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A new member within EIPG


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

The EU Parliament voted its position on the Unitary SPC


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

Reform of pharma legislation: the debate on regulatory data protection


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

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The new MHRA’s framework for clinical studies

May 26, 2023 , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

The repositioning of the United Kingdom as a global leader for clinical development of medicinal products can now benefit of the complete renewal of the framework regulating clinical studies run in the country. Announced in March 2023 by the Medicines and Healthcare products Regulatory Agency (MHRA), the new set of measures represents the deepest reform of the sector in the last 20 years. The new package is based upon results of the public consultation run in Q1 2022 in partnership with the Health Research Authority (HRA) and the Department of Health in Northern Ireland, which collected more than 2,000 responses.

As stated in the foreword of the final document, which details the government’s consideration of responses to individual questions, the main objective of the reform is for the UK to capitalise on the opportunity offered by the country’s new position in the global clinical trial landscape. Furthermore, it represents just the initial step of UK’s new regulatory approach, which may include for example a wider use of real-world evidence, novel analytics and data tools. International collaborations are also deemed important, e.g. with the FDA’s Project Orbis and the Access Consortium (Australia, Canada, Singapore and Switzerland) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals of Human Use.

“Our world-first Covid-19 approvals showed how important it is to ensure that regulation is flexible and agile. This overhaul of the clinical trials legislation will do just this – it will move us away from a one-size-fits-all approach to the regulation of clinical trials and help to streamline approvals by removing granular and duplicative regulatory requirements”, said MHRA Chief Science and Innovation Officer Marc Bailey.

According to the Health and Social Care Secretary Steve Barclay, the reform will make the UK more attractive for scientists and researchers. “These changes will help speed up clinical trials, without compromising on safety, and encourage the development of new and better medicines for patients. They come after the government announced additional funding of £10 million for the MHRA to accelerate the delivery of cutting-edge treatments including cancer vaccines”, he said.

The main goals of the reform

Patients are central to the UK’s reform of clinical trials. While efficacy and safety of new medicines under development remain the main target, great attention should be paid to reduce health disparities. To this instance, the MHRA announced the issuing of new guidance on how to ensure diversity of participants enrolled in trials, so to overcome imposed targets or arbitrary quotas. The improved attention to diversity would also support the delivery of trial results more adherent to the effective prevalence and clinical need across the population.

Flexibility and proportionality of the regulatory environment is another key objective of the reform. According to the final document, regulatory requirements should adapt to the current risk of the trial, and researcher should become subject to an overarching duty to consider proportionate approaches to clinical development.

Simplification of regulatory procedures is also expected, for example in the case of studies characterised by a risk similar to that of standard medical care. In this instance, regulatory review of the study protocol should not be needed anymore, substituted by simple “notification scheme” to enable approval.

As said, the attractiveness of the UK as a leading destination for international trials should be supported by streamlined and efficient application processes. This goal should include a new legislative action to integrate the regulatory and ethics reviews of clinical trial applications. Results from a pilot phase will be taken into consideration, as they proved possible to halve the approval times and cut the time from application to recruiting a first patient by 40 days.

All activities relating to clinical development should reflect the ICH Good Clinical Practice (GCP) principles for trial conduct. Regulatory timelines for approval are expected to compete at the international level, so to encourage sponsors to choose the UK as the preferred site to conduct multinational trials. According to the MHRA, the review of an application should take a maximum of 30 days in general, with a maximum of 10 calendar days for a decision to be granted once the regulator has received any final information. As for GCPs, compliance should also extend to service providers of electronic systems that may impact on patient safety.

Sponsors should also benefit from greater flexibility to respond to questions raised by regulators. In particular, the reform aims to amend the Request for Information (RFI) receipt, so that the sponsor has access to RFIs as they are ready rather than waiting for all requests to be made together.

The reform takes in consideration also the possible impact of incoming innovation, for example different types of trials and innovative study designs (e.g. decentralised trials). New guidance should be provided to set out specific details, thus avoiding any duplication. Guidance should be also provided on how to involve patients; family members or carers having a direct experience of the health problem in the design and conduct of a trial.

Transparency of the entire process should be supported by the compulsory registration of the trial in a World Health Organisation public register. A summary of results should also be published within 12 months of the end of the trial, and trial findings should be mandatory shared with trial participants.

Comments from the industry

“We welcome the MHRA and HRA’s commitment to work with our industry to codevelop new regulatory guidance and their pragmatic approach to patient & public involvement and trial diversity. We look forward to working with them to make the UK an attractive destination for clinical trials.”, said Richard Torbett, ABPI Chief Executive.

On 19 May, ABPI further commented from is blog the current situation of clinical development in the UK. According to the association representing the British pharmaceutical industry, enrolment to industry trials decreased by 44% between 2017 and 2021, while UK’s global ranking for phase III trials dropped to the 10th place (from the previous 4th). ABPI also reports revenues and cost savings to NHS England from life sciences companies of more than £10,000 for every patient recruited onto an industry clinical trial between 2016 and 2018.

In view of the release of the independent review commissioned by the government to former innovation minister Lord O’Shaughnessy, ABPI has identified three main steps necessary to support the international competitiveness of UK’s clinical trials sector.

Rapid and smooth regulatory procedures are at the first place, with the request not to delay from the 60 days target for combined regulatory and ethics review, comprehensive of the administrative processes of costing and contracting a clinical trial. Early scientific and regulatory advice and sufficient resources for the MHRA to clear the current backlogs and codevelop new regulatory guidance would be also important.

ABPI also highlights the often-experienced difficulty in recruiting a sufficient number of patients. The suggestion for the government is to take inspiration from UK’s leading position in early-phase (phase I) industry trials in order to improve investment in late-phase trial infrastructure. To this instance, health real-world data may prove important to support the search for eligible patients in a larger population.

According to the industrial representative, the UK is also lacking a nationwide clinical research dashboard to describe its performance in clinical research to global sponsors. This should include metrics on volume, speed, quality, impact, and innovation.


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

October 7, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.