PDA Journal of Pharmaceutical Science and Technology

Quality by design is the foundation of the risk management framework for extractables and leachables (E&Ls) recommended by the Extractables and Leachables Safety Information Exchange (ELSIE). Following these principles during the selection of materials for pharmaceutical product development minimizes the presence of highly toxic substances and decreases the health risk of potential leachables in the drug product. Therefore, in the context of the broad arena of chemicals, it is important to distinguish E&Ls as a subset of chemicals and evaluate this relevant chemical space to derive appropriate analytical and safety thresholds...

The manufacturing of a wide range of biopharmaceuticals, from antibodies and vaccines to cell-based therapies, increasingly takes place in single-use processing equipment. Manufactured in clean rooms and sealed and sterilized, single-use systems (SUS) are ready-to-use and easily scalable. Controls in the ″clean-build″ manufacturing of SUS reduce the probability of occurrence of particulate matter in SUS. However, the size, complexity, and limited transparency of SUS clearly limit the detectability of particulate matter on the interior (fluid-contacting) surfaces of a SUS during a visual inspection, as demonstrated in a recent study...

In the development of a pharmaceutical drug product packaging an important step is to demonstrate acceptable levels of leachable impurities migrating from the packaging material into the drug product during its shelf-life and therapeutic use. Such migration processes can be quantified either by analytical methods (which is often challenging and labor intensive) or (in many cases) through theoretical modeling, which is a reliable, quick and cost-effective method to forecast the level of leachable impurities in the packaged drug when the diffusion and partition coefficients are known...

The Sterile Barrier is one of the most important aspects of the Container Closure Integrity (CCI) for a prefilled syringe (PFS or syringe). This crucial barrier enables the protection of the syringe contents from contamination. The plunger stopper (stopper) is naturally in a stationary position that is controlled by the static friction between the plunger stopper and the syringe barrel wall. When an applied force is greater than the static friction which is commonly known as the Break Loose force, the plunger stopper will move...

In this report, we introduce a rapid sterility testing method for cell-based preparations and its in-process control media/buffers. The selected Rapid Sterility Test (RST) in this work is based on the ScanRDI® system, which detects fluorescently labeled microorganisms with solid phase cytometry. ScanRDI® has been chosen due to its sensitivity for detecting viable microorganisms down to one microbial cell with a shorter time to detection compared to Compendial Sterility Test (CST) method. The RST was validated for a CAR-T cell-therapy product with 4 days of Time to Detection (TTD) and evaluated for in-process control of media/buffers with real time detection method successfully according to USP <1223>, Ph...

An important step in the development of a pharmaceutical drug product is to demonstrate acceptable levels of leachable impurities during the shelf-life and therapeutic use of the drug product. If the diffusion and partition coefficients are known, the concentration profile of a leachable impurity in the drug product can be predicted theoretically at a given temperature and time. With this objective in mind, kinetic experiments were performed to study the migration of low to high molecular weight organic compounds from mono- and multi-layer polyolefin films...

Adopting emerging microbiological methods is often desirable because it enables more advantageous, real time monitoring practices. However, when the newer method measures contamination based on a different detection principle and provides results that are based on different units of measure, a paradigm shift is necessary. That shift can be one of the most difficult challenges in any such project and requires careful consideration. In this paper, we explore the challenges presented by the Bio-Fluorescent Particle Counting (BFPC) technology, when considering that the traditional Colony Forming Unit (CFU) is the gold standard which any change is measured against...

During high-altitude shipping of pre-filled syringes, pressure differentials can cause the elastomer stopper to move unintentionally. This motion represents a risk to container closure integrity and drug product sterility. To understand and quantitate this risk, we combined high-accuracy laser measurements and numerical simulations of stopper motion. We tested the effects of syringe barrel siliconization, stopper design, syringe orientation, and altitude rate on stopper displacement; only the siliconization factor had a significant effect...

USP General Chapter <60> for the detection of Burkholderia cepacia complex (Bcc) members in non-sterile products became official in December 2019. This isolation method requires to confirm the identity of any growth found on Burkholderia cepacia Selective Agar (BCSA) by additional identification tests (refer to the Interpretation section). This article presents a singleplex PCR method to rapidly confirm the membership of any microbial grown on BCSA (& other nutrient medium) in the Bcc group. This method is cost effective as it does not require expensive equipment nor reagents; therefore, it can be easily adopted in the industry...

This commentary outlines a proposed approach for navigating remediation (non-routine sanitization) of contaminated affinity-based resins. Methodology for collection of relevant information and for subsequent decision-making is presented, along with a tool for determining risk to the process associated with proposed return-to-use of remediated resin.

The use of amplified Adenosine Trisphosphate (ATP) Bioluminescence has been established within AstraZeneca as a technique for assessing the sterility of drug product formulations. A platform validation was generated which challenged the technology with a range of organisms and inoculum levels, and the approach to onboarding additional drug products has been designed to maximise the understanding of the drug product behaviour when samples may be limited during the development phases of the life-cycle of a drug product...

Illicit pharmaceutical manufacturing, affecting the quality of drug products, has been frequently reported in Japan. Insufficient good manufacturing practice compliance and lack of quality culture in some pharmaceutical companies have been suggested as the underlying reasons for such cases. We aimed to focus on knowledge management and fostering of quality culture in pharmaceutical companies in Japan to understand their current situation and find a strategy for the availability of high-quality reliable pharmaceutical products...

The measurement of solution composition is proposed as an alternative to titration to determine titration volume, which is the figure of merit for evaluating the hydrolytic resistance of glass containers for pharmaceutical packaging. In the new method, instead of titrating the sample and blank solutions, their compositions are measured by inductively coupled plasma mass spectrometry, and these compositions are converted to titration volume using a set of coefficients and a simple equation. The coefficients were derived using the well-developed thermodynamic data and models for dilute aqueous solutions, which make it possible to calculate pH from solution composition and then simulate a titration as a series of pH calculations as titrant is progressively added to the solution...

With machine learning (ML) we see the potential to better harness the intelligence and decision-making abilities of human inspectors performing manual visual inspection (MVI) and apply this to automated visual inspection (AVI) with the inherent improvements in throughput and consistency. This paper is intended to capture current experience with this new technology and provides points to consider (PtC) for successful application to AVI of injectable drug products. The technology is available today for such AVI applications...

A Contamination Control Strategy (CCS) is a document which focuses on how to prevent contaminations with microorganisms, particles and pyrogens within a sterile and/or aseptic and preferably also in non-sterile manufacturing facilities. This document determines in what extent measures and controls in place are efficient in preventing contamination. In order to efficiently evaluate and control all potential hazards associated with sources of contamination within a CCS, the Hazard Analysis Critical Control Point (HACCP) methodology could be a useful tool to monitor all Critical Control Points (CCPs) related to various sources of contamination...

This publication reviews the reported 'rogue' behavior of biological indicators used for vapor phase hydrogen peroxide processes with attention to the aspects of BI design / configuration to identify factors which may contribute to the reported greater variance in resistance. The contributing factors are reviewed with respect to the unique circumstances of a vapor phase process that adds challenges to H2O2 delivery to the spore challenge. The numerous complexities of H2O2 vapor phase processes are described as these contribute to the difficulties encountered...

Prefilled syringes are commonly used combination products for parenteral drug and vaccine administration. The characterization of these devices are through functionality testing, such as injection and extrusion force performance. This testing is typically completed by measuring these forces in a nonrepresentative environment (i.e. dispensed in-air) or route of administration conditions. Although injection tissue may not always be feasible or accessible for use, questions from the health authorities make it increasingly important to understand the impact of tissue back pressure on device functionality...

The recent emergence of new drug technologies such as mRNA-based (messenger ribonucleic acid) vaccines developed to fight the outbreak of the Corona Virus Disease (COVID-19) global pandemic has driven increased demand for delivery solutions capable of withstanding deep cold storage conditions down to -50°C, and even down to -80°C. While significant data exist for deep cold storage in vials, little evidence is available for pre-filled syringes. Since pre-filled syringes serve as both the storage container and the delivery mechanism, there are additional risks to performance that must be evaluated, such as plunger gliding performance, syringe lubrication, silicone layer stability, and container closure integrity (CCI)...

This publication reviews the evolution of performance standards for aseptic processing as defined by regulatory, pharmacopieal and industry activities. The increasing rigor of the expectations for sterility testing, environmental monitoring and process simulation have made for improvements in capability for sterile manufacturing. The document explains why contemporary requirements are such that satisfying them requires a shift in operating practice from manned clean rooms to isolation technology.

Alternative and rapid microbiological methods are effective and profitable technologies that can be safely use in the pharmaceutical industry. This report studies the efficacy of the Soleris® direct yeast and mold automated method for the quantitative detection of C. albicans and A. brasiliensis at three different microbial bioburden. Validation testing was carried out using an antacid oral suspension (aluminum hydroxide 4% + magnesium hydroxide 4% + simethicone 0.4%). Equivalence of data between detection time vs...