Facilitating Sourcing in the Wake of COVID-19By
European Union (EU) authorities have issued guidance to pharmaceutical companies and suppliers to provide regulatory flexibility when sourcing reagents, starting materials, intermediates, and APIs for medicines deemed crucial in treating patients with the novel coronavirus (COVID-19). The measures are being taken as a means to mitigate potential shortages stemming from supply-chain and manufacturing disruptions.
Providing regulatory flexibility for sourcing activities
EU authorities are taking action to mitigate potential shortages to the supply of crucial medicines to COVID-19 patients. Last week (April 10, 2020), the European Commission, the European Medicines Agency (EMA) and the European medicines regulatory network issued a question-and-answer (Q&A) document to provide guidance to stakeholders on adaptations to the regulatory framework to address challenges arising from the COVID-19 pandemic, with a particular focus on crucial medicines for use in COVID-19 patients. The document explains some regulatory flexibilities that can be applied to help pharmaceutical companies cope with the consequences of the pandemic while ensuring the quality, safety and efficacy for medicinal products made available to patients in the EU.
The Q&A document addresses some of the constraints marketing authorization holders may be faced with in the context of COVID-19. The measures introduced cover different areas of the regulation of medicines such as marketing authorizations and regulatory procedures, manufacturing and importation of active pharmaceutical ingredients (APIs) and finished products (see Figure 1), quality variations, and labelling and packaging requirements with flexibility to facilitate the movement of medicinal products within the EU. Some of the measures are reserved for crucial medicines for use in COVID-19 patients.
The Q&A document was also endorsed by the EU Executive Steering Group on Shortages of Medicines Caused by Major Events, which provides strategic leadership for urgent and coordinated action on possible shortages within the EU during the pandemic.
One aspect of particular importance to pharmaceutical manufacturers and their suppliers related to the supply of APIs and intermediates and related sourcing activities due to supply-chain and manufacturing disruptions. The document specifies that marketing authorization holders (MAHs) in the EU may source starting materials, reagents, intermediates or active substances from alternative suppliers, where that is necessary to ensure supplies to the EU of crucial medicines for treatment of COVID-19 patients (see Figure 1). The Q&A document also specifies that the addition of new manufacturing sites for part or all of the manufacturing process, as well as changes in the site(s) responsible for quality control should also be facilitated.
To reduce the risk of shortages or disruption of supply from manufacturing and/or supply problems, an exceptional change-management process (ECMP) is being made available to MAHs of crucial medicines for treatment of COVID-19 patients. The ECMP will allow for changes to suppliers and/or manufacturing/control sites necessary to reduce the risks of shortages under certain conditions intended to ensure the quality of the medicinal product while deferring the full assessment of the variation.
Under the ECMP, MAHs will be able, on an exceptional basis, to source starting materials, reagents, intermediates or active substances from suppliers not specifically mentioned in the marketing authorization if that is necessary to prevent/mitigate shortages of supplies in the EU. Likewise, MAHs will be able to use manufacturing sites or sites responsible for quality control that are not specifically mentioned in the marketing authorization in cases where the use of an alternative site is necessary to prevent/mitigate shortages of supplies in the EU.
The exceptional change-management process
The ECMP is only available for crucial medicines for use in COVID-19 patients. The ECMP cannot be used for extensions of marketing authorization and is only available for changes required to address supply-chain/manufacturing challenges resulting from the current pandemic with a view to ensure continuity of supplies. Deviations from the requirements in the marketing authorization other than those changes of suppliers and/or manufacturing/control sites are excluded from the ECMP.
MAHs wanting to use an ECMP must notify the relevant national competent authority that granted the marketing authorization or the EMA (in case of centrally authorized products). In the notification, the MAH should specify its intention to use the ECMP for a specific medicinal product and commit to ensure that the quality of the finished product will not be compromised. To this end, the MAH should ensure that the new suppliers/sites abide by the quality standards applicable in the EU and, in particular, that the specifications (both for active substance(s) and finished product) in the marketing authorization are respected. Where required by EU legislation, the manufacturing/control site used under the ECMP should have an EU GMP certificate or have been certified by the authorities of a country with whom the EU has concluded a mutual recognition agreement.
The relevant competent authority will assess the notification and specifically whether the application concerns crucial medicines for use in COVID-19 patients (in case of marketing authorizations granted under the mutual recognition or the decentralized procedure, the reference member state will consult the concerned member states). Within two working days, the MAH will be informed whether the relevant competent authority has agreed to the application of the ECMP. If within two working days following the submission date the relevant competent authority has not raised objections, the application of the ECMP is deemed accepted.
Other measures in the EU to mitigate drug shortages
The ECMP is one way in which the EU is looking to mitigate potential drug shortages related to treating patients with COVID-19. Earlier this month (April 6, 2020), the EMA announced that it is setting up a single-point-of-contact system with pharmaceutical companies for reporting drug shortage or potential drug shortages related to the COVID-19 outbreak (see Figure 1).
The new system is in response to reports that some EU member states are starting to see shortages of certain medicines used for patients with COVID-19 or are expecting such shortages to occur very soon (as reported on April 6, 2020). These include medicines used in intensive care units such as certain anesthetics, antibiotics, and muscle relaxants as well as medicines used off-label for COVID-19. The shortages or potential shortages are being affected by a variety of factors, such as lockdown in factories due to quarantine, logistical issues caused by border closures, export bans, lockdowns in third countries supplying medicines to the EU, increased demand due to the treatment of COVID-19 patients, stockpiling in certain hospitals, and individual stockpiling by citizens and EU member states.
The EU Executive Steering Group on Shortages of Medicines Caused by Major Events is setting up, with the pharmaceutical industry, a system, the i-SPOC (industry single point of contact) system, to fast-track interaction on shortages between industry and the EU Executive Steering Group. With this system, each pharmaceutical company will report directly to the EMA, both for centrally authorized and nationally authorized medicines, anticipated shortages or current shortages of critical medicines used in the context of COVID-19. In parallel, pharmaceutical companies will continue to be required to report such shortages to the relevant national competent authorities.
The i-SPOC system, which is similar to the single point of contact network which was set up in 2019 between the EMA and the national competent authorities to share information on medicine shortages, is based on the appointment of an i-SPOC in each pharmaceutical company, who will feed information on current or anticipated shortages of COVID-19-related medicines to the EMA. The EMA says that this new mechanism will allow better oversight of ongoing supply issues irrespective of the licensing route and a quicker flow of information with the pharmaceutical industry with the objective of mitigating and, if possible, preventing shortages in the context of COVID-19 medicines.