PDA Journal of Pharmaceutical Science and Technology最新文献

An increasing number of pharmaceutical products require deep cold storage at cryogenic conditions, approximately -150°C to -190°C, to maintain stability and/or activity. Previous work has revealed that, at these extreme conditions, a typical pharmaceutical package configuration (vial, stopper, crimp cap) may lose container closure integrity (CCI) due to both the glass transition temperature (-55°C to -70°C) of the rubber stopper used to seal the vial and the different thermal expansion coefficients of the primary packaging components. Importantly, this type of temporary breach in CCI frequently reseals itself when the vial is brought back to ambient temperature. The following study illustrates a CCI test method using laser-based headspace oxygen analysis for identifying both temporary and permanent defects in vial assemblies exposed to cryogenic storage conditions. The method takes advantage of the nitrogen-enriched environment that exists in most cryogenic storage conditions. When vials are placed into cryogenic storage, the cold temperature creates a pressure gradient across the vial seal that, if a leak defect develops, drives nitrogen gas into the vial headspace and, thereby, decreases the headspace oxygen concentration for vials originally packaged with an air headspace. This decrease in headspace oxygen after the cryogenic storage period can be used to identify a breach in CCI, regardless of whether the defect is temporary or permanent. Experimental data obtained for three different vial types (a 2R glass vial, a 2mL plastic CZ vial, and a 2mL plastic Aseptic Technologies [AT] vial) demonstrated that this CCI test method can robustly and readily detect laser-drilled micron-sized positive controls down to 5 μm (the smallest defect size tested) in the body of the vial and type controls prepared using a Ø64 µm wire at the stopper-seal interface (effective defect size varied depending on the vial).

Joint presentation - Ecolab and HiTech Health (CDMO for CGT)The purpose of this presentation is to review the impact cleaning and disinfectant residues can present to an ATMP cGMP manufacturing facility and discuss how to assess and manage these residues.The term "disinfectant residue" can illicit different responses. For some, they pose a risk potential product contamination, or can alternatively be seen as evidence that cleaning and disinfection has been performed. For others it could be a sign of lack of control. With the most recent revision to Annex 1 there has been a renewed focus on control and removal of disinfection residues. This presentation will discuss how to minimize disinfectant residues by regime design and investigate the methodology associated to quantifying residues beyond subjective visual assessment.

The typing of micro-organisms in pharmaceutical factories often relies on expensive and time-consuming molecular techniques. So, the implementation of cheap, fast and reliable typing methods in the routine would speed up the investigation procedures improving the contamination control strategy. The Fourier-transform infrared (FT-IR) spectroscopy is a method that generates spectra, that enables to micro-organisms typing within 3 h. This study aimed to evaluate the FT-IR for typing S. epidermidis strains isolated from an immunobiological pharmaceutical industry in Brazil. Fifty strains were evaluated by FT-IR using IR Biotyper®. A dendrogram was created with the raw data to cluster the separation spectrum and the cut-off value was automatically calculated. Forty-four FT-IR profiles were obtained, a ratio of 1.14 strain/profile. From the five clusters formed, Cluster 1, 2 and 3 (6 strains) were isolated from environmental monitoring of air and operators (EMO). Cluster 4 (3 strains) were isolated from EMO and bioburden assays, suggesting that the environment could be the main source of bacterial contamination in the product analyzed in bioburden assay. Cluster 5 (2 strains) were isolated from EMO and a cell culture lineage used in quality control assays, suggesting that the environment could also be the main source of cell contamination.

Isolators play a critical role in protecting both the product and the environment, as well as the personnel involved in pharmaceutical manufacturing, analytical procedures, and sterility testing. Gloves attached to the windows and doors of the isolator are designed to facilitate intervention, testing, and safety. However, due to their inherent characteristics and vulnerability to puncture or loss of integrity, they are recognized as a significant potential source of contamination. In addition to the possible pathways of contamination transfer, the size of glove holes plays a critical role in determining the risk of contamination. In this study, chlorosulphonated polyethylene (CSM) gloves were exposed to an aerosol containing Bacillus subtilis or Staphylococcus aureus This assessment aimed to ascertain the integrity of the gloves' seal. It was postulated that, below a certain aperture size, gloves used in isolator systems could establish an effective seal even if the external surface of the gloves exhibited modifications. Calibrated holes of different diameters (0.3, 0.5, 1, and 1.5 mm) were created using a femtosecond laser drilling technology. The holes were located on the tip of the middle finger. Based on the context of our study, passage of microorganisms through glove holes of a certain size does occur. Under the experimental conditions chosen, the cutoff for passage was determined to be a 0.5-mm hole, regardless of the microorganism evaluated. Although this study has some limitations, including the lack of a panel of microorganisms evaluated and the investigation of a single glove type called CSM, the high level of "worst case" challenge conditions provides compelling data to support our results. It would now be interesting to carry out studies at different production sites to assess their risk of contamination and relate this to their glove failure.

A challenge facing the biomanufacturing industry is the lengthy timeline for quality control testing that delays critical go/no-go decision making for the rapid release of drug products. The recommended USP methods for bioburden and sterility testing are surface-spread plating method and direct inoculation method, respectively. These compendial methods are reliable; however, results take approximately 5-7 days for bioburden testing (USP< 61>) and no less than 14 days for sterility testing (USP < 71>). ATP-bioluminescence detection is a rapid microbial method (RMM) that can reduce the time to result for both bioburden and sterility testing, taking 18-24 hours and 6 days, respectively. This study aims to evaluate the performance of ATP-bioluminescence in comparison to compendial methods to understand the implications of using this technology in bioburden and sterility testing processes. The research conducted consisted of simulating contamination to assess the detection capabilities of the ATP-bioluminescence assay. Results from compendia and ATP-bioluminescence detection were analyzed for comparability. Findings from this study will provide insight on the use of this platform as an alternative tool for in-process testing.

In pharmaceutical manufacturing, benefit is conferred in detection of specified microorganism (i.e., Burkholderia cepacia complex (BCC), E. coli, Pseudomonas aeruginosa, Salmonella enterica) not readily identified by culture-dependent methods. It's logical to test for the presence of "specified microorganism" using metagenomic analysis before culturing a "specified organism", especially when the organism isn't easy to culture. We developed a metagenomic analysis during enrichment to identify specified organisms. The enriched bacterial community consisted predominantly of Bacillus spp. and Stenotrophomonas spp., each contributing about 97-99% to total taxon abundance in TSB and 1/10× TSB. The specified microorganisms that were observed were Clostridium spp., Burkholderia spp., and Staphylococcus spp. (0.04 - 0.07%) in TSB, otherwise Burkholderia spp., Pseudomonas spp., Salmonella spp., Staphylococcus spp. and Escherichia spp. (0.01 - 1.73%) in 1/10× TSB. PreQ0 biosynthesis (PWY-6703) and guanosine ribonucleotides de novo biosynthesis (PWY-7221) were the most abundant pathways in 1/10× TSB-24 h. BCC chiefly contributed to the toluene degradation (PWY-5180 and PWY-5182) pathways. Initial results demonstrate the potential of the metagenomic approach during enrichment in water-based environments. These results indicate that a metagenomic enrichment approach to evaluating water samples can be useful to monitor specified organisms over time, including oligotrophs such as BCC in 1/10× TSB.

The Milliflex^® Rapid System is a proven automated ATP-based solution used for rapid bioburden and sterility testing. Combining membrane filtration, ATP bioluminescence and imaging, it provides microbial enumeration in significantly less time than traditional methods. Detecting microbial contamination in cell-based products remains a challenge due to filterability issues and interference from mammalian ATP. To address this, a sample processing method has been developed using a selective cell lysis solution and a free ATP removal enzyme effective at both low and high mammalian cells densities. The processing of Chinese Hamster Ovary (CHO) cells ranging from 106 to 107 cells/mL with lysis solution eliminates the mammalian ATP background in 15 minutes. This requires a ratio of 4 mL of lysis solution per mL of sample at 106 cells/mL or 9 mL of lysis solution per mL of sample at 107 cells/mL. CHO cells were inoculated separately with 6 microorganisms including Cutibacterium acnes ATCC 6919 and then processed with the lysis solution before enumeration with the Milliflex^® Rapid System. Results showed a rapid enumeration of the 6 microorganisms with good recovery according to the control.

FDA recommends monitoring differential pressure across filter membranes during sterile filtration process validation. However, few resources are available to help pharmaceutical manufacturers anticipate expected differential pressures during sterilizing filtration of different solutions. To address this gap, Meissner evaluated differential pressures across different filtration membranes using various test solutions at increasing pump speeds. Specifically, we investigated differential pressures across sterilizing-grade PVDF, PES, and PTFE membrane discs, either in series or with downstream 0.4 μm PES analysis discs commonly used in bacterial retention testing. The test solutions employed for this study include saline, grapeseed oil, FBS, and DMEM cell culture media with 10% FBS. These solutions were chosen based on their differing physicochemical properties and their relevance to the pharmaceutical industry. This work will serve as a reference for pharmaceutical manufacturers and help them anticipate differential pressures across sterilizing filter membranes at different pump speeds based on the physicochemical properties of their drug products.

This paper is the result of a round robin activity run by the Technical Committee TC12, Pharma Packaging, of the International Commission on Glass (ICG). The study was motivated by a concern about the risk that the depyrogenation treatment of glass vials, when performed in an abnormal way that deviates from the usual procedure, may have a negative impact on the hydrolytic resistance of the container inner surface. The study was executed by using 10 ml clear type I Borosilicate glass vials representing four different compositions. For the applied depyrogenation process extreme parameters were chosen to with maximum temperature up to 400°C, exposure times up to 72 hours and different amounts of residual water inside as starting conditions. Those treated samples were tested in seven different laboratories as a round robin test.. A large amount of data was obtained, which clearly indicate that the hydrolytic resistance performance of the Type I Borosilicate glass vials is not affected even by such extreme depyrogenation conditions (e.g. 400°C, 72hours and not perfect dried inside). This is an important and useful result, both for glass and pharma companies, based on the 12.000 analytical data collected during the interlaboratory activity.