Clarifications on the Intended Use of USP <61> Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests.

In the execution of its legislated responsibilities, the United States Food and Drug Administration commonly refers to standard test methods detailed in the United States Pharmacopeia (USP). Microbiological test methods (contained in general chapters) are listed in chapters <51> to <80> with details regarded as enforceable where referenced as a test method. USP <61> "Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests" is a globally harmonized chapter that has been successfully employed for the enumeration of microorganisms recoverable from nonsterile finished drug products.

A Nontrivial Analysis of Patient Safety Risk from Parenteral Drug- and Medical Device-Borne Endotoxin.

Background: A thorough and systematic analysis of potential endotoxin-related safety issues from parenteral drugs and devices is important to ensure appropriate current Good Manufacturing Practices, compendial requirements, standards and regulatory guidance. Lately, the US Food and Drug Administration has been expecting pharmaceutical firms to apply an arbitrary safety factor to compendial compliant drug specifications for endotoxin, potentially causing manufacturing challenges, supply issues and additional unwarranted costs.

Objective: The aim of this study was to evaluate data from three disparate sources over an extended period of time, from 2008 to 2021, to determine if there exists an industry-wide risk to patients from parenteral drugs and devices, thereby evaluating if changes to current Good Manufacturing Practices or compendial requirements are indeed warranted.

The impact of ventilation rate on reducing the microorganisms load in the air and on surfaces in a room-sized chamber.

Hospital-acquired infections (HAIs) are a global challenge incurring mortalities and high treatment costs. The environment plays an important role in transmission due to contaminated air and surfaces. This includes microorganisms' deposition from the air onto surfaces.

Intravenous Oncolytic Vaccinia Virus Therapy Results in a Differential Immune Response between Cancer Patients.

is an engineered Wyeth-strain vaccinia oncolytic virus (OV), which has been tested extensively in clinical trials, demonstrating enhanced cytotoxic T cell infiltration into tumours following treatment. Favourable immune consequences to include the induction of an interferon (IFN) response, followed by inflammatory cytokine/chemokine secretion. This promotes tumour immune infiltration, innate and adaptive immune cell activation and T cell priming, culminating in targeted tumour cell killing, i.

Neoadjuvant Intravenous Oncolytic Vaccinia Virus Therapy Promotes Anticancer Immunity in Patients.

Improving the chances of curing patients with cancer who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, nonrandomized biological end point study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the presurgical intravenous delivery of oncolytic viruses to tumors.

Far-UVC (222 nm) efficiently inactivates an airborne pathogen in a room-sized chamber.

Many infectious diseases, including COVID-19, are transmitted by airborne pathogens. There is a need for effective environmental control measures which, ideally, are not reliant on human behaviour. One potential solution is Krypton Chloride (KrCl) excimer lamps (often referred to as Far-UVC), which can efficiently inactivate pathogens, such as coronaviruses and influenza, in air.

Sterility Assurance-Current and Future State.

Manufacture by aseptic processing accompanied by end product compendial sterility testing has been the predominant means of production and disposition of therapeutics requiring the critical quality attribute of sterility. Despite significant advancements in microbiology and epidemiology and innovations in therapeutic products and engineering, there have been minimal advancements in the standards and regulations governing the assurance of sterility. Furthermore, the assurance of sterility of current and future therapies are not well served in a singular fashion, rather therapies occupy optimal locations in a sterility assurance design space within which parametric release is the default and expected mode of product disposition.

Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21.

Background: The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested in combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, the design of successful combination strategies requires a deeper understanding of the mechanisms underpinning CVA21 efficacy, in particular, the role of CVA21 anti-tumor immunity. Therefore, this study aimed to examine the ability of CVA21 to induce human anti-tumor immunity, and identify the cellular mechanism responsible.

Fidelity to Science & Correct Scientific Vocabulary-Microbial Control Versus Contamination Control.

More than at any other moment in our history, it is imperative that we maintain fidelity to sound science and ensure the correct use of the associated scientific vocabulary. This is especially the case with respect to pharmaceutical microbiology and its practice in ensuring adequate controls in the manufacture of safe and efficacious therapeutics. Here, the current state of challenges and headwinds to pharmaceutical microbiology and how these are intimately linked with fidelity to sound science and the correct use of the associated scientific vocabulary are described.

The Boil Test-Strategies for Resistance Determination of Microorganisms.

The terminal sterilization of drugs and devices is the most appropriate means of assuring patient safety in terms of infection prevention. Adoption of terminal sterilization processes requires a supporting and thorough program for control and monitoring of bioburden, especially if a parametric release program of sterilization is desired. Such a control program should necessarily assess and evaluate the associated bioburden (primarily spores), which may resist inactivation and challenge the sterilization cycle.

Microbiological Test Data-Assuring Data Integrity.

Marketed drugs and devices possess specifications including critical microbiological quality attributes purposed to assure efficacy and patient safety. These attributes are legislated requirements intended to protect the recipient patient. Sampling, microbiological testing, interpretation of data for final products, raw materials, and intermediates all contribute to a cohesive assessment in the assurance of finished product quality.

Reducing hospital-acquired infection by quantitative risk modeling of intravenous bag preparation.

Vascular access of patients by peripheral and central venous catheters for the delivery of sterile or aseptically manufactured parenterals is commonly regarded as one of the major causes of blood stream infections. Rigorous evaluation and management of the risks of microbial infection originating from the administration of aseptically manufactured therapies remain imperative to reduce patient infection risks. Healthcare clinicians are continually faced with choosing intravenous (IV) parenteral administration strategies to minimize patient blood stream infection risk.

Quantitative risk modeling in aseptic manufacture.

Expedient risk assessment of aseptic manufacturing processes offers unique opportunities for improved and sustained assurance of product quality. Contemporary risk assessments applied to aseptic manufacturing processes, however, are commonly handicapped by assumptions and subjectivity, leading to inexactitude. Quantitative risk modeling augmented with Monte Carlo simulations represents a novel, innovative, and more efficient means of risk assessment.

Bacterial adhesion: considerations within a risk-based approach to cleaning validation.

Pharmaceutical manufacturing processes are vulnerable to varying degrees of microbial challenge (hazard) quantifiable as microbial ingress, and microbial retention risks affecting raw materials and inputs to the final product. Control over these risks is exacted by both purposefully designed and incidental (or fortuitous) properties of the manufacturing processes. Within the manufacturing environment, equipment cleaning and hold processes are uniquely prone to microbial challenge yet paradoxically demonstrate the greatest potential for mitigation of these risks.

Spo0A directly controls the switch from acid to solvent production in solvent-forming clostridia.

The spo0A genes of Clostridium beijerinckii NCIMB 8052 and Clostridium cellulolyticum ATCC 35319 were isolated and characterized. The C-terminal DNA-binding domains of the predicted products of spo0A from these two organisms, as well as 16 other taxonomically diverse species of Bacillus and Clostridium, show extensive amino acid sequence conservation (56% identity, 65% similarity over 104 residues). A 12-amino-acid motif (SRVERAIRHAIE) that forms the putative DNA recognition helix is particularly highly conserved, suggesting a common DNA target.

Ether-bond scission in the biodegradation of alcohol ethoxylate nonionic surfactants by Pseudomonas sp. strain SC25A.

Pseudomonas sp. strain SC25A, previously isolated for its ability to grow on alcohol ethoxylates (PEG dodecyl ethers) as sole source of carbon and energy, was shown to be capable of growth on the dodecyl ethers of mono-, di, tri- and octaethylene glycols. Comparative growth yields for this series of alcohol ethoxylate nonionic surfactants indicated that, whereas all of the carbon of monoethylene glycol dodecyl ether (MEGDE) was assimilable, only the alkyl chains were assimilated from the higher ethoxamers.

Selection in chemostat culture of a mutant strain of Clostridium tyrobutyricum improved in its reduction of ketones.

Growth of Clostridium tyrobutyricum on mannitol was possible only when an ancillary oxidant was additionally supplied. Hexacyanoferrate(III) in the presence of methylviologen could fulfil this role, which is normally better accomplished by acetate (and some other organic electron acceptors including acetoin, crotonate and 3-hydroxybutyrate). Several ketones, including pentan-2-one, although slowly reducible by the organism were unable to support its batch culture growth on mannitol.