Overcoming device component-related challenges and risks in prefilled syringe development.

The development of protein therapeutics requires stabilization of these labile molecules during shipment and storage. Biologics, particularly monoclonal antibodies, are frequently packaged at high concentration in prefillable syringes traditionally made of glass. However, some biologics are unstable in glass due to sensitivity to silicone oil, tungsten, glue, or metal ions. Syringes made from the plastic cyclic olefin polymer, Daikyo Crystal Zenith® (CZ), with a Flurotec-laminated piston, have none of these issues. This study compared the stability of several proteins including biotherapeutics when stored up to 14 months at 5 °C and 25 °C in prefillable siliconized syringes made of glass or silicone oil-free CZ syringes, and when subjected to mild agitation by end-over-end rotation at room temperature. At each time point, proteins were analyzed by several techniques including turbidity, size exclusion high-performance liquid chromatography, reversed phase high-performance liquid chromatography, ion-exchange chromatography, electrophoresis, and light scattering to monitor changes in aggregation and degradation. The results show that proteins have comparable stability when stored in glass syringes or in syringes made of CZ sterilized by E-beam or autoclave. In addition, proteins stressed by agitation were generally more stable and aggregated less in syringes made of CZ than in ones made of glass.LAY ABSTRACT: Biotherapeutic protein drugs such as monoclonal antibodies are frequently packaged at high concentration in prefillable syringes, which allows the drug to be directly administered by the patient or caregiver. Protein drugs, or biologics, can be unstable, and may aggregate, particularly when shaken. These aggregates can be immunogenic, stimulating the body's immune system to produce antibodies that can reduce the drug's efficacy. Although prefillable syringes are traditionally made of glass, some biologics are unstable in glass syringes due to the presence of substances used in their manufacture, including silicone oil, which is necessary for lubricity. Syringes made from the plastic cyclic olefin polymer, Daikyo Crystal Zenith® (CZ), have none of these issues. This study compared the stability of several biotherapeutic proteins when stored up to 14 months at 5 °C and 25 °C in prefillable siliconized syringes made of glass or silicone oil-free CZ syringes, and when mildly agitated at room temperature. Proteins were analyzed by several techniques to detect changes in aggregation and degradation. The results show that biotherapeutic proteins have similar stability whether stored in syringes made of glass or CZ. In addition, proteins subjected to agitation were generally more stable and aggregated less in CZ syringes than in glass syringes.

Variables Impacting Silicone Oil Migration and Biologics in Prefilled Syringes

Protein Aggregation and Particle Formation in Prefilled Glass Syringes

Silicone-oil migration in prefilled syringes induces smoke-like particulates in ultra-high viscosity formulations.

Impact of Surfactants on the Functionality of Prefilled Syringes

Biologic-device combination products using prefilled syringes (PFSs) and autoinjectors (AIs) are popular for biological products administered subcutaneously. Pharmacokinetic (PK) comparability studies commonly provide the scientific data to support introduction of AI presentations via bridging with PFS. A survey of biological products approved by FDA's Center for Drug Evaluation and Research identified 17 biologics license applications (BLAs) with both PFS and AI presentations for subcutaneous (SC) administration, including 16 approved on February 1, 2018, and one with AI presentation under review. A systematic review on the device parameters and the PK comparability studies bridging the two presentations was conducted. Subsequently, whether device parameters or the PK study design may have influenced the PK comparability study results was evaluated. The reported device parameters for AI and PFS are generally consistent across BLAs, whereas the approach to assess PK comparability varied, including the study design. Most PK comparability studies met bioequivalence (BE) criteria. Upon inspection of the studies that did not meet BE criteria, injection depth of AI and the injection site for either AI or PFS were identified as potential influencing factors to the outcome of PK comparability study. This study represents an initial attempt to identify the potential influencing factors on device bridging, including the characteristics of the device and the clinical pharmacology study. These findings may inform the combination product development strategy, specifically design considerations for device and PK comparability studies.

Evaluation of Incremental Siliconization Levels on Soluble Aggregates, Submicron and Subvisible Particles in a Prefilled Syringe Product

Advanced Characterization of Silicone Oil Droplets in Protein Therapeutics Using Artificial Intelligence Analysis of Imaging Flow Cytometry Data

Combination products, particularly drug/device integrations, have revolutionized therapeutic delivery. However, these innovations bring complex regulatory and biological safety challenges that demand harmonized, risk-based approaches to ensure patient safety. A biological safety assessment is a crucial step in the development process, ensuring finished medical devices or combination products are considered safe from potential biological hazards. However, given the diversity in designs, technologies, intended uses, etc., a one-size-fits-all approach to biological safety is not feasible. Achieving clarity and consensus on regulatory expectations is also essential to ensuring that drug delivery devices meet the necessary safety and efficacy standards. The recently updated ISO 10993 standard further adds to the complexity and the need to harmonize in an area of continually updating standards. Yet, despite the challenges, there are clear benefits from streamlining processes, leveraging supplier data, and clarifying regulatory expectations, such as reduced testing burdens and accelerated time-to-market. This is why our new position paper delivers clarity, consistency and a collaborative roadmap for the biological safety assessment of combination products. It provides a comprehensive overview of the current landscape, highlights key problems, and proposes actionable solutions to streamline the development process. Key themes in the paper that will drive industry momentum include: Biological risk assessments Supplier data and quality interactions Device categorizations ISO vs. USP expectations. For each of these areas, we discuss the problems, impacts, goals and benefits of overcoming those challenges. By reducing unnecessary testing, improving regulatory submissions and accelerating time-to-market, these efforts will ultimately benefit patients by delivering safer products sooner.

Oilfield service companies, like oil and gas producers, use Health, Safety and Environment Management Systems (HSE MS) to implement their HSE policies and continuously improve their HSE performance. With the tragic event in the Gulf of Mexico in April 2010, the implementation of an HSE MS in offshore oil and gas operations moved from a recommended practice to a regulatory requirement. Never has the need for HSE management systems and the alignment between operators and service companies’ HSE MS been more critical. Additionally, companies grow by acquisition and organically. In the case of acquisitions there are typically different HSE policies, management systems and cultures. True continuous improvement can only take place when the two cultures, and the tools used to drive those cultures, are harmonized. Any system must be both robust yet flexible enough to adjust to changing regulatory and business requirements. This paper reviews the experience of a major oilfield service provider in harmonizing several HSE management systems, from both prior independently operating divisions and a major acquisition. This harmonization includes consolidation and alignment of standards and best practices across multiple product lines, manufacturing, research and development, as well as operations and maintenance. Timing allowed the organization to also ensure the alignment with new and existing regulatory requirements, industry standards, and client expectations globally. The new regulations require the ability to demonstrate employee competence in assigned tasks. To ensure alignment with the enterprise competence management program when assessing competence for HSE-related tasks, HSE training professionals worked side by side with HSE subject matter expert professionals during the harmonization process. Use of process improvement teams consisting of HSE professionals from varied geographic operational units and business segments ensured a comprehensive review of client and government requirements, as well as incorporation of cultural and business needs. Finalization of the HSE MS operational controls included review by business leaders expected to implement the harmonized HSE management system. Providing them the opportunity to have input into the process is crucial to their ownership and support of the final product.

Monoclonal antibody (mAb) therapies are rapidly growing for the treatment of various diseases like cancer and autoimmune disorders. Many mAb drug products are sold as prefilled syringes and vials with liquid formulations. Typically, the walls of prefilled syringes are coated with silicone oil to lubricate the surfaces during use. MAbs are surface-active and adsorb to these silicone oil-solution interfaces, which is a potential source of aggregation. We studied formulations containing two different antibodies, mAb1 and mAb2, where mAb1 aggregated more when agitated in the presence of an oil-water interface. This directly correlated with differences in surface activity of the mAbs, studied with interfacial tension, surface mass adsorption, and interfacial rheology. The difference in interfacial properties between the mAbs was further reinforced in the coalescence behavior of oil droplets laden with mAbs. We also looked at the efficacy of surfactants, typically added to stabilize mAb formulations, in lowering adsorption and aggregation of mAbs at oil-water interfaces. We showed the differences between poloxamer-188 and polysorbate-20 in competing with mAbs for adsorption to interfaces and in lowering particulate and overall aggregation. Our results establish a direct correspondence between the adsorption of mAbs at oil-water interfaces and aggregation and the effect of surfactants in lowering aggregation by competitively adsorbing to these interfaces.

Risk Mitigation of Plunger-Stopper Displacement Under Low Atmospheric Pressure by Establishing Design Space for Filling-Stoppering Process of Prefilled Syringes: A Design of Experiment (DoE) Approach

We were interested to read the recent discussion concerning the predrawing of 'emergency' drugs in the obstetric theatre (Cupitt & Dunkley. Anaesthesia 2000; 55: 721. Calow. Anaesthesia 2000; 55: 1226–7) and the call for the experiences of others. We have recently published a national survey of the attitudes and practices of New Zealand anaesthetists with regard to emergency drugs [1]. The results demonstrate no uniformity of opinion or practice in New Zealand and indicate that many factors influence which drugs, if any, are predrawn before a case. Eighty-four per cent of respondents reported that their institution had no policy regarding the predrawing of emergency drugs in their workplace. The most common drugs to be predrawn were succinylcholine, atropine, syntocinon, ephedrine and metaraminol. Twenty-six per cent of respondents reported routinely predrawing such drugs, the majority indicating that they did this to avoid delay and to be prepared – some adding that assistants were too slow in drawing-up during emergencies. Thirty-seven per cent of anaesthetists reported having experienced delay, and 30% errors, while drawing up a drug at the time of a crisis. A number of respondents indicated that the absence of predrawn emergency drugs increased the anaesthetist's stress level even if the patient's outcome was not affected by delay in administering a required drug. Contrary to the widely held view that emergency drugs are rarely used, 86% of respondents had used such drugs in the previous year, and 29% had required them more than five times [1]. There is a significant cost in preparing and discarding syringes on a daily basis. Extending their shelf life is certainly the simplest way to decrease this cost, and it may be relatively straightforward to achieve a shelf life of a week or more. A recent US study investigated microbial contamination in over 700 syringes of six common emergency drugs drawn up in an obstetric theatre under routine clinical conditions [2]. The syringes were covered with clean towels and stored in theatre, unrefrigerated, next to the anaesthetic machine; no microbial contamination was found in any syringe after 8 days. However, consideration is also needed of drug stability, and of the possibility of chemical or particulate contamination from the syringe materials. Adequate quality control probably does require the formal procedures of a hospital pharmacy or licensed pharmaceutical manufacturer, which in many cases would permit shelf lives of several months to be attained – more than offsetting any additional costs. Given proper quality control, the advantages of presenting drugs in a prefilled format are several, and go well beyond the emergency situation. The use of such syringes may well be one method of reducing the very worrying problem of drug administration error [3]. It is well known that the legibility of labels on many ampoules is poor, and that ampoules containing quite different drugs may closely resemble each other, creating what psychologist and systems expert, James Reason, has called a latent error [4, 5] (Fig. 9). In this way, one of the authors recently committed a drug administration error by mistakenly substituting the two left-most ampoules in Fig. 9. Pre-filled syringes replace the error-prone, complex task by which an anaesthetist places several different drugs into individual syringes, with the much safer, production-line process by which a manufacturer prepares a large number of syringes containing the same drug [6]. The standard of user-applied labelling of drugs drawn up in theatre is typically variable and idiosyncratic, often little better than the labelling on ampoules and, at times, frankly dangerous [7]. Standard production methods would virtually guarantee the accuracy of labelling and would facilitate the use of highly legible, printed labels, incorporating the drug-class specific, international colour-codes for anaesthetic drugs. We have adopted such prefilled syringes at Green Lane Hospital (for some 10 drugs) as part of a systematic approach to the reduction of drug administration error (Fig. 10) [3]. In the case of emergency drugs, prefilled syringes could be presented in easily recognizable tamper-evident packs. The contents of these packs could be determined by departmental policy and could be speciality specific. Packs could be available from a different drawer of the anaesthetic trolley, thus physically separated from drugs commonly used during uneventful anaesthesia. Such physical separation and effective labelling would surely assist in reducing the incidence of syringe-swap errors. There would be some extra cost, at least initially, in the adoption of this approach. However, there is a substantial cost associated with iatrogenic harm, and recent calls for greater patient safety by the US Institute of Medicine [8] reflect a growing public intolerance of error in healthcare. At the least, the additional expenditure involved with providing emergency drugs in prefilled syringes would be minimal and, as Calow suggests, would be very likely to reduce risk to the patient. In addition, our data suggest the provision of prefilled emergency drugs would also reduce stress for the anaesthetist [1]. The cost involved would be greatly reduced by economies of scale. Therefore, we believe the time is long overdue for pharmaceutical companies to move towards abandoning poorly labelled and time-wasting ampoules as obsolete, and to provide all injectable drugs in prefilled syringes clearly labelled according to internationally agreed standards.

Carcinogenicity testing of IL-10: principles and practicalities.

The scope of Implantable Drug Delivery Systems (IDDSs) comprehends a variety of sterile therapeutic implements placed inside the body to exert a certain therapeutic action for extended duration. They are classified under different categories from pharmaceutical science and regulatory perspectives. The novelty and variety of IDDSs prevent the application of a uniform regulation for all IDDS products; therefore, sponsors face regulatory challenges to register and market their products. This review investigates pharmaceutical science literature and the United States Food and Drug Administration (US FDA) regulatory guidance to find how any IDDS is classified, regulated, and introduced in the market. The regulatory classification of any IDDS, as a ‘drug’, ‘medical device’ or a ‘combination product’, is the cornerstone in determining the regulatory pathway, which decides the quality control requirements preceding the marketing approval. IDDSs are generally recognized as combination products as they consist of two or more regulated components (drugs, medical devices or biological products) combined prior to use to function as a single entity. Although robust and defined US FDA regulatory pathways exist for each component independent of one another, the regulatory pathways for combination products are less formalized.