regulatory compliance Archives - European Industrial Pharmacists Group (EIPG)

A new member within EIPG


The European Industrial Pharmacists Group (EIPG) is pleased to announce the Romanian Association (AFFI) as its newest member following the annual General Assembly of EIPG in Rome (20th-21st April 2024). Commenting on the continued growth of EIPG’s membership, EIPG President Read more

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

EC Communication (part 2): a Critical Medicines Alliance to support European pharma supply chain

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by Giuliana Miglierini

After last week’s examination of the first part of the Commission’s Communication, specifically targeted to short-term actions to prevent and mitigate critical medicine shortages, in this second post we will address the announced mid- and long-term structural measures, focused on the creation of the Critical Medicines Alliance, the diversification of supply chains and the role of international partnerships.

The Critical Medicines Alliance

The second part of the Commission’s Communication details the structural measures to strengthen the secure supply of pharmaceuticals in the EU, with particular reference to critical medicines. An objective that, according to the Commission, may require the development of new pieces of legislation, such as the EU Critical Medicines Act. To this instance, the preparatory study should be launched by the end of 2023, and followed by the impact assessment.

In the meantime, the improved coordination of the industrial approach to the management of shortages in the EU should be pursued by the Critical Medicines Alliance, to be created in early 2024. The Alliance will bring together all involved stakeholders; its activities should start from a shared analysis of vulnerabilities in the supply chain of the critical medicines on the Union list (i.e over-dependency on a limited number of external suppliers, limited diversification possibilities, limited production capacities, etc).

The result of this exercise should be the identification of useful tools to address vulnerabilities of a limited number of critical medicines with the highest risk of shortages and impact on healthcare systems. To this regard, several lines of actions are identified in the Communication, starting from the issuing of a dedicated guidance and common criteria for the coordinated procurement of critical medicines (e.g. green production and prioritisation of supplies in Euro-pe at times of critical shortages). A better quantification of demand and the consequent possibility to compensate and incentivise industry for its effort in these directions are other expected outcomes.

Medium-term contractual incentives are proposed as a tool to improve predictability of supply and to attract new manufacturing investments in Europe, together with the use of capacity reservation contracts modelled on EU FABs. These last instruments were launched by the HERA Authority during the pandemic in order to reserve manufacturing capacities for vaccines and obtain a priority right for their manufacturing in case of a future public health emergency.

The second line of action of the Alliance would address the diversification of global supply chains for critical medicines, including the identification of priority countries to be involved in strategic partnerships on the security of supply (see also below).

The third pillar should see the Alliance involved in the coordination and harmonisation of efforts to identify security of supply needs for critical medicines, on the basis of the above-mentioned identified vulnerabilities. Actions cited by the Communication, such as the Services of General Economic Interest (SGEI) coordinated at the EU level, should be compatible with the state aid framework. The Alliance may also represent the dedicated location where member states may better discuss the possibility of a new Important Project of Common European Interest (IPCEI) focusing on sustainable manufacturing of critical medicines (including off patent medicines).

Stockpiling, skills and financial support

EU stockpiling of critical medicines is another area of activity of the Critical Medicines Alliance. The goal is to overcome current limitations typical of national stockpile programmes; the development of a common strategic approach and a Joint Action on stockpiling has been announced for the first half of 2024, based on the previously mentioned vulnerability analysis and on the experience of the Union Civil Protection Mechanism (UCPM, that will continue to be part of the EU approach) and the rescEU stockpile.

The Alliance should also address the need for new and updated skills to work in the pharmaceutical sector, so to cope with the increasing impact of digitalisation, the evolution of the regulatory environment and the green transition. Pharmacists are cited in the Communication, as their curricula could be easily adjusted to accommodate education and training on new skills. Attention should be paid to increasing STEM (Science, Technology, Engineering and Mathematics) graduates. A Pact for Skills is the measure identified to actively involve key actors in educational and training activities aimed to fill industry skills gaps.

The Alliance would also play a significant role in better leverage and align EU and national funding: a goal deemed important in order to support improved long-term investment predictability for the private sector, and to avoid duplication of efforts. Among other tools cited by the Communication to reach it, the proposed Strategic Technologies for Europe Platform (STEP) is also inclusive of pharmaceuticals, biotechnologies and medical technologies. The creation of a Sovereignty Seal to promote synergies amongst existing programmes, and the Technical Support Instrument to enhance the administrative capacity of member states in managing shortages and producing critical medicines are among other proposed tools.

Diversification of supply chains

A second, fundamental line of action identified by the Commission addresses how to better diversify the complex, global pharmaceutical supply chain, also by means of new international partnerships with third countries. According to the Communication, the EU industry needs to have access to a broad range of essential inputs; to this regard, new strategic partnerships with third countries for production of critical medicines and active ingredients should be based on concrete actions of mutual interest.

The EU has 42 preferential trade agreements in place with 74 different trading partners, and a new one is under negotiation with India. The Commission also recalled the importance of bilateral meetings with China on issues affecting access to medicines supply chains, and of the dialogue with Latin America.

An improved regulatory convergence is another main objective of the planned actions at the international level, so to increase GMP compliance of medicinal products marketed in the EU and manufactured by extra-UE partners. To this instance, the Communication mentions the work of international bodies such as the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) and ICMRA (International Coalition of Medicines Regulatory Authorities) for the harmonisation of standards for pharmaceuticals, and the WHO support to improved regulatory convergence. Many free trade and mutual recognition agreements (MRAs) signed by the EU also contain this type of obligation, and in some cases the sharing of non-sensitive market knowledge to anticipate possible problems too.

A new network of international partners should be created by the Commission within a year, in conformity with applicable state aid and antitrust rules. The network activities would focus on crisis preparedness and supply diversification. The Communication mentions also different international initiatives already in place, such as the Global Gateway to support local manufacturing of health products and announced another Team European Initiative in Africa on health security and pandemic preparedness and response. Another ongoing initiative is the EU-Latin America and Caribbean Partnership on manufacturing and access to vaccines, medicines and health technologies. The EU will also continue to support the provision of critical medicines in humanitarian contexts.


Trends for the future of the pharmaceutical manufacturing

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By Giuliana Miglierini

The technological evolution of pharmaceutical manufacturing towards the full implementation of the Industry 4.0 paradigm is rapidly advancing. Digitalisation of productions is supported by the wide spread of automation, devices connected to the Internet of Things, and machine learning algorithms able to keep entire processes under control. Looking at pharmaceutical development, new types of treatments are emerging, also requiring a retuning of current approaches. Results from a survey among experts and industry insiders (56 respondents from 13 different countries) run by Connect in Pharma show new challenges are to be faced in the incoming years by the pharmaceutical industry in order to maintain its market position.

The combined value of the global pharmaceutical market in 2022 is estimated to be approx $650 billion. The main component reflects pharmaceutical manufacturing (US$ 526 billion in 2022, data Insight Slice), while the global pharmaceutical packaging market value is roughly US$131 billion (data Fact.MR).

Many different factors supporting the transformation of pharmaceutical manufacturing have been identified by Connect in Pharma, ranging from ageing of population to Covid19 and Ukraine crisis, to climate change and pressures on energy costs, up to the shortage of healthcare professionals. The final conclusions and opportunities identified by the report indicate new partnerships and collaborations (mainly with startups, and small and medium-sized companies) will remain fundamental to support competitiveness, together with growing investments in tech-driven innovations. Involvement of patients and healthcare professionals in identifying unmet needs and optimal solutions is another item to be considered in order to increase adherence to therapy, suggests the report.

Digitalisation still waiting to full exploit its potential

Innovation in automation and digitalisation of processes has been introduced in the pharmaceutical sector at a slower pace compared to other industrial sectors, due to its higher regulatory barriers. About one third (28%) of respondents to the survey indicated their companies are developing artificial intelligence (AI) or other digital tools for application in the manufacturing and packaging process. The main drivers towards the implementation of such systems are more efficient data collection, reduction of manufacturing down times and human errors, and the use of machine learning to support continuous manufacturing. Better workflow integration and anticounterfeiting, and the ability to share supply chain data with regulators are also relevant. These are all objectives that would need to provide new specific training to the workforce, e.g. on AI or tools for augmented reality.

One of the main barriers that, according to the report, is still slowing down the full potential of AI and digitalisation in the pharmaceutical industry is represented by the need to comply to regulations, including data integrity and security. The human factor may also prove relevant, as many people (including top management) may be reluctant to accept this change in technology. The availability of data scientists with a deep knowledge of the pharmaceutical sector is another critical point to be addressed.

Advances in drug delivery technologies

Connect in Pharma’s report also shed light on some drug delivery technologies that, despite not being an absolute novelty, are gaining relevance for the development of new products and treatments.

The moving of pharmaceutical pipelines towards a continuously increasing number of new biologic / biosimilar products, including mRNA-based and gene therapies, requires the availability of manufacturing and packaging capacities able to accommodate the specific needs of such often very unstable macromolecules. New drug delivery systems have been developed in recent years to provide answers to this need, among which is inhalation technology.

Dry powder inhalers and nasal delivery devices are the preferred formulations for the 50% of respondents to the survey that indicated actions are ongoing to develop new products using inhalation technologies. According to the report, these devices might prove particularly useful to deliver drugs that need to rapidly pass the blood-brain barrier in order to become effective, as well as for the delivery of vaccines. Fast absorption and higher bioavailability compared to other routes of administration are other elements of interest for inhalation technologies, which is also believed to be able to contribute to the reduction of carbon footprint.

Once again, the regulatory environment resulting from the entry into force of the EU Medical Devices Regulation (especially for drug-device combination products), together with the need to demonstrate patient safety and satisfactory bioavailability of these devices, are among the main barriers to their development, says the report. Inhalation technologies may also give rise to a new generation of delivery devices connected to the Internet of Medical Things (IoMT).

Another major trend identified by Connect in Pharma refers to the development of new drug delivery systems for injectable medicines (50% of respondents). This area is greatly impacted by the entry into force of the revised Annex 1 to GMPs, on 25 August 2023, that will increase the requirements for aseptic manufacturing. According to the report, main areas of innovation in this field may include new devices for injectable drug delivery, namely targeted to diabetes (the leading area of innovation), intravitreal ocular injection, autoimmune diseases, oncology, respiratory therapy, and pain management.

Connected devices

Diabetes is a highly relevant field of innovation also with respect to the implementation of connected devices, those embedded sensors and electronics allow for the real-time collection of data on self-administration of the therapy by patients, and their forwarding to health professionals. AI algorithms further enhance the potential of connected devices delivering diabetes treatments, as they support the real-time monitoring of insulin concentration in blood, and the consequent level of insulin delivered by the device. According to Connect in Pharma, other positive characteristics arising from the use of connected devices refer to the possible increase of patient adherence and compliance to treatment, resulting in improved patient outcomes and more personalised treatment.

Regulatory barriers are once again a main burden to the wider spread of connected devices, says the report, due for instance to the ultimate control over the sharing of data, and the choice if to implement single-use or reusable devices. Manufacturing costs, cybersecurity, and patient hesitancy are other hurdles identified by respondents to the survey.

The challenges for sustainability

The green policies put in place especially in the EU are calling industry to revise its processes and products to decrease their environmental impact, improve sustainability of manufacturing and packaging processes, so to eventually meet the climate targets fixed for 2050. According to the report, the global healthcare sector would be responsible for 4.4% of global net emissions. Connect in Pharma’s survey indicates 66% of involved companies are working to implement more sustainable practices. These may include for example the use of recycled materials in secondary packaging, the implementation of energy efficient technologies, and the development of more ecofriendly drug delivery systems. Costs have been identified as the main barrier to transition, together with the lack of common definitions. According to some of the experts, a wider use of data to monitor manufacturing systems and processes may help in improving the overall efficiency and in lowering the carbon footprint. Transport, for example, has a great impact on the sustainability of packaging.


ECA’s guide to compliant equipment design

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By Giuliana Miglierini

The legislative evolution of the last decades emphasised requirements for equipment used in pharmaceutical productions. This is even more true with the entry into force of the new Annex 1 to the GMPs, characterised by many new requirements impacting on different manufacturing processes (i.e. production of water for injection, sterilisation, Form-Fill-Seal and Blow-Fill-Seal technologies, single use systems, lyophilisation, etc.).

Each pharmaceutical process requires the careful design of the needed equipment in order to provide the expected efficiency and performance. Furthermore, some equipment may be used for different industrial applications (e.g. pharmaceutical, cosmetic or food), thus needing a fine tuning to reflect relevant requirements. In pharmaceutical manufacturing, a further step of complexity may be represented by the need to handle highly potent active pharmaceutical ingredients, requiring isolators to segregate production, etc.

To facilitate the correct design of equipment compliant to GMPs, a new guidance document has been published by the ECA Foundation. The document was initially drafted in German by a task force of experts in pharmaceutical technology and engineering and published by Concept Heidelberg, and it has now been translated in English

Elements relevant to reach compliance

The first part of the document discusses general requirements that should always be part of the design of GMP-compliant equipment. Four different points of attention are listed: the equipment must not adversely affect the product quality, it must be easy to clean, it must comply with applicable technical rules, and it must be fit for its intended use.

As for the first point, “The question is rather what is tolerable without adversely affecting the product quality”, states the guidance. Avoidance of contamination and cross-contamination are the main goals of cleaning activities, both for sterile and non-sterile medicinal products. There are several issues to be taken in mind from this perspective, including the presence of endotoxins, sealing points, the efficiency of cleaning-in-place (CIP) processes, or the presence of unreachable dead leg areas. According to the guidance, the 3D/6D rule for the prevention of dead legs in water systems often used for specification would not always be correctly applied, due to some confusion in terminology. Official GMPs are also deemed “very vague”, as they are not drafted by engineers and apply to an extremely wide range of different equipment and processes. “Consequently, the question is, which technical rules have to be followed or where the actual state of the art can be looked up”, says the document. Many different references are possible, from pharmacopeia monographs and regulatory guidelines, to ISO standards, and other documents published by international professional bodies.

Qualification and calibration of equipment should always be targeted to the specific product, as it is an essential in proving compliance to the intended use. Regulatory compliance of submitted documentation is not less important, and it greatly impacts on change control and implementation of new productive technologies.

Risk analysis (RA) is the tool introduced in 2005 by ICH Q9 to evaluate all items which may impact on the design of productive processes and related equipment. There is no standard methodology to run risk analysis, the choice depends on the process/product under assessment. According to the guidance, RA can be performed both from the perspective of the product and the equipment, the latter being also considered a GMP risk analysis.

Design and choice of materials

Materials (and coating materials where relevant) used to build pharmaceutical equipment should be completely inert. Pharmaceutical equipment must comply with the EC Directive on Machinery 2006/42/EC and DIN EN ISO 14159. The ECA guidance discusses material selection (plastics or stainless steel); hygienic system design is also addressed by many different guidelines, e.g. those published by the European Hygienic Engineering and Design Group (EHEDG). An important item to consider is service life considerations for the materials used (EHEDG Document 32), as well as their chemical-physical characteristics and materials pairing.

Particularly critical are process contact surfaces, as they may impact product quality. Establishment of specific requirements is thus needed. The guidance focuses its attention on austenitic stainless steels (i.e. CrNiMo steels 1.4404 and 1.4435). The main elements to be assessed are the risk of corrosion, the risk of contamination of the product or process medium and the cleanability of the metallic surface. Topography, morphology and energy level are the main characteristics to be used to describe surfaces, addressing respectively the geometric shape, chemical composition and energy required per unit area to increase the size of the surface. The guidance provides a detailed discussion of all different aspects of surface treatment methods, and the hygienic design of open and closed equipment. Other sections discuss the optimal design of pipework and fittings, connections, welding and seam control. Detailed information is also provided on equipment of electrical engineering, measurement and control technology, as well as the process control technology (PCT) measurement and control functions.

A highly critical area within a pharmaceutical facility are cleanrooms, for which the design of the equipment and the choice of materials is even more stringent. Elements to be considered include stability/statics as concerns dynamic loads, smoothness of the floor, tightness of external façades and of enclosing surfaces of cleanrooms. Smooth nonporous surfaces are required, together with avoidance of molecular contamination, resistance to the intended cleaning or disinfection agents and the cleaning procedure, simple and tight integration of various fittings, efficient and rapid implementation of subsequent functional and technical changes. The ECA guidance document goes deeper into relevant requirements for all elements that are part of the design of a compliant cleanroom.

Documentation and automation

User requirement specifications (URS) are the key document to demonstrate equipment is fit for the intended use, as stated by GMP Annex 15 (2015). The ECA guidance suggests translating the URS in a technical version to be submitted to the potential equipment supplier, so to ensure the design would reflect product and quality-relevant requirements, being thus GMP compliant.

The management of documentation along the design life cycle of a new piece of equipment is also taken into consideration, with the different construction phases identified according to Good engineering practices (GEP): conceptual design, basic design/engineering, and detailed design/engineering.

The extensive use of data to monitor and document pharmaceutical manufacturing process represents another area of great attention. Requirements relevant to the design of validated computerised systems, data protection and data integrity must be kept in mind. ECA’s experts highlight the need to carefully delimitate areas subject to validation and their extention, particularly with reference to automated systems. Differences between qualification and validation of automated systems are also addressed, including equipment that might either be defined as “computerised” or “automated” system. Regulatory reference for validation is GAMP 5, while qualification refers to Annex 15.


FAT and SAT, a critical step for the introduction of new equipment

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by Giuliana Miglierini

There are two key moments to be faced to introduce a new piece of equipment in a pharmaceutical plant: a factory acceptance testing (FAT), usually performed by its manufacturer to verify the new equipment meets its intended purpose, prior to approve it for delivery and once arrived at its final destination and installed, a site acceptance testing (SAT) run by the purchasing company and is part of the commissioning activity.

According to an article published in Outsourced Pharma, the commissioning of a new piece of equipment poses many challenges, and criticalities needs to be considered both from the business and regulatory point of view. Pharmaceutical plants are very complex and often customised upon the specific business needs, and the delivery of a new equipment requires the interaction of many different parties, both internal and external to the purchasing company. FAT, SAT and commissioning activities require a careful planning and detailed responsibilities for all participating parties to be included within the Commissioning and Qualification Plan (CQV plan). A possible responsibility matrix is suggested by the authors to provide clarity and ensures ownership of activities.

FAT, assessing the equipment at the manufacturer site

FAT and SAT testing involve the visual inspection of the equipment and the verification of its static and/or dynamic functioning, in order to assess the actual correspondence to the user requirement specifications (URS). While FATs are usually based on simulations of the equipment’s operating environment, SAT testing occurs at the final site after installation, thus it reflects the real operating conditions and environment in order to support qualification.

There are many different elements to be considered during FAT testing, including for example verification of the existing site drainage, piping, or room dimensions, or the position of the handle for accessibility, as well as software design specification, interface, and device integration.

The FAT exercise is always highly recommended, as it is essential to solve in advance (before shipment to the final destination) any error or malfunctioning of the equipment, that otherwise might occur at the purchasing company’s site. This results in the optimisation of the delivery and commissioning process, with important savings in terms of both time and costs for the purchasing company. To ensure for the transparency of FAT testing, the entire procedure (that requires usually 1-3 days, depending on the complexity of the equipment to be verified) is usually performed in the presence of a third party inspector and customer representative.

A comprehensive set of documentation should be always available to support FAT, including URS, drawings, checklists and procedures, calibrations and certifications, data sheets, references, etc. Raw data acquired during FAT are transmitted to the customer for analysis and validation. FAT should take into consideration all aspects relevant to the evaluation of the safety and functionality of the equipment and its compliance to URS, GMPs and data integrity. To this regard, it is also important for the engineering team called to run the new equipment at its final location to learn and share knowledge with the manufacturer along the entire commissioning process, so to increase the first-hand direct experience. According to the article, this is also critical to authorise the shipment of the equipment to the final destination, a step that should always be performed by an authorised, trained, and approved subject matter expert.

 SAT acceptance testing

All criticalities emerged during the FAT exercise are then checked again at the final site, after installation and verification; additional test cases may also be added to the SAT protocol to check for potential failure modes. SAT testing is performed once all connections between the new equipment and other machines/softwares are in place, under the real operating parameters, and may be witnessed by a representative of the equipment’s manufacturer.

Results from SATs may thus differ from those obtained from the FAT previously run by the manufacturer. From the regulatory point of view, SAT testing is a key element to demonstrate the compliance of the equipment to GMP requirements and to support the overall quality and safety of pharmaceutical productions. In this case too, many are the possible elements to be inspected and verified, including interlocks, ventilation, internal box pressure, electrical/hydraulic connections and safety systems, visual checks of components, training of the operators, etc.

A plan for each testing phase

FAT planning begins at the very moment of the purchasing company placing the order for the new equipment, and it has to reflect all URS to be checked for acceptability of the manufactured apparatus. This step in the design is critical and calls for a strict and positive communication between the manufacturer and its customers, a key point to take into consideration all elements that should enter the project.

All identified items and procedures to be challenged during FAT and SAT testing are usually addressed within the CQV plan, that connects the design phase to user requirements specifications and the other elements impacting the commissioning and qualification processes (i.e. system impact assessment, design specification, functional risk assessment, hardware / software specifications, Installation / Operational / Performance Qualification), including deviations and change management. The plan specific to SAT testing should include the scope, test specifications and logs, a test summary, the Commissioning report and the final Certificate of Acceptance.

Transparency and a robust statistical approach should represent main targets along the entire commissioning and validation procedure, that may be run with the assistance of external consultants. All activities that shall enter the regulatory dossiers should always be justified and documented, also under the perspective of data integrity. The Outsourced Pharma’s article also suggests paying a particular attention to controls on data provided by the manufacturer in the case a risk-based leveraging is applied.


ICMRA published a Reflection paper on remote inspections

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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.