Since the development of intravenous therapies, the presence of particulate matter in injectable drugs has been a concern for clinicians. 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, the United States Pharmacopeia (USP) has established fixed limits for the amount 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 not distributed if the amount exceeds the set limit. Test procedures for determination of the presence of particulate matter are set by the USP and manufacturers are required to follow these industry standards.
Particulate matter in injectables that are intended for intramuscular and subcutaneous administration would not carry the same risk as for intravenous administration, but industry standards still apply and limits are determined under review by the regulators (e.g. FDA).
Context for this Medical Communication
On October 5, 2019, the World Federation of Hemophilia (WFH) received the following information from representatives of Roche/Genentech/Chugai, manufacturers of emicizumab (HEMLIBRA):
During a routine examination of drug product batches, as part of our quality assurance systems and processes, hardly visible, translucent particles were identified in Hemlibra® (emicizumab), outside our particle specification.
These particles are inherent to the drug product and based on toxicology and safety assessments and review of available data, the benefit/risk profile of Hemlibra remains unchanged as a result. They consist of protein (Hemlibra drug substance) and silicone oil (PDMS, polydimethylsiloxane). Silicone oil is a non-toxic, organic polymer that is included in all parenteral medicines. Translucent particles are commonly observed and present in other approved biologics.
We have informed health authorities in March 2019. The European Medicines Agency (EMA), US Food and Drug Administration (FDA), Swissmedic, Health Canada, and the Ministry for Health, Labour and Welfare (MHLW) in Japan all agreed with our assessment that the benefit/risk profile of Hemlibra remains unchanged, and have supported the continued distribution of Hemlibra to patients to avoid therapy interruption. We have submitted the results of our final analysis to the health authorities and continue to engage with these health authorities.
We are committed to producing high quality products for our patients, which is why we have rigorous manufacturing monitoring, controls and testing in place for all our medicines, including Hemlibra.
After the WFH was informed of this issue on October 5, 2019, representatives from Roche/Genentech/Chugai were available to answer questions.
The following points were presented to the WFH:
Based on the information that the WFH has available at this time, including information on the assessments of regulatory health authorities, the WFH does not recommend a change in prescribing practice nor interruption in the use of emicizumab for patients already using the product.
Further, the WFH has the following recommendations:
Any patient or caregiver who has questions or concerns about this matter should contact their Hemophilia Treatment Center. The WFH will continue to closely monitor this matter and provide additional updates as warranted.
United States Pharmacopeia. https://www.usp.org/biologics. Accessed October 6, 2019.
Tawde SA. Particulate matter in Injectables: Main cause for Recalls. Journal of Pharmacovigilance (2014) 3(1):1000e128.
Tran T, Kupiec TC, Trissel LA. Particulate Matter in Injections: What is It and What are the Concerns? International Journal of Pharmaceutical Compounding (2006) 10(3):202-204.
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