Antonio Scatena
Director of Sales and Marketing
Gateway Analytical, an Aptar Pharma Company
Mark Broadley
Vice President of Operations
BioCentriq
Paul Dyer
Field Application Scientist
Halo Labs
Beate Wagner
Managing Senior Physician and Deputy Medical Director ICCT
The Central Institute for Blood Transfusion and Immunology at Tirol Kliniken GmbH
Samuel Molina
Executive Director of Therapeutic & Cellular Solutions Manufacturing Science & Technology Labs
The American Red Cross
Particulate matter is a pervasive and ongoing concern in the production and manufacturing of pharmaceuticals. The issue of particulate matter contamination has been recorded and discussed for years in injectable and parenteral medicine circles. Many recorded recalls have been due to the presence of particulate matter. To combat the occurrence of particulate matter, the pharmaceutical industry created USP 〈790〉, the legally enforceable chapter for visually inspecting injectable and parenteral medicines. This chapter ensures that products are free from visible defects, including particulate matter.
Visual inspection of medicines is a critical step in the manufacturing cycle, allowing companies to identify and remove products containing visible particles. However, detecting and removing contaminated units during visual inspection is based on detection probabilities. For the cell and gene therapy industry, applying USP 〈790〉 is problematic for reasons such as the use of cryopreservation bags, products requiring frozen storage conditions, the use of small volumes, the limitation of observing foreign particles hidden among cells, and drug product formulations appearing cloudy or turbid.
Cell and gene therapy developers are currently at a critical juncture where implementing a particulate control strategy is not just an option but a pressing need for future success. While traditional pharmaceuticals have developed methods to address and manage particulate contamination, the complexity of cell and gene therapy formulations and reliance on disposable products and single-use systems require innovative strategies to control and remediate particles.
During the annual International Society for Cell & Gene Therapy (ISCT) meeting in Vancouver this year, Dr. Samuel Molina, Executive Director of Therapeutic & Cellular Solutions MSAT at the American Red Cross and the Co-Chair of the ISCT Manufacturing Materials Safety and Technology (MMST) Working Group, led a roundtable discussion titled “Let’s Talk Particulates: Working Towards Best Practices.” The roundtable featured a panel of four experts sharing insights and recommendations on implementing a particle control strategy, assessing the potential health impacts of particulate matter on the patient, and proactively working with service providers to ensure product quality as it relates to particles.
Dr. Elaine Peters, Director of Analytical Capabilities for Cell and Gene Therapy at Genentech, began the roundtable discussion by addressing the inevitability of particles in cell and gene therapy products and advocating for therapeutic developers to acknowledge the presence of particles, examine their final products to characterize particulates and trace their origins from single-use systems, the process, the materials, or facilities. Dr. Peters recommended that through this process, therapeutic developers should begin with foreign/extrinsic and intrinsic particles, assess patient safety impacts, determine acceptable levels, and identify possible controls. Mark Broadley, VP of Operations at BioCentriq, advised that USP <790> is a foundational guideline for cell and gene therapy developers to use despite its challenges in CGT/ATMP, citing how elements of USP <790> are effective in implementing a lifecycle approach for particle management while noting the challenges for small-volume products and the fact that assessing the risk and impact of particles is crucial for future particle management. Mr. Broadley stressed the need for therapeutic developers to adopt a lifecycle approach to particle management, noting that while achieving zero particles is unrealistic, it is essential to continuously reduce their presence by examining particle types and assessing their risks.
The topic of particle characterization transitioned into discussing analytical methods with Dr. Paul Dyer, Field Application Scientist of Halo Labs, advising that traditional analytical methods are still being used to identify particles but pose a challenge because the cells can interfere with the analytical approach, noting that membrane microscopy for counting and identifying particles is limited with cell therapies because the cells obscure observation of extrinsic and intrinsic particles. As Dr. Dyer stated, if you cannot count or measure the particles, you cannot manage them, noting that instrumentation and technology now exist to count and identify subvisible particles obscured by cells, such as technologies used by cell therapy developers to identify microparticles which they observe as distinct from cellular particle components. The topic of implementing a particle control strategy was closed by discussing issues with managing particles in the clinical setting with Dr. Beate Wagner, Managing Senior Physician and Deputy Medical Director ICCT for the Central Institute for Blood Transfusion and Immunology at Tirol Kliniken GmbH, describing how there are two different expectations of regulation from a manufacturing standpoint. One expectation as the therapeutic manufacturer is for non-contaminated cellular drug products according to compendial particle release testing and health authority regulations. This contrasts when at the bedside using transfusion sets to administer the particle-free therapy; there is no information at all on particulate expected to be generated during or as part of routine use of the infusion set. Dr. Wagner also recounts that there is consent in Germany and other countries about the harm of particles in IV and coronary infusions to the point where inline filtration is recommended to remove particles. She noted this practice is not feasible for cell therapies since the cells are essentially presented as particulates in solution.
The roundtable transitioned to discussing the potential health impacts of particles on the patient and the currently available information on the subject. The topic began with discussing the clinical focus and potential health impact of particles from final infusion to patient delivery, also known as “the last mile.” Elaine Peters notes that issues may arise from the final infusion to the patient where products need to be particle-free, especially when some products are known to form rosettes during manufacturing or clumps after freeze-thaw cycling. The conversation progressed to discussing different patient populations and those more vulnerable to risks associated with particles, such as children and patients in advancing age groups. Dr. Beate Wagner notes that questions will arise about whether particle standards or sizes need to be reduced for the pediatric population, non-oncology patients, or those who are elderly. Dr. Wagner also mentions that several studies on pediatric ICU patients indicate they are more prone to complications than adults, noting the difficulty this poses for particle control because particle size and character can be challenging to measure, especially when incompatible drugs are mixed during treatment.
The discussion around patient safety also ventured into a discussion about infusions to the patient and how mature regulations in parenteral drugs can pose challenges for cell and gene therapies. It was a consensus across the expert panel that there needs to be more guidance on what happens at the bedside post-release and the necessity to aid doctors and clinicians in determining whether the administration process requires filtration and the types of particles to expect so they can evaluate the medical impact to the patient. As the conversation circled back to revisit the necessity of particle control and identification, the panel acknowledged the challenges of creating regulatory structures for these therapies, citing the complexities of applying regulatory acceptance criteria from protein and small molecule therapeutics to the area of cell therapies.
The roundtable discussion closed with the last topic, proactively working with service providers to ensure product quality. It emphasized the need for therapeutic developers and manufacturers to collaborate with service providers and other developers in the CGT space to engage in these discussions and learn together. The discussion started with a review of Annex 1 for Europe and the FDA regulations for drugs and medical devices in the United States of America and speculating whether cell and gene therapies are being infringed on or inhibited in any way by new regulations. The first glaring observation is the absence of attention to single-use systems and related questions about the control of particles in single-use bags, emphasizing the lack of certificates of analysis for such materials. As noted by Elaine Peters, the regulators are learning at the same pace as the therapeutic developers, so it is our responsibility to collect the data and educate them, and additionally for the CGT community to come together to engage in these discussions and learn together.
Dr. Dyer also acknowledged the need to open conversations with regulators on the topics of particles and patient safety, especially considering that there is pushback within the parenteral world of legacy systems that are highlighted in USP <788> as being compendial methods but are insensitive or not adequately fitted to the modern day in terms of finding particles within cell therapies. However, you still have drugs that are being released on those particle counts and are being administered to patients. Dr. Wagner added that on the clinical side, you flush the system after administering cells back to the patient; however, there is no information on whether you should flush the whole system before you give the cells back to the patient, which has the potential to lower the particle burden across the entire dose.
Dr. Molina led the conversation back to the particle data not being shared, whether from case reports not being examined by the clinic or developers and service providers sharing information about particles in their processes or investigations. Mark Broadley furthered the conversation by discussing the viewpoint of the CDMO and how sharing client data is not possible, which inhibits more extensive discussions and collaborations with others on the topic of particles. However, Mr. Broadley is optimistic that maturity in the market and industry, combined with forums such as the roundtables at ISCT, will help us arrive at the point of collaboration and data sharing on topics as important as particles in cell and gene therapies. Dr. Peters supported this point of data sharing and collaboration, noting the two entities that possess the most information about particles are service providers and the regulators, so coming together in forums such as these is imperative to finding solutions to the particle problem.
The cell and gene therapy industry has a long journey to navigate on the topic and potential issues surrounding particles in drug therapies. However, many companies have already taken steps to reduce particle bioburden in their products and processes, and guideposts do exist for us as an industry to help us better adapt the current regulations to fit our needs. The particulate roundtable discussion at ISCT is one of many collaborative discussions our industry requires to solve the particulate issue best and bolster the quality of our medicine and patient outcomes in the future.
*The contributors of this article have provided comments on behalf of the International Society for Cell & Gene Therapy (ISCT) Process Development and Manufacturing Committee (PDM), Manufacturing Materials Safety and Technology (MMST) Working Group.
References
1. USP <790> “Visible Particulates in Injections”
2. USP <788> “Particulate Matter in Injections”
3. Annex 1 “Manufacture of Sterile Medicinal Products”
4. Van Boxtel T, Pittiruti M, Arkema A, et al. WoCoVA consensus on the clinical use of in-line filtration during intravenous infusions: Current evidence and recommendations for future research. The Journal of Vascular Access. 2022;23(2):179-191. doi:10.1177/1129729821989165
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