PDA Journal of Pharmaceutical Science and Technology最新文献

Many on-body delivery systems (OBDSs) for subcutaneous (SC) delivery require a change in primary container closure system (CCS). This necessitates compatibility and stability testing with original packaging materials and distribution and assembly, which are often laborious and time-consuming. Exploring new primary CCSs rather than using an original CCS can introduce risks, prolong timelines, and increase costs. In this study, 21 US-based combination product experts completed a double-blinded online survey between 6 October and 20 November 2023. The survey included 15 screening questions and 23 survey questions, including questions about compatibility issues between new CCSs and drug and stability testing for new CCSs. The largest proportion of participants (28.6%) reported that 5%-10% of the products that they had worked directly on had experienced compatibility issues between a new CCS and a drug, with a weighted mean of 11.9%. The most common compatibility issues were particulate challenges in 55.6%, sterility in 27.8%, and leachables in 16.7%. Most respondents (76.2%) rated the timeline showing that using an original CCS can save 12-24 months as somewhat (38.1%) or very (38.1%) representative. Most participants (57.1%) estimated that the range of direct costs, including development costs, drug product, engineering runs, line changes, and other costs, when using an OBDS with a new CCS is $10-15 million, 38.1% estimated <$10 million, and 4.8% estimated $21-25 million. Most participants (80.9%) reported that challenges in the primary CCS qualification/validation process delay entry of combination products into clinical trials or delay their commercial launch. The weighted mean of the delay was 9.7 months. Using an original CCS during combination product development would therefore be of significant economic benefit to the development of combination products in terms of time, cost, and risk.

Mycoplasma testing is a mandatory assay for all cell-derived products as part of the microbial control strategy. The compendial methods include an indicator cell culture method and a culture assay. Because the culture assay takes 28 days, the time-to-result (TTR) is one of the longest in the microbiology laboratory. Besides this, the compendial Mycoplasma methods are highly complex, subjective, and need strict segregation of labs to avoid cross-contamination with Mycoplasma. The pharmaceutical industry is seeking faster solutions, like nucleic acid testing (NAT)-based methods. There are alternative and rapid NAT methods on the market enabling a reduction of the TTR to approximately 1 day (1). Although some of these NAT methods offer partial automated solutions (e.g., nucleic acid extraction), many of them still require strict separation of test areas to avoid false-positive results and provide only limited hands-on-time reduction and simplification. In contrast, the BioFire® Filmarray® technology is a NAT method that is easy to use thanks to a closed process-a so called "lab in a pouch"-and provides the result within only 2 hours, including sample preparation. Besides the risk reduction of human errors due to the limited manual work involved, the automation can also lead to improved data integrity compared to the compendial method. This paper describes the roadmap of implementation of the BioFire^® Filmarray^® technology. The approach from feasibility studies to validation and regulatory submission for a monoclonal antibody (mAb)-based product is provided. As a first, J&J received regulatory approval from several agencies (including the US FDA and the EMA) to apply this technology for a biopharmaceutical product and has started global roll-out to additional products and testing sites. Understanding the risk concomitant with introducing new methods is essential to develop an appropriate validation, implementation, and filing strategy. The process applied at J&J for the first product will be shared in this publication.

Driven by more patient-centric at-home treatments, the pharmaceutical industry is shifting toward subcutaneous drug formulations, particularly for biologics. This aids in simplifying patient self-administration, improving adherence, and reducing healthcare costs. Hence, there is an increasing need for optimized drug containment systems, as these will frequently be used by non-professionals in home settings. This study evaluates the break-loose and gliding forces (BLGFs) as well as the inorganic and organic leachable profiles of cartriQ^® 3 mL ready-to-use (RTU) cartridges to ensure safe and effective drug delivery. The cartridges, made from FIOLAX^® clear Type I borosilicate glass, underwent hot forming into tubular cartridges, ensuring a hydrolytic resistance of not more than 80% of the ISO 4802-1 limit, followed by washing, siliconization, and steam sterilization. Testing was conducted after accelerated aging over up to 24 weeks at 40°C using ultrapure water, histidine buffer, and phosphate buffer as model solutions. Key performance metrics, including BLGF, siliconization performance, and levels of inorganic leachables, for example, boron, sodium, silicon, and select organic leachables, were assessed following ISO 21881 and ICH Q3D guidelines.

Sterile drug products' endotoxin specifications are set in accordance with a compendial method that considers a patient population's body weight and the threshold pyrogenic dose for the particular route of administration (e.g., parenterally, subcutaneously, intrathecally). These specifications are designed to prevent pyrexia (fever) from occurring. For intravenously derived products, the threshold pyrogenic dose is 5 EU per kg body weight. All clinical studies supporting the pyrogenic dose have only incorporated adult (>18 years) recipients of intravenous standard endotoxin. These studies have not considered the potential for children to respond differently to administered endotoxins. Here, an evaluation is reported using patient fever data from the FDA Adverse Events Reporting System (FAERS) to assess potential child patient age (<1 to 18 years) and body weight implications to parenteral product endotoxin specifications. Data indicate that the response to endotoxin by children is not uniform across the body weight range of individual age groups (<1, 1-2, 3-4 years, etc.). Furthermore, that children <3-4 years of age appear more prone to pyrexia. Notwithstanding the inherent limitations and caveats in this study, the sum aggregate of information suggests the necessary adoption of worst case (5^th percentile of population body masses) for children aged <3-4 years.

Mollicutes class (e.g. mycoplasma species) are notorious bacterial contaminants in eukaryotic cell cultures, known for being particularly difficult to detect and eliminate. Their presence can negatively impact the health of cultured cells, decrease bioreactor yields, interfere with in vitro tests and, in some cases, cause disease. Accordingly, mycoplasma testing represents a common bottleneck in the manufacturing process for which compendial mycoplasma tests may not be suitable due to their lengthy turnaround times. This is even more true, in the case of short shelf-life products, that requires short turnaround time for manufacturing. To address the need for more rapid test methods, pharmacopoeias have provided guidance on the use of mycoplasma Nucleic Acid Amplification Techniques (NATs) as an alternative to compendial methods for lot release testing and in-process testing. In this article, we summarize the discussion of a group of pharmaceutical experts who met to propose recommendations and a path forward for the method validation and method suitability testing of a new mycoplasma nucleic acid-based test, the BIOFIRE® Mycoplasma Test. In contrast to conventional NATs, which require a significant amount of hands-on time from highly skilled operators, BIOFIRE® Mycoplasma test provides a closed and fully automated "lab in a pouch" NAT system. This innovative solution offers minimal hands-on time, minimal user training and skill, and delivers the results in about one hour. This paper offers a summary of the different working sessions held outlining key recommendations for validating the BIOFIRE® Mycoplasma test for release of commercial drug products.

This white paper explores current practices and industry experiences for establishing the Limit of In Vitro Cell Age (LIVCA) in biologics manufacturing. As per the International Council for Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH), characterization and testing of banked cell substrate is a critical component of the control of biotechnological and biological products. Regulatory agencies require the establishment of LIVCA for the use of master cell bank (MCB) and working cell banks (WCBs) in commercial manufacturing of biologics to demonstrate that the maximum in vitro cell age of cells used in the production process has no impact on product quality and process consistency over the duration of cell culture expansion and manufacturing process. This white paper reviews the methodologies for genotypic, phenotypic, and product quality characterization for LIVCA while highlighting the necessity of aligning industry practices with regulatory expectations to expedite market approval. It discusses the strategies for implementing LIVCA, regulatory guidelines, expectations that shape different industry practices, and provides an overview of approval experiences including those based on data derived from production cells expanded under pilot plant scale or using representative scale-down models. Through a collaborative approach involving industry leaders based on an industry-wide survey coordinated by the BioPhorum Operations Group (BPOG), we aim to streamline and accelerate LIVCA timelines, while ensuring robust manufacturing processes and adherence to high compliance standards as companies design and implement their LIVCA strategies efficiently and effectively to support commercialization applications.

While alternative and rapid microbiological methods (ARMM) have gained broader acceptance in Europe and the United States, where guidance on their validation and implementation has been made available by the European Pharmacopoeia and United States Pharmacopoeia and their use has been supported by both regulators and industry groups, their adoption in other regions such as Asia Pacific has been more limited. This article aims to review the regulatory landscape for ARMM in the Asia Pacific region, focusing specifically on sterility and mycoplasma testing. It will examine relevant pharmacopoeial chapters and local guidelines in key pharmaceutical markets, including China, Taiwan, Japan, South Korea, India, Indonesia, Thailand, and Vietnam. The analysis will be limited to markets with their own pharmacopoeia, providing a comprehensive guide to navigating the landscape of existing and future regulations while assessing the readiness of these markets to adopt these new technologies.

The use of Bio-Fluorescent Particle Counting technologies as a rapid, alternative method to monitor microbial contamination in water and cleanroom air samples has been of interest to the pharmaceutical industry for several years. These technologies are a non-growth-based method that use the detection of particle scatter and intrinsic fluorescence to categorize detected particles as biologic or non-biologic. As a result, the systems report in a unit of measure not equivalent to the colony forming unit. Although guidance on the validation of alternative microbial methods is available, significant challenges can exist when validating non-growth based alternative methods compared to the growth-based compendial method. Collaborators in the Modern Microbial Methods (M³) industry working group provide thoughts and recommendations on a method validation pathway for the non-growth-based bio-fluorescent particle counting technology. Technology specific recommendations on the primary and secondary validation are provided with considerations on the applicability of individual validation parameters and associated acceptance criteria for this emerging technology that does not rely on the colony-forming unit.

Drug products and medical device extracts are chromatographically analysed via non-targeted analysis to detect, identify, and quantify organic leachables; GC/MS addresses primarily volatile and semi-volatile organic leachables. Identities of compounds detected by GC/MS are often secured by mass spectral matching (MSM), where the mass spectrum is compared to reference spectra from a spectral library. Compounds whose reference spectrum closely matches the analytical spectrum are candidate identities for the compound of interest. Even when rigorously applied, MSM can lead to incorrect candidate identities. Avoiding misidentifications is important as reporting misidentified compounds can severely impact toxicological risk assessment, potentially leading to false conclusions about patient safety. The retention index (RI) is an effective means of evaluating an identity secured by MSM. The agreement between an experimental RI and a reference RI likely corroborates or refutes an MSM identity, although in certain cases the RI comparison may be inconclusive. The use of RI matching to corroborate MSM-based identities was investigated. Experimental and calculated RI values from the NIST23 library were compared to experimental RI values. Both classes of NIST23 RI values correlated well with the experimental RI obtained for 3140 compounds with confirmed identities, leading to the development of a strategy where reference RI-information from NIST23 can be used to support, accept, or reject candidate MSM structures. Using a confusion matrix, it is concluded that within the boundaries set for mass spectral matching (MSM>85; top 5 ranked candidates), an absolute difference in RI between the experimental value and the NIST reference value (|ΔRI|) of equal or lower than 20 showed a high identification precision and corroborates proposed identified. A |ΔRI| value higher than 50 showed a very low precision, which consequently rejects these identifications. |ΔRI| values between 20 and 50 are indiscriminate, meaning that while the identity proposed via MSM is accepted, it is considered to be tentative and uncorroborated.