regulatory authorities Archives - European Industrial Pharmacists Group (EIPG)

Home  /  The ICMRA collaborative hybrid inspection pilot (CHIP)  /  regulatory authorities

The EU Parliament voted its position on the Unitary SPC


by Giuliana Miglierini The intersecting pathways of revision of the pharmaceutical and intellectual property legislations recently marked the adoption of the EU Parliament’s position on the new unitary Supplementary Protection Certificate (SPC) system, parallel to the recast of the current Read more

Reform of pharma legislation: the debate on regulatory data protection


by Giuliana Miglierini As the definition of the final contents of many new pieces of the overall revision of the pharmaceutical legislation is approaching, many voices commented the possible impact the new scheme for regulatory data protection (RDP) may have Read more

Environmental sustainability: the EIPG perspective


Piero Iamartino Although the impact of medicines on the environment has been highlighted since the 70s of the last century with the emergence of the first reports of pollution in surface waters, it is only since the beginning of the Read more

•••

The ICMRA collaborative hybrid inspection pilot (CHIP)

January 22, 2024 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.


EMA/EFSA joint report on human dietary exposure to residues of veterinary medicines, pesticides and feed additives

February 17, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

The presence of residues of veterinary medicines, feed additives and pesticides in food of animal origin may pose exposure risks for human health. The topic has been historically approached under different perspectives according to the specific reference legislative framework and the respective authority involved in regulating and monitoring the products. The European Medicines Agency (EMA) and the European Food Safety Authority (EFSA) are among the main regulators involved in setting and verifying the legally binding maximum residue limits (MRLs) for chemical substances, together with the European Chemicals Agency (ECHA).

EMA and EFSA received in 2020 a mandate by the European Commission to work at the development of a harmonised approach to the assessment of dietary exposure to residues of veterinary medicines in food of animal origin. The comparison of the current situation run by the two agencies included only exposure assessment methods used in the regulatory areas, which are all based on traditional deterministic approaches. The resulting recommendations have recently been published in the form of a joint report.

EMA/EFSA experts focused on key concepts and features in order to provide a general agreement on the basic “building blocks” of a recommendable harmonised methodology, leaving the setting up of more detailed methodological aspects targeted to the different sectorial applications to a further phase of discussion. The document shall now be assessed by the European Commission and, if adopted, may request the implementation of specific action targeted to the different sectors to reach a better harmonisation. The Technical Report to be submitted to the Commission may also contain other elements to be considered.

Meanwhile, on 9 February 2023 the Commission implementing Regulation (EU) 2022/1255 designating antimicrobials or groups of antimicrobials reserved for treatment of certain infections in humans entered into force. The regulation lists a wide range of antibiotic, antiviral and antiprotozoal active substances. Those use is from now on excluded to treat animals, so to preserve their efficacy in humans. The measure is part of the broader approach against antimicrobial resistance, and it aims to promote a more prudent and responsible use of antimicrobial medicinal products in animals, including very strict rules on their veterinary prescription for prophylactic and metaphylactic use.

The main issues examined by the EMA/EFSA report

Sectorial legislations in the field of medicinal products (managed by EMA), food (EFSA) and chemicals (ECHA) may greatly differ from one another in the approach and methodologies chosen to define exposure limits and to run risk assessments referred to residues of veterinary medicinal products, feed additives, pesticides and biocides. This lack in harmonisation may lead to significantly different outcomes in the assessment of the same active substance, especially when it is characterised by a dual use for applications in different sectors.

There are several pieces of legislation in place aimed to guarantee a high level of protection of both human and animal health and the environment [Commission Regulation (EU) 2018/7829, Regulation (EC) No 1107/200910 and Commission Regulation (EC) No 429/2008], as well as sectorial legislations in the pharmaceutical, food, and feed additives fields that may diverge at the level of data requirements, purpose of the required studies, methodologies for exposure assessment, consumption models, etc.

In general terms, exposure studies are usually run using radiolabeling to trace the fate of a substance and to characterise its metabolites and their concentration in edible tissues/food commodities from target animals. The “residue of concern” (RoC) considered in the dietary exposure assessment is most commonly estimated assuming that metabolites have the same pharmacological/ toxicological potential as the parent compound. The difficulty of measuring the concentration of all compounds in residue monitoring often leads to the selection of a marker residue to be traced.

Health Based Guidance Values (HBGVs, or Reference Values) corresponds to the concentration of a chemical that may present hazards for the human, animal or environmental health; they are listed in the EFSA Open Food Tox Database, as well as in similar WHO and US-EPA databases.

HBGV, as well as acceptable daily intake (ADI) in case of chronic risk and the acute reference dose (ARfD) in case of acute risk, can be used in association with the estimated dietary exposure to the RoC to evaluate the risk of exposure.

The report initially discusses the different approaches and models currently in use by EMA, EFSA, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Joint Meeting on Pesticide Residues (JMPR). Reference is made to the alternative definitions for the establishment of residue limits related to veterinary medicinal products charactering the different sectorial legislation, as well as to methods to assess the related hazard.

The Theoretical Maximum Daily Intake model (TMDI, or diet-based approach), for example, is used by EMA to estimate the risk from life-long exposure to residues in food commodities from animals treated with veterinary medicinal products. This model has been already abandoned by JECFA and EFSA, that switched respectively to the Feed Additives Consumer Exposure (FACE) and Pesticide Residue Intake Model (PRIMo 4), as better suited to estimate age-dependent exposure scenarios based on individual food consumption data. The report also discusses the Global Estimated Chronic Dietary Exposure (GECDE) model, and the International Estimated Daily Intakes (IEDI) model. This last one is based on the WHO GEMS Food Cluster diets, estimating average per capita consumption figures based on international trade and production statistics of foods.

A further level of complexity in the assessment has to be considered for substances with dual uses, such as veterinary medicines and pesticides. In such instances, it is important to note that maximum residue limits/levels may vary for the same substance in the same animal commodity, as their concentration may differ in different tissues and/or organs (i.e., muscle, fat, liver, kidney, eggs, or milk). This may result in uncertainties at the level of the enforcement of the appropriate level and residue definition by different authorities.

The recommendations for future harmonization

The analysis and evaluation of the performance of the many available methods led EMA and EFSA to conclude that the observed differences in exposure assessment could be primarily attributed to the type and use of consumption and occurrence data. Other possible elements impacting on the obtained result may include the chosen calculation model and exposure model, the exposure to residues from multiple uses, and the use of commodity definitions and combined exposure from multiple species. Different timelines in the implementation of scientific innovation may have also contributed to the observed divergences.

The final goal of the exercise was to obtain a most realistic exposure assessment possible based on the available methodologies. The so identified “preferred methodology” focuses on data sources and models, includes also alternative proposals on a number of items, and it might represent the “blueprint” for a future harmonised methodology. EMA and EFSA’s recommendations pay particular attention to exposure assessment as the first step of a risk assessment; as for risk characterisation, no specific recommendations have been developed during this round of discussions.


ICMRA published a Reflection paper on remote inspections

January 21, 2022 , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

Remote inspections have become a widely used approach since the last two years to ensure the oversight of the compliance of pharmaceutical productions to regulatory requirements, as the prolonged lockdown periods determined by the pandemic made very difficult the maintenance of the regular schedule for on-site inspections.

A Reflection paper on the so gathered experience has been recently published by the International Coalition of Medicines Regulatory Authorities (ICMRA); the document addresses from the point of view of regulatory authorities the many issues encountered to establish appropriate modalities to interact at distance with the industrial counterparts by mean of digital technologies and suggests the best practices for the future. The analysis focused especially on remote GCP and GMP inspections.

The Reflection paper was drafted by a working group chaired by the UK MHRA and inclusive of representatives from the US FDA, EMA, Health Canada, Swiss-medic, HPRA Ireland, AEMPS Spain, ANSM France, PEI Germany, MHLW/PMDA Japan, TGA Australia, ANVISA Brazil, HSA Singapore, WHO and Saudi FDA.

The lack of a uniform definitions and approaches

Each national competent authority adopted during the pandemic its own approach to remote inspections, evaluating this type of opportunity on a case-by-case basis, making use of established quality risk management principles and tools to reach their decision (par. 3 of the Reflection paper enlists the more widely used parameters for risk assessment and management).Among the factors entering this preliminary evaluation are the regulatory compliance history of the inspectee, the scope of the inspection (pre-approval, routine or for cause), and the inherent risk associated with the activities conducted by the site, the types of products and the need for the product.

The term used to identify the at distance interaction with the company to be inspected also assumed a quite wide variability; “distant assessment”, “remote evaluation”, “desktop assessment” or “remote assessment” are other frequent declinations used to define oversight procedures run by using digital technologies, both at the national and international level.

The choice of the specific term to identify this sort of practice depends upon many different factors, including the type of inspection and of the involved facilities, and the local national legal frameworks governing inspections as well as protection of personal data. The specific areas or sites to be included in the official review of activities, documents, facilities, records, etc. have proved also highly variable, as they may include not only the manufacturing site, but also investigator sites of a clinical trial, the sponsor’s and/or contract research organisation’s (CRO’s) facilities, or any other establishments deemed appropriate by the regulatory authority running the inspection.

Should the preliminary risk assessment had discouraged the possibility to conduct a remote inspection, the on-site inspections were usually postponed until the termination of lockdown measures in the interested countries. Hybrid or collaborative inspections represent another opportunity used to handle critical cases: the first ones involve the assessment or inspection to be conducted using a mix of remote and on-site activities, the second see two or more regulatory authorities collaborating to perform a conjunct inspection of a specific site.

According to the Reflection paper, it thus appears highly unlikely that a unique and fully harmonized approach to remote inspections in all scenarios might be developed for the future. “While the ICMRA group have found remote inspections an enabling tool to maintain at least a minimal regulatory oversight during the pandemic, it is not the view of the group that remote inspections would fully replace an on-site inspection programme”, states the document.

The main issues encountered

The possibility to conduct inspections, evaluations or assessments at a distance/virtually is based on the implicit availability of a robust IT and communication infrastructure; this has proved a fundamental requirement to smoothly share and review all the relevant documentation and ensure access from remote to systems and plants. Virtual tours of the manufacturing facilities are a typical example, for which the availability of solid “hardware and software that can provide an appropriate field of vision, clarity and stabilisation of the picture, while simultaneously facilitating conversation between the inspector and tour host” is essential to enable the real-time transmission of images and sounds captured by the in charge on-site staff by mean of smart devices or more advanced systems as smart-glasses.

In international inspections, the difference in time-zone and the availability of real-time, online translation services have also proved critical in many instances, especially if parallel sessions of discussion were needed. The possibility for inspectors to access on-line the relevant documentation requires the availability of the inspected company to provide credentials to enter in a read-only mode its proprietary document management systems and repositories. To this instance, confidentiality issues often led many companies to provide access to IT systems by mean of a specifically appointed member of the staff, in charge of accessing in real-time the systems and made available all the documentation as indicated by the inspectors.

The main areas of attention

The Reflection paper identifies four different areas for which remote assessment/inspection proved to be particularly useful during the pandemic period.

In the case of virtual tours, the indication coming from ICRMA experts is to limit the use of prerecorded video tours only in exceptional circumstances, and never for inspection of high-risk activities, as the inspector may not be in the right conditions to effectively verify all details needed to evaluate the suitability of the facility.

“Direct access to documentation by inspectors is an expectation, electronically or otherwise, whether the inspection is on-site or remote”, states the Reflection paper. The alternative intervention of site staff may be acceptable, but it should not negatively impact the results of the assessment. Furthermore, this modality may also prove quite time consuming for both the inspector and the inspected company. ICRMA also supports the possibility for regulators to access documentation after the closure meeting, and upon the formal closure of the inspection, in order to facilitate the drafting of the report or to clarify a deficiency already raised.

GCP and GMP inspections

Specific issues for both GCP and GMP inspections are addressed in two dedicated chapters of ICRMA’s Reflection paper.

“It should be noted that within the EU remote inspections at investigator sites are not considered to be feasible”, writes ICRMA. The motivation has to be found mainly in the need to avoid any further impact on the clinical sites during an health emergency like the pandemic, andin the issues posed by local frameworks for data protection. The Reflections paper provides a list of clinical areas not suitable for remote inspection.

As for GMP inspections, not all regulatory authorities adopted the same approach during the pandemic; in general terms, this sort of practice has been judged acceptable by ICRMA to handle emergency situations with restrictions to travels in place, but it cannot fully substitute onsite inspections of manufacturing sites. More specifically, the experience of the past two years shows that remote inspection proved unfeasible for sites requiring detailed observation, as those performing aseptic manufacturing or handling potent active ingredients with low Permitted Daily Exposure.