Best Practices for Microbial Challenge In-use Studies to Evaluate the Microbial Growth Potential of Parenteral Biological Products; Industry and Regulatory Considerations.

Microbial challenge in-use studies are performed to evaluate the potential for microbial proliferation in preservative-free single dose biological products after first puncture and potential accidental contamination during dose preparation (e.g. reconstitution, dilution) and storage. These studies, in addition to physicochemical in-use stability assessments, are used as part of product registration to define in-use hold times in Prescribing Information and in the pharmacy manual in the case of clinical products. There are no formal guidance documents describing regulator expectations on how to conduct microbial challenge in-use studies and interpret microbial data to assign in-use storage hold-times. In lieu of guidance, US Food and Drug Administration (FDA) regulators have authored publications and presentations describing regulator expectations. Insufficient or unavailable microbial challenge data can result in shortened in-use hold times, thus microbial challenge data enables flexibility for health care providers (HCPs) and patients, while ensuring patient safety. A cross-industry/FDA in-use microbial working group was formed through the Innovation & Quality (IQ) Consortium to gain alignment among industry practice and regulator expectations. The working group assessed regulatory guidance, current industry practice via a blinded survey of IQ Consortium member companies, and scientific rationale to align on recommendations for experimental design, execution of microbial challenge in-use studies, and a decision tree for microbial data interpretation to assign in-use hold times. Besides the study execution and data interpretation, additional considerations are discussed including use of platform data for clinical stage products, closed system transfer devices (CSTDs), transport of dose solutions, long infusion times, and the use of USP <797> by HCPs for preparing sterile drugs for administration. The recommendations provided in this manuscript will help streamline biological product development, ensure consistency on assignment of in-use hold times in biological product labels across industry, and provide maximum allowable flexibility to HCPs and patients, while ensuring patient safety.

Practical Applications of Biofluorescent Particle Counting in Environmental Monitoring Investigations.

Investigations into environmental monitoring (EM) excursions can be prolonged and do not always result in clear root causes or corrective and preventative actions. This article outlines how biofluorescent particle counting (BFPC) can be used in investigations to eliminate the inherent delays of culture-based methods. The application for investigations supplements routine EM, acting as a risk-reduction tool enabling real-time detection of viable microorganisms in air samples and supporting root cause analysis and remedial actions. The article includes guidance on how to use the technology, a real case study involving a mold excursion, and examples of business benefits achieved by various companies.

Continuous Microbiological Environmental Monitoring for Process Understanding and Reduced Interventions in Aseptic Manufacturing.

This paper provides recommendations for quality oversight, manufacturing operations, and industry perspective of regulatory expectations to enable aseptic facilities to move toward real-time and continuous microbiological environmental monitoring, thereby reducing interventions and future replacement of Grade A settle plates and nonremote active air sampling. The replacement of traditional monitoring with biofluorescent particle-counting systems provides an improvement in process understanding and product safety and reduces operator manipulations, assuring product quality and real-time process verification. The future state pharmaceutical technology roadmaps include gloveless isolators with real-time and continuous monitoring for aseptic manufacturing.LAY ABSTRACT: This paper advocates the use of an alternative and relatively new method of monitoring the air for contamination in biopharmaceutical manufacturing facilities. The alternative method is based on a type of instrument the authors refer to as a biofluorescent particle counter (BFPC). The BFPC method has the advantage of being able to detect airborne microorganisms continuously and to record the actual time of detection. The replacement of traditional monitoring with BFPC systems can provide better data, which can be used to improve the understanding of contamination risks in complex manufacturing processes, ultimately providing more confidence in product safety. The authors present data showing the suitability of BFPC. This immediate result is very useful for picking up early any possible contamination and should, therefore, provide a better way to monitor and control the risk of contamination. As traditional monitoring methods require manual manipulation, an additional advantage of BFPC systems is that they can reduce manual manipulations. Elimination of all interventions is a goal in the industry, because although they are tightly controlled, interventions are an unwanted potential source of contamination.