PDA Journal of Pharmaceutical Science and Technology最新文献

Cobalt (Co) alloys are used extensively in a wide range of medical devices due to their biocompatibility, durability, and properties. In 2017 the European Chemical Agency (ECHA) proposed to classify Co metal as a category 1B carcinogen (i.e. presumed to have carcinogenic potential for humans), as a reproductive hazard category 1B (i.e. presumed human reproductive toxicant) and as a category 2 mutagen. Even more, the European Medical Device Regulation (MDR) requires that medical devices contain > 0,1 w/w of substances that are category 1 A and 1B (CMR). As far as the European Medical Device Regulation, it is not specified if the Co content and concentration had to be determined/measured on the entire product or only on the product components. The object of this work is the comparison of Co profile in three different suppliers of stainless-steel needles as is and after being processed (i.e. sterilized) and then provide the proper interpretation and application of MDR requirements. The study and the extractable profile demonstrate the low cobalt content on needles and on a total syringe, thus suggesting to consider the Co content only on the syringe component.

Luer systems, for example Luer-needle hub with syringe's Luer cone tip and its Luer lock Adapter, are common interface on medical devices. One of the key questions in this application is about the safety guaranty and dose accuracy. It is then crucial to study the sealing between these elements. In this study we combine the use of Finite Element Analysis (FEA) and Multiscale Contact Mechanics (MCM) to analyze the connectivity and sealing performance of a glass syringe and a plastic needle Luer hub.This methodology has been applied before to the contact between glass and rubber and this is the first time that it is used for the contact between glass and plastic materials. The use of FEA allows to calculate the contact pressures and the nominal area of contact. The surface topographies of the two surfaces were measured, over a wide wavelength range (mm to nm). Subsequently, the air and liquid interfacial flow (leakage) is calculated using Persson's MCM theory which considers the roughness and elasto-plasticity of the interfacial surfaces. The theoretical predictions are compared to experimental leak measurements by pressure decay method. Further analysis is conducted, evidencing the key features that are responsible for a good sealing.

This publication reviews the background that shaped the execution of moist heat for terminal sterilization across the global healthcare industry. Despite the clear benefits to patient safety afforded by terminal treatments, narrow regulatory expectations and misinterpretation of scientific principles progress towards broader implementation has been minimal. This paper outlines a means to expanded implementation addressing the need for balancing processing delivering sufficient lethality to reliably destroy the pre-sterilization bioburden while preserving the essential quality attributes of the product. This is accomplished by delivering the correct sterilization process with adjustments to the time-temperature conditions.

A robust environmental monitoring program is essential to properly estimate and identify microorganisms in cleanrooms, ensuring that microbial contamination remains acceptably low and that a good state of control is maintained in the manufacturing areas. The incubation conditions are important to support optimal microbial recoveries, considering that there is no single culture medium, temperature, and incubation time that can recover all microorganisms. In particular, molds are quite sensitive microorganisms, and some species may have very specific nutritional and environmental needs. In this study, a two-phase approach was used to identify a single incubation-temperature approach that could recover most of the cleanroom microbial flora, with a focus on molds. Phase 1 included a growth promotion study performed in the laboratory using pharmacopeial and in-house strains, comparing different media (Sabouraud Dextrose Agar [SDA] and Tryptone Soy Agar [TSA]) at single or dual incubation-temperature approaches for 5 or 6 days. Phase 2 was based on an in-situ study in which sampling was performed in different areas of a pharmaceutical facility and the recoveries at different incubation conditions were compared. In addition, extension studies of Phase 1 and Phase 2 were performed to get a better understanding of growth requirements for in-house molds. The results showed that an incubation on TSA at 25°C-30°C for 3-4 days was able to recover most tested microorganisms in Phase 1 and a large variety of microorganisms in Phase 2, indicating that the single incubation-temperature is an optimal approach for the recovery of microorganisms in cleanrooms. Exceptions were noted for one strain of the species Cutibacterium acnes, a microaerophilic bacterium for which anaerobiosis and higher temperatures were needed, and two mold strains (Sistotrema brinkmannii and Stereum hirsutum), indicating that those molds required a specific media (SDA) for their proliferation. The results showed that TSA incubated at the single or dual incubation-temperature approach cannot compensate for the absence of SDA for some environmental molds that may be atypical in cleanrooms. Therefore, in addition to TSA, certain monitoring with SDA at, for example, cleanroom entrance points may be beneficial to recover molds with very specific nutritional requirements.

In this study, a computational fluid dynamics (CFD) model was developed to predict all relevant phenomena occurring during a moist heat sterilization process at a high level of temporal and spatial resolution. The developed CFD model was used to simulate the distribution of, for example, pressure, temperature, and residual air within a large-scale industrial steam autoclave (multiphase flow models), which was not published until now. Moreover, the thermodynamic behavior and distribution of fluids and temperatures inside the sterilization load were simulated and were verified with measurements. Based on the obtained sterilization temperature profiles in connection with the sterilization environment (e.g., non-condensable gases, natural convection), bacterial inactivation could be simulated. A complete moist heat sterilization process was simulated, including all relevant phenomena inside an autoclave chamber and a Peritoneal Dialysis Bag System (PDBS), which represents a complex sterilization item. To verify the simulation results, simulated pressures and temperatures were compared with measurement data for both the autoclave chamber and the PDBS. The results show that the simulated and measured values were in excellent accordance. By using the novel CFD model, the distribution of steam and residual air inside the autoclave chamber, as well as the natural convection inside the sterilization load, could be precisely predicted. To predict the inactivation of Geobacillus stearothermophilus inside different moist heat environments, the CFD model was extended with bacterial inactivation kinetics based on measurement data. The simulation results clearly indicate that our developed CFD model can be used to predict the inactivation kinetics of bacteria, depending on the sterilization temperature profile of the sterilization process as well as the moist heat sterilization environment, and to resolve the kinetics in time and space. Therefore, the developed CFD model represents a powerful tool that might be used in the future to predict, for example, "worst case" locations for any given autoclave and sterilization load or any other relevant process parameter, enabling the operator to develop an effective sterilization process.

Leachables are quantified and identified to enable their quantitative toxicological safety risk assessment (qTSRA). The leachable's reported concentration and identity must meet certain quality expectations to be suitable for qTSRA. In this Correspondence, the author considers accuracy and protectiveness as competing key quality attributes and suggests that protectiveness is the proper quality attribute for qTSRA, as qTSRA is based on the foundation that a leachable's potential adverse effect on patient health and safety must not be underestimated. Considering this conclusion, means of making concentration estimates and proposed identities protective are discussed.

Challenges in manufacturing of high concentration antibody formulations have seldom been discussed. These are observed mainly form late downstream operations where antibody gets concentrated to its final strength, to final fill finish processing and containerization of the product. Present paper summarizes challenges typically observed in manufacturing and processing of high concentration antibody products and provides turnkey solutions to these typical challenges in order to have their consistent and robust manufacturing process. IgG1 has been used as model protein for studying the challenges and providing solutions to them. The late downstream challenges like increased viscosity limiting further concentration can be resolved by used of viscosity modifying agents in the formulation. Replacement of conventionally used 'A' screen membranes with 'D' screen or using single pass TFF can further provide advantage in targeting higher concentrations for same protein with lesser shear and aggregation. Using 0.5μm/0.2μm asymmetric or bilayered membrane instead of conventional 0.2μm membrane resulted in better flux while filtration of high concentration IgG1 formulation. In process holding time during filling operation was optimized to be <60min based on the nozzle drying time for high concentration IgG1 formulation. Appropriate control strategy of replacing filling nozzles and performing periodic fill weight check was proposed for fill finish process of high concentration IgG1 formulation.

Microbiological contamination may cause microbial proliferation and consequently additional problems for pharmaceutical companies through production stoppage, product contamination, investigations of process deviations, out-of-specification results and product disposal. This is one of the major concerns of the regulatory health agencies. Microbiological load (bioburden) may represent a potential risk for patients if the sterilization process is not effective and/or due to the production of toxins. Although bioburden can be eliminated by terminal sterilization or filtration processes, it is important to monitor the amount and determine the identity and characteristics of the microorganisms present prior to final processing. The application of microorganism identification systems is crucial for identifying the type of contamination, which can be extremely useful for investigating. The aim of this study was to evaluate the profiles of microorganisms identified in bioburden assays from solutions, culture medias, and products (SCP) from a pharmaceutical industry facility. From 2018-2020, a total of 1,078 samples from 857 different lots of SCP were analyzed and isolated microorganisms were identified. A prefiltering step was included after March 2020, in order to reduce the bioburden before sterilizing filtration. Criteria for the definition and management of microorganisms identified were evaluated after an integrative bibliographic review, and three groups were proposed (critical, objectionable, and nonobjectionable microorganisms). For the samples that did not include prefiltering (n=636), 227 (35.7%) presented microbial growth. For those that included prefiltering, before prefiltering (n=221), 60.6% presented microbial growth, and after prefiltering, this value was reduced to 4.1%, which can be attributed to a contamination during the sampling or a wrong filtering. From the samples that presented microbial growth, 678 microorganisms were identified as bacteria and 59 as molds and yeasts. A total of 120 microorganisms (56 and 27 Gram-positive and negative bacteria, respectively, 31 yeasts, and six filamentous molds) could not be identified, and the remaining microorganisms were classified as objectionable (n=507; 82.2%), nonobjectionable (n=103; 16.7%) and critical (n=7; 1.1%). Most of the bioburden species (>80.0%) were considered objectionable microorganisms. A process for classification and management of bioburden analysis results based on a literature review of pathogenic and physiological characteristics of the microorganisms was proposed.