PDA Journal of Pharmaceutical Science and Technology最新文献

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.

As biopharmaceutical manufacturing evolves toward digitalization, the need for structured, interoperable, and regulatory-compliant data is intensifying. Digital Reference Materials (dRMs), the machine-readable counterparts of physical reference standards, have emerged as critical tools for enhancing data integrity, enabling automated quality control (QC), and supporting regulatory transparency. This article explores the definition, structure, and implementation of dRMs within the pharmaceutical landscape. It examines regulatory initiatives such as the FDAâs eCTD 4.0 and KASA, pharmacopeial digitization efforts, and pioneering commercial applications like Merck/MilliporeSigma's ChemisTwin™. Technical foundations, such as XML, JSON, and AnIML formats, are discussed alongside their integration into laboratory systems such as LIMS, ELNs, and CDS platforms. Special attention is given to the challenges of implementing dRMs in chromatography, where method-specific variability complicates standardization. Ultimately, dRMs are positioned as enablers of intelligent manufacturing, supporting AI-driven analytics, digital twins, and harmonized global quality systems. This work underscores the strategic imperative for stakeholders to invest in digital infrastructure, standards, and collaboration to fully realize the potential of digital reference materials in modern pharmaceutical development.

Alternative and rapid microbiological methods (ARMM) used in biopharmaceutical manufacturing have potential advantages over current compendial methods in that they can enable faster product release and improved process monitoring and quality assurance. There is value in community-wide discussion on ARMMs to help understand the challenges of ARMM adoption in biopharmaceutical manufacturing. The National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) attempted to understand the successes and challenges around ARMM adoption through surveys, interviews, and a facilitated Active Listening Meeting between industry and FDA representatives. Through these interactions, it was observed that many organizations have successfully implemented ARMMs in approved manufacturing processes, suggesting an absence of significant regulatory obstacles to implementation. Further, five key elements impacting technology adoption were identified: technology readiness, vendor support, organizational adoption readiness, business case/economics, and regulatory interaction. The Active Listening Meeting format proved valuable for fostering honest and informal conversations between both sponsors and regulators.

Drug product leachables are substances that are leached from the drug products manufacturing system components during manufacturing operations, drug product packaging systems during storage over shelf-life, and delivery systems during administration. Medical device leachables are substances that are released from medical devices during their clinical use. Thus, packaged drug products and medical devices are profiled for leachables (and/or extractables as probable leachables) to establish that the levels of leachables are sufficiently small that they present a negligible risk of adversely affecting patient health. This profiling is accomplished by screening the drug product or extracts of the medical device for released organic substances via nontargeted analysis (NTA) employing chromatographic methods coupled with mass spectrometric detection.The topics of how many possible organic extractables and leachables (E&L) there are and what are the most commonly reported organic E&Ls has been widely discussed in the E&L community of practice.One means of charting this universe of organic extractables and leachables is to review and collate those substances that have been encountered over the course of performing E&L studies. To this end, Nelson Labs Europe, a major contract research organization performing E&L testing for decades, has collated the results of several thousand E&L studies performed over the past several years, representing modern best practices in E&L assessment. These collated results, considering only those compounds reported with confirmed identities, are summarized and discussed herein. Although the use of compounds with only confirmed identities limits the number of considered compounds somewhat, so doing ensures that potentially false identifications and not published and do not result in a biased analysis of the collected information.