Rapid Sterility Test Systems in the Pharmaceutical Industry: Applying a Structured Approach to Their Evaluation, Validation and Global Implementation.

The current compendial sterility test has a 14-day incubation time and is often the time-limiting step in the Assess and Release Process of pharmaceutical products. There is an ever-increasing number of technologies available on the market that have benefits in addition to faster Time to Result, such as standardization and automation of readout (eliminating analyst subjectivity) and improved data integrity (including eliminating the need for contemporaneous verification of the result by another analyst). Regulators have been encouraging the pharmaceutical industry to adopt these innovative systems; however, it has taken a considerable time before receiving the first approvals from various health authorities (including both the European Medicines Agency and Food and Drug Administration) for the use of an alternative and rapid sterility test for the release of sterile drug product lots.

Non-inferiority testing for qualitative microbiological methods: Assessing and improving the approach in USP 1223.

The United States Pharmacopoeia (USP) presents two approaches for showing non-inferiority of an alternate qualitative microbiological method versus a compendial method. One approach compares the positive rates for the alternate and compendial methods at one spike level, while the other one compares multiple most probable number (MPN) estimates from a multi-spike design using a t-test. In this paper, we discuss these approaches under certain assumptions and propose a third approach that can be used for both single and multiple dilutions, which we call the generalized MPN (gMPN) approach.

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.

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.

A comparison of spiking experiments to estimate the detection proportion of qualitative microbiological methods.

The detection proportion of a qualitative microbiological test method is the probability to detect a single micro-organism. A general expression for the moment estimator of the detection proportion is provided. It depends on the distribution of the spikes used in a validation study through its moment-generating function.

Equivalence testing for similarity in bioassays using bioequivalence criteria on the relative bioactivity.

Similarity in bioassays means that the test preparation behaves as a dilution of the standard preparation with respect to their biological effect. Thus, similarity must be investigated to confirm this biological property. Historically, this was typically conducted with traditional hypothesis testing, but this has received substantial criticism.

A Phase 2 Randomized Dose-Finding Study With Esmirtazapine in Patients With Primary Insomnia.

The antidepressant mirtazapine is an alternative to classical hypnotics, and this study investigated the efficacy and safety of esmirtazapine (Org 50081, the maleic acid salt of S-mirtazapine) in patients given a diagnosis of primary insomnia after acute (2-day) treatment. Patients aged 18 to 65 years with primary insomnia were randomized to receive placebo or 1.5-, 3.

Validation of qualitative microbiological test methods.

This paper considers a statistical model for the detection mechanism of qualitative microbiological test methods with a parameter for the detection proportion (the probability to detect a single organism) and a parameter for the false positive rate. It is demonstrated that the detection proportion and the bacterial density cannot be estimated separately, not even in a multiple dilution experiment. Only the product can be estimated, changing the interpretation of the most probable number estimator.

A comparison of test statistics for the recovery of rapid growth-based enumeration tests.

This paper considers five test statistics for comparing the recovery of a rapid growth-based enumeration test with respect to the compendial microbiological method using a specific nonserial dilution experiment. The finite sample distributions of these test statistics are unknown, because they are functions of correlated count data. A simulation study is conducted to investigate the type I and type II error rates.

Is it possible to reduce the incidence of weekend oocyte retrievals in GnRH antagonist protocols?

A retrospective analysis of a large, randomized clinical trial (Engage) assessed whether adjusting the start day of ovarian stimulation and/or day of human chorionic gonadotrophin (HCG) trigger could minimize oocyte retrieval during weekends without adverse effects on clinical outcome. Patients received recombinant FSH/gonadotrophin-releasing hormone (GnRH) antagonist regimens, with stimulation starting on day 2 or 3 of menses. HCG was administered when at least three follicles of ⩾ 17 mm were present on ultrasound scan or 1 day later.

Comparative incidence of ovarian hyperstimulation syndrome following ovarian stimulation with corifollitropin alfa or recombinant FSH.

Corifollitropin alfa is a novel recombinant gonadotrophin with sustained follicle-stimulating activity. A single injection can replace seven daily injections of recombinant follicle-stimulating hormone (rFSH) during the first week of ovarian stimulation. All cases of ovarian hyperstimulation syndrome (OHSS) with corifollitropin alfa intervention in a gonadotrophin-releasing hormone antagonist protocol have been assessed in three large trials: Engage, Ensure and Trust.