API suppliers Archives - European Industrial Pharmacists Group (EIPG)

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

Environmental sustainability: the EIPG perspective


Piero Iamartino Although the impact of medicines on the environment has been highlighted since the 70s of the last century with the emergence of the first reports of pollution in surface waters, it is only since the beginning of the Read more

EMA’s recommendations to prevent medicines shortages

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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.


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

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by Giuliana Miglierini

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

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

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

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

Key factors for remote inspections

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

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

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

New forms for CEPs applications

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

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

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

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

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

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