By Barbara Unger, Unger Consulting Inc.
While communications from health authorities continue to pour in regarding actions they are taking to mitigate the impact of the COVID-19 pandemic, the EMA published three new items that merit attention from the life sciences industry. Two of them result from the pandemic; the third has been under development. We cover these in detail below, but they include:
- Delay in the due date for risk assessments to be performed by MAHs regarding the potential formation of nitrosamine compounds in APIs and human medicinal products
- Delay in the application date for implementation of the new Medical Device Regulations (MDR)
- Publication of draft Annex 21 to the EU GMP Guidelines for consultation
Risk Assessments For Potential Nitrosamine Formation
We previously addressed this topic, including an update based on new information that the EMA published on Dec. 20, 2019. Briefly, on Sept. 19, 2019, the EMA identified actions that must be taken by marketing authorization holders (MAHs) of human medicinal products containing chemically synthesized APIs. The firms are to identify potential risks for the formation of nitrosamines. If these risk factors are present, firms need to test for the presence of these compounds and make changes to the manufacturing process to minimize their formation.
Step 1 of the activities required by firms is the completion of a risk assessment to identify products that may be at risk of nitrosamine contamination. Previously, the deadline for the completion of the risk assessments was the end of March 2020. On March 27, 2020, the EMA announced that the completion date for the risk assessments is delayed until Oct. 1, 2020. The delay takes into account the challenges faced by companies in completing the risk assessments, including the challenges of working with CMOs that may be manufacturers of the API in the dosage form and the shift in industry and health authority priorities accompanying the COVID-19 pandemic. The EMA encourages manufacturers to submit the outcome of their risk assessments before October 2020 if they are completed or, more importantly, if they identify a risk to their products. Firms should communicate with their competent national authority as soon as possible if testing confirms the presence of nitrosamines, even if the level is below the limits set by health authorities. Please note, the announcement includes a variety of templates for use in completing the exercise required by the authorities.
The European Directorate for the Quality of Medicines & Healthcare also established a website on the topic titled “The EDQM’s response to nitrosamine contamination.” This is a centralized collection of all information needed to complete the assessments and other valuable information.
Potential Deferred Application Date For Eu Medical Device Regulations (MRD)
On March 25, 2020, the EC announced that it is working on a proposal to defer the application date of the Medical Devices Regulation for one year. This regulation was approved by the European Parliament and European Council in March 2017 and April 2017, respectively. It represents the culmination of activities that began in September 2012 with the adoption of a proposal for a regulation of the European Parliament and of the Council on medical devices to replace the three directives that currently govern medical devices in the EU. The three directives being replaced may be found HERE, HERE, and HERE. Manufacturers of current devices were given three years, until May 2020, to come into compliance with the new requirements. The current effective date for implementation of this regulation is May 26, 2020. The intent is to submit the proposal for this delay by early April so that it can be adopted by the European Parliament and Council by the end of May 2020. According to the EC, “This will take the pressure off national authorities, notified bodies, manufacturers and other actors so they can focus fully on urgent priorities related to the coronavirus crisis.”
The new regulations include significant improvements over the current system and apply to devices and their accessories distributed commercially and for use in investigational studies. For the benefit of those who aren’t deeply involved in the implementation of the regulation, some of the new requirements, when compared to the existing device requirements, include but are not limited to:
- The scope of products covered has been expanded
- The concept of a “Qualified Person” is introduced and their responsibilities are identified
- Requirements for more rigorous post-market surveillance plans and implementation of an EU-wide Medical Device database are implemented.
- The responsibilities of the members of the supply chain are identified to ensure compliance with the regulation. This includes but is not limited to manufacturers, distributors, importers, and the EU Authorized Representative.
- Some devices will be reclassified, particularly to a higher class. And some devices that were previously exempt are now included.
- A “unique device identifier” number is implemented to increase supply chain security.
- Systematic clinical evaluation will be conducted for Class IIa and Class IIb devices.
- Under the MDR regulations, all currently approved devices must be recertified to be consistent with current requirements. Thus, no products will be subject to grandfathering.
Draft Annex 21
The draft Annex 21, Importation of Medicinal Products, has been released for targeted comment from March 20 through June 20, 2020. This follows the publication of a Concept Paper on March 2015.
The four-page draft annex identifies requirements for those who import human and veterinary products from areas outside the European Union (EU) and the European Economic Authority (EEA). Products that do not have a marketing authorization in the EU or products that are “directly re-exported” are not within the scope of the annex. The annex specifies the obligations of the Manufacturing Import Authorization holder (MIA), who brings the product into the EU/EEA. The document makes frequent reference to Annex 16 of the EU GMP Guide, Certification by a Qualified Person and Batch Release. The annex includes six sections, not including the scope section, as follows:
- Principles. This section identifies fundamental concepts for the annex, beginning with the definition of the term “importation.” After the materials have been imported into the EEA/EU and cleared customs, QP certification takes place for medicinal products, and QP confirmation takes place for intermediates that will be subject to additional processing. The QP certifying the drug product must ensure it was made under conditions equivalent to the EU GMPs and tested in the EU, unless the site of manufacture outside the EU is the subject of a Mutual Recognition Agreement (MRA). Further, a written agreement should be in place for the manufacturing sites and those who perform importation activities, consistent with requirements in Chapter 7 of the EU GMP Guide.
- Pharmaceutical Quality Systems. The sites that import product should have a quality system consistent with the requirements in Chapter 1 for the actions they conduct. In addition, the site that performs QP certification for the imported products, including those that are imported for export, should have the following in place to permit preparation of Product Quality Reviews as described in Chapter 1:
- Written agreements should be in place that specify the responsibilities of the MAH, the importer(s), and the third-country manufacturer.
- When sampling of the imported product is conducted in a third country, the PQR should include an assessment of this practice and justify the reliance on this practice. Also included in the PQR should be a review of deviations and investigations related to the transport of the product.
- Results of analytical tests performed upon import testing should be compared with the Certificate of Analysis results. Trends or discrepancies should be identified, documented, and investigated as appropriate.
- Premises and Equipment: The importing site should have facilities adequate for their intended purpose of importing products or intermediates. These materials should be retained under quarantine until testing is complete and they are released. If products are not subject to physical quarantine, the process should provide equivalent security.
- Documentation: The manufacturing import authorization holder (MIH), where QP certification takes place, must have access to batch documentation. Other MIHs that do not include QP certification must have appropriate access as needed. Purchasing and shipment documentation should be available at the MIH site and available for inspection at the MIA holder where QP certification is performed. This should identify the product origin site, identify the site where import occurred, and shipping and customs information and documentation as necessary. Further, there should be documented evidence that the third-country manufacturer is qualified and subject to periodic audits.
- Operations: The site where QP certification occurs must ensure an adequate stability program is implemented. A third-country site may conduct the studies if the QP can ensure the site is adequate. The QP must ensure that safety features are added to the packaging where necessary and must ensure that reference and retention samples are maintained consistent with Annex 19 of the GMP Guide, Reference and Retention Samples.
- Complaints, Quality Defects, and Product Recalls: Arrangements should be in place among the participants in the supply chain to ensure that complaints, qualify defects, and recalls are conducted as required in Chapter 8 of the EU GMP Guide, Complaints and Product Recall.
It is essential to stay up to date with temporary changes that regulatory authorities are implementing to assist in addressing the COVID-19 pandemic, including enforcement discretion in given circumstances and accelerated approvals governing the use of medicinal products and devices. It is, however, equally important to stay up to date with the more routine guidance published by health authorities and the delays in the implementation of other requirements. While there seems to be substantial coverage on the former, we will focus on the latter set moving forward and make every effort to provide timely updates.
About The Author:
Barbara Unger formed Unger Consulting, Inc. in 2014 to provide GMP auditing and regulatory intelligence services to the pharmaceutical industry, including general GMP auditing and auditing and remediation in the area of data management and data integrity. Her auditing experience includes leadership of the Amgen corporate GMP audit group for APIs and quality systems. She also developed, implemented, and maintained the GMP regulatory intelligence program for eight years at Amgen. This included surveillance, analysis, and communication of GMP related legislation, regulations, guidance, and industry compliance enforcement trends. Unger was the first chairperson of the Rx-360 Monitoring and Reporting work group that summarized and published relevant GMP and supply chain related laws, regulations, and guidance. She was co-lead of the Rx-360 Data Integrity Working Group from 2017–2019 and remains a group member. You can contact her at firstname.lastname@example.org.