be affected by random fluctuation over time, systematic change due to the natural course of the disease or measurement errors, thus making it difficult to assign a causal attribution of treatment effect.

Binary endpoints refer to states of disease that cannot change without intervention, for example if life expectancy substantially exceeds that achievable without treatment. In such instances, binary endpoints are deemed acceptable to isolate treatment effect with sufficient certainty. Dichotomised endpoints similarly refer to pre-established thresholds, which are not possible to cross without treatment.

The patients population

A main challenge in single-arm clinical trials is represented by the limited number of patients available for recruitment. This reflects the external validity of study results, when transposed to the general population for routine treatment.

To this instance, assumptions made on the natural course of the disease are very important and must apply to the trial population, so to reflect the hypothetical control group. The reflection paper also mentions the possible bias deriving from selection mechanisms associated with prognosis and highlights the need to always specify and document the subject selection process to support the correct assessment of the benefit-risk balance.

Furthermore, the potential impact of unknown prognostic or predictive variables cannot be controlled in SATs, for example with reference to biomarker-selected populations or to the possible differentiation between subgroup heterogeneity.

External (extra-study) information is critical for the analysis and interpretation of SAT results; it should always be pre-specified in the study protocol, including the precise and a priori definition of control conditions.

The approach to statistical analysis

A specific chapter addresses the principles to be used for the statistical analysis of results. More particularly, if an SAT is intended to provide pivotal evidence, the level of the analysis should be the same as for confirmatory trials, according to ICH Q9.

It is thus important to define a priori a clear success criterion, to be justified on the basis of available external information. To this instance, the reflection paper underlines the high criticality of unplanned changes to the SAT study design once the experimentation had started, as amendments might be considered potentially data driven.

Methods to address multiplicity should also be pre-planned and adhered to in order to control the probability of false positive conclusions. Not less important is the predefinition of the primary analysis set, which should include all subjects that entered the SAT upon providing in-formed consent in order to avoid any bias. The reflection paper addresses the possible cases in which exclusion of some patients from the set is considered acceptable. The approach to avoid the occurrence of missing data is also described.

The pre-defined detailed statistical analysis plan should also be available before the start of the SAT, and it may be based both on the use of non-parametric or parametric statistical methods. The statistical analysis model used for estimation of the treatment effect should be fully pre-specified and justified. Critical points to be considered include the lack of calibration against a control and the distribution of the trial population in comparison to the target population. Sensitivity analyses should always be considered in order to support the robustness of the estimates resulting from the analysis of study results. The reflection paper also discusses how to approach the definition of the threshold values used to assess outcomes at the endpoint level.

EMA’s 3-year work plan for the Quality domain

July 7, 2023

Annex 11, Annex 15, Annex 16, Annex 4, Annex 5, assessor-inspector joint inspections, autogenous veterinary vaccines, Chapter 4, cooperative supervision, decentralised manufacturing, distant assessment, ema, EudraGMDP records, GMDP IWG, GMP Guide, GMP standards, guidance on data integrity, harmonised approaches, hybrid inspections, ICH Q12, ICH Q13, ICH Q7, ICH Q9, ICRMA, inspection capacity, inspections of the repositories system, International API programme, MAHs responsibilities. Nitrosamines LLE report, mutual recognition agreements. MRAs, new manufacturing technologies, novel veterinary medicinal products, PIC/S, reliance, scientific advice, security, sharing of information, sterile inspections, strategic goals, supply chain, supply chain dependance, tactical goals, traceability, Veterinary Regulation, work plan for the Quality domain

by Giuliana Miglierini

The European Medicines Agency has released the input notes made by the GMDP Inspectors Working Group (IWG) as for the drafting of the 3-year workplan for the Quality domain. The document, which reflects the objectives of the Network Strategy and Regulatory Science Strategy, addresses many aspects which may affect the overall efficiency of the pharmaceutical supply chain, both at the routine and specific level.

The document identifies a number of strategic goals aimed at improving the overall integrity and resilience of the pharmaceutical supply chain and the product quality, and to optimise the im-pact of new technologies. Description of the tactical goals follows, i.e., the projects and actions to be activated in order to reach the above-mentioned strategic objectives.

Improved traceability of the supply chain

Strategical goals include the enhancement of traceability, oversight and security for both the human and veterinary medicine supply chain. Four different actions are planned at the tactical level, starting from a better sharing of information regarding manufacturers, distributors, pro-ducts and their respective compliance. To this instance, actions to improve EudraGMDP records are expected.

Inspections of the repositories system should also be tackled by means of a liaison with the Ex-pert Group in inspectional procedures. The implementation of the new Veterinary Regulation should be addressed paying attention both to GDP for veterinary medicines and active substances. Improvement of the inspection capacity may benefit from the development of a specific training curriculum for GDP inspectors; to this instance, the IWG suggests a possible collaboration with PIC/S, through the EU4Health Joint Action 11 and the associated Work Programme 6.

Enhanced inspector capacity

Another strategic goal set forth by the GMDP IWG aims to improve inspector capacity building at EU and international level. To this regard, suggested actions include the support to the international API programme, comprehensive of the provisions of the new Veterinary Regulation related to API inspections and controls. Veterinary specific GMP guideline annexes 4 and 5 should be harmonised in collaboration with PIC/S. The collaboration should also include ongoing initiatives on inspection reliance, in order to better identify barriers preventing member states from accepting inspection results from other trusted authorities. PIC/S and the International Coalition of Medicines Regulatory Agencies (ICRMA) should also collaborate with the GMDP IWG to reach an agreement on shared definitions, best practices and harmonised approaches for distant assessment and hybrid inspections. The pilot programme for sterile inspections should be also finalised, with participation of all member states. Routine assessor-inspector joint inspections are suggested, as well as a training course specific to the new Annex 1.

The development of a harmonised, EU level guidance on data integrity is the tool identified by the GMDP IWG to reinforce responsibility of marketing authorisation holders (MAHs) for product quality. This goal may be achieved by adapting the current guidance published in the form of Q&As into Chapter 4 and Annex 11 of the GMP Guide, in collaboration with the WHO and PIC/S. A better attention on MAHs responsibilities and to the supervision of API manufacturers should also build upon the recommendations contained in EMA’s lessons learnt report (LLE) on Nitrosamines.

Critical manufacturing sites and new technologies

The review of long-term risks resulting from dependency on limited number of manufacturers and sites should support a better supply chain resilience. The review should be aimed to the identification of sites manufacturing a significant number of products or producing medical pro-ducts for a significant number of markets within the European economical area (EEA). The GMDP IWG also suggests performing cooperative supervision of these sites between member states and other strategic partners.

A better understanding of the possible implications resulting from the introduction of new manufacturing technologies has been also deemed important to regulate the new supply chains. To this instance, the indication of the IWG is to consider if a specific GMP annex would be re-quired in order to support the adoption of new and innovative technologies. As for decentralised manufacturing, this topic should also be evaluated in the GMP Guide to medicinal products other than advanced therapies.

Amendments to current guidelines

The document of the GMDP IWG details the specific guidelines that would need consideration in view of the proposed interventions.

Many actions are planned to achieve their objectives by the end of 2023. More specifically, the IWG expects to provide the EU Commission with the final text of the GMP for novel veterinary medicinal products and for autogenous veterinary vaccines. GMPs should be also revised to include Nitrosamines LLE recommendations to MAHs, so to ensure adequate quality agreements are in place with manufacturers.

The same deadline should apply to the development of specific training material on ICH Q9, addressing risk identification and risk management. This action would support EU members of the Expert Working Group (EWG) and should be coordinated with the dedicated PIC/S expert circle. A similar action is planned with respect to ICH Q12 on lifecycle management and ICH Q7 (GMP for active substances), as well as to other quality guidelines for veterinary medicines. The GMDP IWG is also expected to support the EWG in developing the new ICH Q13 guideline on continuous manufacturing.

Annex 15 on the Qualification and Validation may be revised by Q2 2024 in order to include considerations on new technology in facilities, products and processes, including also the possible extension of LLE recommendations to APIs.

The end of 2024 is the date indicated for the review of GMPs for advanced therapy medicinal products in order to include the new provisions of the revised Annex 1. The same deadline applies to the possible revision of Annex 16 on the certification by a Qualified Person and batch release, in order to provide further guidance on batch traceability according to LLE recommendations. The end of next year may see also the drafting of the final text of Annex 4 on the manufacture of veterinary medicinal products other than the immunological ones, based on comments received on the concept paper and the resulting draft text. A similar action is planned for Annex 5 on the manufacture of immunological veterinary medicinal products.

Chapter 4 (Documentation) and Annex 11 (Computerised systems) of the GMP Guide should be revised to assure data integrity in the context of GMP. The proposed deadline for these actions is Q1 2026.

Support to scientific advice and communication

A specific chapter of the GMDP IWG document is dedicated to actions deemed to support scientific advice activities. In this case too, target dates are provided for the completion of the different actions. These include the provision to the EU Commission of scientific advice on GMP standards to be included in the implementing act on GMP for veterinary medicinal products and active substances.

At the international level, the IWG plans to continue its efforts to reach a better convergence through existing mutual recognition platforms and programmes and to support the EU Commission to establish and maintain mutual recognition agreements. Collaborations with ICRMA, the EDQM, Chinese and Indian regulators should be also continued, as well as the dialogue with interested parties and stakeholders.

The new MHRA’s framework for clinical studies

May 26, 2023

ABPI, clinical development, clinical research dashboard, clinical trials, early scientific advice, independent review, innovative study designs, international collaborations, MHRA, notification scheme, patient centricity, patient recruitment, proportionate approach, public consultation, real-world evidence, reform, regulatory advice, regulatory and ethics reviews, regulatory flexibility, regulatory timelines, request for information, risk-based approach, summary of results, UK government, WHO public trial register

By Giuliana Miglierini

The repositioning of the United Kingdom as a global leader for clinical development of medicinal products can now benefit of the complete renewal of the framework regulating clinical studies run in the country. Announced in March 2023 by the Medicines and Healthcare products Regulatory Agency (MHRA), the new set of measures represents the deepest reform of the sector in the last 20 years. The new package is based upon results of the public consultation run in Q1 2022 in partnership with the Health Research Authority (HRA) and the Department of Health in Northern Ireland, which collected more than 2,000 responses.

As stated in the foreword of the final document, which details the government’s consideration of responses to individual questions, the main objective of the reform is for the UK to capitalise on the opportunity offered by the country’s new position in the global clinical trial landscape. Furthermore, it represents just the initial step of UK’s new regulatory approach, which may include for example a wider use of real-world evidence, novel analytics and data tools. International collaborations are also deemed important, e.g. with the FDA’s Project Orbis and the Access Consortium (Australia, Canada, Singapore and Switzerland) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals of Human Use.

“Our world-first Covid-19 approvals showed how important it is to ensure that regulation is flexible and agile. This overhaul of the clinical trials legislation will do just this – it will move us away from a one-size-fits-all approach to the regulation of clinical trials and help to streamline approvals by removing granular and duplicative regulatory requirements”, said MHRA Chief Science and Innovation Officer Marc Bailey.

According to the Health and Social Care Secretary Steve Barclay, the reform will make the UK more attractive for scientists and researchers. “These changes will help speed up clinical trials, without compromising on safety, and encourage the development of new and better medicines for patients. They come after the government announced additional funding of £10 million for the MHRA to accelerate the delivery of cutting-edge treatments including cancer vaccines”, he said.

The main goals of the reform

Patients are central to the UK’s reform of clinical trials. While efficacy and safety of new medicines under development remain the main target, great attention should be paid to reduce health disparities. To this instance, the MHRA announced the issuing of new guidance on how to ensure diversity of participants enrolled in trials, so to overcome imposed targets or arbitrary quotas. The improved attention to diversity would also support the delivery of trial results more adherent to the effective prevalence and clinical need across the population.

Flexibility and proportionality of the regulatory environment is another key objective of the reform. According to the final document, regulatory requirements should adapt to the current risk of the trial, and researcher should become subject to an overarching duty to consider proportionate approaches to clinical development.

Simplification of regulatory procedures is also expected, for example in the case of studies characterised by a risk similar to that of standard medical care. In this instance, regulatory review of the study protocol should not be needed anymore, substituted by simple “notification scheme” to enable approval.

As said, the attractiveness of the UK as a leading destination for international trials should be supported by streamlined and efficient application processes. This goal should include a new legislative action to integrate the regulatory and ethics reviews of clinical trial applications. Results from a pilot phase will be taken into consideration, as they proved possible to halve the approval times and cut the time from application to recruiting a first patient by 40 days.

All activities relating to clinical development should reflect the ICH Good Clinical Practice (GCP) principles for trial conduct. Regulatory timelines for approval are expected to compete at the international level, so to encourage sponsors to choose the UK as the preferred site to conduct multinational trials. According to the MHRA, the review of an application should take a maximum of 30 days in general, with a maximum of 10 calendar days for a decision to be granted once the regulator has received any final information. As for GCPs, compliance should also extend to service providers of electronic systems that may impact on patient safety.

Sponsors should also benefit from greater flexibility to respond to questions raised by regulators. In particular, the reform aims to amend the Request for Information (RFI) receipt, so that the sponsor has access to RFIs as they are ready rather than waiting for all requests to be made together.

The reform takes in consideration also the possible impact of incoming innovation, for example different types of trials and innovative study designs (e.g. decentralised trials). New guidance should be provided to set out specific details, thus avoiding any duplication. Guidance should be also provided on how to involve patients; family members or carers having a direct experience of the health problem in the design and conduct of a trial.

Transparency of the entire process should be supported by the compulsory registration of the trial in a World Health Organisation public register. A summary of results should also be published within 12 months of the end of the trial, and trial findings should be mandatory shared with trial participants.

Comments from the industry

“We welcome the MHRA and HRA’s commitment to work with our industry to codevelop new regulatory guidance and their pragmatic approach to patient & public involvement and trial diversity. We look forward to working with them to make the UK an attractive destination for clinical trials.”, said Richard Torbett, ABPI Chief Executive.

On 19 May, ABPI further commented from is blog the current situation of clinical development in the UK. According to the association representing the British pharmaceutical industry, enrolment to industry trials decreased by 44% between 2017 and 2021, while UK’s global ranking for phase III trials dropped to the 10th place (from the previous 4th). ABPI also reports revenues and cost savings to NHS England from life sciences companies of more than £10,000 for every patient recruited onto an industry clinical trial between 2016 and 2018.

In view of the release of the independent review commissioned by the government to former innovation minister Lord O’Shaughnessy, ABPI has identified three main steps necessary to support the international competitiveness of UK’s clinical trials sector.

Rapid and smooth regulatory procedures are at the first place, with the request not to delay from the 60 days target for combined regulatory and ethics review, comprehensive of the administrative processes of costing and contracting a clinical trial. Early scientific and regulatory advice and sufficient resources for the MHRA to clear the current backlogs and codevelop new regulatory guidance would be also important.

ABPI also highlights the often-experienced difficulty in recruiting a sufficient number of patients. The suggestion for the government is to take inspiration from UK’s leading position in early-phase (phase I) industry trials in order to improve investment in late-phase trial infrastructure. To this instance, health real-world data may prove important to support the search for eligible patients in a larger population.

According to the industrial representative, the UK is also lacking a nationwide clinical research dashboard to describe its performance in clinical research to global sponsors. This should include metrics on volume, speed, quality, impact, and innovation.

PIC/S new guidance documents for GDP inspectors

April 17, 2023

acceptable temperature limits, Aide-memoire, alarms, calibration, CAPAs, change control, cleaning procedures, complaints, computerised systems, contracts, delegation, Designated Responsible Persons, documentation management, environmental controls, expired/obsolete goods, falsified medicines, FEFO, GDP inspections, GDP inspectors, GDP training, general aspects, goods receipts, guidance document, key responsibilities, maintenance, Management review and monitoring, manufacturers, Mean Kinetic Temperature, on-site auditing, operations, outsourced activities, PE 011-1 wholesale distribution, periodic review, personnel, pest control procedures, PI 044-1, PIC/S, PIC/S GDP Guide, picking, Premises and Equipment, PS/ INF 22/2017, Q&As, QRM, qualification of customers, qualification of suppliers, quality agreements, Quality management, Quality systems, recalls, returns, risk assessment, security of the premises, segregation requirements, self-inspections, stock rotation, suspected falsified medical products, temperature conditions, temperature monitoring, temperature-sensitive products, transportation

By Giuliana Miglierini

Two new guidance documents for GDP inspectors have been issued by the Pharmaceutical Inspection Cooperation Scheme (PIC/S) Expert Circle on GDP, and are available on the PIC/S’ website.

The ‘AideMemoire on the Inspection of Good Distribution Practice for Medicinal Products in the Supply Chain’ (PI 0441) and a ‘Questions & Answers (Q&A) document regarding the PIC/S GDP Guide’ (PS/INF 22/2017) both entered into force on 1 February 2023.

Main contents of the AideMemoire

The AideMemoire aims to support GDP inspectors in the understanding the process of GDP inspections. The document is expected to be used for training and planning of inspections. Its adoption is voluntary, as the PIC/S GDP Guide for inspections is a legally nonbinding document unless it has been declared a legal standard in the jurisdiction of a PIC/S Participating Authority. The AideMemoire addresses inspections in wholesale distribution sites of entities holding a wholesale distribution licence according to national legislation (i.e. including importing, exporting, holding, or supplying distributors), as well as manufacturers performing any distribution activities. GDP inspections should be thorough and conducted under normal operating conditions.

The AideMemoire is organised in the form of 10 tables that could be used by inspectors as check lists of items to be investigated during inspections of manufacturers and wholesale distributors.

The first table addresses general aspects of GDP inspections, such as the accuracy of the Licence/ application in detailing relevant activities and products. Lists of prescription only medicines (POM), sales without prescription (P), or General sales list/Over the counter (GSL) products are some examples, together all other possible items that may be handled by wholesales distributors, including medical gases, products requiring storage at low temperature and controlled drugs according to national laws.

Preliminary activities also include the review of previous inspections and the assessment of corrective/preventative actions (CAPAs) outlined in the company response. Change should also be verified, namely in the case of high risk operations that may affect the risk profile of the organisation.

Table 2 lists items referred to Quality management. Inspectors should check, for example, the availability of procedures and logs for change control and deviation management. Quality Risk Management (QRM) principles should have been applied to outsourced activities, leading to the definition of specific activities falling under GDP rules, approval, auditing of suppliers, etc. An appropriate procedure should be available also for activities referring to Management review and monitoring and QRM.

Issues referring to personnel are discussed in table 3. An organisation chart and job descriptions should be available, the latter reflecting also key responsibilities and indication of Designated Responsible Persons. Inspectors should verify GDP training received by personnel, also with reference to specific aspects such as falsified medicines or temperaturesensitive products. Availability of a regular GDP training programme and training records should be checked. Personnel should have received specific training in SOPs relevant to their role, to be adequately assessed and documented. These should also include aspects relative to health, hygiene and clothing requirements.

The check list referred to Premises and Equipment is detailed in table 4. It includes among others items reflecting segregation requirements (e.g. identification, design and management of segregation areas) for hazardous or radioactive products, falsified medicines, products not authorised for the approved market, expired products, etc.

Cleaning and pest control procedures are also addressed in this section, as well as temperature and environmental controls and the appropriate monitoring of fridge or cold storage conditions. As for the equipment, inspectors should verify planned maintenance and calibration and their respective records. Alarms should also be checked, as well as computerised systems including validation, security and access restrictions. Appropriate qualification and validation procedures should be in place for all relevant equipment according to QRM principles, and risk assessment should be also available.

Table 5 lists all items referring to documentation management, including procedures and records. The qualification and approval of suppliers and customers according to QRM principles is addressed in Table 6, discussing Operations. This section also addresses the availability of goods receipts to be checked against purchase orders, including details of the temperature conditions during transportation and checks at receipt for products with special storage requirements or nonconforming products. Stock rotation according to the First Expiry First Out principle (FEFO) should be verified by inspectors, among items referred to storage. Aspects referring to the security of the premises also fall under this section, as well as the destruction of expired/ obsolete goods. Inspectors should address also picking operations, supply notes and records and procedures for import/export.

Table 7 refers to the management of complaints, returns, suspected falsified medical products and recalls, which should all be handled according to relevant procedures. Requirements and documentation to be verified for outsourced activities are listed in table 8. These include for example the availability of quality agreements, and contracts including clear responsibilities and audits schedules.

Procedures, plans and records referring to selfinspections are listed in table 9. Items to be verified by GDP inspectors include among others the selection of auditors, their training and independence, CAPAs implementation and verification. The last table addresses issues relative to transportation, including planning, outsourcing, temperature monitoring, GDP training of drivers, etc.

Q&As on PIC/S GDP Guide (PE 0111)

The second document published by PIC/S consists in a list of Questions & Answers specifically referred to the PIC/S GDP Guide (PE 0111). Contents are organised in the form of a table detailing the relevant chapter number and title, paragraph number, question and answer. The latter also make reference to other paragraphs of the GDP Guide to be considered. The sequence of topics is similar to that of the previously examined guidance document for inspectors.

Questions referred to Chapter 1 address issues referred to Quality management and Quality system, outsourced activities, management review and monitoring. Effectiveness of the QS, for example, may be measured by inspectors with reference to deviations and CAPA analysis or to the impact of QRM functions. Frequency of periodic review and responsibilities for ensuring GDP compliance of outsourced activities are also addressed.

Personnel and definition of responsibilities, including key positions and delegation, are detailed in Chapter 2, while Q&As referred to Premises and Equipment go deeper in contents of Chapter 3 (i.e. including the definition of “acceptable temperature limits” and use of Mean Kinetic Temperature for monitoring).

The following chapters and related Q&As address the proper management of Documentation (Ch. 4) and Operations (Ch. 5). The later details some aspects of suppliers and customers qualification, storage, picking. The management of complaints, returns and particular categories of medicinal products refers to Chapter 6. As for outsourced activities (Ch. 7), Q&As addresses onsite auditing, while selfinspections are treated in Chapter 8. Q&As referred to Transportation (Ch. 9), for example, refer to national legislations as for the need for the transportation company to hold a wholesaler licence.

Draft ICH M13A guideline on bioequivalence open for consultation

March 17, 2023

analysis of the parent drug, AUC, bioavailability, bioequivalence, biopharmaceutics classification system, biowaiver, capsules, chewable tablets, Cmax, comparative in vitro dissolution studies, comparator, comparator product labelling, data analysis, endogenous compounds, fasting and fed BE studies, fixed-dose combination products, granules, high-risk products, ICH E3, ICH E6, ICH M13A, ICH M13B, ICH M13C, ICH M9, immediate-release solid oral dosage forms, low solubility drug substances, multiple comparator products, multiple-dose studies, oral suspension, orally disintegrating tablets, parallel design, pharmacokinetic endpoint, pharmacokinetics bioequivalence studies, powders, primary metabolites, public consultation, randomised single-dose two-period two-sequence crossover studies, sampling, standardised fasting conditions, study design, study population, summary statistics, systemic circulation, tablets, test products, unadjusted measured drug concentrations

By Giuliana Miglierini

The draft ICH M13A harmonised guideline “Bioequivalence for immediate-release solid oral dosage forms” was endorsed by the International Council for Harmonisation on 20 December 2022 and is now open for consultation. Comments can be forwarded until 26 May 2023; publication of the final document is expected by May 2024.

The new guideline will then be implemented as a European guideline, replacing the current EMA guideline on the investigation of bioequivalence (BE) for oral dosage forms. The ICH M13A is the first of a planned series intended to address scientific and technical aspects of study design and data analysis, so to better support BE assessment both during development and post approval. The guideline covers immediate-release (IR) solid oral dosage forms delivering drugs to the systemic circulation (i.e. tablets, capsules, and granules/powders for oral suspension). Different approaches from those suggested in the guideline are possible, provided they are scientifically justified; applicants are thus encouraged to seek the advice of the relevant regulators in order to share a common approach to development.

Key concepts of the M13 series

The determination of bioequivalence to the originator is a fundamental step in the development of generic and biosimilar medicines. BE plays also an important role for some innovator products, as well as for post-approval changes of formulation and/or manufacturing process. BE is determined in terms of bioavailability of the products under comparison after administration, within predefined limits to ensure safety and efficacy. In vivo BE studies for certain orally administered IR solid oral dosage forms can be waived according to the ICH M9 guideline on Biopharmaceutics classification system (BCS)-based biowaiver, which has already superseded Appendix III of the EMA guideline.

The M13A guideline addresses study design containing multiple comparator products or test products, but not the acceptance of comparator products across different regulatory regions, as this greatly varies according to local legislations. The process of regulatory decision making based on BE is also excluded from the guideline.

The planned M13 series should also include the ICH M13B guideline, focused on biowaiver considerations for additional strengths not investigated in BE studies, and ICH M13C discussing data analysis and BE assessment for highly variable drugs, drugs with narrow therapeutic index, and complex BE study design. It should also address data analysis considerations, for example in the case of adaptive BE study design.

Pharmacokinetics (PK) bioequivalence studies and comparative in vitro dissolution studies are the main tools for BE determination for IR solid oral dosage forms with systemic action. These principles can be also applied to other non-orally administered drug products with immediate action (e.g., certain rectal, inhalation, and nasal drug products), provided BE may be derived from measures of systemic exposure.

The ICH E6 guideline on Good Clinical Practice should also be considered while conducting BE studies, in order to ensure the data integrity of all data generated in the trials.

The main contents of the ICH M13A

Chapter 2 of the ICH M13A guideline discusses the general principles to be used for the establishment of bioequivalence. These include the selection of the study population and the choice of the pharmacokinetic endpoint to be used in the BE studies. Healthy subjects should be the preferred choice, unless there are ethical concerns linked to the safety of the pharmaceutical products under assessment. In any case, inclusion and exclusion criteria should always be clearly reported in the study protocol. The main target of BE studies should be the detection of differences in the in vivo release characteristics between the products. Elements to be considered to select the study population are discussed in the draft guideline.

As for the study design, the recommended suggestion is for randomised, single-dose, two-period, two-sequence crossover studies comparing two formulations, as single-dose studies may better detect differences in the rate and extent of absorption. Multiple-dose studies may be conducted in patients should the single-dose design be not affordable for safety/tolerability or ethical reasons. A parallel design may be indicated for drugs with long elimination half-lives, requiring a prolonged washout period. Alternatives are also acceptable upon scientific justification.

The choice of the test product should be also discussed and justified, and it should be representative of the product to be marketed. As for the comparator, the selection of the batches to be used for BE studies should be based on assay content. The strength of the product to be used in the BE study depends on the dose proportionality in PK and solubility of the analyte.

The draft also indicates standardised fasting conditions should be the preferred choice to run BE studies, as they support a better discrimination between the PK profiles of the product and the comparator. Both fasting and fed BE studies should be conducted for high-risk products, due to their complex formulation design or manufacturing process that may impact differently on their in vivo performance, due to different gastrointestinal (GI) conditions. This is the case, for example, of low solubility drug substances formulated in the form of solid dispersions, microemulsions, lipid-based formulations, nanotechnologies, or other specialised technologies.

Analysis of the parent drug should be the preferred choice to demonstrated bioequivalence. Primary metabolites are considered acceptable in the case of pro-drugs which are rapidly eliminated. Stereoselective assays measuring individual enantiomers should be also considered while assessing chiral drugs.

Specific paragraphs address the setting up of sampling, the need to avoid occurrence of Cmax at the first post-dose sampling time point, the possibility to use truncated AUC for drugs with long half-life and considerations on early exposure.

How to analyse and present data

Specific sections of the guideline discuss how to present and report data obtained from BE studies. The study documentation should include the complete evidence of the protocol, conduct, and evaluation, and it should be written according to the ICH E3 guideline “Structure and content of clinical study reports”.

Unadjusted, measured drug concentrations in a suitable biological fluid should be always provided for both the product and the originator, for each subject participating in the study. Any deviations should be clearly identified. A suggested list of PK’s parameters to be tabulated for each subject-formulation combination is provided, together with summary statistics to be reported. Not less important is the statistical analysis performed on raw data. To this instance, the model of choice for the analysis should be pre-specified in the study protocol. Cmax and AUC(0-t) should be the preferred PK parameters to establish BE.

Chapter 3 discusses specific topics that may impact on the determination of BE. Among these is the presence of endogenous compounds identical to the drug under evaluation, thus requiring the determination of their baseline concentration in the biological fluids of interest. The draft guideline also specifies that both orally disintegrating tablets (ODTs) and chewable tablets should be administered in BE studies according to the comparator product labelling with regard to intake of water. The comparator product labelling should also represent the main reference for BE studies involving tablets, granules, and powders labelled as being only intended to be dispersed in a liquid before administration as an oral suspension. Considerations are also provided for fixed-dose combination products and the dependance of the drug solubility on pH.

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