EU Focus Archives - European Industrial Pharmacists Group (EIPG)

European Council’s conclusions on the European Innovation Agenda and research infrastructures


by Giuliana Miglierini The European socio-economic framework is undergoing a profound transformative moment, as a result of the new vision impressed by the von der Leyen Commission, with its goals in the field of the Digital and Green transitions. The Read more

EMA’s new Quality Innovation Expert Group (QIG)


by Giuliana Miglierini Innovative approaches to the development manufacturing and quality control of medicines are becoming the new paradigm to be faced both from an industrial and regulatory perspective. Not only innovative technologies for delivery, such as mRNA vaccines, many Read more

ICMRA report on best practices against antimicrobial resistance


by Giuliana Miglierini Antimicrobial resistance (AMR) is the consequence of mutations that allow microbes to survive pharmacological treatment. Resistant strains can often be tackled only by a limited number of therapeutic options: according to a systematic analysis published in The Read more

ICMRA report on best practices against antimicrobial resistance

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

Antimicrobial resistance (AMR) is the consequence of mutations that allow microbes to survive pharmacological treatment. Resistant strains can often be tackled only by a limited number of therapeutic options: according to a systematic analysis published in The Lancet, an estimated 1.27 million deaths occurred in 2019 due to unresponsiveness to available medicines.

As a part of its effort against AMR, the International Coalition of Medicines Regulatory Authorities (ICMRA) has published a report discussing successful regulatory and non-regulatory best practices in the field of AMR.

The report was drafted by ICMRA’s Work Group led by Health Canada, and inclusive also of the European Medicines Agency, UK’s MHRA, and regulators from Japan, Argentina, Nigeria, Saudi Arabia and Sweden. For each of the nine case studies, Annex 2 presents a table summarising the problem under examination, the proposed solution, results and consequent recommendations.

Regulatory flexibility

The US’ Biomedical Advanced Research and Development Authority (BARDA) focused on innovative approaches to developing supporting data packages required for regulatory review of certain non-traditional therapies. Public-private partnerships are the preferred vehicle to manage R&D projects and to reach regulatory approval by the FDA. The main targets for BARDA are new antimicrobials to treat antibiotic-resistant secondary bacterial infections and bioterrorism infections. Selected proposals shall lead to the development of candidate medical countermeasures (MCMs), based on a regulatory master plan inclusive of a tentative schedule for regulatory milestones. Partners may also benefit from BARDA’s expertise in the field of animal studies, flexible manufacturing and clinical study design. A Memorandum of Understanding was also signed with the FDA to provide a coordinated framework for the development of MCMs.

Antimicrobials for veterinary use

Antimicrobials for veterinary use include some products for human use. It is thus important to act in the animal sector to limit the selection pressure for the development and spread of resistant pathogens in both animals and humans.

The project led by Health Canada in collaboration with the Public Health Agency of Canada (PHAC) focused on the implementation of the Veterinary Antimicrobial Sales Reporting (VASR) system, aimed to collect data on the total quantity of antimicrobials sold or compounded by animal species. The activation of the system in 2018 followed some changes to Canada’s Food and Drugs Regulation (FDR): manufacturers and importers have to report annual sales of medically important antimicrobials intended for veterinary use based on active ingredients listed in List A. The acquired data are collected and screened by the Veterinary Drugs Directorate and validated and analysed by PHAC’s CIPARS.

Regulatory agilities during the Covid-19 pandemic

Regulatory flexibility has been one of the main tools used to respond to the Covid-19 pandemic. Health Canada’s main goal was to expedite the regulatory review of health products without compromising their safety, efficacy and quality standards. A temporary regulatory pathway was introduced in September 2020 by a Interim Order, and new transition measures were approved in September 2021 to allow the review, authorisation and oversight of Covid-19 medicines under the FDR. A procurement strategy for Covid vaccines, treatments and diagnostics was also adopted by the Government, based on advanced purchasing agreements with different companies. Another Interim Order allowed the activation of a temporary regulatory pathway to facilitate clinical trials of candidate Covid-19 products. Flexibilities to Drug Establishment Licensing (DEL) and GMPs were also introduced, and collaborations with other international regulatory bodies activated (including the EMA open pilot).

Non-prescription availability of antibiotics

UK’s MHRA focused on the case of tyrothricin-containing lozenges, a combination product available for sale at pharmacies since 1968, and that underwent a restriction of prescribing in 2018, following a NHS’s guidance advising prescriptions for the treatment of acute sore throats should not be routinely offered in primary care. The UK’s Commission on Human Medicine considered MHRA’s request of advice on the feasibility to remove the product from the market. As a result, the MHRA interacted with the Marketing authorisation holder to verify the possibility of a reformulation to exclude the antibiotic active ingredient. The action of impacted also on the education of the wider public towards the responsible use of antibiotics.

Reimbursement models for novel antimicrobials

The Public Health Agency of Sweden addressed the issue of antimicrobial market failure. Not all the few available antibiotics launched during the last decade are accessible in all European countries, due in some instances to unfavourable sales prospects. A pilot project was launched in 2018 to test a new, partially delinked reimbursement model based on a minimum annual guaranteed revenue at nation level for the pharmaceutical company (on the basis of estimated clinical needs). Security of supply of antibiotics within 24 hours and a security stock located in Sweden were the requests to interested companies.

Selective antibiograms to inform antimicrobial choice

The choice of the most appropriate antimicrobial is usually based on an antibiogram, a laboratory test used to evaluate the susceptibility and resistance profile of bacterial isolates to various antimicrobial active ingredients. The Swedish Medical Products Agency (SMPA) focused on the use and selective reporting of antibiograms of urinary cultures for Enterobacteriaceae from patients with symptoms of cystitis. The analysis included six different antibiotics for men and five for women, since the fluoroquinolone ciprofloxacin is no longer recommended to treat cystitis in women. This selective reporting allowed to decrease fluoroquinolone prescriptions of 46% in 15 years.

Feedback on prescriber data

SMPA also provided some feedback to prescribers on their antibiotic prescribing practices. The tool was implemented at the national, regional, local and also individual level, in order to raise knowledge and information, and influence prescription habits. Prescribers’ data at a high resolution level (prescriber identifying codes) are used to elaborate relevant trends. Statistics on antibiotic use at regional and national level are freely accessible at the National Board of Health and Welfare website.

Common infections in outpatient care

The Sweden’s Rainbow Pamphlet provides treatment recommendations for common infections in outpatient care. The initiative was launched in 2010 by the Swedish Strategic Programme for the Rational Use of Antimicrobial Agents and Surveillance of Resistance (STRAMA); it can be accessed in paper form or through the STRAMA mobile application. The use of the Rainbow pamphlet has been supported also by communication campaigns targeted both to healthcare professionals and the public.

Methods for monitoring AMR in the environment

The monitoring of antibiotics’ diffusion in the environment is relevant with respect to the One- Health approach, which focuses on the harmonised surveillance across human, veterinary and food sectors.

The SMPA launched two projects aimed to better identify indicators to be used for the monitoring of antibiotic resistance in the environment: EMBARK (Establishing a Monitoring Baseline for Antimicrobial Resistance in Key environments) and Antibiotikasmart Sverige (Antibiotic Smart Sweden). The current main gaps in knowledge include the abundance and prevalence of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) occurring naturally. Furthermore, antimicrobials may enter the environment at different points along the lifecycle of human and veterinary medical products, with processes still to be fully clarified.


The FDA warns about the manufacture medicinal and non-pharmaceutical products on the same equipment

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

A Warning Letter, sent in September 2022 by the US FDA to a German company after an inspection, addresses the possibility to use the same equipment for the manufacturing of pharmaceutical and non-pharmaceutical products. The FDA reject this possibility, that is considered a significant violation of cGMP.

The letter addresses the lack of process validation for the manufacturing of over-the counter (OTC) drugs and of qualification documentation proving acceptance criteria were met and the process was under control. Deficiencies were reflected in the batch records missing important pieces of information. Aspects pertaining cleaning validation were also found critical.

The requests of the FDA

The Warning Letter asks the company to provide the FDA with a full qualification programme of the equipment and facility. This should include a detailed risk assessment for all medicinal products manufactured using shared equipment. Plans are also needed on how to separate the manufacturing areas for pharmaceutical and non-pharmaceutical productions.

Furthermore, the program for cleaning validation should be reviewed to include at least (but not limited to) drugs with higher toxicities or potencies, drugs of lower solubility in their cleaning solvents and that may result difficult to clean. Maximum holding times before cleaning and swabbing locations for areas that are most difficult to clean should be also provided. A retrospective assessment of the cleaning process has to be included in the required CAPA plan; change management for the introduction of new manufacturing equipment or a new product should be also discussed.

The FDA also addressed many other violations, such as the lack of robust laboratory controls, identity testing of incoming raw materials including active ingredients (APIs), and the inability to demonstrate the respect of minimum USP monograph specifications and appropriate microbial limits for drug manufacturing. Management and controls on data integrity were also found deficient.

The European perspective

In the EU, the possibility to use the same equipment and premises for the manufacturing of both pharmaceutical and non-pharmaceutical products can be referred to the provisions set forth by Chapter 3 (Premises and Equipment) of the EU GMPs.

The document clearly states that the “premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination”.

The application of Quality Risk Management principles is used to assess the specific risk of cross-contamination and the consequent measures to be put in place. Dedicated premises and equipment may be needed in some cases, especially if the risk cannot be adequately controlled by operational and/or technical measures, the product has an unfavourable toxicological profile, or relevant residue limits cannot be satisfactorily determined by a validated analytical method. Attention should also be paid to the positioning of equipment and materials, so to avoid confusion between different medicinal products and their components, and to guarantee the correct execution of process controls. Particular provisions are needed in the case dusty materials are used, also with respect to cleaning validation.

All cleaning procedures should be available in written form, designed to allow for an easy and thorough cleaning (including drains, pipework, light fittings, ventilation points and other services). In the case of exposed materials, the interior surfaces of the premises should be smooth and easy to clean and disinfect.

All documentation needed to support the above mention requirements should be prepared according to Chapter 4 (Documentation) of the European GMPs.

EMA’s Guideline on shared facilities

The European Medicines Agency (EMA) published in 2014 a guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities.

Threshold values expressed in terms of Permitted Daily Exposure (PDE) or Threshold of Toxicological Concern (TTC) are the key parameters to be used to run the risk assessment. The so determined threshold levels for APIs can also be used to justify carry over limits used in cleaning validation. EMA’s guideline discusses how to address the determination of the PDE, also with respect to specific types of active substances (e.g. genotoxic, of highly sensitising potential, etc.)

The WHO guidelines

The World Health Organisation released in 2011 its GMP guideline Annex 6 (TRS 961) on the manufacturing of sterile pharmaceutical products. Clean areas are the location of choice for such productions. High-risk operative areas for aseptic manufacturing are classified in Grade A, with Grade B representing their background zones. Grade C and D areas are reserved to less critical steps of the production process.

A frequent and thorough sanitation is important, coupled with disinfection with more than one biocide and/or a sporicidal agent, as appropriate. The effectiveness of the cleaning procedure should be closely monitored to exclude the presence of contaminants, both in the form of vital and not vital particulate.

The guideline specifically mentions the case of preparations containing live microorganisms (such as vaccines), that can be prepared in multiuser facilities only if the manufacturer can demonstrate and validate effective containment and decontamination of the live microorganisms. To transport materials, the conveyor belt should be continuously sterilised as a requirement to pass through a partition between a Grade A/B and a processing area of lower air cleanliness.

A “Comparison of EU GMP Guidelines with WHO Guidelines” was published by the German Federal Ministry for Economic Cooperation and Development (BMZ) to support the understanding of differences between the two approaches, and with a special emphasis to the alleged higher costs of implementation and compliance to EU GMPs.

Analysing the requirements relative to premises and equipment, they aim to guarantee the suitability of rooms to the intended tasks, minimise the risk of failure and cross-contamination and ensure easy cleaning and maintenance. According to the BMZ, EU’s and WHO’s requirements are the same, even if the WHO guideline is more detailed in some aspects (to this instance, the BMZ document was published prior to the release of the new Annex 1 to the GMPs). The theme of equipment is also discussed in other WHO guidelines, i.e. the “WHO good manufacturing practices: starting materials” and the WHO guidelines on transfer of technology in pharmaceutical manufacturing.

Cleaning and sanitation should be addressed according to the provisions set forth by the ISO 14644 family of technical standards. Cleaning validation is also treated in Appendix 3 of the WHO TRS 937 Annex 4. Cleaning validation should be used as the main tool to ensure the removal to pre-established levels of all residues of an API of a product manufactured in any equipment with direct contact to the surface, so that the next product manufactured using the same apparatus would be not cross-contaminated.

According to the BMZ, indications on qualification, process validation and cleaning validation contained in Annex 15 of EU GMPs (paragraph 6) should be integrated with the contents of the ICH Q2 guideline. The only two points of the EU GMPs not covered by the WHO’s guide refer to the allowance that toxic or hazardous substances can be substituted under special conditions for the validation process and the indication that “Test until clean” is not considered an appropriate alternative to cleaning validation.


Patient involvement in the development, regulation and safe use of medicines

by Giuliana Miglierini

The Council for International Organizations of Medical Sciences (CIOMS) has published the CIOMS report on “Patient involvement in the development, regulation and safe use of medicines”.

The report marks an important step forward towards a harmonised approach to patient involvement through the entire medicines’ lifecycle and under all the different perspectives which are part of it. The document is the result of four years of work by the CIOMS Working Group XI on Patient involvement in the development, regulation and safe use of medicines, in collaboration with other relevant stakeholders. Comments were collected during two meetings in Switzerland and Uganda and a public consultation phase.

The report offers recommendations on how to systematically involve patients along the pathway leading from early development and regulatory processing to marketing and monitoring of the safety and efficacy in the real-world contest of use of a medicine. Remaining challenges and practice gaps are also discussed. CIOMS’s secretary Dr. Lembit Rägo gave a presentation at EMA’s Joint PCWP-HCPWP Meeting held in Amsterdam on 4 March 2020.

CIOMS is an international umbrella organisation jointly established by WHO and UNESCO in1949. Members include representatives of the biomedical scientific community, national academies of sciences and medical research councils, jointly committed to develop guidance on health research and policy including ethics, medical product development and pharmacovigilance. CIOMS is an ICH Observer since 2016, and many of its guidelines served as the basis to develop ICH’s ones.

Structure and ethical guiding principles

The CIOMS report consists of eleven chapters and five appendices. After the discussion of the landscape and the guiding principles that should inspire patient involvement, CIOMS has addressed the possible contribution arising from patients aimed to advancing treatments, for each of the steps of development of a new product. Chapter 5 addresses specifically the use of real-world data and evidence generated by patients, a central theme in many new policies in the healthcare sector. The document includes also chapters discussing product labelling and rapid safety communications, as well as additional risk minimisation. Clinical practice guidelines are discussed in Chapter 9. Attention is also paid to low- and medium-income countries and to pandemic considerations.

The rich section discussing case studies includes how to address a medication formulation created to meet patients’ and doctors’ needs and, under the regulatory perspective, the case of EMA’s public hearing on valproate as an example of patient involvement. Partnerships between industry and patient groups for therapy development are also discussed, as well as patients’ engagement in early development plans for a novel treatment. Other case studies address patient involvement in the developing of additional risk minimisation measures and patient activism to counter AIDS denialism and improve access to HIV medicines in South Africa.

The CIOMS report should be read as a pragmatic handbook, recommending ‘best practice’ to serve as a guide, but not necessarily to be entirely adopted. Its contents have been developed on the basis of ethical considerations and fundamental principles of bioethics, highlighting the importance of the opinion of patients as expert partners in the use of medicines. Only patients “can meaningfully contribute their preferences, concerns, understandings, and lived experiences of a medical condition to improve medicine development and use”, states the document.

Another key principle is the respect for persons, which should be always treated as autonomous and making independent decisions, while protection should be provided to persons with diminished autonomy. The result of this vision is a shared decision-making between clinicians and patients, also known as the patient-as-partner approach to medicine. The approach should also include the adequate protection of patients’ personal data and the understanding of their tolerance or acceptance of the risk connected to the use of a certain medicine.

The promotion of wellbeing (beneficence) and the avoidance of harm (nonmaleficence) are other ethic principles inspiring the report. The exercise should take into consideration not only the pharmacological profile of the medicine, but also its possible impact at the logistic, psychological, financial, and social level, as well as opportunity costs. Access to medicines remains a central issue in many instances; to this regard, the report states that “Thus, despite understanding the ethical obligation to provide medicines, individuals or institutions may not necessarily act to fulfil this obligation”.

The concept of “justice” includes modalities for the recruitment of patients for clinical studies, and the fair access and distribution, and knowledge of medicines. Informed consent remains a fundamental principle to be always and freely exercised, while informed assent can apply especially in the case of young children and adults who do not have the legal capability to give consent.

Not only medicines; the patient perspective is fundamental

Contents of the CIOMS report on patient involvement does not apply strictly only to medicinal products, but also to the broader range of products consisting of vaccines, medical devices, drug-device combinations, and diagnostics. All these products are subject to regulatory scrutiny and approval and are aimed to treat or prevent a illness, to make a diagnosis, or to maintain or alter the way the body works.

Patients are identified as the individuals using these products, often flanked and supported by their families, caregivers, patient organisations, and patient representatives. The contribution of patients is deemed essential to correctly identify medical needs on the basis of their daily experience of the health condition. The patient’s perspective can inform early development of new medicines, as well as provide data on safety and efficacy during the post-marketing phase of the lifecycle. All views should be gathered, including the ones arising from often marginalized communities of patients, or those of family carers and other caregivers.

This sort of information may be collected by involvement of patient organisations in the different phases of development and commercialisation, even though there are still some barriers to be overcome. The main one is represented by the cultural shift needed to end seeing patients are passive subjects: they should be regarded as true “research partners” in the development, regulation and safe use of medicines. Other existing barriers include legislative and regulatory burdens as well as language and communication obstacles.

Patient participation to development should be incentivised through reimbursement of time and expenses, suggests the report, while maintaining the independence of patient organisations in order to build a long-lasting and respectful relationship. Digital technologies are suggested as a tool to improve the transparency of communication and to enable telemedicine.

Training should be also provided (for example by patient organisations) in order to optimise patient involvement in the different activities. According to the report, it should include information on medicines-related sciences, ethics of health-related research, clinical trial methodology and interpretation, and medicines legislation and regulation.

Patient involvement in research and development

Patients should be involved in research activity from the very early phases, so to provide their input on candidate medicines. To this instance, key activities may include the definition of research goals and expected treatment benefits, the planning and design of clinical trials and the clear and timely circulation of emerging research information. Preferences of users on formulation and packaging may be also obtained.

The report suggests using well-designed “patient preference studies” as a mean to better understand important elements under the patients’ perspective relevant to their medical conditions and treatment (or prevention).

The regulatory approval process should increasingly take into consideration patients’ opinions on the benefits and risks of a certain medicine, as well as on information arising from the continuous monitoring of side effects. The recommendation is to strengthen the inclusion of patients as members of formal scientific and decision-making committees or working groups on specific scientific aspects of medicine regulation.

Data management and protection and product information

Patient-centred initiatives” are the tool suggested by the CIOMS report in order to better involve patients in the planning and management of real-world data arising from their daily use of medicines. Patients should be enabled to control the actual protection of their data and privacy, and how data are collected, stored, managed and released. Digital technologies represent the preferred tool to reach this objective, and they can also support patients in playing a more active role in the management of their real-world data.

Product information (i.e. the information leaflet contained in each package) is an essential element of a medicine, as it supports its correct use by the patient. The format and clarity of product information has been long debated; the CIOMS report supports the involvement of patients in drafting this information, as a way to improve its relevance and contents. A better compliance to treatment remains a main target, and it may benefit from the information patient scan provide on local customs and traditions, health literacy, and healthcare structures.

Additional risk minimisation measures and safety information

Many innovative therapeutic approaches are characterised by a risk profile significantly higher compared to more traditional treatments. In such instances, the report indicates that the standard information provided to patients may prove insufficient, and additional risk minimization measures may be needed. These measures may create an extra burden on patients, which maybe subject for example to regular testing or need to take extra care. It would be thus important to gather patients’ opinion right from the design and development of the additional measures.

Patients may also contribute to plan how the measures are communicated and put in practice (also using digital technologies where appropriate).

A key pharmacovigilance activity is the rapid dissemination of safety information in case issues arise with the safety of a medicine. To this instance, the report suggests patients to be involved in the decision about issues needing urgent communication, the groups of patients to be informed, and how the information can be designed for patients. Patient organisations can play a central role in the dissemination of such type of information.

Clinical practice guidelines and pandemic preparedness

Patients should be also involved in the development of clinical practice guidelines, aimed to describe how medicines should be used in day-to-day healthcare. This is deemed important in order to overcome the possible bias between patients’ expectations about benefits of the treatment and the consequent acceptance of risks, and the view of these items proper of clinicians and other healthcare professionals.

The importance of patient involvement in the above discussed points has become clear through the experience gathered during the Covid-19 pandemic. The report highlights the importance to consider the lack of knowledge on how new medicines and vaccines are developed and the consequent need to address public concerns about vaccination, the need to deal with misinformation and to provide comprehensive information for patients to make an informed decision.


Current inspection trends and new approaches to the monitoring of post-inspection activities

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The European Federation of Pharmaceutical Industries and Associations (EFPIA) has published its Annual Regulatory GMP/GDP Inspection Survey 2021, highlighting the more recent trends in inspections and how the pandemic affected this critical verification process of pharmaceutical productions. Meanwhile, UK’s regulatory authority MHRA launched the Compliance Monitor Process pilot, aimed to use eligible consultants as Compliance Monitors to supervise companies in the delivery of actions identified in the Compliance Protocol agreed with the regulatory authority.

Main trends in inspections

The main effect of the lockdowns has been the implementation of new ways to run inspections. The recommendation resulting from EFPIA’s report is now for virtual tools combined with onsite presence; to this instance, data gathered in 2021 show that the two modalities of inspection have a similar duration (2.9 days for on-site inspections vs 2.8 days for virtual ones). The report also indicates there is still a backlog of inspections due in 2020, the critical period of the pandemic; suggestions to manage expiring GMP/GDP/ISO-certificates include a one-year prolongation of current certificates, a dedicated communication process between the industry and regulators in the case of issues with the registration in third countries, and a planning of inspections based on the quality history of the site.

Domestic inspections confirming the trend observed since 2016, are almost double of the number of foreign inspections. These last ones focused in 2021 on only 23 countries, compared to the 44 countries visited by inspectors in 2017. EU’s countries were the most visited ones, with some 350 inspections reported vs the 150 of US, confirming the importance of European pharmaceutical manufacturing. According to the report, 2021 saw an increased attention to GDP inspections, while the percentage of sites with no inspections remains stable for six years.

A new mix of inspection tools

The use of new tools, additional to physical on-site presence, has now become a routine possibility accepted by many regulatory authorities. Many different approaches have been tested during the pandemic, including different inspections tools. Different combinations of tools cannot be considered to be equivalent, according to EFPIA. In general, a mixture of physical presence, document review and virtual presence flanked by the sharing of experience, collaboration and reliance is deemed suitable to confirm compliance and capability while supporting a risk-based efficiency.

Data show that the number of virtual inspections was higher in 2020 compared to 2021; the last year saw an increase of on-site presence vs 2020 and a mixture of virtual and on-site inspections. According to the report, only seven European countries have experience with the implementation of virtual inspection tools (Germany, Denmark, Finland, Ireland, Italy, Poland and Sweden). As a consequence, the impact of mixed virtual and on-site domestic inspections in 2021 was lower in EU member states that, for example, in the US, Brazil, Russia and Singapore.

There is still space for improvement

EFPIA’s survey presents the respective advantages and disadvantages of on-site inspections vs virtual tools. The implementation of the new modalities is far from being accomplished, the process is still on the learning curve, says the document.

While the remote, virtual interaction allows for a greater flexibility of the inspection process, it may result stressful for some people; furthermore, it impacts on the way work is organised, as it needs a flexible schedule and time to prepare for the next day meetings. Also, the style of communication changes to become less natural and more focused. Overall, virtual inspections appear to be more efficient when performed in real-time, as it would be for on-site inspections. While being less costly, due to avoiding extensive travelling, virtual inspections require a careful preparation, including the availability of a suitable IT infrastructure and connectivity. Documents are also often required in advance of the meetings to be shared with regulators.

How to further improve inspections

According to EFPIA, the future of inspections calls for improved collaboration and reliance in order to increase the knowledge shared by the different inspectorates and overcome the limits intrinsic to self-dependency. The expected final outcome of the new approach to inspections is an improvement in the decision-making process. Inspection frequency may be set every 1 to 5 years on the basis of a risk-based evaluation.

Collaboration, reliance and delegation appear to be the new mantras to guide the actions of regulators: the focus suggested by EFPIA is on inspections run by domestic authorities, coupled to the implementation of Mutual Recognition Agreements (MRA) to avoid duplication of efforts. According to the report, it would be needed to harmonise the scope of existing MRAs and to establish new ones between the EU and PIC/S participating authorities (e.g. Argentina, Brazil, South Korea, Turkey and UK). The European legislation should be also updated to include the concept of listed third countries, as already in place for the importation of active substances under the provisions of the Falsified Medicines directive.

The report also suggests a qualitative tool that would fulfil the legal requirements for “inspections” and may prove useful to support inspection planning on the basis of the knowledge of the GMP compliance history of the site, the footprint history of critical and major deficiencies and the type of inspection to be run. These elements lead to the identification of the hazards to be considered, including the intrinsic risk and the compliance-related one. The final output of the tool takes the form of a risk-ranking quality metric, to be used to establish the frequency of inspection for a certain site and the number and level of expertise of the required inspectors, as well as the scope, depth and duration of routine inspections.

All these items may form the basis for the drafting of a GMP inspection “Reliance Assessment Report”, which would also include the statement about the name of the hosting national competent authority and the basis on which country reliance has been established. Such a document may be then used to support regulatory decisions. According to EFPIA, the suggested approach would benefit of a better knowledge of the site inspected by the local NCA, a better insight in the local culture and less barriers to the interaction, with optimisation of resources. A better transparency of the inspection process is also expected, as a non-compliant site may negatively impact on the reputation of local inspectorates. Identified pre-requisites to allow the implementation of such an approach are the availability of high-quality standards at the local level and the evaluation of national regulatory systems by and independent body (e.g. PIC/S or the WHO Global Benchmarking Tool).

UK’s pilot of a Compliance Monitor Process

A new approach that may represent a first example towards the new paradigm of collaboration and reliance has been undertaken in the UK, where the Medicines and Healthcare products Regulatory Agency (MHRA) launched in April 2022 a pilot project focused on the Compliance Monitor (CM) Process (see more here and here). The pilot is part of MHRA’s delivery plan 2021-2023 and will focus on the CM supervision process for appropriate GMP and GDP Inspection Action Group (IAG) cases.

According to the MHRA, the new process would allow companies to concentrate on the delivery of the required improvements without the need to use resources to manage MHRA supervision inspections to assess compliance remediation activities. On the regulatory side, the MHRA should be able to concentrate on the delivery of the routine risk-based inspection programme. The risk-based approach to supervision and monitoring is also expected to limit the number of potential shortages of supply.

The CM process is based on the figure of eligible consultants acting as Compliance Monitors (CM) in charge of working with the company to deliver the remediation actions identified in a Compliance Protocol (CP) agreed with the MHRA. The supervision by the CMs is expected to contribute to lower the need of on-site inspections with respect to the current process managed by the IAG. The CP also includes the transmission to MHRA of high-level updates at fixed intervals of time, which should include only exceptions to the agreed timelines or significant related compliance issues which were identified. Once completed the CP protocol, the CM informs the regulatory authority that the company is ready for inspection, so that the MHRA can verify onsite the possibility of its removal from IAG oversight.

CMs will be selected by the involved company from a dedicated register and accepted as suitable for that case by the MHRA. At least five years’ experience in independent audits of GMP/ GDP companies is needed to be eligible as CM. Furthermore, not having been personally the subject of MHRA regulatory action and/or significant adverse findings in the previous three years,  a suitable CV and the completion of a MHRA training as CM. All details on requirements for the CM role and application are available at the dedicated page of the MHRA website.

Suitability criteria to act as a CM for the specific case include as a minimum a sufficient experience of the dosage form manufactured, testing activities being performed, or distribution activity being carried out and a written confirmation of absence of Conflict of Interest. These criteria will be assessed by the company selecting the CM.

BIA’s view of the reliance in the UK medicines regulatory framework

The UK’s BioIndustry Association (BIA) contributed to the debate on the reliance in the UK medicines regulatory framework with a Reflection Paper. According to BIA, the MHRA has a well recognised status and history as a valued contributor to the global regulatory ecosystem and a point of reference for the regulatory decision-making which should be preserved also in the future.

BIA recalls the role played by the MHRA in the development of the concept of regulatory reliance at the EU level, as a way to support the agile management of resources and simultaneously focusing on core and innovative national activities across all stages in the product lifecycle. The central concept sees regulators from one country to rely on the decision and assessments of trusted authorities from another country in order to speed up the timeline of regulatory procedures. At the end of the process, each regulator remains fully responsible and accountable for all its decisions.

BIA also highlights the contribution of reliance to the advancement of good regulatory practices and international networks of regulators, so to better allocate resources potentially taking into account also the respective fields of specialisation. The proposal is for a list of accepted reference regulatory authorities as a way to recognise the evolution of partnerships over time. Examples of recognition pathways already active in the UK are the EC Decision Reliance Procedure (ECDRP) and international work-sharing through the Access Consortium and Project Orbis, through which the MHRA may act as the reference regulatory agency in many procedures.

BIA also warns about the risks of a sudden interruption at the end of 2022 of the reliance pathway, that would have a highly disruptive impact on companies and patients.



PIC/S Annual Report 2021

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The Annual Report of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) resumes the many activities and results achieved in 2021, despite the ongoing pandemic that required remote coordination and on-line virtual meetings. To this regard, a written procedure has been used to manage important decisions. PIC/S also supported the harmonisation of the distant assessment procedures used by the various regulatory authorities to run GMP inspections during the pandemic period.

The non-binding co-operative arrangement between international regulatory authorities aims to implement harmonised GMP standards and quality systems in support to harmonised inspection procedures. PIC/S’ new strategic plan for 2023-2027 will be presented at the PIC/S 50th anniversary in 2022. The PIC/S Committee has elected Paul Gustafson (Canada/ROEB) as the new Chairperson for the period 2022-2023; he takes the place of Anne Hayes (Ireland/HPRA).

New memberships and re-assessments

Last year saw the entry into the PIC/S scheme of the Brasilian Agência Nacional de Vigilância Sanitária (ANVISA), one of the main regulators of South America, representing the largest market for medicinal products for this geographic area. ANVISA is the 54th member of PIC/S.

Five other membership applications continued the process of assessment. These include the application of Armenia’s Scientific Center of Drug and Medical Technologies Expertise (SCDMTE), that was requested to update its documentation; the preliminary report should be issued soon.

The Bulgarian Drug Agency (BDA) will benefit of a partial assessment of its application, due to the fact the agency already went through an audit under the EMA Joint Audit Programme (JAP) whose report was shared with PIC/S. Health Canada will also collaborate to this assessment under a MRA procedure.

The Jordan Food and Drug Administration (JFDA) also filed a membership application, as well as another regulator from Africa, the Saudi Food & Drug Authority (SFDA), whose preliminary report is soon expected.

Particularly complex is the case of the application by several Competent Authorities of the Russian Federation that jointly submitted a complete membership application in December2020. A larger team, consisting of a Rapporteur and several Co-Rapporteurs, shall be nominated to better manage the procedure. The involved Russian authorities are the Ministry of Industry and Trade of the Russian Federation (Minpromtorg Russia), the Federal Service for Surveillance in Healthcare (Roszdravnadzor), including the “Information and Methodological Center for Expertise, Accounting and Analysis of Circulation of Medical Products” (FGBU “IMCEUAOSMP” of Roszdravnadzor),the Federal “State Institute of Drugs and Good Practices” (FSI “SID & GP”), and the Federal “Scientific Center for Examination of Medical Devices” of the Ministry of Health of the Russian Federation (FSBI ”SCEMD”).

Among authorities undergoing the pre-accession procedure is the Chinese regulatory agency National Medical Products Administration (NMPA), whose application will be assessed by Jacques Morenas (France/ANSM) as Rapporteur and Raphael Yeung (Hong Kong SAR, China/PPBHK) as Co-Rapporteur.

Reviewing of the pre-accession application is also ongoing for the Analytical Expertise Center (AEC) of the Ministry of Health of Azerbaijan, the Bangladesh’s Directorate General of Drug Administration (DGDA, this 2-year timeframe for the pre-accession expired in February 2021, and a new application was required) and the Drug Regulatory Authority of Pakistan (DRAP), that was invited to apply for membership subject to the implementation of the PIC/S GMP Guide.

PIC/S also run a Joint Reassessment Programme (JRP) in parallel with the EU’s JAP to re-evaluate its members for equivalence on a regular basis. In 2021 the JRP included the reassessment of regulatory authorities from Indonesia (NADFC), New Zealand (Medsafe), and South Africa (SAHPRA).

PIC/S also established new contacts in 2021 with other non-member authorities, including Cameroon’s Laboratoire National de Contrôle de Qualité des Médicaments et d’ Expertise, China’s Institute of Veterinary Drug Control, Cuba’s Centro para el Control Estatal de Medicamentos, Equipos y Dispositivos Médicos (CECMED), and Montenegro’s Institute for Medicines and Medical Devices.

New guidances and revisions of existing ones

Among the new guidances adopted in 2021 are the Annex 2A for the Manufacture of ATMP for Human Use and Annex 2B for the Manufacture of Biological Medicinal Substances and Products for Human Use, that entered into force on 1 May 2021 (PE 009-15). The documents were finalised by the PIC/S Working Group on the revision of Annex 2 of the PIC/S GMP Guide.

The Working Group on Data Integrity issued two other guidance documents that entered into force on 1 July 2021, the Guidance on Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (PI 041-1) and a restricted Aide Memoire on inspection of data management and integrity (PI 049).

PIC/S also issued the Good Practice Guidelines for Blood Establishments and Hospital Blood Banks (PE 005) and the related Aide Memoire to Inspections of Blood Establishments and Plasma Warehouses (PI 008), that entered into force on 1 June 2021. The dedicated Working Group will now address the revision of PI 019 (PIC/S Site Master File for Source Plasma Establishments) and PI 020 (PIC/S Site Master File for Plasma Warehouses).

PIC/S and EMA’s joint Working Group on Annex 1 reviewed the comments received to the second public consultation and drafted the final version of the Annex.

The Working Group on Harmonisation of the Classification of Deficiencies is finalising the revision of the PIC/S SOP on Inspection Report Format (PI 013-3) in order to align it with the abovementioned PI 040-1. The Working Group on Controlling Cross-Contamination in Shared Facilities is as well finalising the revision of its Guidance on Cross-Contamination in Shared Facilities (PI 043-1).

PIC/S is also working to harmonise its GMP Guide and Annexes to the rules established by the European Union, in collaboration with EMA through the PIC/S-EMA Joint Consultation Procedure. Many chapters and annexes of the PIC/S-EU GMP Guide were considered during 2021, including Chapter 1 (Pharmaceutical Quality System), Chapter 4 (Documentation) and Annex 11 (Computerised Systems), Annexes 4 and 5 (Veterinary Medicinal Products), Annex 13 (Investigational Medicinal Products), Annex 16 (Certification by an Authorised Person & Batch Release), and Annex21 (GMP Obligations for Importation to the EU).

Virtual training in the pandemic period

Four virtual training events were organised in 2021, among which a PIC/S webinar for inspectors on ICH Q12 (Pharmaceutical Product Lifecycle Management) that was attended by around350 participants from 50 agencies and 44 different jurisdictions.

The webinar on Distant assessment/Remote Virtual Inspection co-organised with the EU Commission Expert Sub-Group on Inspections in the Blood, Tissues and Cells Sectors (IES) was attended by around 325 participants.

The 2021 PIC/S annual seminar was hosted by the Ministry Food and Drug Safety (MFDS) of the Republic of Korea, and saw the participation of 315 inspectors from 54 authorities.

The 2nd meeting of the PIC/S Expert Circle on Controlling Cross-Contamination in Shared Facilities (CCCISF) was virtually hosted and was attended by 375 participants.

Last year saw also the provision of new harmonised and standardised GMP training activities for inspectors under the PIC/S Inspectorates’ Academy (PIA) initiative, a web-based educational centre also involved in setting up a standardised qualification process of inspectors.


EDQM, the RTEMIS scheme for remote inspections and new application forms for CEPs

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

Starting in 2022, the Real-Time Remote Inspections (RTEMIS) programme, established by the European Directorate for the Quality of Medicines & HealthCare (EDQM) as a pilot in November 2020 to provide a tool to face travel restrictions due to Covid-19, has turned permanent. Companies applying for Certificates of suitability to the monographs of the European Pharmacopoeia (CEPs) may thus receive a notification for a RTEMIS inspection, as a part of the activities of the EDQM. The Directorate is responsible in cooperation with the participating agencies, for assessing the GMP compliance and CEPs applications relative to manufacturing sites of active pharmaceutical ingredients (APIs). The final GMP certificate issued from the NCA incorporates, following the positive closure of a remote inspection clearly states that the inspection was performed as a “distant assessment”.

Companies can adhere to the RTEMIS programme on a voluntary basis; the tool will complement the other modalities available to the EDQM to inspect manufacturers of pharmaceutical active ingredients, i.e. on-site inspections and documentation-based GMP assessment. As for on-site inspections, RTEMIS is also subject to the payment of fees. According to the Directorate, remote inspections cannot replace the on-site ones in terms of value and effectiveness, but many prove useful to assess GMP compliance for companies which have been already inspected. The RTEMIS scheme will thus form the third pillar for the supervision of GMP compliance of API manufacturers registered in the EDQM’s CEP scheme.

To qualify for an RTEMIS inspection, the concerned company should make available a suitable IT infrastructure and hardware to support the remote interaction with the EDQM’s team. To this regard, the notification letter will also include details about the expected infrastructural requirements; interested companies can contact the EDQM HelpDesk for further information.

The pilot phase to validate the RTEMIS scheme for remote inspections ran by the EDQM with reference to several manufacturing sites in India, selected on the basis of their GMP compliance history and a risk assessment, and which participated to the project on a voluntary basis. According to EDQM, suitable Corrective and Preventative Action Plans were developed by the inspected companies to address minor and major deficiencies identified during the inspections, leading to a degree in GMP conformity that the Directorate indicates as “satisfactory”.

Key factors for remote inspections

The pilot phase of the RTEMIS programme closed at the end of 2021 and led to the identification of several key factors to be respected in order to guarantee the success of remote inspections. During this period, RTEMIS inspections ran by the EDQM with the support of European Economic Area (EEA) inspectorates.

At a minimum, an appropriate IT infrastructure and hardware at the inspected site should be available to support a stable connection with the EDQM’s inspectors. During the preparatory phase of the inspection great attention should be paid to choose a suitable web conference application, running connectivity tests before the established date for the inspection, as well as a secure platform for the sharing of all relevant documentation (often in advance of the inspection). The selection of the IT tool to be used can benefit of the initial support from the EDQM’s IT department. Another important feature that should be always kept in mind refers to the possibility to run parallel sessions of discussion between the inspectors’ team and the staff and experts of the inspected company.

In remote inspections, participants are often located far apart, for example EDQM’s inspectors based in Strasbourg (F) may interact with an inspected company in China or India. The great difference in time zone requires a great flexibility on both sides to set the schedule for connections. Flexibility is also needed to face the many challenges posed by remote inspections, often requiring approaches significantly different from the traditional ones used for on-site inspections. Digital connected tools such as smart glasses may be used, for example, by the staff at the inspected site to allow inspectors to perform a real-time virtual tour of the plants.

New forms for CEPs applications

The EDQM also updated all forms to be used to apply for the release of Certificates of Suitability to the European Pharmacopoeia monographs. The forms to be used in case of a new application, revisions and sister files are available at the dedicated page of the EDQM’s website

The revision is intended to facilitate the transfer of data the EDQM’s new IT tools, which have been implemented starting 1 April 2022. The new forms also better reflect data available within the EMA’s SPOR – Organisation Management Services (OMS) system, including company details, names and addresses. The EDQM recommend communicating other additional data linked to the ones present in EMA’s website, i.e. the ORG_ID and LOC_ID.

 Applicants should also insert localisation data for their manufacturing sites, in the form of GPS coordinates. To this instance, the internationally recognised WGS 84 system should be used, using latitude and longitude (with the + and – symbols) expressed in degrees to at least five decimal places, as described in policy document PA/PH/CEP (10) 118.

Tables detailing the marketed medicinal products containing a certain active substance and the respective list of accepted Active Substance Master Files/Drug Master Files (ASMFs/DMFs) have been also updated, in order to better reflect the commercialisation history of the products and the quality assessments already performed.

EDQM also advises companies to use the form “change of contact details” as the preferred tool to inform the Directorate about the change of the contact person for one or more CEP dossiers (ref. policy document PA/PH/CEP (10) 86).

EDQM’s website is also undergoing a complete revision, aimed to improve the user experience and to ensure a quick and easy access to all relevant information. The new version of the site will be accessible from the same web address www.edqm.eu and is expected to be online in April 2022.  


The Made in Europe partnership for manufacturing

, , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The availability of a robust framework to support a sustainable European manufacturing system is undoubtedly a priority in the challenging times we are experiencing. In the pharmaceutical sector, the reshoring of productions of both active ingredients and finished medicinal products is already a key point of the new EU Pharmaceutical Strategy and of the consequent ongoing revision of the legislation governing the sector.

A broader action addressed to the entire European industrial system was launched in 2019 within the framework programme Horizon Europe (HE) 2021-2027: the Made in Europe manufacturing partnership aims to become the main driver for sustainable manufacturing in Europe. The partnership was modelled with the contribution of the European Commission, member states and the European Factories of the Future Research Association (EFFRA); the latter is also the leading entity in charge of coordinating the initiative, which include all actors taking part to the manufacturing ecosystem (i.e. academia, industry, non-governmental organisations and the public sector).

The main goals of the Made in Europe partnership

The two themes of ecological and digital transitions central to the policies of the von der Leyen Commission are the main source of inspiration for the Made in Europe partnership. The availability of a European manufacturing environment able to compete on global scenarios thanks to its technological leadership is the main objective of the initiative. Many challenges need to be faced to reach it, especially in the field of the integration of technologies based on artificial intelligence to fully exploit the potential of industrial data, the reshaping of a circular economy and a high flexibility in response to emerging trends and issues.

The Made in Europe partnership represents a common platform for national and regional manufacturing technology initiatives, including the required disciplines and technologies. The principles governing its actions are described in a guidance document available at the EFFRA website; a Strategic Research and Innovation Agenda (SRIA) is also available.

According to the guidance document, manufactured goods represented in 2018 83% of EU exports, and accounted for a annual trade surplus of 286 billion euro. Despite this very high surplus, the document warns it may be not sufficient to cover deficits arising from the purchase of non-manufactured goods and services. Also considering these factors, the balance moved from a surplus of € 22 billion in 2017 to a deficit of € 25 billion in 2018. This situation may now dramatically evolve further, due to the high increase of costs of energy and raw materials experienced in the last month, as a consequence of the war occurring at the Eastern boundaries of the EU. A situation that might make harder for the EU to also face the competition of Asiatic economies.

The guidance document identifies twelve challenges to be faced by the European manufacturing industry, starting from the need to strongly reduce to the minimal level its environmental impact. To this instance, optimisation of resource efficiency and the carbon intensity of the entire supply chains are among the main factors to be addressed, leading to the opportunity for European-made environmental-friendly but high-priced products. This switch also supports the development of circular models for the economy, and the use of next-generation sustainable materials and products, requiring to manage profound changes if the manufacturing systems and related supply chains. Recycling and re-manufacturing may play in the future an important role in redefining products’ life cycle. The resilience and agility of the European manufacturing industry shall be also tackled, in order to limit the impact of sudden crisis, as occurred with the Covid-19 pandemic or now with the Ukraine war. This goal calls for the availability of flexible and reconfigurable production lines within a country or region, suggests the document. The pharmaceutical sector already experienced criticalities during the Covid-19 arising from the dependence from extra-EU supplies; the same applies to all European industrial sectors, and according to the Made in Europe partnership it should be faced through achieving manufacturing sovereignty and technological leadership in key areas and critical value chains. A very challenging objective, that requires a coordinated European effort on manufacturing.

As for competition from other economies, the document warns that big public-private manufacturing partnerships are being launched also in Asia and America (i.e. Made in China). Environmental and social aspects should be jointly considered in the location/relocation of manufacturing companies, to account for the environmental sustainability of the businesses coupled to the requirements arising from a EU’s population mainly living in urban areas.

The challenges of digitalisation

Many of the above-mentioned targets identified by the Made in Europe partnership may benefit from the potential offered by the implementation of digital technologies to accelerate innovation and industrial transformation, thus leading to the improvement of the overall efficiency of manufacturing. Data are becoming a central driver for the creation of value, but companies are called to better understand the data economy also from a non-technological point of view. Cybersecurity should be also carefully addressed, as digitalisation is reflected by a higher vulnerability to cyber attacks.

Digitalisation also impacts on the availability of new business models, such as “manufacturing-as-a-service” and “collaborative product-service engineering”. Automated systems governed by artificial intelligence are now widely available in many industrial plants, and attention should be paid to modes of interactions between collaborative robots and human operators. Nevertheless, the availability of trained and skilled human staff is considered as a major barrier and threat by the Made in Europe partnership, particularly for SMEs.

The planned actions

Six different calls for actions in the field of green and digital transitions were launched by the Made in Europe manufacturing partnership within the Horizon Europe work programme 2021-2022. The total available budget is around € 1 billion. Topics of interest included AI enhanced robotic systems for smart manufacturing, zero-defect manufacturing towards zero-waste, laser-based technologies for green manufacturing, manufacturing technologies for bio-based materials, advanced digital technologies for manufacturing, and data-driven distributed industrial environments.

The Made in Europe partnership was also involved in calls about reconfigurable production process chains, products with complex functional surfaces, excellence in distributed control and modular manufacturing, intelligent work piece handling in a full production line, ICT Innovation for manufacturing sustainability in SMEs, and digital tools to support the engineering of a circular economy.

A consultation on possible topics to be included in the HE work programme 2023-2024 is still open to comments and can be accessed by the dedicated webpage at the EFFRA website. A summary document is also available presenting potential recommendations and discussion topics received up to now. New possible lines of actions may address the availability of “excellent, responsive and smart factories & supply chains” , how to achieve a circular products and climate- neutral manufacturing, new use models referred to new integrated business, product-service and production approaches, and models for a human-centered and human-driven manufacturing innovation.


The Faculty of Pharmacy in Brno is once again a part of Masaryk University

, , , , , , , , , ,

by Aleš Franc

In 2020, the Faculty of Pharmacy of the Veterinary and Pharmaceutical University Brno was transferred to the framework of Masaryk University (both are located in Brno, Czech Republic). This short communication discusses the background to this event.

Faculty of Pharmacy, Masaryk University (1952 – 1960)
The Faculty of Pharmacy was established at Masaryk University (MU) based on a 1952 government decree. It had eight departments divided into groups. A Garden of Medicinal Plants and a Faculty Pharmacy were also built for the needs of the faculty in Brno. According to statistics from 1956, 75 % of graduates went to work in pharmacies and 5-7 % found employment in the pharmaceutical industry. However, based on a government decree, the faculty was abolished in 1960, and the study was merged with the Faculty of Pharmacy of Comenius University in Bratislava, which has existed since 1952 and became the only pharmaceutical faculty in Czechoslovakia. In 1969, the Faculty of Pharmacy of Charles University was established with its seat in Hradec Králové. In 1991, shortly after the collapse of socialism in Czechoslovakia, the Faculty of Pharmacy in Brno was renewed within the University of Veterinary and Pharmaceutical Sciences Brno.

Faculty of Pharmacy, Masaryk University (2019 – present)
Masaryk University was founded in 1919 as the second Czech university. According to the number of students in accredited study programs, it is the second-largest university in the Czech Republic. It has ten faculties and operates, among others, its Mendel Museum, the Scala University Cinema, the University Center in Telč, and the Antarctic Polar Station. According to QS Top Universities, Masaryk University has long been ranked among the top universities.
In 2019, negotiations were started between MU and University of Veterinary and Pharmaceutical Sciences on the inclusion of the faculty back into the MU framework. The move took place in July 2020. Teaching continues in the existing premises on the UVPS campus, which MU rented for five years. In the future, the faculty is to become part of the university campus. For current students and employees, the transition to MU means the possibility of cooperation with other faculties, such as the Faculty of Medicine and the Faculty of Science.
Thanks to the transfer to Masaryk University, the Faculty of Pharmacy will be able to use the facilities of teaching hospitals and the close contact with patients; also very strong scientific research facilities with the perspective of further development of pharmaceutical sciences. For example, Masaryk University has a Centre for Medicinal Plants, which has been connected to the Garden of Medicinal Plants since the 1950s, when the faculty was still part of MU. Other pharmaceutical disciplines can significantly enrich the research topics addressed at MU in the direction of biologically active substances of various origins, their production, and especially processing into modern pharmaceutical forms. At the same time, there is scope for the development and commercial exploitation of various activities, especially in the field of preclinical contract research.

Department of Pharmaceutical Technology
Currently, the Faculty of Pharmacy has six departments: Department of Applied Pharmacy, Department of Natural Drugs, Department of Pharmaceutical Technology, Department of Pharmacology and Toxicology, Department of Chemical Drugs and Department of Molecular Pharmacy.
The Department of Pharmaceutical Technology, which is closest to the pharmaceutical industry and whose employee is also the author of this article, operates within the Faculty of Pharmacy. It deals with the formulation, preparation, manufacture, evaluation, protection, and other aspects associated with pharmaceutical dosage forms. Regarding the focus on the pharmaceutical industry, a new program has been opened for cooperation with partners from the commercial sector. Oncomed manufacturing a.s. and medac GmbH became the first general partners.

The above has been processed according to materials available on the websites of the Faculty of Pharmacy MU and Masaryk University, Brno, Czech Republic.

Aleš Franc is Associate professor, Department of Pharmaceutical Technology at Masaryk University


ICMRA published a Reflection paper on remote inspections

, , , , , , , , , , , , , , , , , , , , , , , , ,

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.