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UK will participate to European research programmes


by Giuliana Miglierini The divergent road opened as a consequence of the Brexit, in January 2021, between the European Union (EU) and the United Kingdom (UK) is now converging again as for the possibility for UK researchers to participate to Read more

Insights to the Industrial Pharmacist role for the future


A concept paper from EIPG Advisory Group on Competencies vol.2, 2023 This paper is an update of the previous EIPG paper and intends to raise awareness of the changing requirements of the professional profile of Industrial Pharmacists for Pharmacists at Read more

EMA’s reflection paper on AI in the pharmaceutical lifecycle


by Giuliana Miglierini The rapidly evolving role of artificial intelligence (AI) and its possible application in the pharmaceutical field led the European Medicines Agency (EMA) to publish a draft Reflection paper on the use of AI along the entire lifecycle Read more

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The New Pharmaceutical Legislation

September 15, 2023 , , , , , , , , , , , , , , , , , , , ,

by Jane Nicholson

To celebrate the 70th Anniversary of the foundation of the Belgian Association of Industrial Pharmacists (UPIP-VAPI) a Seminar on “The New Pharmaceutical Legislation” was held on 8th September in the European Parliament. The meeting was arranged in conjunction with the General Assembly of the European Industrial Pharmacists Group (EIPG) with attendance from participants of at least 15 European countries.

Frank Peeters, President of UPIP-VAPI opened the meeting and Alexia Rensonnet, a Board Member, described the new legislation as the largest reform in the past 20 years. The existing directive and regulations are to be replaced by new legislation with the objective of creating a single market to ensure all patients have timely and equitable access to safe, effective and affordable medicines whilst continuing to offer an attractive and innovation friendly market for suppliers.

Lilia Luchianov, Policy Officer at DG Sante – European Commission, said that the new legislation envisaged a leaner regulatory environment through simplification, regulatory modernisation and digitalisation. There will be access to both innovative and established medicines and incentives for innovation so that European companies remain globally competitive. Regulatory responsibilities will be shared between the EU and Member States. As well as changes to the General Pharmaceutical Legislation there will be changes to the Orphan and Paediatric legislation. Pre-authorisation support and a faster approval process including “targeted approach” rather than the current “one size fits all” are proposed.

The proposed reduction of protection for innovative products and the market launch conditions were questioned by several participants. Some of the current challenges for the Commission were said to be that pricing, reimbursement and procurement are a national competence.

In response to the current growing concerns on shortages, the Commission’s suggestions include the publication of an EU list of critical medicines, improved coordination of monitoring, earlier industry notification of shortages and withdrawals, improved industry shortage prevention plans, stronger coordination by the EMA and more legislative powers for the Member States and the Commission. During the discussion period Maggie Saykali, Director of the European Fine Chemical Group challenged the Commission to provide economic conditions for the manufacture in Europe of raw materials used by the pharmaceutical industry. Rather than dependence on China or India, European supply of raw materials would enormously improve security of supply of pharmaceuticals as well as improve worldwide environmental sustainability.

Par Tellner, Director of Regulatory, Drug Development and Manufacturing for the European Federation of Pharmaceutical Industries and Associations presented EFPIA’s views on the proposed revision to the pharmaceutical legislation. Whilst he welcomed the opportunities for regulatory modernisation such as simplification of the EMA structure by reducing the Scientific Committees from 5 to 2 and abolishing product licence renewals there are a number of challenges ahead. These include the notable reduction of research and development incentives, the added burden for industry to implement environmental risk assessments and the actual root causes of non-availability of medicinal products in the markets of Europe.

Jean-Paul Pirnay, head of LabMCT, Queen Astrid Military Hospital presented the past present and future of bacteriophage therapy. Wherever you find bacteria, you find phages which have been used since 1923 with the establishment of the Phage Institute in Tblisi (GEO). Although abandoned in the West many years ago, the Russian USSR has kept using phage therapy. Some isolated laboratories have been further developing and using phages and it has been shown that you need a handful of phages to target one bacterial spp.

Jean-Paul’s laboratory has helped establish a phage bank in a controlled environment. A single phage API can be produced according to a monograph. Individual phages can then be mixed together to target a particular bacterium. 100 seriously ill patients with resistant bacteria have been treated in 35 hospital of 29 cities and 26 phages were found to be needed. Eradication of the target bacterial infection was found in 61% of cases. In addition, phages were found to be synergistic when used with antibiotics. Jean-Paul considers commercially viable broad spectrum phage cocktails may be produced in the future.”

Geert Verniers (Lector SCM and Researcher BM-expertise center VIVES University) and his colleague described the use of Drones in the transportation of medicinal products,biological samples and tissues. With traffic congestion on roads causing gridlock around many hospital centres and personalised medicines needing urgent delivery from one area to another, the use of drones for professional transportation is compelling. Various significant points for consideration were discussed. These included the type of drone, drone pilots and Cargo Ports, the design of routes and the complexity of regulation, environmental impact, vibration problems and temperature control.

Following a lengthy discussion period, Frank Peeters thanked the speakers for their interesting contributions and all those responsible for this meeting being held in the European Parliament.


EMA’s recommendations to prevent medicines shortages

June 9, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

Continuity of medicinal product supply is still representing a key issue for European countries. The HMA/EMA Task Force on the Availability of Authorised Medicines for Human and Veterinary Use has published a new guidance document in the form of recommendations for the industry on best practices to be adopted to prevent shortages of human medicines.

The recommendations are targeted at marketing authorisation holders (MAHs), wholesalers, distributors and manufacturers. The specific role of each actor is detailed, and highlights are provided on how to optimally approach the prevention and mitigation of shortages. The document refers to the harmonised definition of shortage agreed by EMA and HMA, i.e. “A shortage of a medicinal product for human or veterinary use occurs when supply does not meet demand at a national level“.

Different players for different roles

The pharmaceutical supply chain is characterised by many different actors, each of which plays a specific role in the development, manufacturing and distribution of medicinal products.

Marketing authorisation holders are the ultimate responsible for the monitoring of all activities needed to timely produce and distribute their products. This means MAHs should oversight the entire supply chain, from suppliers of active ingredients (APIs) to end users, in order to continually align demand with supply, evaluate the actual impact of a shortage, and establish the more suitable prevention or mitigation strategies. According to the guidance, reference should be made to the “ISPE Drug shortages prevention plan – Holistic view from root cause to prevention” in order to build a suitable quality culture integrated into product lifecycle; compliance to ICH Q10 is also recommended.

Manufacturers include both APIs suppliers and producers of the medicinal product, which should possess a in depth knowledge of their processes and issues that may impact on product availability. This is even more true for contract manufacturing organisations (CMOs), as a problem with their manufacturing capacity may impact many different customers. Wholesale distributors have general visibility of stock levels and product flow and can identify early signals of a potential medicine shortage. They are subject to national laws as for their obligations to ensure continuity of supply to patients.

As for institutions, national competent authorities (NCAs) are responsible for the coordination of the response to a shortage by means of regulatory tools and strategies. Existing regulatory flexibility can be used, while NCAs cannot intervene in pricing, sourcing, and clinical practice. NCAs are also responsible to communicate actual shortages from their websites.

EMA’s responsibilities relate to shortages of centrally authorised products and coordination of the EU response to supply issues due to major events or public health emergencies. The Agency is also responsible for the publication of a public catalogue for shortages assessed by the CHMP and/or PRAC committees, and for the publication of information on critical shortages monitored at EU level.

National health service providers are responsible for the setting up of policy and operational aspects needed to guarantee the timely access to medicines (i.e. reimbursement schemes, purchasing arrangements, clinical guidelines, etc.). In case of a shortage, they are called to indicate available alternatives, and to issue specific clinical guidance for healthcare professionals if needed.

The overall sustainability and accountability of health systems is the major goal for national Ministries of Health, to be tackled by mean of legislative initiatives. End users include healthcare professionals responsible for appropriate prescribing and for the identification of available alternatives in the case of a shortage affecting their patients. Timely information to patients, in particular for specific diseases, may be provided by patients representative groups, which may also collect feedback on the impact of shortages for patients.

Ten recommendations to prevent shortages

The guidance highlights the importance to notify as soon as possible to NCAs any potential or actual shortage, in order to timely face the increased demand for alternative product suppliers. To this instance, MAHs and wholesalers are in the best position to monitor available stocks and report at early stages about possible issues.

An improved transparency would be needed as for the provided shortage information, to avoid patients’ concerns and the consequent risk of stockpiling and to avoid duplication of efforts. To this instance, MAHs are called to provide all available information requested by the notification form, including also multi-country information (e.g. related to API suppliers).

MAHs should also have a shortage prevention plan in place, addressing the entire life cycle of the specific product from sourcing of raw materials to manufacturing capacity and distribution. Wholesale distributors are also called to develop similar plans focusing on their specific role. Prevention plans should include an analysis of vulnerabilities and risks of interruption of supply, the assessment of the robustness of the supply chain arrangements and controls as well as of the need of revalidation, and the availability of a medicine shortage risk register to identify products of clinical importance by therapeutic use and availability of alternatives.

MAHs and wholesalers should also have a shortage management plan to be activated in case of issues with the availability of a certain product. To this instance, the capacity of available alternative manufacturing sites is critical, including CMOs which should always be kept timely informed by MAHs. A possible approach suggested by the guidance sees the development of a dashboard to continuously monitor signals for potential supply disruption. Procedures to identify true shortage points would also be needed to overcome the current limitation of the automated order systems.

The punctual implementation of Pharmaceutical Quality System according to ICH Q10 and ICH Q12 is also deemed fundamental to prevent any delay related to regulatory procedures that may impact on product availability. Product quality reviews (PQRs) are suggested as a possible tool to capture appropriate data and trends for continuous improvement.

The overall resilience of the supply chain should be supported by the justification of the adoption of the just-in-time supply model, particularly when limited alternatives are available. MAHs and wholesalers should guarantee the availability of suitable contingency stocks to face any unexpected delay.

Sub-optimal communication among different stakeholders should be also addressed by means of an improved cooperation, including a two-way communication system extending also to potential or actual shortages. Critical points of attention are identified in the intra-company communication between different departments, those between local MAH representatives and manufacturer, and the availability of information on stock levels to entities entitled to supply medicines to the public via ordering portals. Specific criteria for communication, together with the description of key processes and supply chain maps should be developed by each stakeholder.

Stockpiling is another critical practice to be avoided in order to ensure the fair and timely distribution of medicines. To this instance, healthcare professionals are called not to order or dispense more stock than normal in case of shortage, while MAH stock allocation practices between different countries should also take into account the clinical need of patients, and not just economic factors. Parallel trade should be also avoided as far as possible. NCAs should duly justify any decision to limit this practice, while companies should seek advice from their relevant authorities of the exporting country in case of critical shortages.


Webinar: Pharmacovigilance as a specialization and the role of the Pharmacovigilance Risk Assessment Committee (PRAC)

May 8, 2023 , , , , , , , , , , , ,

EIPG webinar

Next EIPG webinar is to be held on Wednesday 31st of May 2023 at 17.00 CEST (16.00 BST) in conjunction with PIER and University College Cork. Sofia Trantza, a pharmacist with long experience as a Qualified Person for Pharmacovigilance in the Pharmaceutical Industry, currently representing Greece at the European Medicines Agency (EMA) as a member of the Pharmacovigilance Risk Assessment Committee (PRAC) will present the role and the procedures of the latter as a European body responsible for providing recommendations to EMA on any questions relating to pharmacovigilance activities in respect of medicinal products for human use.

According to the World Health Organization (WHO) pharmacovigilance (PV) is defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. During the pandemic, this science went more popular than ever, and many people got familiarized with it. A very important role at the activities of this speciliazation plays the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA).

Webinar attendees will gain understanding of:

  1. What is pharmacovigilance and what it represents for the public health.
  2. The process of reporting adverse reactions at national and at European level.
  3. The main activities and procedures in this discipline.
  4. The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA).
  5. The role and the responsibilities of PRAC Committee.
  6. The processes that PRAC is engaged in and how the work of this Committee is reflected in these processes.

This is an event for members of EIPG member organisations. Contact your national association EIPG representative for further information.


Webinar: ICH Q12 Product Lifecycle Management – open road or dead end?

March 24, 2023 , , , , , , , , , , , , , , , , , , ,

Next EIPG webinar is to be held on Tuesday 18th April 2023 at 17.00 CEST (16.00 BST) in conjunction with PIER and University College Cork. Graham Cook, former Pfizer’s Quality Intelligence and Compliance Information team leader and chair of EFPIA’s Manufacturing and Quality Expert Group (MQEG) will explain the context for the development of the ICH Q12 guideline on Product Lifecycle Management.

The ICH Q12 Product Lifecycle Management guideline reached step 4 in the ICH process in November 2019 – where are we with the adoption of this guideline? This webinar will provide an overview of the content, and discuss the opportunities and implications for implementation of Q12 by industry and regulators.

Graham Cook is a pharmacist with a Ph.D. in pharmaceutics. He was appointed to the British Pharmacopoeia Commission between 2010 and 2021 and chairs the Medicinal Chemicals (MC2) Expert Advisory Group and the Analytical Quality by Design Working Party. Between 2012-2018 he was Chairman of the American Society for Testing Materials (ASTM) International E55 Technical Committee developing pharmaceutical manufacturing standards and continues to serve as a member of the E55 Executive Committee. He was a past chair of Pfizer’s Quality by Design Council and previous roles include Technical Director supporting Wyeth Europa Manufacturing and External Supply, and Director Formulation Development for Wyeth Consumer Healthcare (Richmond, Virginia, USA).

This is an event for members of EIPG member organisations. Contact your national association EIPG representative for further information.


Review of the pharmaceutical legislation, the proposals of the industrial associations

February 10, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

The Staff Working Document on “Vulnerabilities of the global supply chains of medicines” published by the European Commission on 17 October 2022 identified several issues related to the current, often difficult situation experienced by pharmaceutical supply chains. Among these are the increasing complexity and specialisation, challenges linked to the production process and technologies, the lack of geographical diversification and other dependencies, the need to unlock the potential of data to improve supply and demand predictability, and a perceived regulatory complexity.

The same issues have been widely debated under different perspectives during recent months as a possible contribution to the current revision of the pharmaceutical legislation, a major goal of the EU Commission’s Pharmaceutical Strategy for Europe together with the New Industrial Strategy for Europe.

The structured dialogue with stakeholders has been the tool chosen to facilitate the interaction and exchange of opinions in order to optimise the development and implementation of the new pieces of legislation. We resume some of the latest proposals arising from the main industrial associations on how to better achieve this very challenging objective.

EFPIA proposals for action

In November 2022, the European Federation of Pharmaceutical Industry Associations published a report to illustrate its proposals for action to tackle shortages of medicines and to improve the efficiency and robustness of the supply chain.

Five key principles form the basis of nine operative proposals. A standard definition of a shortage and an interoperable IT European monitoring/notification system would be needed in order to build a harmonised EU prevention and mitigation system. Epidemiological data are deemed essential to better analyse patient demand, so to improve transparency in the overall supply chain by means of the European Medicines Verification System (EMVS). Targeted shortage prevention plans (SPP) should be developed to prevent the risk of shortages for critical products and to manage safety stocks on a risk-based approach. Regulatory mitigation measures for shortages would also be of help in improving flexibility. At the global level, the maintenance of global open supply chains should be the goal, supported by the strong existing EU manufacturing and R&D footprint, and where appropriate, targeted incentives for the diversification of supply chains.

“The current revision of EU pharmaceutical legislation is a golden opportunity to reverse the trends of the last 25 years. It is our once-in-a-generation chance to reinvent the regulatory framework to ensure we have a modern approach that matches our ambition to be a hub of medical innovation”, writes EFPIA’s director general Nathalie Moll in a recent post, published on the association’s website.

In its Regulatory roadmap to Innovation of January 2023, EFPIA focused on how to achieve a more agile and streamlined regulatory framework, so to shorten the period needed for approval of a new active substance (currently 426 days, vs 244 days in the USA, 306 in Canada, 313 in Japan or 315 in Australia). Innovative approaches to clinical trials, including complex clinical trials (CCTs) and decentralised trials (DCTs), and the development of clear guidance on the use and regulatory acceptance of real-world data (RWD) and real-world evidence (RWE) are among the eight areas of possible immediate actions identified by EFPIA.

A dynamic regulatory assessment pathway based on early and iterative dialogue on data, international data standards and technology, and cloud-based submission modalities would support EMA and HTAs in accepting iterative data generation as part of the evaluation procedures.

As for drug-device combinations and in-vitro diagnostics, EFPIA suggests adopting an integrated EU pathway for the assessment, including the possibility for parallel advice with Notified Bodies. A clearer definition of unmet medical need would also be needed, as well as the full digitalisation of regulatory processes. A common definition of shortage coupled to the setting up of a European reporting system (possibly the already existing EMVS) would support the collection of real-time information and activation of alerts. Epidemiological data should be elaborated and released by the European Centre for Disease Control (ECDC).

The Variation Regulation is also under review by the EU Commission. EFPIA’s proposal is to incorporate the considerations for pharmaceutical product lifecycle management set forth by the ICH Q12 guideline, and to develop a vaccine-specific annex to the Variation guideline.

EFPIA also identified four areas requiring legislative change to accelerate pharmaceutical innovation in Europe. These include the possibility to redesign EMA’s committee structure in order to speed up the efficiency of regulatory assessment and decision-making process from EMA approval to EC decision.

Expedited regulatory pathways (ERP) are still of limited use in the EU, according to EFPIA. The suggestion is to embed the PRIME scheme in the new legislation to ensure its optimal use and allocation of sufficient resources. The creation of a new legal category for drug-device combination products, to be regulated as medicinal products, would also accelerate the approval of this increasingly important type of therapeutic option.

The transition from paper leaflets to electronic product information (ePI) should be also supported within the new pharmaceutical legislation, while considering the still present difficulties that may be experienced by elders and people not having access to computers or mobile devices. A new, centralised ePI repository/database would also be needed.

Medicines for Europe, focus on access and prevention of shortages

The 2022 of Medicines for Europe (MfE), representing the generic, biosimilar and value-added medicines industry, focused its lobbying activities mainly on access to medicines and prevention/ mitigation of shortages.

The economic and geopolitical crisis highly impacted the sector, which suffers strict price caps requirements in market policies. In a recent letter to the EU institutions, Medicines for Europe highlights the possible link between the shortages of amoxicillin and amoxiclav antibiotics and the low pricing and procurement policies in place in many EU member states.

“There are significant risks of more medicine shortages in 2023”, writes the association, which may be tackled by concrete policy reforms and industry commitments.

The economic model for generic medicines in Europe is identified as the structural root cause of shortages, requiring manufacturers to run their plants at the maximum capacity in order to “remain profitable as GMP rules require continuous investment in manufacturing plant upgrades”. This leaves little space to accommodate requests for increased production in order to face shortages. Other measures that, for MfE, impacted on the consolidation of supply chains and generic markets include the requests set forth by the Falsified medicines directive, as well as the Brexit, the Covid emergency and the current war scenarios.

The letter also identifies some possible short- and medium-term measures useful to mitigate the risk of shortages and improve the efficiency of the generic’s supply chains.

The first ones include the request for more regulatory flexibility for packaging, to facilitate the distribution of the available products in different member states. Clearer thresholds for nitrosamines and the need to avoid new regulations that may have a disproportionate impact on low margin medicines are also suggested. A better dialogue on immediate measures to tackle the cost of inflation on generic medicines would also be beneficial, says MfE, which also agrees on the need to better estimate demand surges on the basis of available data and epidemiological analysis.

The association of the generic and biosimilar industry shares also the importance of a rapid digitalisation of the medicines regulatory network in order to fully exploit the potential of big data. On the medium-term (2025), this may prove important to achieve objective related to the implementation of the ePI, the reduction of variations, the management of API sources, the harmonisation of packs and a better handling of requirements at national level.

Suggested actions at the legislative level include the introduction of legal guidance on the implementation of the criteria established by the Public Procurement Directive. The Transparency Directive may take example from Canada, where prices for generics varies according to the variation of the demand. A Medicine Security Act might represent the legislative tool to support investments in manufacturing diversification and greener technologies.

MfE also highlights some threats resulting from political choices such as national stockpiling requirements, that can increase costs and reduce cross-country solidarity. A preferred approach would be that of the European strategic reserve concept, based on rolling reserves. The real usefulness of joint procurement should also be better evaluated, especially with reference to OTC and other medicines directly dispensed by community pharmacies.

A note published in November 2022 focused on the still greatly unused potential of value-added medicines, a sector which according to MfE may benefit by a re-evaluation of the current innovation model, leading to a increased attention to the entire lifecycle of a medicine and on off-patent molecules. The request to the EU Commission is to fully acknowledge value added medicines in the EU pharmaceutical legislation as a separate group of medicines, with its own dedicated regulatory pathway and proportionate data exclusivity incentives.

The vision of the ATMP sector

The vision of the advanced therapies (ATMPs) sector, represented by the Alliance for Regenerative Medice (ARM), was illustrated in an event held in November 2022 at the European Parliament.

The declining competitiveness of the EU and how to ensure patients’ access to transformative treatments have been subjects of the debate. Many of the newly approved treatments fall under the ATMP categories of medicinal products (cell and gene therapies, tissue therapies), that according to ARM would require a better suited policy and regulatory framework to fully exploit their potential. “The same policies and approaches that brought us yesterday’s biomedical innovation simply will not work for the cell and gene therapies of today and tomorrow. The EU has led before — and can lead once again — but the time to act is now.” said Timothy D. Hunt, chief executive officer of ARM.

According to data by ARM, the number of ongoing industry clinical trials in Europe involving ATMPs is increasing very slowly (just 2% at the end of June 2022). More in detail, only one phase 1 study was initiated in Europe in the first half of 2022, says the association, and the region accounted for just 11% of new trials involving ATMPs and started in the same period. Many EU’s approved advanced therapies are also suffering, with 23 ATMPs withdrawn from the market. The reduced interest of the sector towards Europe is also acknowledged by the declining number of developers headquarters (-2% vs the previous five years): a trend opposite to that of North America and, especially, the Asia-Pacific region


Comments to the draft ICH guidelines Q2(R2) and ICH Q14

November 25, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The public consultation on the two draft guidelines ICH Q2(R2) on the validation of analytical procedures and ICH Q14 on analytical procedure development closed at the end of July 2022.The European Medicines Agency published in August two documents summarising comments received (ICH Q2(R2) and ICH Q14).

Many industrial organisations contributed to the consultation with their point of view on the two draft guidelines. In the next phase of the procedure (step 3 of the ICH process), comments will be reviewed by the ICH Q2(R2)/ICH Q14 Expert Working Group (EWG). We summarise for readers some of the main comments received from industrial stakeholders. A webinar organised byEIPG on the implications and opportunities of the revision of ICHQ2 and the ICHQ14 was presented by Dr Phil Borman, Senior Fellow & Director Product Quality at GSK on 15thJune 2022 (recording and slides are available at the webinars page of EIPG’s website).

Key principles from the EIPG’s webinar

During the webinar, Dr Borman gave a comprehensive picture of the process of Analytical Quality by Design (QbD). The systematic approach to method development starts with the identification of the predefined objectives (Analytical Target Profile, ATP). The understanding and control of the analytical procedure are at the core of the process, and they should be pursued according to principles of ICH Q8. Analytical QbD covers both the drug product (ICH Q8) and the active ingredient (Q11). This means that a similar framework to ICH Q8 and Q11 can be applied also for analytical procedures. The ATP is made up of the sum of performance characteristics, precision, range (including sensitivity), and bias/accuracy.

According to ICH Q2(R1), published in 1994, the objective of validation of an analytical procedure is to demonstrate its suitability for the intended scope. Revision of both guidelines started in 2019, based on a Concept paper published in 2018. ICH Q2(R2) covers the validation of the analytical protocols and reports, while ICH Q14 refers to the development of the analytical procedure and its lifecycle management.

Key features of the new drafts include the fact that no additional expectations / mandated requirements for pharmaceutical analytical scientists are present, the possible use of “enhanced approaches” and the clear link between performance characteristics and their related criteria and the validation study. The Q2(R2) guideline shall apply to both small molecules and biologics and includes the possibility to use prior knowledge (e.g., from development or previous validation) as a part of the validation exercise. Assay for the determination of robustness can be conducted, for example, during development. Other key features highlighted by Dr Borman include the possible use of Platform analytical procedures to reduce the number of validation tests and the possibility to use any type of calibration model (including multivariate calibration).

The expected benefits refer to the possibility to reduce the existing burden associated with post-approval changes to analytical procedures and the use of Established Conditions.

As Dr Borman explained, the ATP could form the basis of a Post Approval Change Management Protocol (PACMP), thus favouring the reporting of changes between technologies at a lower reporting category. A more performance driven and flexible approach to validation is expected following the entry into force of the new ICH Q2(R2) guideline. The selection of validation tests shall be based on the concrete objective of the analytical procedure.

Comments to ICH Q2(R2)

The overview of comments relative to the draft ICH Q2(R2) published by EMA consists of a 72-page document, divided into a first section containing general comments and a second focused on specific comments.

APIC, representing manufacturers of active ingredients and API intermediates, focused on the fact that “uncertainty is not part of the validation whereas it has a reality in practice and part of the discussion between laboratories”. The measurement of uncertainty is also considered linked to the Total analytical error (TAE), a concept that would not be adequately addressed in the guideline.

EFPIA, on behalf of the biopharmaceutical industry, asked for a better connection between the two guidelines ICH Q2 and Q14, starting from the alignment of the respective titles. Improved consistency in the use of some terms was also suggested (e.g. ‘performance criteria’). Improved clarity and greater flexibility should be applied to the concept of working and reportable ranges. The association also asked to provide more examples for multivariate analytical procedures using different models to facilitate the understanding of their validation and lifecycle management.

Medicines for Europe, representing manufacturers of generic and biosimilars, asked to provide a more specific methodology for reportable range validation. The association requested some clarification about the possibility of using the minimal requirements of the performance characteristics for the addendum method validation strategy.

The European Association of Nuclear Medicine (EANM) focused its intervention of radiopharmaceuticals, a class of substances that should be considered a special case and therefore be excluded from the scope of the guidance. The request assumes that other approaches different that those discussed may be applicable and “acceptable with appropriate science-based justification”. The same request also applies to the draft ICH Q14 guideline. The EANM contribution also highlighted aspects specific to radiopharmaceuticals that should be considered, including the strength of the radioactivity content, the unavailability of radioactive standards of the active substance, and the need of specific techniques for radioactivity determination. The suggestion is to refer to the specific guideline on the validation of analytical methods for radiopharmaceuticals jointly developed by the EANM and the EDQM.

According to the International Society for Pharmaceutical Engineering (ISPE), there are many sections of the draft Q2(R2) guideline that may pose challenges due to lack of alignment and fragmentation of contents. A revision of the structure is thus suggested, together with the harmonisation of terms with those listed in the Glossary. ISPE also highlighted the opportunity to better clarify the distinction between validation elements and recommended data applicable to multivariate analytical procedures vs traditional analytical methods.

The ECA Foundation/European QP Association reported a very critical position on the two draft guidelines, clearly stating that ICH Q2 and Q14 should integrate with one another. According to ECA, the corresponding US guideline “USP <1220> is far superior”. Many of the points reported above with respect to the general section of the overview are discussed in more deep detail within the part of the document listing specific comments.

Comments to ICH Q14

The same structure of the document also applies to the 54-page overview summarising the results of the consultation on ICH Q14 guideline.

According to the Plasma Protein Therapeutics Association (PPTA), representing manufacturers of plasma-derived and recombinant analog therapies, the draft would be too focused on chemical methods, with just a residual attention to biological methods.

APIC asked for improved discussion of the capability (and uncertainty) of the method of analysis, a fundamental parameter to assess its appropriateness for the intended use within the defined specification range. According to the association, more specific reference should be made in relation to development data that can be/cannot be used as validation data.

ISPE suggested adopting a more detailed title for the guideline; something similar has also been suggested by EFPIA. ISPE also addressed the issue of reproducibility, that may be influenced by external factors across multiple laboratories. Multivariate analysis is also discussed, suggesting adopting additional requirements for the multivariate elements while maintaining the same approach to other analytical procedures.

EFPIA would prefer to avoid the use of the term “minimal” in favour of other expressions denoted by a less negative connotation (e.g., traditional, suitable/historic, classical, fit for purpose) with reference to the validation approach. The availability of training case studies is considered important to support the alignment between industry and regulatory agencies on expectations for regulatory change management, especially with reference to multivariate models. EFPIA asked that the paragraph discussing the relationship between ICH Q2 and Q14 should not address what should be submitted to regulatory agencies. Discussion of OMICS methods used in quality control of complex biological products should be included in the annexes.

ISPE asked to avoid reference to geographic regions, as the final goal is to reach harmonisation. A clearer statement of the scope would be advisable (a possible example is provided), as well as a better linkage to the ICH Q12 guideline on pharmaceutical product lifecycle management.

Specific comments include the suggestion of the PPTA to define all acronyms at first use in text and to include them in the Glossary. According to Medicines for Europe, it would be advisable to add characterisational assays (other than release/stability) for biosimilars. Furthermore, the scope of the guideline should focus on the risk assessment and availability of the analytical knowledge needed to select the most appropriate method for a specific application. Activities deemed to the submission of the regulatory CTD dossier should remain confined to the complementaryQ2 guideline.


Webinar: The impact of pharmaceuticals on the environment

October 28, 2022 , , , , , , , , ,

At the next EIPG webinar to be held on Wednesday 9th November at 17.00 CET (16.00 GMT) in conjunction with PIER and University College Cork, Bengt Mattson will present the impact of pharmaceuticals on the environment and what industrial pharmacists can do to help decrease the potential environmental impact.

Understandable concerns have been expressed regarding the presence of pharmaceuticals in the environment. Environmental protection contributes to safeguarding the health and safety of future generations. However, medicines play a critical role in ensuring a high level of public health.

Bengt has been the co-chair of the European industry’s Inter-Associations Task Force on Pharmaceuticals in the Environment for the past 8 years. He will discuss R&D initiatives, which influence green manufacturing and design safe, rational and effective use of medicinal products and the correct disposal of any unused or expired medicines.

The competence of industrial pharmacists in participating in these initiatives will be discussed.

This is an event for members of EIPG member organisations. Contact your national association EIPG representative for further information.


Trends in Drug delivery and Formulation

August 5, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

According to the 2021 Global Drug Delivery & Formulation Report, signed by Kurt Sedo, Vice President Operations, PharmaCircle LLC and published in a three-part series on Drug Development & Delivery, the Covid-19 pandemic seems to have had little impact on the regulatory approvals of new dosage forms and formulations. A positive sign from the pharmaceutical ecosystem, considering the difficulty to maintain normal operative conditions, the issues with international supply chains and the many hurdles to regulatory activities posed by the emergency.

According to Kurt Sedo, products newly approved by the FDA and based on new chemical entities have been the less affected, as they reflect a larger benefit for patients. On the other hand, are generics, together with new dosage forms and new formulations. Simple dosage forms continue to represent the great part of new approvals, while biologics prevail in terms of NCEs for injection.

The FDA approved in 2021 a total of 31 new products under the Biologics Licence Application (BLA) procedure, slightly more than in the previous two years. The increase is mainly linked to the higher number of vaccines and cell and gene therapies, while approval of biologic medicines maintained stable.

Approval trends by category of product

A marked decrease characterised Abbreviated New Drug Approvals (ANDA) (627 in 2021, vs 903 in 2020 and 962 in 2019). New Drug Applications (NDA) also slightly decreased. Analysing this category by type of product, the decrement is marked for new molecular entities and new dosage forms, while an opposite trend can be observed for new active ingredients and new formulations/new manufacturers.

As for administration route, the report indicates a marked prevalence of injection in all geographic areas (US 55%, EU 36%, JP 59%); oral drugs also continue to be highly represented. The author warns about the difficulty to reliably interpret the figures for European and Japanese approvals, as “The European Medicines Agency (EMA) approvals relate only to specific classes of pharmaceutical products and don’t capture the full range of products. The Japanese Pharmaceutical Medical and Medical Devices Agency (PMDA) published approvals are hard to access and properly assess”.

Looking more in detail at the injection route of administration, intravenous injectable products remain the leading category (US 39%, EU 38%, JP 38%), followed by subcutaneous injection. Simple solutions with or without a dedicated delivery device were the most commonly approved injectable simple dosage forms in 2021. Tablets and capsules remained the favoured oral dosage forms, while granules and pellets are especially represented in paediatric formulations.

Small molecules are the more represented category of active ingredients (US 64%, EU 74%, JP 52%), followed by antibodies and peptides; this last category of API offer the advantage of a possible formulation as non-injectable dosage form.

A deeper insight on the main approvals

Part 2 of the series debates the main products approved in 2021. The trend hints to a higher interest towards products and technologies targeted to wider patient populations and more diverse applications. According to Sedo, mRNA and gene therapy platforms have decrease their appealing due to need of validation for applications different than vaccines in the first case and safety and durability concerns in the latter.

Skytrofa (Ascendis Pharma) is a pegylated form of the growth hormone lonapegsomatropin-tcgd for injection or subcutaneous administration, using the dedicated rechargeable and reusable auto-injector. The weekly administration is the main advantage, overruling the need of daily injections.

Invega Hafyera (Janssen Pharmaceuticals), containing paliperidone palmitate as the active ingredient, has been approved in the US to treat adult schizophrenia by intramuscular injection every 6 months. Despite the parent molecule has already lost its exclusivity, Kurt Sedo highlights the remarkable lifecycle management of the Invega family of products, which allowed Janssen to maintain significant revenues for almost 20 years.

Tyrvaya (Oyster Point Pharma) is indicated to treat dry eye using the nasal delivery route. The formulation containing varenicline is administered using the Aptar’s CPS Spray Pump, representing the first approval for this type of technology platform. The possibility to overcome issues in treating ocular conditions connected to the difficulty many patients may experience with the administration of classical ocular drops is the main point of innovation.

Acuvue Theravision (Johnson & Johnson Vision Care) are contact lenses firstly approved in Japan and containing ketotifen to treat allergic conjunctivitis. In this case too, the approach may be replicated to administer other types of drugs in the eye. Issues may be represented by the difficulty of patients in using contact lenses and the need to stabilise the active ingredient to prevent leaching.

Cabenuva Kit (ViiV Healthcare) contains the combination cabotegravir – rilpivirine to treat HIV infection. Firstly, approved in Canada, it is administered monthly by intramuscular injection. Long-acting formulations can prove interesting to overcome compliance issues which may result in serious consequences for patients, as already proved in the case of hepatitis.

The monoclonal antibody Susvimo (anibizumab; Genentech) is formulated as a refillable ocular implant to treat wet acute macular degeneration. After implantation, the intravitreal injections using the Port Delivery System (PDS) occur every 6 months.

Other relevant technologies mentioned among new 2021 approvals include the Medicago Virus Like Particles (VLP) technology, which uses tobacco-related plants as bioreactors to produce noninfectious VLP that mimic the target virus, and LICA technology (Ionis), based on Ligand Conjugated Antisense (LICA) to favour the interaction of ligands and their respective receptors.

The Denali Transport Vehicle (TV) platform uses specific antibodies, enzymes, oligonucleotides, or proteins to link to the transferrin receptor of the blood vessel wall in the brain, thus providing a way to pass the blood-brain barrier by endocytosis.

MedRing (Ligalli) is a smart vaginal insert containing a miniaturised liquid formulation drug container with pump, battery, antenna, electronics, and sensors to monitor various biometric parameters (e.g. glucose or ovulation status).

Q-Sphera (Midatech Pharma) provides a bioencapsulation process using a microfluidic device to obtain discrete droplets without use of surfactants, toxic solvents, biphasic mixtures, shear, or heat forces.

Products in the pipelines

Part 3 of the series addresses the expectations for new approvals of products still in the pipelines The trend shows a higher percentage of early-stage products (research and pre-clinical phases), which is attributed to the higher interest of investors towards new companies able to fill the pipelines with early stage projects. The impact of Covid-19 has proved to be more relevant on projects at the clinical stage.

Small molecules still represent the main focus of development (59% in 2021/22), even if a drop has been observed from values recorded in 2015/16 (66%). Biological products may pose issues due to their highly speculative nature, suggests the report, while oligonucleotide and RNA products still represent only the 2% of the total in the pipelines; a more mature technology are antibodies (12%).

Cancer continues to be the leading therapeutic area of development, followed by infectious diseases and drugs to treat the central nervous system. The report indicates a very high attrition rate for anti-infectives under development, while many anti-cancer therapeutics in the pipelines may be me-too products pursuing validated therapeutic mechanisms. As seen above, injectable formulations maintain the leading position also for products under development (52%), followed by oral formulations.


EMA’s consultation on draft Q&As on remote certification of batches by QP

June 3, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The last two years saw the implementation of a high degree of regulatory flexibility as a mean to respond to the many challenges posed by the travel bans consequent to the pandemic. After this “experimental” phase, regulatory authorities are now considering the possibility to allow the routine implementation of some remote procedures in the field of pharmaceutical production.

It is the case of the remote certification/confirmation of batches by the Qualified Person (QP): after the publication of a draft guideline in the form of Q&As (EMA/INS/169000/2022), the European Medicines Agency (EMA) has launched a short public consultation which will remain open up to 13 June 2022. Comments may be sent by email.

The guideline offers EMA’s point of view on the requirements for the physical attendance at the authorised manufacturing site applying to QPs in order to routinely run the remote certification of batches, outside emergency situations. The document has been drafted by the GMDP Inspectors Working Group; it is composed of four questions and their relative answers and it addresses some considerations arising from the experience gained on the application of the guidelines for human and veterinary medicines issued during the pandemic. These last ones were elaborated in cooperation between the European Commission, the Coordination group for Mutual recognition and Decentralised procedures – human (“CMDh”), the Inspectors Working Group, the Coordination group for Mutual recognition and Decentralised procedures – veterinary (“CMDv”) and EMA.

The Agency also warns that the contents proposed by new Q&As’ guideline may be subject to any other interpretation by the European Court of Justice, which is the ultimate responsible for the interpretation of the EU legislation.

The contents of the Q&As

The routine remote certification or confirmation of batches may in future apply to the activities carried out by the QPs within the EU and European Economic Area (EEA), with reference to manufactured or imported human and veterinary medicinal products and investigational medicinal products.

The first answer clarifies that it could be possible for the QP to routinely run remote batch certification or confirmation only if this type of practice is accepted by the relevant national competent authority (NCA) of the member state where the authorised site is located. To this instance, it should be noted that some NCAs may request some specific requirements to authorise the routine remote certification procedure, for example with reference to the location of the QPs.

Should the remote certification be allowed on a routine basis, specific requirements should be met in order to validate this practice, starting from its full compliance to the EU legislation and EU GMP guidelines.

The answer to question 2 specifies that all activities should take place in an EU/EEA country, and that the time spent by the QP at the authorised site “should be commensurate with the risks related to the processes” hereby taking place. To this instance, it is of paramount importance the ability to demonstrate that the QP acting from remote has maintained full knowledge of the products, manufacturing processes and pharmaceutical quality system (PQS) involved in the remote certification/confirmation of batches. That also means that the QP should be highly reliant on the PQS of the authorised site, and this would be only possible by spending an adequate time on-site to verify the adequacy of the PQS with respect to the processes of interest. The pharmaceutical quality system should also include details of all the procedures used for the routine remote certification/confirmation of batches. The possible use of this type of remote procedure by the QP should be also clearly mentioned in the technical agreement governing the relationship between the authorisation holder and the QP, which should also specify all cases requiring the presence on-site of the QP. A robust IT infrastructure should be in place to guarantee the remote access of the QP to all the relevant documentation in the electronic format needed to achieve bath certification/confirmation, according to the provisions described in Annex 16 to the GMPs (Certification by a Qualified Person and Batch Release). To this instance, presence on-site should be always considered to solve issues that cannot properly be addressed from remote. The demonstration of the presence on-site of the QP falls under the responsibility of the Manufacturing/Importers Authorisation (MIA) holders.

These are also responsible to make available to the QPs all the hardware and software needed to guarantee the remote access to the relevant documentation (e.g. manufacturing executions systems, electronic batch records system, laboratory information systems etc.) as well as batch registers. All IT systems used for remote batch release should comply with the requirements of Annex 11 to the GMP (Computerised Systems).

On the same basis, it should be possible for NCAs to contemporaneously access for inspection all documentation and batch registers involved in routine remote certification/confirmation at the authorised site of batch release. MIA holders should also guarantee the QP is the only allowed person to access the batch certification/confirmation function and batch register, that the transferred data are complete and unchanged, and that an adequate system for electronic signatures is in place.

Question 3 simply clarifies that some members states may have some specific requirements about the country of residence of the QP, for example it should be the same where the authorised site involved in the remote certification procedure is located.

The last question discusses technical requirements linked to IT-security and data integrity for remote access, a type of procedure presenting a higher intrinsic risk in comparison to the same activities carried on-site. Here again, the main reference is Annex 11; all equipment and software used for remote certification of batches should always reflect the current technological developments.

Among the suggestions made by the Q&A draft guideline is the precise identification of all hardware transferred off-site to the QP, that should be inventoried and kept updated. Hard disks should be encrypted, and ports not required, disabled.

Attention should also be paid to the configuration of any virtual private network (VPN) used by the QP to improve the security of the connection to the IT infrastructure of the authorised site and to prevent unauthorised accesses. Authentication should be based on recognised industry standards (e.g. two-factor or multifactor authentication, with automatic date of expiry). The transfer of data should be secured by strong transport encryption protocols; assignment of individual privileges and technical controls falls under the responsibility of the MIA holder


Revision of the PIC/S GMP Guide: Annex 13 and Annex 16

April 1, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The entry into force of EU Regulation 536/2014 “Clinical trials”, at the end of January, resulted in the parallel updating of some international guidelines. In particular, a new version of the GMP Guide PE016 was published by PIC/S (Pharmaceutical Inspection Co-operation Scheme) on 1st February 2022. The revision included Annex 13 on the manufacturing of Investigational Medicinal Products (IMPs), and the new Annex 16 on the certification and batch release to be performed by Authorised Persons (AP) (click here to access all PIC/S guidance related to GMP). The revision of PIC/s guidelines is aimed to reflect the last changes occurred in the corresponding EMA documents, so to maintain the alignment between the two regulatory references (as established by the cooperation agreement between EMA and PIC/S). PIC/S has invited all non- EEA Participating Authorities and applicants to transpose the new Annexes 13 and 16 into their own GMP Guides.

The new Annex 16

Annex 16 represents a completely new addition to the PIC/S GMP guide; the EU Annex 16 (part of the EU GMP Guide) was initially considered to be too EU-specific and difficult to transpose for PIC/S purposes. Following a consultation in 2017, PIC/S Participating Authorities agreed to make an attempt to transpose EU Annex 16, as the adaptation may support a better harmonisation of GMP standards at the international level.

Annex 16 refers to both human and veterinary medicinal products which are subject to the PIC/S Participating Authority or are made for export. Furthermore, the Annex applies to investigational medicinal products for human use, “subject to any difference in the legal provisions and more specific guidance published by PIC/S Participating Authorities under national law”. With reference to imported medicinal products, each PIC/S Participating Authority may independently and voluntary decide whether to adopt the guidance as a legally-binding standard.

Certain types of medicinal products (e.g. blood and immunological products) are not addressed by the Annex, as they are regulated by national laws and fall under the competences of National authorities; to this instance, Annex 16 applies to the certification process performed by the AP and to the subsequent release of the batches.

The marketing authorisation holder (MAH) remains the sole responsible for the safety, quality and efficacy of the marketed products. Authorised Persons are required to check each single batch to verify compliance to national and GMP requirements, as well as to those detailed within the marketing authorisation (MA). After certification by the AP, batches of finished products can be transferred to saleable stock and/or export. Specific and documented agreements are needed should this require transfer to a site different from the certification’s one. Authorised Persons should be clearly identifiable, with reference to any quality defect leading to investigation or batch recall. APs certifying the release of the finished product are responsible for verifying the conditions of storage and transport for the batch and the sample, if sent separately, and of all testing required upon importation (including sampling, where needed).

A formal Quality Risk Management (QRM) process is required when sampling is performed at a manufacturing site located in another jurisdiction; Annex 16 provides detailed guidance on the elements to be considered in this exercise. Documentation of the continuous training received by the AP in charge of certification and batch release should be always available, with specific reference to the product type, production processes, technical advances and changes to GMP.

Annex 16 provides detailed guidance on how to conduct the process of certification of each batch of finished product, independently of the number of sites involved. With reference to specific manufacturing or control steps performed at different sites, their respective AP has to provide confirmation of the performed activities, sharing responsibilities with the AP in charge of the final batch release.

The certification process should take into consideration the entire supply chain of both the active substance and the finished product, including manufacturing sites of the starting and packaging materials. The AP responsible for certification should be able to access results of the audits performed at the sites involved, in order to check the consistency of all activities with those described in the MA and within GMPs. Audits run by third parties should reflect requirements set forth in Chapter 7 of the PIC/S GMP Guide.

In particular, suppliers of active substances should comply with GMP and GDP requirements relating to the supply of the active ingredient used to the finished product manufacturing. Excipients should also fulfil GMP requirements, and be possibly manufactured and supplied in accordance with the PI 045-1 guideline. Specific guidance may also apply for other types of products, i.e. biological active substances and medicinal products for human use or radiopharmaceuticals. Annex 16 provides templates for the confirmation letters to be used for the partial manufacturing of a medicinal product and for the content of Batch Certificates.

The revision of Annex 13

Annex 13 has been revised in order to reflect the contents of the new EU Regulation n. 536/2014 on clinical trials, which will replace EU Annex 13. PIC/S Annex 13 discusses the manufacturing of Investigational Medicinal Products (IMP), apart from the reconstitution phase, which is not considered to be part of the process. Provisions set forth by Annex 13 should be taken into consideration with reference to the re-labelling or re-packaging of IMPs and to the preparation of radiopharmaceuticals used as diagnostic investigational medicinal products, occurring in hospitals, health centres or clinics and performed by pharmacists or other persons legally authorised in the country concerned.

All activities should refer to an appropriate Pharmaceutical Quality System to be in place, according to requirements set forth in Chapter 1 of Part 1 of the PIC/S GMP Guide.

 The characteristics of IMPs may intrinsically evolve along the development process, as new data become available that may require changes to, for example, the formulation or the dosage form. This has to be reflected into the respective product specifications and manufacturing instructions, that should also evolve in parallel and be fully traceable and documented. Annex 13 indicates that all deviations should be registered and investigated, and preventive and corrective actions put in place. The new Annex provides detailed guidance on the different items to be considered within the product specification file, as well as for the proper management of personnel, premises and equipment.

All the documentation generated during the clinical development phases should fulfil requirements specified by the PIC/S GMP Guide, Part I, Chapter 4. To this instance, relevant documentation includes specifications and instructions, orders, manufacturing formulae and processing instructions, packaging instructions and batch records. Detailed guidance is provided also for production, including packaging materials and manufacturing operations, the modification of comparator products, blinding operations, and the packaging and labelling of the IMP. Annex 13 also offers guidance on how to perform quality control and batch release, and how to address outsourced operations, complaints and recalls and or the destruction of batches of IMP products.


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