Background information:
Since the development of intravenous therapies, the presence of particulate matter in injectable drugs has been a concern for clinicians and patients. While some particles can come from outside sources (e.g. when the product is prepared for use), others are “intrinsic” to the manufacturing process specific to the drug. In the latter case, sources for these particles may be the solution itself and its ingredients, contact with components used in manufacturing (e.g. tubing) or the product’s package (e.g. rubber stopper). In some cases, intravenous infusion of injectables which contain particulate matter has been associated with harm. Accordingly, regulators have established fixed limits on the amount of particulate matter in preparations intended for intravenous use and states that, prior to dispensing, all containers of intravenous preparations shall be inspected to the extent possible for the presence of observable foreign, and particulate matter in their contents and that these preparations are not distributed if the amount exceeds the set limit. Test procedures for determination of the presence of particulate matter are set by regulators and manufacturers are required to follow these industry standards.
Context for this Communication
On August 16, 2023, the EHC received the following statement from representatives of Takeda, manufacturers of Baxject II/Baxject II Hi-Flow® Reconstitution Devices:
“Takeda has identified and addressed a manufacturing issue that impacted BAXJECT II and BAXJECT II Hi-Flow reconstitution devices that were produced by our contract manufacturer between October 2021 and January 2022. These devices were co-packaged for use in conjunction with certain Takeda hemophilia medications (RECOMBINATE, RIXUBIS, ADVATE, ADYNOVATE and FEIBA) and shipped to countries where these medications are approved for use with these specific devices. We’ve identified the countries with impacted BAXJECT II and BAXJECT II Hi-Flow device lots in market, and we are systematically working with regional and local health authorities to correct this issue and to ensure hemophilia patients have access to their medicines.
Device reports indicated that particles were observed near the luer port of the reconstitution device prior to administration of the medicine, either when the luer port cap was removed as part of the reconstitution preparation process or in the syringe after the medicine was reconstituted. There were no reports leading to serious adverse events or death, and no adverse events identified that could be attributable to the presence of particles in the BAXJECT II and BAXJECT II Hi-Flow reconstitution devices.
Only the devices produced by the contract manufacturer between October 2021 and January 2022 are impacted. No quality issues have been identified in the Takeda hemophilia medications (RECOMBINATE, RIXUBIS, ADVATE, ADYNOVATE and FEIBA).”
On the EMA website:
“Takeda has decided to voluntarily replace BAXJECT II and BAXJECT II Hi-Flow reconstitution devices produced at Takeda’s contract device manufacturer between October 2021 and January 2022 for use in conjunction with RECOMBINATE, RIXUBIS, ADVATE, ADYNOVATE and FEIBA.
This is a precautionary measure and is due to the potential presence of particulate matter in the luer port of the BAXJECT II / BAXJECT Hi-Flow reconstitution device co-packaged with the medicinal products RECOMBINATE, RIXUBIS, ADVATE, ADYNOVATE and FEIBA.
There has been a small number of complaints for the BAXJECT II device that concern the presence of particulate matter before administration. It is important to note that there is no quality issue with medicine itself. No particulate matter has been identified in the active product or water for injection (WFI) diluent. The safety profiles of all products remain consistent with the product labels. There have been no adverse events identified that were attributable to the presence of particles in the BAXJECT II / BAXJECT II HiFlow devices in our Global Safety databases. »
EHC Statement
The EHC herewith communicates the following:
- There has been a small number of complaints for the BAXJECT II and BAXJECT II Hi-Flow reconstitution devices that concern the presence of particulate matter before administration.
- This issue is not related with any medicine produced by Takeda (RECOMBINATE, RIXUBIS, ADVATE, ADYNOVATE and FEIBA) or with the diluent used for the reconstitution of these products, but with the device (BAXJECT II) that is used to mix the medicine and diluent, before administration.
- There hasn’t been any presence of particles in the medicine/diluent reported.
- These devices are co-packaged with the medicine and the diluent.
- No adverse events linked to the particulate matter have been reported.
- Takeda has decided, as a precautionary measure, to voluntarily replace the devices manufactured between October 2021 and January 2022.
The EHC has the following recommendations:
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- The EHC expects that Takeda will conduct a full review of their manufacturing and quality control processes to determine how they may better ensure that all products that are used in their medicine packages meet their industry standard on the limits to particulate matter.
- The EHC expects that Takeda conduct a retrospective review of all possible adverse events in patients exposed to the reconstituted products administered with these devices.
- The EHC requests notification by Takeda of any regulatory feedback of this manufacturing issue that changes the risk-benefit assessment and has requested any follow-up on this matter after having completed their manufacturing process and quality control review.
- Any patient or caregiver who has questions or concerns about this matter should contact their Haemophilia Treatment Centre or National Member/Patient Organisation.
- The EHC calls on Takeda, as any industry player, to inform patient communities and healthcare providers when there are potential safety issues in a transparent, collaborative and timely manner, with all relevant information (batch numbers, countries).
The EHC will continue to closely monitor this matter and provide additional updates as needed.
Jim is aged 66 and has Haemophilia A with a high titer inhibitor which he developed at age 14.
Maria Elisa Mancuso (MD, PhD) is a Haematologist and works as a Senior Haematology Consultant at the Center for Thrombosis and Haemorrhagic Diseases of IRCCS Humanitas Research Hospital in Rozzano, Milan, Italy. She is Adjunct Clinical Professor at Humanitas University. She obtained a post-degree in Clinical and Experimental Haematology and a PhD in Clinical Methodology. She is involved in clinical research and has published several original articles in peer-reviewed journals a The Lancet, Blood, Journal of Thrombosis and Haemostasis, Haematologica, Thrombosis and Haemostasis, British Journal of Haematology and Haemophilia. She is reviewer for several peer-reviewed journals and member of the Editorial Board of JTH. She is a member of several scientific societies (ISTH, WFH, ASH, EAHAD, SISET, AICE) and was a medical member of the Inhibitor Working Group of the European Hemophilia Consortium. She is co-chair of the ADVANCE Study Group. She has acted also as co-chair of the Scientific and Standardization Subcommittee of ISTH on FVIII, FIX and rare bleeding disorders. She has been involved as principal and co-investigator in several clinical trials, and she takes care of both children and adults with hemophilia and other congenital bleeding disorders with a specific scientific interest in novel therapies, prophylaxis, inhibitors, and chronic hepatitis C.
As a patient with factor II deficiency, the diagnostic and treatment of rare bleeding disorders is a matter dear to my heart. My motivation to participate in the work of the ERIN committee is to improve both diagnostic and treatment for patients with rare bleeding disorders across Europe.
Economist and financial expert by profession, executive coach and trainer by passion and haemophilia advocate by every drop of my blood through my son (who has severe haemophilia A with inhibitors). Bringing a good decade of practical experience from the corporate insurance world, laser focus, growth mindset and resilience from my own experience, offering you anything I can just do, in hope that together we can make life more fulfilled for those impacted by bleeding disorders.
Amy Owen-Wyard is a Registered Mental Health Nurse. With experience working with children, young people, their families and adults with severe and enduring mental health conditions. Amy was also involved in a service improvement to provide a holistic care approach for those in general hospitals to support both their mental and physical health, whilst sharing her expertise and knowledge in mental health with the wider multidisciplinary team.
