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Nitrosamine impurities, potential carcinogens, were identified in human blood pressure medications known as “sartans” in 2018. The risk that these compounds cause cancer in humans is reported to be very low. However, in an abundance of caution, the European Medicines Agency (EMA) requested that marketing authorization holders perform analyses to determine whether the raw materials and manufacturing conditions had the potential to result in nitrosamine formation, identify if nitrosamine compounds are present in their APIs and drug products, and, if so, mitigate the risk of their formation. The results of these analyses are submitted to the relevant authority. I addressed these requirements, along with early enforcement actions, in my previous article “New EMA Requirements On Nitrosamines — What ALL Pharma Companies Need To Know.”
This article provides an update to the topic as described in the June 23, 2020 report Lessons Learnt from Presence of N-nitrosamine Impurities in Sartan Medicines. It is based upon the outcome of a stakeholder meeting in late 2019 (slide decks may be found here), including comments submitted to the EMA regarding its proposals. We cover, at a high level:
- The recommendations and path forward suggested by the European regulators and
- Lessons learned from the GMP sampling, testing, and inspection processes
For readers interested in this topic from either a regulatory or scientific perspective, the EMA report is a must read because of the concepts and principles associated with control of impurities in both API and drug product.
The EMA’s June 20, 2020 update to its nitrosamine web page notes that the recommendations “apply to all medicines,” with the goal to reduce the risk of impurities and better address the response to unexpected impurities when they are identified. It does not apply to only nitrosamine impurities in the sartans, ranitidine, and metformin, although these have been the most prominent human drugs associated with the events. The recommendations also do not appear to be limited to chemically synthesized drugs. The statement that these “apply to all medicines” could be interpreted to include recombinant proteins and other biologic products. It would seem logical that they could apply to antibody-drug conjugate products, as impurities and their control are important for those products, too. In this respect, it appears broader than the EMA request from September 2018, which identified requirements for all chemically synthesized products.
The report includes four pages of specific recommendations across a variety of topics, 40 in total. The recommendations address revisions to guidelines, improvement in communication with patients and the healthcare community, cooperation with healthcare authorities around the world, development and use of IT solutions to facilitate information sharing, additional training for key stakeholders, and regulatory process improvements.
Below, we take each of the areas of recommendations and provide some granularity.
- Recommended revisions to guidelines, 21 in total, is the broadest category and may be among the most difficult to implement effectively in the short term. Briefly, this category includes but is not limited to:
- Updating guidance to marketing authorisation holders (MAHs) and manufacturers to stress the importance of process knowledge; to require more effective audits of API and intermediate manufacturers; and to address the requirement in the variations guidelines regarding documentation for adding or changing API manufacturers or manufacturing processes and ensuring that MAHs and others are “subject to effective, proportionate and dissuasive penalties if product quality is not appropriately ensured.”
- ICH should consider updates to guidance addressing control of impurities and clarification regarding the use of recovered reagents that may be a source of impurities. This reflects the fact that recovered solvents were identified as one of the potential contributors to nitrosamine impurities.
- With regard to GMP guidelines, it is recommended that they provide expectations for technology transfer and supplier qualification and for lot-specific supply chain traceability of materials and components, and that they clarify expectations for validation of facilities, equipment, utilities, and processes in API manufacture. The focus on the APIs is important because that’s where the nitrosamine formation generally happens and may be possible to control.
- With regard to the sampling and testing, the group recommends strengthening and supporting the European Directorate for the Quality of Medicines and Healthcare’s (EDQM) leadership in management of the testing workload and ensuring that laboratories are capable of analyzing suspected impurities at very low levels of detectability.
- External communications with healthcare professionals and patients should be refined to take advantage of additional tools and alternative opportunities for communication, such as social media. The group should also consider releasing lot or batch numbers of the medicines that are impacted where this is feasible.
- International cooperation should be expanded and should include those countries active in export. I assume this means those countries exporting APIs, most likely India and China. Workloads should be shared, and coordination and communication should be efficient.
- The Data Solutions recommended seem to be a component of international cooperation and include updating or developing new databases with appropriate information. Again, recognizing the importance of the ability to track and trace API through a global drug product supply chain, the report recommends the European regulatory network should “Populate existing databases or linked repositories for centrally and nationally authorised products with information on manufacturers of finished products and APIs in order to establish a link between API and finished product manufacturers and medicinal products across all EU markets, taking into account the potential use of ASMFs and CEPs.”
- Training should address quality assessors and members of the Rapid Alert Network (RAN) and Incident Review Network (IRN). Quality assessors should be trained on the chemistry of mutagenic impurities and relevant control strategies to prevent or limit their formation. The networks should receive additional training to ensure their activities are coordinated and efficient, with minimal unnecessary overlap.
- Among the more interesting of the seven recommendations under the heading of “Other Considerations” is development of a model for determining when a preapproval inspection (PAI) is to be conducted at an API manufacturer. Unlike with the FDA, this isn’t routine for European authorities. Also included here is the need for guidance for GMP inspectors on how to evaluate the control strategies addressing impurities. Finally, two of the recommendations in this area seem to link to the challenges of tracking and tracing components through the supply chain, taking parallel imports into consideration when evaluating product with a quality defect, and developing an agreement on a common definition for “quality defect.”
The recommendations will be considered and incorporated as appropriate into existing work being performed regarding nitrosamine contaminations. Those recommendations that require international cooperation will be discussed with the appropriate parties. Needless to say, change is not going to happen quickly.
Specific Lessons Learned Related To GMPs
The first eight pages of the report provide background, an excellent description of the timeline of the unfolding events, and several pages of recommendations. Most recommendations focus on revision of guidelines. The remaining 90 pages, along with an introduction section, cover five topics, each with its own “lessons learned” component; the two bolded items we cover in detail below:
- Preventing the presence of mutagenic impurities
- Handling such incidents efficiently
- Improving market surveillance, including sampling, testing, and GMP inspections
- Communicating with the public and healthcare professionals and
- Working with international partners
Incident Handling: Section 3.3 (page 50) of the technical background section of the publication identifies eight lessons learned from these events with regard to effectively managing these types of events. Several learning points reflect challenges in tracking and tracing product made with suspect API. The lessons learned regarding incident management include but are not limited to:
- Links could not quickly be established between marketing authorizations and API manufacturers and this limited the efficiency of the response from health authorities and others.
- Not all MAHs could readily identify which batches of finished product were made with an API from a specific manufacturer that was of concern. Similarly, API manufacturers had little or no information on the finished dosage form in which lots of their API was used.
- The parallel import process complicated identification of drugs made using suspect APIs.
- Enhanced use of appropriate IT tools could permit more efficient tracking of the actions of National Competent Authorities (NCAs) and ensure the entire network was kept up to date. The report references the use of massive spreadsheets and e-mail communications that are not efficient.
- The responsibilities of the RAN and IRN were not clear and resulted in duplication of effort.
- The complexity of issues made it challenging for the Safety Working Party (SWP) to quickly assess and communicate the risks.
- When many medical products made by multiple dosage form manufacturers use API manufactured by a single manufacturer, the potential public health impact is substantial. Reliance on sole-sourced APIs should be identified and addressed.
- Terminology always complicates these efforts. For example, some called this an “incident” and others called it a “crisis.” Further, not all countries classified this event as a “quality defect”; it was sometimes referred to as a process impurity issue.
Sampling and Testing: Section 4.1.4 (page 56) identifies lessons learned with regard to sampling and testing. The challenges in detection of mutagenic impurities include the need for specialized instruments and analytical methods with very sensitive limits of detection that needed to be modified and validated for each active substance or drug product. The lessons learned regarding sampling and testing include but are not limited to:
- Regulators faced challenges in identifying which API was used in the drug products because sponsors often listed alternate API suppliers in their filings. Yet again, the issue of tracking and tracing product components is identified as a challenge that likely remains today.
- EU legislation permits sampling of APIs during inspections conducted in the European Economic Area (EEA). Inspections of API manufacturers located outside the EEA are limited to instances of for-cause inspections or are carried out only at the request of a member state. Thus, testing of APIs was limited for the EU regulators.
- Analysis of APIs was the most reasonable way to assess the presence of nitrosamines but was limited as described in No. 2 above.
- The Official Medicines Control Laboratory that could conduct such testing was limited to those who could obtain the specialized instruments and acquisition of costly reference materials.
- Better communications could have been managed if points of contact had been identified for each stakeholder group.
- The Official Medicines Control Laboratories did not always have access to the analytical methods used by the API manufacturer or pharmaceutical company.
GMP Inspections: Section 4.2 (page 57) addresses GMP inspections, challenges, and lessons learned. The report concludes that one of the reasons for the presence of nitrosamines in the APIs was that these manufacturers lack process knowledge that would have been established during process development. Failure to adequately implement GMP controls during API manufacture compounds this lack of development knowledge and can perpetuate or worsen the presence of undesirable impurities. While the MAH is ultimately responsible for the quality of its drug product, it may lack knowledge of the synthetic process and be unable to assess the potential for formation of harmful impurities during manufacture of the API. Ultimately, “Insufficient knowledge of the development of their active substance and poor design of the active substance manufacturing process were identified as the main causes for the presence of Nitrosamines.” The lessons learned from the GMP inspection process include but are not limited to:
- Inspections demonstrated that incomplete process development and process knowledge were not sufficient.
- GMP inspections did not generally evaluate the process knowledge that led to process validation and process control.
- GMP inspectors did not routinely evaluate the adequacy of development studies, nor do they inform the licensing authority of these shortcomings.
- Improvement in GMP guidances could address the “grey areas” that are not routinely covered during inspections or considered in GMP assessments.
The story of nitrosamine contamination in “sartans” and other drugs has spanned the globe and been impacted by complex supply chains and a variety of failures that resulted in drugs containing potentially carcinogenic impurities. The complex global supply chains create challenges in tracking and tracing the source of APIs in various drug products made by multiple manufacturers and MAHs. This is further complicated by the API manufacturers’ lack of process knowledge that resulted in unintended impurities. The lack of adequate oversight by the dosage form manufacturers that purchase and use these APIs is also at fault here, particularly with oversight of changes in the manufacturing process. Now that the European authorities have proposed 40 recommendations, it will take time to determine which are implemented and what forms the implementation takes. We all know that revisions to guidelines, including those from ICH, can take several years. In this case, it is important to exercise the due diligence to bring third-party countries on board to understand this effort and appreciate what it means for product quality and patient safety.
The take-home lessons for manufacturers and sponsors is to ensure adequate understanding of the synthetic chemistry processes for APIs and intermediates used in manufacture of generic drugs. MAHs should provide adequate oversight of the firms with which they contract. All of this is easier said than done and is not without financial impact to the parties involved. I am sure we have not heard the last on this topic, and we will continue to monitor the situation and progress in this area.
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