What happens after IP loss of protection

November 11, 2022

biological molecule, biosimilar, Central and Eastern Europe countries, competition, competitors, costs reduction, data exclusivity, data protection, entry on the market, EU4 markets, generics, intellectual property protection, IP rights, IQVIA, length of protection, loss of exclusivity, lost of protection, market access, market exclusivity, open competition, originator, orphan drug exclusivity, paediatric drug exclusivity, patent protection, period of exclusivity, Pharmaceuticals, prices of medicines, RDP, Regulatory, return on investment, small molecules, SPC, Supplementary Protection Certificate, supply chain sustainability, therapeutic areas, volumes growth

by Giuliana Miglierini

What does it happen under a competitiveness perspective once intellectual property (IP) protection for medicinal products expired? And what is the impact of the new entries on generics and biosimilars already in the market?

The role of competitor entry on the market has been analysed in a report by IQVIA.

The document focuses on loss of protection (LOP), thus including in the analysis all products that are free from any form of IP rights (patent protection, SPCs, RDP, market exclusivity/loss of exclusivity, data exclusivity, orphan/paediatric drug exclusivity). According to the report, there are many elements to be considered while assessing the impact of IP rights, among which are regulatory issues, prices policies, competitiveness landscapes. Finally, all the previously mentioned issues are today facing a higher pressure due to the incumbent global situation, characterised a generalised economic crisis especially in Europe. One of the main goals of the EU Commission is to increase the attractiveness of the internal market as a key innovative region for investment in the pharmaceutical sector.

The main trends of the past six years

The IQVIA’s report takes into consideration the group of medicines that have lost protection across the past six years (2016–2021), for a total of 118 molecules; it also analysed the impact of the alignment of the regulatory data protection (RDP) rules in Europe occurred in late 2005, as well as the entry of new countries in the EU occurred in 2004 (Czech Republic, Estonia, Cyprus, Latvia, Lithuania, Hungary, Malta, Poland, Slovakia and Slovenia). EU’s enlargement also included Romania (2007), Bulgaria (2007), and Croatia (2013). Many of the products considered in the analysis were innovative medicines, representing approx. 13% of the total European pharmaceutical expenditure at their peak.

According to IQVIA’s data, the total European pharmaceutical market at list prices valued € 1 trillion in 2016-2021. Over the same period, all protected products counted for 37% of total expenditure on pharmaceuticals (€ 377 billion). Medicinal products that lost protection represented roughly 10% of the total EU market value (€103 billion).

Forms of IP protection

Just more than a half (51%) of products that lost protection in years 2016-2021 were subject to a Supplementary Protection Certificate (SPC), while the RDP mainly refers to older cardiovascular, or combination medicines. Eleven years is the current average length of protection in Europe (-4.2 years; it was 15.2 years for authorisations granted in 1999-2005); the decrease can be attributed to the entry into force of the European centralised system, that diminished the impact of delays to LOP. Market exclusivity also depends on the specific form of IP protection chosen, as it may vary the calculation from different starting dates for IP filing.

IQVIA’s data show that SPC represents 32% of the final form of protection; this sums to 19% of SPC followed by paediatric extension. SPC provides a maximum of 15 years of protection, with an average of 14.4 years. Medicines under regulatory data protection are 31% of total (8 years data exclusivity + 2 years market exclusivity +1 year for a significant new indication), the patented ones 11%. Smaller fractions are covered by orphan drug exclusivity (5%) or orphan drug extension followed by paediatric extension (2%). Considering sales values, the preferred constraining form of protection for small molecules is SPC (93%), followed by RDP (83%); SPC plus paediatric extension occurs in 50% of cases for biologics. Small molecules are also often subject (80%) to patent plus other forms of exclusivity (orphan/paediatric extension). According to IQVIA, the undergoing discussion on the review of the European IP legislation may lead to an alignment of the RDP duration to the US standard (5 years for small molecules, 12 years for biologics).

The impact of the different legislation governing patent litigation in the EU vs the US should also be taken into consideration.

Access and competition

Access of new generic and biosimilar medicines in the European market is a long debated issue, as historically it often proved difficult to determine the precise date of patent expiry and to find an alignment between different countries on this fundamental issue.

According to IQVIA’s report, in the years 2016-2021 the duration of access to major EU markets was 36 days. Competition for small molecules has reduced the cost by approx. 41%, with a volume growth of ~27%; the overall savings for the payer was -8% CAGR for the years 2016-2021. Biologics also increased their volumes year-on-year (23%). Less evident are savings for payers (8% increase in 2016-2021), but many biologics benefit of confidential discounts for hospital supplies.

Competition is very peculiar to the European market landscape, with 92% of molecules having competitors recorded by sales value. A very small niche (2%) of small, low value products proved to be less attractive; the remaining 6% refers to products under development. The biosimilar sector is particularly challenging, as only the largest molecules are attractive from the competition point of view; about 30% of products without a competitor in development are biologics.

Central and Eastern Europe countries are still the preferred ones for early access to competitors, compared to the EU4 markets (Germany, France, Italy, Spain), due to dates for LOP that are in many cases still subject to some variation. On the contrary, EU4 markets account for 89% of sales of available molecules; many countries have no recorded sales for 25% of the available originator molecules.

Data by IQVIA indicates that, at a macro-level, the system has reduced the cost of medicines open to competition by 28%, while the volume of treatment increased 27%. Despite this encouraging trend, treatment paradigms shifting were also observed before LOP.

As for therapeutic areas, RDP protected medicines that underwent LOP were mainly referring to anti-hypertensive (73%) and combination products (61%). The higher proportion of SPC protected products was found in systemic anti-fungals (60%), oncology medicines and HIV/anti-virals (45% each). Immunology and lipid regulators are often protected using SPC plus paediatric extension (60% and 50%, respectively)

The importance of intellectual property rights

Estimates of investments in pharmaceutical R&D are approx. €39 billion/year, according to the report. Return on investment relies heavily on IP rights, a theme that is central also to the ongoing review of the EU’s pharmaceutical and IP legislations. Many new treatments are on their way towards approval, especially in the field of advanced therapies; according to IQVIA, more than 60% are first-in-class therapeutics.

Two core concepts support the current European framework for intellectual property rights: a period of exclusivity applying to new compounds (patent protection + SPC), followed by open competition once all IP expired. At this stage, competitors can access open data and manufacturing formulations. Prices are often regulated at the national level to incentivise competition and to positively impact on treatment opportunities available to patients.

The current fragility of supply chains for pharmaceutical productions may pose many challenges to originator companies which remain the sole provider of a medicine after loss of protection. A risk highlighted by IQVIA’s report is a too pronounced decrease of prices to support competition, and thus the sustainability of the market.

Access to innovative medicines is another challenge identified, referring to countries where the originator did not launch its product, and neither the competitors did. Furthermore, competitor entry often refers to low-value medicines. This despite future loss of protection for the years 2026-2030 should refer mainly (55%) to biologic molecules, compared to 43% for the period 2021-2025.

How to approach drug substance supply in new product introduction (NPI) processes

October 7, 2022

active pharmaceutical ingredients, active substance, adherence to schedule, API, best practices, biopharmaceuticals, BioPhorum, business review, capacity modelling, clinical milestones, collaborative industrial approach, COPQ, demand forecasts, demand sensitivities, feedback on performance, gap analysis, governance, indication, investigational medicinal products, manufacture review, master data, master service, material supply agreement, materials evaluation, materials risk analysis, metrics, new product introduction, NPI, NPI supply chain, operational performance, OTIF, ownership. RACI matrix, pharmaceutical production, Product Lifecycle Demand and Supply Strategy, product lifecycle materials requirements, qualification process, raw materials, request for information, RFI, roles and responsibilities, specifications, standard industrial master data set, supplier, supplier qualification, supplier selection, supply, supply agreements, supply forecasts

by Giuliana Miglierini

A key issue to be faced during pharmaceutical development refers to the supply of the active pharmaceutical ingredients and other raw materials to be used for the manufacturing of the first batches of investigational medicinal products, and then up to commercial production once approved.

Changes of specifications can frequently occur during experimentation, thus leading to the need to modify supply requirements for clinical programs. This is more true when dealing with biopharmaceutical investigational products, for which the traditional models for forecasting and demand processes may prove unfitted. The result is a lower robustness and predictability at early stages of the new product introduction (NPI) manufacturing processes. The complexity of the NPI supply chain is also impacting on manufacturing operations, with possible delays in the clinical program and launch schedule.

These issues have been addressed in the document “Guidelines for materials introduction supporting drug substance delivery”, published by the B2B organisation BioPhorum. A summary of its contents has been published in Bioprocess Online.

A good internal communication is fundamental

The ability to produce robust supply forecasts for new product introduction bases on a detailed knowledge of the planning of different activities to be run for a timely launch. Role and responsibilities have to be clear, as well as the information to be collected and timely shared between the manufacturing and commercial departments of biopharmaceutical companies.

The availability of such information is crucial to reduce the variability intrinsic in the NPI process for a biopharmaceutical product, which costs much more compared to a traditional smallmolecule based one. Reducing variability also impacts on the ability to better compete in the often highly dynamic market for biosimilars, or to address the launch of a new biotherapeutic under the correct perspective. Issues may be encountered also with respect to the regulatory approval processes, which may require different time lengths in different geographic areas or countries. This adds another uncertainty factor to estimates of the quantities of product to be manufactured.

Upon this considerations, the BioPhorum document identifies four key issues to be addressed to provide for a timely NPI process, including capacity and lead-time restrictions or oversupply, late change evaluation and implementation, governance issues and network complexity and in-licensed (or non-platform) products.

The availability of a good NPI process may avoid to incur many problems once operations are in place; all the needed master data information to support the use of raw materials should also be present and correct. BioPhorum’s suggestion is to include NPI processes in the creation of master service and supply agreements for the supply of raw materials, as they help to reach clarity on what a supplier can deliver and what it cannot.

A four steps methodology and roadmap

The document by the BioPhorum describes the results of a project aimed to develop a materialsbased methodology and roadmap to support improved NPI processes, on the basis of a collaborative industry approach to identify and implement best practices.

The result is a four steps process referring to the different activities needed to set up materials introduction and supply. The proposed different steps include the establishment of product lifecycle materials requirements, materials evaluation, supplier selection and qualification, and a manufacture and business review. Each of them should be supported by specific tools and checklists to be developed internally by the company. The governance of the process should involve senior supplier/manufacturer nominees to formally approve the package of deliverables at each stage gate.

Establishing product lifecycle material requirements

For each of the four steps of the NPI process, the BioPhorum document offers detailed lists of information to be collected and of expected outcomes.

Stage gate 1 addresses the establishment of product lifecycle material requirements, usually corresponding to the activation of first time in human studies (FTIH). Data to be collected include specifications of raw materials (e.g. order of magnitude, grade, supply options, environmental-health-safety (EHS) or geographic issues, etc.) as well as master data such as recipe information, plant diagram, list of equipment and process information. At the clinical level, information on the demand sensitivities on indication and clinical milestones and decision points should support the first estimates of the supply and demand plan, to be then expanded to agree on lifecycle forecasts.

The output may take the form of a ‘Product Lifecycle Demand and Supply Strategy’, a document discussing the long-term supply, demand and manufacturing of the product. Starting from the initial planning, the strategy should evolve through the creation of a data store specific for biopharmaceuticals, and the execution of gap analysis for in-licensed products. The strategy should also include a rough capacity modelling and description of ownership and the definition of a RACI matrix (responsible, accountable, consult, inform) to clarify roles and responsibilities with respect to each task, deliverable, or action. Information should be also available on high level technology requirements (both at the internal and external level). Strategic suppliers should be involved in early activities and materials risk analysis should be initiated.

Materials evaluation

Stage gate 2 refers to the information to be gathered from suppliers on the basis of requests for information (RFI) on materials. This should include all the different aspects relevant to the selection of the supplier, including capacity and costs, contacts, technical specifications and audit history, availability of samples, EHS aspects and business systems (e.g. availability of an appropriate ERP system).

This information should facilitate the identification of supplier that might be able to support the predicted or proposed growth of the product over its lifecycle. Stage gate 2 is also part of the risk management process to be run to validate the activation of full production.

Outputs include the sharing of forecasts and sensitivities with suppliers as needed, the establishment of a standard industrial master data set for biopharmaceuticals, as well as of business acceptance criteria.

Supplier selection and qualification

Stage gate 3 addresses the qualification process to finally select the most suitable suppliers and close the corresponding material supply agreements. The RFI and other information gathered in the previous step represent the basis of this exercise, aimed to develop a supply chain resilience strategic approach. The signature of the initial contracts is the final mark of formal selection, and should be supported by an agreement with the supplier on forecast and schedule for the supply, as well as of the business acceptance criteria.

Manufacture and business review

Stage gate 4 refers to the assessment of the operational performance of the supply chain for raw materials, a key activity in order to ensure continuity of supply and to promptly intercept any emerging issue on the basis of trends analysis.

Tools needed to this instance include the definition of appropriate metrics to monitor supplies (e.g. adherence to schedule, “On time in full”-OTIF, “Cost of poor quality”-COPQ). Information on the innovation potential of the supplier and the provision of a feedback on its performance is also deemed important. Any issue should be timely discussed between the supplier and the biopharmaceutical company, and confirmation of the production schedule agreed upon.

ACT EU’s Workplan 2022-2026

September 16, 2022

Accelerating Clinical Trials in the EU, ACT EU, basket trials, change management startegy, clinical research, clinical trial methodology, clinical trial safety monitoring, clinical trials, Clinical Trials Regulation, communication campaigns, communication strategy, complex clinical trials, CTR, data analytics, data sources, deliverables, ema, EMRN, EU clinical trials dashboard, European Commission, European Medicines Regulatory Network, European Pharmaceutical Strategy for Europe, expert groups, flexibility, GCP, Good Clinical Practice, governance, HMA, ICH E6(R2) guideline, innovative clinical trial designs, issues for sponsors, KPIs, large multinational clinical trials, mapping of existing initiatives, master protocols, multi- stakeholders platform, patient recruitment, pilot phases, RACI, regulatory network responsibility assignment matrix, scientific advice, strategy, study design, timeline, training, umbrella trials, Workplan 2022-2026

by Giuliana Miglierini

The implementation phase of the Accelerating Clinical Trials in the EU (ACT EU) initiative, launched in January 2022 by the European Commission, started with the publication of the2022-2026 Workplan jointly drafted by the Commission, the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA).

The final target is to renew how clinical trials are designed and managed, so to improve the attractiveness of Europe for clinical research and the integration of results in the current practice of the European health system.

The 2022-2026 Workplan details the actions and deliverables planned according to the ten priorities identified by ACT EU. The drafting of the document took as primary reference also the recommendations of the European Medicines Regulatory Network (EMRN) strategy to 2025 and the European Commission’s Pharmaceutical Strategy for Europe.

Steps towards the full implementation of the CTR

The first priority of action should see the completion by the end of 2022 of the mapping of already existing initiatives within the EMRN and ethics infrastructure. This exercise represents a fundamental step to achieve a detailed picture of the current clinical trials regulatory landscape, characterised by the presence of various expert groups working in different areas.

The results of the mapping will form the basis to plan and implement a new strategy for the governance of the entire framework governing clinical trials, including the clarification of roles and responsibilities to the Network and its stakeholders. The expected outcome is the rationalisation and better coordination of the work done by different expert groups and working parties, as reflected by a new regulatory network responsibility assignment (RACI) matrix. The analysis and setting up of the new framework should start from the core governance bodies (Clinical Trials Coordination and Advisory Group (CTAG), Clinical Trials Coordination Group (CTCG), Commission Expert Group on Clinical Trials (CTEG) and Good Clinical Practice Inspectors Working Group (GCP IWG)), to then extend to other parts of the Network further.

The full implementation of the Clinical Trials regulation (Reg. (EU) 536/2014) by mean of the launch of monthly KPIs tracking of the planned activities is another key action. A survey to identify issues for sponsors and the consequent implementation of a process to prioritise and solve them are planned for the second half of 2022. The beginning of 2023 should see the launch of a scheme to better support large multinational clinical trials, particularly those run in the academic setting. One year later, at the beginning of 2024, a one-stop shop to support academic sponsors should also be launched.

An important action for the success of ACT EU should see the creation of a multi-stakeholder platform (MSP) to enable the interaction and regular dialogue of the many different stakeholders working in the field of clinical trials under different perspectives, both at the European and member state level. The platform should be launched by Q2 2023, with the first events run under its umbrella planned for Q3 and is expected to help in the identification of key advances in clinical trial methods, technology, and science.

Methodological updates in clinical trials

Another key step in the renewal of the European framework for clinical trials is linked to the updating of the ICH E6(R2) guideline on “Good Clinical Practice” (GCP). A targeted multi-stakeholder workshop on this theme is planned for Q1 2023, while the resulting changes should be implemented in EU guidance documents by Q3 2023. New GCPs should take into better consideration the emerging designs for clinical trials and the availability of new sources for data and are expected to “provide flexibility when appropriate to facilitate the use of technological innovations in clinical trials”. This action also includes the development of a communication and change management strategy to support the transition to the revised GCP guideline, and the updating of other relevant EU guidelines impacted by the change.

The opportunity to introduce innovative clinical trial designs and methodologies shall be addressed starting from decentralised clinical trials (DCT), with the publication of a DCT recommendation paper by the end of 2022. A workshop on complex clinical trials should be also organized to discuss issues linked to study design, such us umbrella trials and basket trials or master protocols. New technologies may support innovative approaches to the recruitment of eligible study participants and new ways to capture data during clinical trials. The publication of key methodologies guidance is an expected deliverable, together with a improved link between innovation and scientific advice.

A new EU clinical trials data analytics strategy is expected to be published by the end of 2022, while the first half of next year should see the development of a publicly accessible EU clinical trials dashboard and a workshop to identify topics of common interest for researchers, policy makers, and funders. These activities are targeted to fully exploit the opportunities offered by data analytics, so to identify complex trends from the large base of data about clinical trials collected by the EMRN. The existence of multiple data sources is a main barrier currently affecting the possibility to access, process and interpret these data.

Another priority is to plan and launch a targeted communication campaign to engage all enablers of clinical trials, including data protection experts, academia, SMEs, funders, Health Technology Assessment (HTA) bodies and healthcare professionals. Up to 2024, this action will also support sponsors in remembering the importance of training linked to the application of the CTR and the mandatory use of the Clinical Trials Information System (CTIS). All other communication needs across all priority actions will also be handled under this action.

Scientific advice, safety monitoring and harmonised training

The current framework sees the involvement of different actors who interact with sponsors at different stages of product development to provide them with scientific advice. A simplification of the overall process should be pursued by grouping of key actors in clinical trials scientific advice in the EU, “with the aim of critically analysing the existing landscape in line with stakeholder needs”. The Workplan indicates several pilot phases should be run to identify the better way to address this topic, which should benefit especially academic or SMEs sponsors that may have less experience of regulatory processes. Planned activities include a enhanced intra-network information exchange, the running of a survey among stakeholders and the operation of a first pilot phase by Q4 2024, to then optimise and expand the advice process upon results.

The establishment of clinical trial safety monitoring is another central theme of action, that should see member states involved in a coordinated work-sharing assessment. Key activities should include the identification of safe CT KPIs by the end of 2022 and a review of IT functionalities for safety, and it will be run in strict connection with the EU4Health Joint Action Safety Assessment Cooperation and Facilitated Conduct of Clinical Trials (SAFE CT). Training of safety assessors and the development of a harmonised curriculum thereof shall be also considered, as well as the alignment of safety procedures for emerging safety issues potentially impacting clinical trials.

The development of a training curriculum informed by regulatory experience should support the creation of a renewed educational ‘ecosystem’ characterised by bidirectional exchanges to enable training on clinical trials. This action is target mainly to better engage universities and SMEs, and it should include also training provided by actors other than the regulatory network.

EMA’s Industry stakeholders group (ISG)

July 15, 2022

Coordination Committee, critical medical devices, ECDC, ema, Emergency Task Force, ESMP, European Commission, European Shortages Monitoring Platform, Executive Steering Group on Shortages of Medical Devices, expert panels on medical devices, extended mandate, HERA, human medicines, i-SPOC, industrial organisations, Industry stakeholders group, investigational products, IRIS platform, ISG, lists of medicines under assessment, manufacturers, MDSSG, Medicines Shortages Steering Group, MSSG, notified bodies, observers, paediatric plans, preparedness, public health emergency, recommendations, rolling review, scientific advice, Scientific Committees, Screening panel, Secretariat, shortages of medical devices, shortages of medicines, sponsors, streamlined procedure, systematic assessment, thematic expert panels, WHO, working parties

by Giuliana Miglierini

The Industrial Stakeholder Group (ISG) is a new initiative recently launched by the European Medicines Agency (EMA) in order to favour the dialogue with the industrial stakeholders. The first meeting of the ISG, the 21 June 2022, focused on the mandate of the Group and on the three priority topics to be addressed during the pilot phase: the Emergency Task Force (ETF), the issue of shortages of medicines and medical devices and the medical device expert panels.

The initiative is part of the activities planned by EMA for the implementation of its extended mandated, as for Regulation (EU) 2022/123.

The mandate of the ISG

The main scope of the ISG is to provide a dedicate forum to capture the industrial point of view and proactively inform on open issues during the implementation of EMA’s extended mandate. The ISG will focus on human medicines and will complement other existing tools, such as industry platform meetings, bilateral meetings, topic or project related meetings. The outcomes obtained from the pilot phase will form the basis of an analysis to evaluate if to extend the scope to other initiatives.

The Chair of the ISG is nominated by the Agency’s Executive Director; the group is composed by one member and one alternate from selected EU industry organisations relevant to the subject of discussion, on the basis of a call for expression of interest. Additional representatives of selected organisations and observers may also participate to specific meetings, according to the topics on the agenda. Observers include the European Commission, EMA’s committees (e.g. CHMP, ETF, CMDh, SPOC WP, SMMG), the EU Network, Notified bodies; ad-hoc observers may be also invited from member states and stakeholder groups.

Appointed members will be responsible to liaise with the respective industrial rganisations, so to contribute the discussion with their point of view and to keep them updated on the outcomes of the ISG meetings. The current schedule includes four quarterly meetings per year; the next two are fixed for the 26 September and 22 November 2022. The summary report of each meeting will be available in EMA’s website.

The Emergency Task Force

The new Emergency Task Force (ETF) builds upon the experience gathered during the pandemic and acts within EMA to advise and support on medicines for public health emergencies and preparedness.

The ETF is in charge of coordinating all efforts following the declaration of a public health emergency by health authorities, in strict coordination with all other relevant bodies including the European Health Emergency preparedness and Response Authority (DG HERA), the European Centre for Disease Prevention and Control (ECDC), the WHO and the European Commission.

The new ETF started operating on the new mandate on 22 April. Its composition is based on expertise, and it includes representatives of EMA’s Scientific Committees and Working Parties as well as selected patients and healthcare professionals and clinical trials experts from various member states.

There are three distinct area of activities for the Task Force. Scientific advice and support to clinical trials for the development of medicines to be used during the emergency will be directly managed and assessed by the ETF, free of charge and flowing a fast-track procedure. The new streamlined procedure should lead to the outcome in 20 days; deceleration criteria are also considered, i.e. premature evidence to address the medical need, high workload or lack of urgency. Expected benefits include the reduction of the use of medicines with insufficient evidence of efficacy and the increase of safe and harmonised use across the EU of new products from the pipelines ahead of authorisation. Activities of the ETF will cover all stages of development, from pre-authorisation (e.g. rolling applications or paediatric plans) to post-authorisation (e.g. major changes), investigational products and compassionate use.

The systematic assessment of the available evidence on medicines will be the focus of the scientific reviews, while recommendations will target medicines not yet authorised or topics of particular scientific or public interest. These may include, for example, the monitoring of new outbreaks and epidemics and the information on potential radiological, chemical or bioterrorism agents.

All lists of medicines under assessment to address a declared emergency will be made public to increase transparency, as well as the CHMP opinions on the use of medicines not yet authorised, Product Information, EPARs end Risk Management Plans.

Two dedicated mailboxes are also available, the first for sponsors of clinical trials to request EMA/ETF support for facilitating CTA and approval and sponsors agreement to conduct larger multinational trials ([email protected]), the second for manufacturers to discuss with EMA/ETF their development programs or plans for scientific advice prior to any kind of formal submission ([email protected]).

Shortages of medicines

EMA’s extended mandate in this area include the monitoring and mitigation of shortages of critical medicines and medical devices, and the setting up, maintenance and management of the European Shortages Monitoring Platform (ESMP). The action also includes the establishment of the Medicines Shortages Steering Group (MSSG), which will be supported by the Working Party of singles points of contacts in the members states (the EU SPOC Network) and a network of contact points from pharmaceutical companies (the i-SPOC system). A corresponding Executive Steering Group on Shortages of Medical Devices (MDSSG), to be created by February 2023, will be in charge of adopting the list of categories of critical medical devices and to monitor their supply and demand.

According to Regulation (EU) 2022/123, pharmaceutical companies are required to identify a i-SPOC to act as the reference contact for EMA should the Marketing Authorisation Holder (MAH) have medicinal products be included in the lists of critical medicines. All information has to be provided through the IRIS platform; the registration process opened on 28 June 2022 and is comprehensive of two steps (the IAM preliminary requirement for the creation of the account and the following IRIS submission).

Scheduled milestones will see the establishment of a list of the main therapeutic groups for hospital care (due by 2 August 2022), the registration of i-SPOCs from MAHs (by 2 September 2022), and the definition of shortages of medical devices and in vitro diagnostics (by 2 February 2023). The ESMP platform is expected to go live by 2 February 2025, and will represent a single reference point to make information available on shortages, supply and demand of medical products, including the marketing status and cessation.

Expert panels on medical devices

Regulation (EU) 2022/123 establishes the hangover of expert panels on medical devices from the Joint Research Centre (JRC) to EMA, thus adding a completing new type of activity for the Agency.

The new Secretariat is coordinating the activities of the Screening panel composed by 70 experts in charge of the decision whether to provide a scientific opinion, eleven thematic expert panels and expert panels sub-groups (for a total of approx. 130 experts), and a Coordination Committee inclusive of the Chair and vice-Chair of all the expert panels.

The main task of the expert panels is to provide opinion to the notified bodies for certain high-risk medical devices and in-vitro diagnostic, for the assessment of their clinical and/or performance evaluation. EMA is specifically involved in the coordination of the Clinical Evaluation Consultation Procedure (CECP) for medical devices and Performance Evaluation Consultation Procedure (PECP) for in-vitro diagnostics. Further details on the procedures and their interfaces with the ETF is available here.

IVD regulation in force: new MDCG guidelines and criticalities for innovation in diagnostics

June 10, 2022

(EU) 2017/746, assessment, classification, clinical evidence, development, EU reference laboratories, Eudamed, European Commission, European database of medical devices, expert panels, in vitro diagnostic medical devices, in-house devices, IVD regulation, IVDR, MDCG, Medical Devices Coordination Group, multi-centre performance studies, notified bodies, performance evaluation, post-marketing surveillance, Q&A document, Regulation (EU) 2022/112, risk-based approach, safety, Stella Kyriakides, transition period, UDI, Unique Device Identifier

by Giuliana Miglierini

The new regulation on in vitro diagnostic medical devices (IVDR, Regulation (EU) 2017/746) entered into force on 26 May 2022. The new rules define a completely renewed framework for the development, validation and use of these important tools supporting the diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of a disease, in line with technological advances and progress in medical science. “Diagnostic medical devices are key for lifesaving and innovative healthcare solutions. Today we are marking a big step forward for the patients and the diagnostics industry in the EU. The COVID-19 pandemic has underlined the importance of accurate and safe diagnostics, and having stronger rules in place is a key element in ensuring this is the case for EU patients.”, said Stella Kyriakides, Commissioner for Health and Food Safety

The European Commission also published a Q&A document to facilitate the comprehension of the new framework.

The main contents of the IVDR

The risk-based approach for the classification and development of in vitro diagnostics is at the core of the IVDR. There are four different classes of IVDs: class A (low individual risk and low public health risk), class B (moderate individual risk and/or low public health risk), class C (high individual risk and/or moderate public health risk) and class D (high individual risk and high public health risk). The assessment of the quality, safety and performance of IVDs by independent notified bodies shall be based on more detailed and stringent rules. Higher-risk categories will also be subject to further assessment by newly created scientific bodies acting under the auspices of the European Commission, such as the expert panels and the network of EU reference laboratories. Twelve expert panels have been established up to now.

Each single IVD will be associated to a Unique Device Identifier (UDI), so to facilitate its traceability along the entire life cycle. The identifier will also serve to locate the relevant information about a diagnostic marketed in the EU within the European database of medical devices (EUDAMED), where also a summary of safety and performance will be publicly available for medium- and high-risk devices. The database will also contain information about all economic operators and provide a repository for the certificates issued by notified bodies.

The new regulation strengthened the framework for post-marketing surveillance of IVDs, asking for a closer coordination of the vigilance activities by all member countries. The IVDR also introduced reinforced rules on clinical evidence and performance evaluation, including an EU-wide coordinated procedure for authorising multi-centre performance studies, and a specific regime for devices manufactured and used in the same health institution (in-house devices).

Difficulties in the timely implementation of the (EU) 2017/746 regulation may still be possible due to the lack of a sufficient number of notified bodies, as only seven have been designated up to now, established in only four countries (Germany, France, the Netherlands and Slovakia), while eleven other applications were pending in May 2022. To solve this issue, Regulation (EU) 2022/112 was adopted. A transition period up to May 2025 applies to devices that require a notified body certificate already under the previous Directive (around 8%, vs about 80% according to the IVDR); other classes of IVDs benefit of different transition periods (May 2025 for class D, May 2026 for class C and May 2027 for class B and A sterile).

Q&As on the interface with the Clinical Trial regulation and UDI

The Medical Devices Coordination Group (MDCG) published a Q&A document (MDCG 2022-10) to provide guidance on the interface between Regulation (EU) 536/2014 on clinical trials for medicinal products for human use (CTR) and the IVDR.

The guideline addresses the requirements for assays used in clinical trials, that may include IVDs carrying a CE mark for the intended purpose, IVDs developed in-house and devices for performance studies. Only the devices falling on the definition of an IVD with regards to their intended purpose are subject to the IVD legislation. The guideline also provides suggestions on assays likely to be considered IVDs, as they are used for medical management decisions of trial subjects within the trial.

Another Q&A guideline (MDCG 2022-7) provides clarifications on how to apply the Unique Device Identification system to both medical devices and in vitro diagnostics.

Topics covered by the document include the need for a new UDI-DI assignment in case the number of items in a device package changes or for single-use reprocessed devices, the requirement for economic operators to maintain a registry of all UDIs of the devices which they have supplied or with which they have been supplied, or the requirement of a new UDI-DI for substance-based medical devices, in case of formula quantity changes or additional claims.

The MDCG also addressed the assignment and use of the Basic UDI-DI and the determination of the ‘grouping’ for design or manufacturing characteristics, including the case of devices comprising a patient and a physician facing module, and the contents of the Declaration of Conformity (DoC). Labelling is also addressed, as well as rules for systems and procedure packs (SPPs) and configurable devices, as well as those applying to retail point of sale, promotional packs and marketing related samples.

The impact of the IVDR on innovation

The issues linked to the IVDR implementation and their impact on innovation and diagnostic laboratories, including the development and use of in-house devices, have been analysed by the BioMed Alliance In Vitro Diagnostics Task Force, and published in HemaSphere.

The Task Force identified two main challenges to be faced by the academic diagnostic sector. The first one impacts on the possibility to use in-house IVDs, based on the demonstration that no equivalent CE-IVD kit is present on the market or when the specific needs cannot be met at the appropriate level of performance by an equivalent CE-IVD. The strict exemptions applying to in-house IVDs (e.g. prohibition of transferring to other legal entities, compliance with EN ISO 15189 and justification of use, etc.) may impact also on the potential for innovation in the diagnostic sector.

The second challenge refers to the not so clearly defined boundaries between CE marked-IVDs, modified CE-IVDs, Research Use Only (RUO) tests, and in-house IVDs. The Task Force recalls the immediate applicability of the General Safety and Performance Requirements specified in Annex I of the IVDR, as they have not been included in the approved amendment of the implementation timeline.

Furthermore, only tests meeting economic viability may in the future be transferred from the academia to the industry, while rare or complex tests would probably remain excluded. According to the paper, the cost of diagnostics shall likely increase, and the academa should carefully consider how to support further research into rare or complex diagnostics in order to ensure their availability to patients.

Following the results of a survey among medical societies on current diagnostic practices, several suggestions are made to better support the implementation of the IVDR, namely by mean of the availability of diagnostic equivalents of the European Reference Networks for rare diseases and a concerted action involving all stakeholders. A joint biomarker-to-test pipeline between the IVD industry and research/academic labs would also be useful to facilitate the initial development and local application of innovative diagnostics within healthcare institutions or diagnostic reference networks with specific expertise, to then transfer them to manufacturers above a certain production volume.

Key issues in technical due diligences

May 6, 2022

active ingredients, Anne Ettner, Anthony Grenier, batch records, change control, CMC dossier, CMO, Common Technical Document, compliance, containment capability, Contract Manufacturing Organisation, cross-contamination, CTD, executed batch records, inspection reports, integration, manufacturing facility, manufacturing process, medicinal finished products, multi-site acquisitions, Norbert Pöllinger, Outsourced Pharma, printed components, process validation reports, quality agreements, raw materials, reformulation, regulatory due diligence, specifications, stability studies, supply agreements, technical due diligence, technical fit, technology transfer

by Giuliana Miglierini

Financial due diligence is a central theme when discussing mergers and acquisitions (M&A). Not less important for the determination of the fair value of the deal and the actual possibility to integrate the businesses are technical due diligences, assessing the technological platforms and product portfolios to be acquired. A series of articles published in Outsourced Pharma discussed, under different perspectives, the main issues encountered in technical due diligences. We provide a summary of main messages to be kept in mind while facing this type of activity.

Technical due diligence of pharmaceutical products

The third millennium is being highly characterised by the closure of many M&A operations in the biopharma sector as a way to support the transfer of new technological platforms from their originators – usually an innovative start-up or spin-off company – to larger multinational companies. The latter are usually managing advanced clinical phases of development and regulatory procedures needed to achieve market authorisation in the territories of interest.

Furthermore, the acquisition of already marketed products often represents a way to renew the product portfolio or to enter new markets. Should this be the case, an article by Anthony Grenier suggests that a main target is represented by the understanding of how the products were maintained on the market by the seller company.

The restructuring of assets following acquisition may require the transfer of products manufacturing to sites of the acquiring company, or the possibility to use the services of a Contract Manufacturing Organisation (CMO). These are all issues that should enter the technical due diligence, that usually includes the exchange of information about the product, equipment, manufacturing, quality, and regulatory aspects of the deal.

The regulatory and quality perspectives

Regulatory due diligence takes into consideration the approval status of the interested products in target markets. Relevant documentation to be examined include the CMC dossier (Chemistry, Manufacturing, and Controls) and/or the Common Technical Document (CTD), and the current status of approval procedures undergoing, for example, at the FDA in the US or the European Medicines Agency in the EU. A possible issue mentioned by Anthony Grenier refers to the assessment and management of dossiers relative to unfamiliar markets, that may differ as for regulatory requirements and thus need the availability of dedicated internal resources or consultants. This type of considerations may impact also on the selection of CMOs; the transfer of older dossiers is also challenging, as they often do not reflect current requirements and standards and may require significant investments (including the request of additional studies) to support the submission of variations.

A visit to the facility manufacturing the product during the second round of bidding, in order to better understand issues related to the technology transfer, is also suggested. Technical documentation available to assessors should include copies of batch records and specifications for raw materials, active ingredients, and drug products. Analysis of the annual trends in manufacturing may be also useful, as for example a high number of rejected batches may indicate the need for a reformulation of the product.

From the quality perspective, the due diligence should also examine issues with supply or quality agreements, and the date of the last revision of documents. Examples of relevant documentation to be examined include process validation reports, change control lists, stability studies, inspection reports, etc.

The manufacturing perspective

In a second article, A. Grenier examined technical due diligence from the perspective of manufacturing, equipment and logistics.

The manufacturing process is key to ensure the proper availability of the product in the target markets, and it should be correctly transferred to the acquiring company or the CMO. To this instance, executed batch records are important to provide information on actual process parameters, processing times, and yields. Here again, process validation reports and master supply agreements provide information on the robustness of the processes and the steady supply of raw materials.

Consideration should also be paid to the transfer of any product-dedicated equipment involved in the manufacturing or packaging process, including its actual ownership. The time period for technology transfer should be long enough (at least 12 months) to ensure for the proper execution of all operations.

From the logistics point of view, it is important to understand the need to update printed components to reflect the new ownership of the product, a task that may result complex should it be marketed in many different countries and/or in many different dosage forms. Inventories of all raw materials, APIs, and packaging components should be also assessed, paying a particular attention to narcotic products for which specific production quotas may be present in some countries (e.g. the US).

Technical due diligence of entire facilities

M&A deals often involve the acquisition of one or more manufacturing facilities and other complex industrial assets. Anthony Grenier also examined the key factors impacting on this type of technical due diligence.

The “technical fit” between the two companies involved in the deal is a primary target for assessment, in order to evaluate the achievable level of integration and the existing gaps in experience to be filled. This may refer, for example, to the acquisition of a manufacturing plant for non-sterile products that would need to be converted for aseptic manufacturing: a goal that may require the building of new areas, thus the availability of enough space to host them. Experience of the staff is also highly valuable, as well as the successful introduction of new equipment.

Capacity of the plant should also be considered, neither in excess or defect with respect to the effective needs in order to avoid waste of resources or need of new investments. Experience of the seller company in CMO may be also relevant, as it may be used to fill some of the excess capacity. To this instance, the fields of specialisation and the availability of containment capability to avoid cross contamination are important parameters to be considered.

Compliance of the facility to regulatory requirements arising from the different target markets should also be assessed, as it impacts on the positive outcomes of inspections.

Highly complex technical due diligences

Technical due diligence becomes even more complex in the case of multi-site acquisitions. In this case, visits to assess specificities of the single facilities involved in the operation may be needed. The above mentioned parameters of technical fit, capacity and compliance should be always considered, and the take-at-home message from the A. Grenier is for the acquiring companies to “look for the weakest links that would prohibit them from bringing their product or technology to the sites to be acquired”. Capacity optimisation may be needed, for example.

The different steps of technical due diligence have been also examined in another article by Anne Ettner and Norbert Pöllinger published in Pharm. Ind.. They presented a mind map that clarifies the complexity of the items that should enter the due diligence process, and lists typical documents and questions that should be taken into consideration. Examples and case studies are also provided relative to the assessment of starting materials, the evaluation of the pharmaceutical formulations and that of the production process.

Trends in the development of new dosage forms

April 16, 2022

3D printing, advanced therapies, APIs, Artificial Intelligence, auto-injectors, bioavailability, biological macromolecules, biological medicines, capsules, chewable gels, compliance, confectionery-derived dosage forms, continuous manufacturing, controlled-release, cross-contamination, digital pills, dosage forms, effervescent tablets, excipients, extendedrelease formulations, extrusion, Felicity Thomas, fictional coating, fixed-dose combinations, formulation, geriatric patients, high potency APIs, i.v. administration, infusions, injectable medicines, intranasal dosage forms, isolators, lipid nanoparticles, lyophilisation, micronisation, mini-tablets, multi-particulates, nanomilling, nanotechnology, oral solid dosage forms, orally disintegrating tablets, OTC, over-the-counter medicines, paediatric patients, parenteral administration, PAT, personalised dosage forms, Pharmaceutical Technology, process analytical technologies, RABS, self-administration, small molecules, soft gel, spray drying, stability, tablets

by Giuliana Miglierini

Oral solid dosage (OSD) forms (i.e. capsules and tablets) historically represent the most easy and convenient way for the administration of medicines. Recent years saw an increasing role of new approaches to treatment based on the extensive use of biotechnology to prepare advanced therapies (i.e. cellular, gene and tissue-based medicinal products). These are usually administered by i.v. injections or infusions, and may pose many challenges to develop a suitable dosage form, as acknowledged for example by the use of new lipid nanoparticles for the formulation of the mRNA Covid-19 vaccines.

The most recent trends in the development of new dosage forms have been addressed by Felicity Thomas from the column of Pharmaceutical Technology.

The increasing complexity of formulations is due to the need to accommodate the peculiar characteristics of biological macro-molecules and cellular therapies, which are very different from traditional small-molecules. Bioavailability and solubility issues are very typical, for example, and ask for the identification of new strategies for the setting up of a suitable formulation. The sensitivity of many new generation active pharmaceutical ingredients (APIs) to environmental conditions (i.e. temperature, oxygen concentration, humidity, etc.) also poses many challenges. Another important target is represented by the need to improve the compliance to treatment, to be pursued through the ability of patients to self-administer also injectable medicines using, for example, specifically designed devices. The parenteral administration of medicines has become more acceptable to many patients, especially in the case of serious indications and when auto-injectors are available, indicates another PharmTech’s article.

According to the experts interviewed by Felicity Thomas, there is also room for the development of new oral solid dosage forms for the delivery of biological medicines, as well as for OSD forms specifically designed to address the needs of paediatric and geriatric patients.

Some examples of technological advancements

Productive plants based on the implementation of high containment measures (i.e. isolators and RABS) are widely available to enable the entire manufacturing process to occur under “sea led” conditions, thus allowing for the safer manipulation of high potency APIs and the prevention of cross-contamination. Process analytical technologies (PAT), digital systems and artificial intelligence (AI) can be used to improve the overall efficiency of the formulation process. This may also prove true for previously “undruggable” proteins, that thanks to the AI can now become “druggable” targets denoted by a very high potency (and a low stability, thus asking for specific formulation strategies).

Advances in material sciences and the availability of new nanotechnology can support the development of oral formulations characterised by improved efficacy and bioavailability. To this instance, the article mentions the example of new softgel capsules able to provide inherent enteric protection and extended-release formulation. Functional coating, non-glass alternatives for injectables, and new excipients may also play an important role in the development of new formulations, such as controlled-release products, multi-particulates, orally disintegrating tablets, intranasal dosage forms, fixed-dose combinations.

The ability to establish a robust interaction with the suppliers enables the development of “tailor-made” specifications for excipients, aimed to better reflect the critical material attributes of the drug substance. The ability to formulate personalised dosage forms may prove relevant from the perspective of the increasingly important paradigm of personalised medicine, as they may better respond to the genetic and/or epigenetic profile of each patient, especially in therapeutic areas such as oncology.

Not less important, advancements of processing techniques used to prepare the biological APIs (for example, the type of adeno-viral vectors used in gene therapy) are also critical; to this regard, current trends indicate the increasing relevance of continuous manufacturing processes for both the API and the dosage form.

Injectable medicines may benefit from advancements in the understanding of the role played by some excipients, such as polysorbates, and of the interactions between the process, the formulation and the packaging components. Traditional techniques such as spray drying and lyophilisation are also experiencing some advancements, leading to the formulation of a wider range of biomolecules at the solid or liquid states into capsules or tablets.

New models for manufacturing

API solubility often represents a main challenge for formulators, that can be faced using micronization or nano-milling techniques, or by playing with the differential solubility profile of the amorphous vs crystalline forms of the active ingredient (that often also impact on its efficacy and stability profile).

As for the manufacturing of OSD forms, 3D printing allows the development of new products comprehensive of several active ingredients characterised by different release/dissolution profiles. This technology is currently represented, mostly in the nutraceutical field, and may prove important to develop personalised dosage forms to be rapidly delivered to single patients. 3D printing also benefits from advancements in the field of extrusion technologies, directly impacting on the properties of the materials used to print the capsules and tablets.

Artificial intelligence is today of paramount importance in drug discovery, as it allows the rapid identification of the more promising candidate molecules. Smart medical products, such as digital pills embedding an ingestible sensor or printed with special coating inks, enable the real-time tracking of the patient’s compliance as well as the monitoring “from the inside” of many physiological parameters. This sort of technology may also be used to authenticate the medicinal product with high precision, as it may incorporate a bar code or a spectral image directly on the dosage form. Dosage flexibility may benefit from the use of mini-tablets, that can be used by children as well as by aged patients experiencing swallowing issues.

The peculiarities of the OTC sector

Over-the-counter (OTC) medicines present some distinctive peculiarities compared to prescription drugs. According to an article on PharmTech, since the mid-‘80s the OTC segment followed the dynamics characteristic of other fast-moving consumer packaged goods (FMCG) industries (e.g., foods, beverages, and personal care products), thus leading to a greater attention towards the form and sensory attributes of the dosage form.

The following switch of many prescription medicines to OTC, in the ‘90s, reduced the difference in dosage forms between the two categories of medicinal products. Today, the competition is often played on the ability to provide patients with enhanced delivery characteristics, for example in the form of chewable gels, effervescent tablets for hot and cold drinks, orally disintegrating tablets and confectionery-derived forms. The availability of rapid or sustained-released dosage forms and long-acting formulations, enabling the quick action or the daily uptake of the medicine, is another important element of choice. Taste-masking of API’s particles is a relevant characteristic, for example, to make more acceptable an OSD form to children; this is also true for chewable tablets and gels, a “confectionery pharmaceutical form” often used to formulate vitamins and supplements.

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

March 25, 2022

certificate of acceptance, commissioning, Commissioning and Qualification Plan, CQV plan, customer representative, data integrity, equipment, Factory acceptance testing, failure modes, FAT, GMP, installation qualification, manufacturer representative, operational qualification, Outsourced Pharma, performance qualification, qualification, quality, raw data, real operating conditions, regulatory compliance, responsibility matrix, safety, SAT, Simulation, Site acceptance testing, statistical approach, third party inspector, transparency, URS, user requirement specifications, visual inspection

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.

Investing in formulation as success’ factor

February 11, 2022

active pharmaceutical ingredient, animal pharmacokinetic, API, bioavailability, chylomicrons, complex biopharmaceuticals, Developability Classification System, drug delivery systems, drug development, Drug Development and Delivery, early formulation, enabling technology, Felicity Thomas, first-in-human assessment, GLP toxicity, Jessica Mueller-Albers, lipid nanoparticles, manufacturability, micronisation, nanomilling, Pharmaceutical Technology, pre-formulation studies, predictive models, proof-of-concept studies, PROTACS, proteolysis-targeting chimeras, small therapeutic areas, solubility, stability, systemic oral small-molecule drugs

by Giuliana Miglierini

Formulation is a critical step in the development of new medicinal products, as it directly influences the bioavailability, release profile and stability of the active ingredient, overall impacting on both the efficacy and safety of the medicine.

While in the traditional approach the definition of the final formulation was a quite late step along the development process, new models of R&D greatly focus on early formulation as a way to optimise both time and costs of drug development. It is thus important to identify the optimal formulation strategy as early as possible: a quite challenging goal in many instances, especially in the case of last generation complex biopharmaceuticals which may prove difficult to formulate. An article by Felicity Thomas, published in Pharmaceutical Technology discusses how to address early formulation strategies to maximise the chance of success.

Limits and challenges of formulation

The main objective of the drug development process remains the same, reducing as much as possible the time-to-market so to fully exploit the marketing exclusivity period granted by the patents protecting an innovative medicine.

To this instance, some key aspects should be considered in order to rapidly establish the most appropriate formulation, with a special attention to achieving an early access to first-in-human assessment and proof-of-concept studies.

Scaling-up of the formulation process is another critical issue, as it requires a careful consideration of all the steps needed to establish the final manufacturing process at the commercial scale. This exercise is fundamental in order establish the critical quality attributes and process parameters, thus reducing the risk of a change of the initial formulation to make it suitable to the final manufacturing process.

As explained by Jessica Mueller-Albers, strategic marketing director Oral Drug Delivery Solutions, Evonik, the increased pressure to speed up formulation is also connected to the fact “many new drugs target small therapeutic areas, where it is essential for pharma companies to be first in the market from an economic perspective.”

The availability of enabling technologies is fundamental to early formulate niche medicinal products, moving away from the classical mass production. The trend initiated with the development of mRNA Covid-19 vaccines may represent a change of paradigm in drug development, suggests Jessica Mueller-Albers. Lipid nanoparticles (LNPs) are an example of enabling technology that has been widely employed to formulate the mRNAs used in Covid-19 vaccines. LNPs may take many different forms, i.e. liposomes, lipoplexes, solid lipid nanoparticles, nanostructured lipid nanoparticles, microemulsions, and nanoemulsions (see more in Drug Development and Delivery).

Other types of emerging technologies are also widely investigated, such as proteolysis-targeting chimeras (PROTACS). These are heterobifunctional nanomolecules, containing one moiety recognised by the E3 ligase and chemically linked to a ligand (small molecule or protein) able to bond to the target protein. The final outcome is the formation of a trimeric complex, through which it becomes possible to transfer ubiquitin molecules to the target protein. The mechanism represents an alternative approach to “knock down”, as it enables the degradation of the target protein, offering many advantages compared to the use of classical inhibitors.

Another challenge to be faced during formulation development is the need of a broad and specialised expertise in the different domain of drug development, including also material characterisation, drug metabolism and pharmacokinetics. According to Stephen Tindal, director, Science & Technology, Europe, Catalent, this is particularly true for small companies, which are often the focus of early development activities before acquisition of the projects by larger multinationals. As explained in the Pharmaceutical Technology’s article, a possible approach is to use small teams of experts to manage the preclinical phases of development.

The many challenges of early formulation

The solubility of the active pharmaceutical ingredient (API) in aqueous media is often one of the main challenges to be faced in formulation studies, impacting also on the final bioavailability of the drug in the target body compartments and/or fluids. Estimates indicates that at least 70% of new APIs are poorly soluble.

Other challenging points to be taken into consideration include the possible presence of different polymorphic forms, each characterised by its own stability and properties, and potentially giving rise to conversion from one another during the formulation and/or manufacturing process (see more in the article by A. Siew, Pharmaceutical Technology). The often limited amount of API in the early phases of development and the difficulty to evaluate the dose range on the basis of the available data are other critical point to be considered.

The development of an appropriate bioavailable formulation is often based on preclinical data obtained from animal pharmacokinetic and GLP toxicity studies, followed by pre-formulation studies to assess API’s properties (e.g. solubility, stability, permeability, etc.) in commonly used solvents and bio-relevant media. Drug delivery systems might be used to solve solubility issues, to then scale the identified formulation on the selected technology platform to be used for manufacturing (see more in Drug Development and Delivery).

The principles of the Developability Classification System (DCS) may be also considered to better assess the physicochemical and biopharmaceutical characteristics of a new API that may impact of the formulation process.

Some possible approaches to early formulation

The experts interviewed by Felicity Thomas have indicated some possible approaches useful to addresses formulation issues. For systemic oral small-molecule drugs, for example, the use of a solution as the delivery vehicle may allow to reduce the needed amount of API, thus supporting lower costs to reach Phase I proof of concept in healthy volunteers. Various techniques are also available to favour solubilisation and bioavailability of the active ingredient, i.e. hot-melt extrusion, spray drying, coated beads, size reduction, lipid-based approaches, etc. The optimisation of particle size by mean, for example, of micronisation and nanomilling techniques is another option. Co-administration with lipids can enhance the lymphatic transport of lipophilic drugs, as it favours its incorporation into chylomicrons at the intestinal level, and the subsequent delivery to the lymphatic system in the form of chylomicron–drug complexes.

Many algorithm-based platforms and predictive models are also available to support formulators in the selection of excipients and solubilisation methods, avoiding the need of extensive testing. The implementation of real-time adaptive manufacturing is another possible tool, useful to optimise the formulation on the basis of emerging clinical data.

The European Medicines Regulatory Network Data Standardisation Strategy

January 28, 2022

ADaM, CDISC SDTM, CDISC SDTM8, CDM, CeSHarP, common data model, data ethics, data governance, data protection, eAF, eCTD, eCTD v4.0, ema, EMRN, EMRN Strategy 2025, eRMP, EU Data Governance Act, EU Data Strategy, European Health Data Space, European Medicines Regulatory Network, GVP, HL7 FHIR, HMA, ICH E2C (R2), ICH E2E, ICH M11, ICSR, individual patient data, inspections, internal consultation, interventional studies, ISO IDMP, metadata, mHealth, observational studies, product information, PSUR, public survey, raw data, real-world data, regulatory documents, regulatory procedures, risk management, risk-based tracking procedures, RMP, RWD, safety, SDO, Standards Development Organisations, traceability

by Giuliana Miglierini

The availability of interoperable data is a “must” to ensure the smooth sharing, use and re-use of data along the entire regulatory process. A new document – the European Medicines Regulatory Network Data Standardisation Strategy – has been issued by the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) to provide guidance to all authorities members of the European Medicines Regulatory Network (EMRN) on how to approach issues related to the definition, adoption and implementation of international data standards.

As data contains the higher informative value, regulatory procedures are undergoing a phase of deep rethinking in order to pay greater attention to the underlying data, leaving behind the traditional assessment of regulatory documents prepared using those data. Furthermore, the secondary use of data may support optimised regulatory decision-making processes.

The EMRN Data Standardisation Strategy – one of the main deliverables of the HMA-EMA Joint Big Data Steering Group (BDSG) workplan – builds upon the EU Data Strategy and the goals of the EMRN Strategy 2025. The FAIR principles (Findable, Accessible, Interoperable and Reusable) have been identified to govern the acquisition, conservation and use of data.

A more standardised approach to be adopted by the EMRN shall make possible to reduce the current manual and technical workload needed to manage regulatory documents and data, which are often submitted using a variety of different formats. According to the Strategy, a review of the mechanisms of data governance is also needed to include the responsibilities for oversight of data standardisation work and for the periodic updating of the EMRN data strategy. Further assessment of the expected costs and benefits is needed to make available the final roadmap for the implementation and prioritisation of measures suggested by the Data Standardisation Strategy.

Adopt, adapt, develop

The document was drafted on the basis of initial internal consultations on current practices for the management of scientific data; the inventory of the current IT systems in use by members of the EMRN was also created. In a second phase, a public survey was conducted among all stakeholders; current and new standards under development were identified by analysis of a selection of Standards Development Organisations (SDOs) active in the healthcare sector.

The exercise led to the identification of three different categories of actions, respectively referred to the adoption by the EMRN of currently available standards, the adaptation of available standards to include additional requirements, and the development of entirely new standards.

A total of eight principles have been identified to guide the standardisation of data to be used for regulatory purposes. First of all, high-quality data standards developed by accredited SDOs should always be adopted, on the basis of voluntary and consensus-based processes. EMA-HMA’s suggestion is to use such standards in place of (unique) local or proprietary standards, unless not compatible with the EU legislation or otherwise impractical. This would also support the creation of the European Health Data Space (part of the EU digital strategy) and facilitate the sharing and re-use of data and the governance of data privacy according to the draft EU Data Governance Act. The principles of data protection and data ethics by design are another fundamental requirement, as well as the collaboration with stakeholders in order to be informed about their needs. An alignment and consolidation of requirements from other regulations and guidelines is also envisaged; assessment of requirements for both human and veterinary regulatory practices should be run in order to avoid duplication of efforts or creation of competing standards.

Four domains for the management of data

The EMRN Data Standardisation Strategy identifies four different domains for the adoption of common standards: Medicinal Product, Healthcare & study data, Safety & risk management and Submissions. Recommendations for each of the four domains are discussed in the document.

The Medicinal Product domain includes product information, substance information, manufacturing and quality information.

Standards such as the ISO IDMP (IDentification of Medicinal Products) – based on the HL7 FHIR (Fast Healthcare Interoperability Resources) standard – are already in place, for example, to feed EMA’s SPOR system, but additional FHIR resources would be needed to structure key product information in already existing projects. To this regard, the Strategy suggests to implement and adapt ISO IDMP specified substance group levels 2 and 4 by the associated HL7 FHIR message exchange format, so to capture active substances and excipients in a structured format. This approach would also better support inspections (together with the availability of a standardised template for all inspections data), traceability of the origin of all substances used to manufacture a certain medicinal product, and the adoption of risk-based tracking procedures to assess the interactions between product quality and inspections of manufacturing sites.

The Healthcare and study data domain refers to data acquired during clinical development (i.e. data from interventional and/or observational studies) and the development of a common data model (CDM) for individual patient data and mobile health (mHealth) devices.

Many projects are already active, e.g. the ICH M11: Clinical electronic Structured Harmonised Protocol (CeSHarP), an initiative that would need further tuning to include some additional requirements. The possible use of raw data from interventional studies is also under assessment (e.g. CDISC SDTM – Study Data Tabulation Model, and ADaM-Analysis Data Model).

A new CDM standard would also be needed to exploit the full and harmonised potential of real-world data (RWD) and metadata obtained from healthcare records and disease registries. To this instance, a particular attention should be paid to mHealth applications installed on personal smart-devices, a fast-growing segment giving rise to the availability to big quantities of data.

The Safety and risk management domain refers to pharmacovigilance activities and includes Individual case safety reports (ICSR), Product safety update reports (PSUR), and environmental risk assessment (ERA) and risk management plans (RMP).

ICSR might be optimised by adoption of the HL7 FHIR based messaging standard and the inclusion of -omics data (genomics, proteomics and metabolomics) of patients. According to the Strategy, a new structured, electronic format for PSURs built upon the ICH E2C (R2) periodic benefit- risk evaluation report guidelines would be also beneficial for the work of regulatory authorities. The CDISC SDTM8 standard for data collection of risk assessment data represents a possible option to better handle data referred to environmental risk assessments. A structured, electronic risk management plan (eRMP) format should be also created to overcome the current paper template format; the new standard may find inspiration in the ICH E2E Pharmacovigilance Planning guideline and the EU Guideline on good pharmacovigilance practices (GVP) Module V – Risk management systems.

The Submissions domain includes the dossier management and the structured application form. Version 4.0 of the electronic Common Technical Document (eCTD v4.0) is more flexible compared to the previous one; for example, it supports the re-use of Pdf documents across sequences and eCTD dossiers and the submission of other data formats within the dossiers. The wider use of structured data will make the use of Pdf files less common, in favour of electronic Application Forms (eAF) based on data exchange standards such as HL7 FHIR to manage regulatory application along the entire life cycle of a medicine.

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Technology & Research Archives - Page 2 of 3 - European Industrial Pharmacists Group (EIPG)

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