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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

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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.


The new Annex 21 to GMPs

March 11, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The new Annex 21 to GMPs (C(2022) 843 final) that EIPG gave a significant contribution in reviewing the original draft and thoroughly presented it within a webinar to its members on August 2020, was published by the European Commission on 16 February 2022; the document provides a guideline on the import of medicinal products from extra-EU countries. The new annex will entry into force six months after its publication, on 21 August 2022. Its contents should be read in parallel with the EU Guide to Good Manufacturing Practice for Medicinal Products and its other annexes, those requirements continue to apply as appropriate.

Annex 21 details the GMP requirements referred to human, investigational and/or veterinary medicinal products imported in the European Union and European Economic Area (EEA) by holders of a Manufacturing Import Authorisation (MIA). The new Annex does not apply to medicinal products entering the EU/EEA for export only, as they do not undergo any process or release aimed to place them on the internal market. Fiscal transactions are also not considered as a part of the new annex.

The main principles

According to Annex 21, once a batch of a medicinal product has been physically imported in a EU/EEA country, including clearance by the custom authority of the entrance territory, it is subject to the Qualified Person (QP) certification or confirmation. Manufacturing operations in accordance with the marketing authorisation or clinical trial authorisation can be run on imported bulk and intermediate products prior to the QP certification/confirmation. To this regard, all importation responsibilities for both medicinal products and bulks/intermediates must be carried out at specific sites authorised under a MIA. These include the site of physical importation and the site of QP certification (for imported medicinal products) or QP confirmation (for bulk or intermediate products undergoing further processing).

Marketing authorisation holders (MAHs) for imported products authorised in the EU remain in any case the sole responsible for placing the products in the European/EEA market. Annex 21 requires sites responsible for QP certification to verify an ongoing stability program is in place at the third country site where manufacturing is performed. This last one has to transmit to the QP all the information needed to verify the ongoing product quality, and relevant documentation (i.e. protocols, results and reports) should be available for inspection at the site responsible for QP certification. QP’s responsibilities also extend to the verification that reference and retention samples are available in accordance to Annex 19 of the GMPs, and that safety features are placed on the packaging, if required.

Importation sites should be adequately organised and equipped to ensure the proper performance of activities on imported products. More specifically, a segregated quarantine area should be available to store the incoming products until the occurrence of release for further processing or QP certification/confirmation.

European GMP rules or equivalent standards shall be followed for the manufacturing of medicinal products in third countries due to be imported in the EU. The manufacturing process has to comply to the one described in the Marketing Authorisation (MA), the clinical trial authorization (CTA) and the relevant quality agreement in place between the MAH and the manufacturer. The respect of EU GMP rules or equivalent standards should be documented through regular monitoring and periodic on-site audits of the third country manufacturing sites, to be implemented by the site responsible for QP certification or by a third party on its behalf.

The QP of the importation site is also responsible for the verification of testing requirements, in order to confirm the compliance of the imported products to the authorised specifications detailed in the MA. The verification of testing requirements can be avoided only in the case a Mutual Recognition Agreement (MRA) or an Agreement on conformity assessment and acceptance of industrial products (ACAA) is in place between the European Union and the third country where the production of the medicinal product is located.

All agreements between the different entities involved in the manufacturing and importation process, including the MAH and/or sponsor, should be in the written form, as indicated by Chapter 7 of the EU GMP Guide.

The Pharmaceutical Quality System of the importing site

According to the European legislation (Chapter 1 of the EU GMP Guide), all activities performed in the EU with reference to the manufacturing and distribution of pharmaceutical products should fall under to umbrella of the company’s Pharmaceutical Quality System (PQS). This is also true for sites involved with importation activities, those PQS should reflect the scope of the activities carried out. A specific procedure should be established to manage complaints, quality defects and product recalls.

More in detail, the new Annex 21 establishes that sites responsible for QP certification of imported products (including the case of further processing before export with the exception of investigational medicinal products) have to run periodic Product Quality Reviews (PQR). In this case too, the respective responsibilities of the parties involved in compiling the Reviews should be specified by written agreements. Should the sampling of the imported product be conducted in a third country (in accordance with Annex 16 of the GMPs), the the PQR should also include an assessment of the basis for continued reliance on the sampling practice. A review of deviations encountered during transportation up to the point of batch certification should be also available, and a comparison should be run to assess the correspondence of analytical results from importation testing with those listed by the Certificate of Analysis generated by the third country manufacturer.

Full documentation available at MIA sites

The QP’s certification/confirmation step for an imported batch has to be paralleled by the availability of the full batch documentation at the corresponding MIA holder’s site; in case of need, this site may also have access to documents supporting batch certification, according to Annex 16. Other MIA holders involved in the process may access batch documentation for their respective needs and responsibilities, as detailed in the written agreements. A risk assessment is needed to justify the frequency for the review of the full batch documentation at the site responsible for QP certification/confirmation; the so established periodicity should be included in the PQS.

Annex 21 also lists the type of documents that should be available at the importation sites, including the details of transportation and receipt of the product, and relevant ordering and delivery documentation. This last one should specify the site of origin of the product, the one of physical importation and shipping details (including transportation route, temperature monitoring records, and customs documentation). Appropriate documentation should be also available to confirm reconciliation of the quantities of batches which underwent subdivision and were imported separately.

Requirements set forth in Chapter 4 of the GMPs apply to the retention of the documentation; the availability at the third country manufacturing site of an adequate record retention policy equivalent to EU requirements shall be assessed by the site responsible for QP certification. Should it be appropriate, translations of original documents and certificates should be provided to improve understanding.