PDA Journal of Pharmaceutical Science and Technology最新文献

RFID technology is mainstream in retail where apparel is tracked and inventory is managed with digital reader systems. All items at e.g. Walmart, Nordstrom and H&M are equipped with an RFID tag. Thus, warehouse managers and sales staff have full visibility on the movement and availability of items. The pharma industry is starting to follow this trend.

Prefilled Devices and Combination Drug Products, particularly those with integrated fluid paths or for specific Therapeutic Areas like Ophthalmology, may require final sterilization. Nitrogen Dioxide is a ground breaking novel sterilization technology designed to suit sensitive Prefilled Devices and Combination Drug products. This innovative sterilization process runs at ambient temperature and uses very low sterilant concentration. A SAL ≤10-6 is achieved in a few minutes of exposure, making this new technology highly efficient, without penetrating the drug reservoir. A case study will be shared, illustrating a validated process. This new modality will provide manufacturers with a new gas alternative to consider for their drug product to help ensure product safety for use in patients.

Needle clogging in prefilled syringes can impede drug product injection and negatively impact drug product quality. Computer simulations provide a useful tool to understand clogging mechanisms and elucidate design strategies to minimize or avoid clogging. In this talk, we present multiphysics simulations of clogging in needle syringes prefilled with a monoclonal antibody solution. We use these simulations to evaluate several putative clogging mechanisms, including: (1) fluid ingress into the needle and subsequent solvent evaporation leading to a dried solid plug, and (2) shear-induced jamming driven by rapid plunger compression. We study the impact of solution properties, needle diameter, barrel hub shape, and plunger speed on the onset of clogging. The effect of protein concentration on the solution viscosity is considered. Simulations such as these can offer insight into the critical material, geometric, and operational parameters that increase the probability of clogging, as well as a method to systematically triage drug product formulations based on their clogging probability. Based on these insights, we illustrate how simulations can be leveraged to effectively design prefilled syringes to minimize clogging probabilities for a given drug product formulation.

In February 2023 a restriction proposal to the European Chemicals Agency (ECHA) was submitted by five member countries of the European Union proposing a substantial restriction under the Registration, Evaluation, Authorization and Restriction of Chemical substances (REACH) regulation Annex XV for the use of all PFAS variants, thereby potentialy listing all PFASs as Substances of Very High Concern (SVHC).

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 media, and products (SCP) from a pharmaceutical industry facility. From 2018-2020, a total of 1078 samples from 857 different lots of SCP were analyzed and the 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 the 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%. Microbial growth recovered after prefiltration is likely to be attributed to contamination during sample collection or filtration. 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 Gram-negative bacteria, respectively, 31 yeasts, and 6 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.

Visual inspectors' ability to detect foreign matter in injections must be qualified for each product type or bracketing group, as stated in the United States Pharmacopeia <1790>. The common defect criterion is ″visible″ However, this qualitative lower rejection limit is based on the premise that the nature of human inspection at one site is globally comparable to that at all other sites. If not, the ″visible″ foreign matter can vary among inspector groups for each product, leading to quality differences between sites. Inspectors are trained and qualified using ″visible″ foreign matter samples from their site; therefore, inspectors' ability to detect foreign matter can differ due to different standards. Japanese pharmaceutical companies import injections and perform secondary visual inspections because variations in ″visible″ ability arise due to individual differences among regions. Currently, there is no universal method for comparing ″visible″ rejection zones among manufacturing sites for different products because product-specific standard samples for qualifications cannot be universalized. Therefore, instead of comparing the product-specific ″visible″ standard sample, this study proposes a novel universal particle standard challenge kit to compare sites' or inspectors' inner ″visible″ detection ability. Our results suggest that the proposed kit could evaluate the comparability of ″visible″ at each site and for each inspector but not on sites' ″visible″ standard samples. The primary challenge in implementing a universal standard lies in the inherent bias of inspectors already acclimated to specific products. This study found that an inspectors' foundational ability can be evaluated by canceling the bias via rapid and effective training in cases of simple standard samples. Our results suggest that using a universal standard kit to assess an inspector's fundamental ability to detect ″visible″ foreign matter is feasible. The study does not aim to replace the inspectors' product qualifications but to compare their inner ability for risk assessment.

Data from cell culture processes contain myriad parameters arriving sequentially in phases which may hold vital information for optimizing process runs and ameliorating manufacturing yield. This study analyzed temporal process data from 249 cell culture production batches of an active pharmaceutical ingredient at Roche's Location A manufacturing facility. The titer manufactured is utilized for Roche's Product X, a prescription drug that can treat adults with cancer. We aim to optimize the upstream production phase titer in Chinese hamster ovary cell manufacturing by identifying the most influential features. A phase-incremental (PI) decision tree method is proposed for feature selection and interaction exploration, being model and loss function agnostic while promoting early feature importance for prediction and process control. In this case study, the method is applied to Ensemble of Gradient Boosting Machines, using adjusted R-squared as the penalized loss function. The result leads to better process understanding and enables earlier control in the manufacturing.

A Contamination Control Strategy (CCS) is a strategy that focuses on how to prevent contaminations with microorganisms, particles and pyrogens and manages risks to medicinal product quality and patient safety within a GMP facility. A CCS should reflect on all proactive and retrospective data within a sterile and/or aseptic and/or non-sterile manufacturing environment, to identify all sources of contamination and associated hazards and/or control measures. It should outline associated Quality Risk Assessments (QRAs), Critical Control Points (CCPs) and suggest necessary control measures. An effective way to perform QRA for CCS is adopting the Hazard Analysis Critical Control Point (HACCP) methodology, a proactive risk assessment tool. This tool can be ideally used to monitor all CCPs associated with various sources of contamination.To keep the CCS effective, it is highly recommended to have the CCS reviewed by a multidisciplinary team and updated periodically, and to re-review it as necessary in the event particular issues arise. An annual review of the CCS effectiveness can be performed by constructing an assessment tool in the form of a report. The report provides an overview of all proactive and retrospective Quality Management System (QMS) related data that may have an impact on the CCS. This report then acts as a tool to drive continual improvement of the manufacturing and control methods, as required per EudraLex Volume 4 GMP guidelines Annex 1. This article describes a practical application of setting up an annual CCS assessment within a pharmaceutical manufacturing company to keep the CCS effective. This assessment will facilitate the process of reviewing the effectiveness of all control measures over time and facilitates escalation of issues that are not under control.

The detectability size threshold of visible particles ("visibility" size) in the context of visual inspection of parenteral drug products has been an elusive target for several decades. The current common sense, also reflected in official guidelines, dictates that particles of different shapes and morphologies have different "visibility" size thresholds, which can range between hundreds and thousands of micrometers. This study demonstrates experimentally for the first time that it is possible to define a single, shape- and morphology-independent detectability size threshold, identical across particles of various types, provided that observation conditions and product attributes are kept constant. We propose that, based on the physiology of human visual perception instead of single-dimension measures of particle size (e.g., diameter or length), such a single size-threshold requires the use of area-based size parameters (such as "equivalent circular diameter", or ECD. The experimental results reported here clearly demonstrate that the "visibility" thresholds for particles of various morphologies converge on a single ECD value. In addition, the data reported here show that product attributes, such as container configuration, fill volume, etc. influence the threshold of visibility. Collectively, the findings reported in this paper provide substantial evidence and scientific rationale, as well as unanticipated prospects for standardization of visual inspection qualification practices, ultimately leading to improvement of pharmaceutical product quality.