Legislative Disqualifications as Bills of Attainder

The separation of powers was first introduced into political discussion during the English Civil Wars of the seventeenth century by the political party known as Levellers. The object was to insure that persons be judged by general and prospective rules. If the legislative authority should decide a particular case, it might be tempted through partiality or prejudice to improvise a special rule for the situation. So the separation of powers was intended to achieve that impartiality in government which Aristotle called the rule of law. The doctrine of checks and balances was also introduced into political discussion during the Civil Wars, and with the Stuart Restoration in 1660 it became the official description of the English constitution. King, Lords and Commons were in a condition of equilibrium. Like three distinct powers in mechanics, they jointly impel the machine of government in a direction different from what either, acting by itself, would have done; but at the same time in a direction partaking of each, and formed out of all; a direction which constitutes the true line of the liberty and happiness of the community.\u27 By the time Blackstone wrote these words, the tripartite division of legislative power had already yielded to what we call today the cabinet system

Particulates reduction efforts in Single Use technologies: A case study

Single use technologies require a close collaboration between supplier and end-user with regards to cleanliness issues, primarily focused on particulate contamination. Since a large percentage of drug recalls relate to particulate contamination, and detection of a single visible particle in a dose of injectable drug is considered a critical issue and thus causes significant time and money to remedy, reduction of risk related to particulate contamination is of highest priority. Particulate detection is challenging in single use systems due to the complexity of the devices. As this presentation will show, concerted efforts to reduce particulate generation at all steps of the manufacturing process by using quality by design and risk reduction principles can bring large benefits. This presentation will detail the method used jointly by two suppliers along the manufacturing supply chain for vial stoppers and syringe plungers to improve quality and to decrease the risk of particle contamination in injectable drug products. The stoppering of a vial or prefilled syringe is a critical process step during the manufacturing of drug products since particulates remaining on the stopper or plunger could potentially end up in the product and lead to a product recall. Therefore it is necessary for the stopper supplier to have process capabilities with regards to particle contamination under control. Control starts from the design phase for the stopper, where it is critical to follow quality by design principles. An adequate cleanroom environment and good manufacturing practices drive the final cleanliness of the product, and it is critical to have a continuous improvement program in place. A process fish bone analysis and FMEA is the approach chosen for this case study in order to identify the risk of contamination and in parallel to improve the stopper manufacturing process including the final packaging. Thus, particulate reduction methods were applied all along the supply chain in a successful effort to reduce particulate contamination risk

Embedded particles in single-use films: Cosmetic defect or integrity risk?

Single-use films make up a large fraction of the surface area of single-use systems, and thus must meet stringent requirements not required for typical packaging films: high mechanical integrity and low levels of chemical leachables. Consequently, typical single-use films are relatively thick and contain much reduced levels of chemical additives (processing aids and stabilizers). Reduction of additives may result in a higher probability for finding gel particles embedded within the film. Gel particles, described as translucent unmixed or “un-melted” polymer resin perhaps with increased cross-linking or molecular weight, appear as “fish eye” shaped defects in the film. High temperatures within the extrusion process may chemically degrade gel particles, which then become amber, brown or black in color. In addition, the industrial scale and complex nature of film extrusion processes increases the risk for embedded foreign particle contamination in the film. Are embedded particles in single-use films cosmetic defects, or do they represent significant risk to process reliability (process integrity) or risk to product purity? In an attempt to quantify risk to integrity, tensile testing, flexural durability testing, and a unique pressure burst test were applied to single-use films with varying type and size of embedded particles. For embedded gels, the results show that only extraordinarily large gels impact tensile test results, and only very large gels impact burst test results. Limited evidence shows similar effects for embedded foreign particles. After flexural durability testing, no pinholes were found even when multiple embedded gel particles were present in the film. The test methods applied generate extreme stresses and strains compared to those found in real applications. In addition, the effects appear only with gels much larger than the detection capabilities of on-line inspection systems. Thus the risk of embedded particles to single-use film integrity appears low. Risk of embedded particles in film to product purity is addressed in a separate paper in this conference addressing overall particle contamination risk factors

Particulate contamination in single use systems: Measurement challenges

In conventional biopharmaceutical processes using stainless steel components, the pharmaceutical manufacturer is responsible for process cleanliness. However for single use systems, the pharmaceutical manufacturer “outsources” process cleanliness to the manufacturer of the single use systems, since no rinsing or cleaning occurs prior to implementation. Especially critical applications such as final fill and finish or aseptic processes demand a high degree of cleanliness with respect to particulate contamination. Although single use component assembly occurs in carefully controlled cleanroom environments, risks arise for particulate contamination from incoming components, cutting and welding operations, and human activity during manually intensive assembly processes. While visual inspection may detect “visible” (\u3e 100 microns) particles, the probability of detecting particles on fluid contacting surfaces within single use components remains low due to the difficulty of seeing through translucent or turbid plastics. Extraction (flushing, washing) of fluid contact surfaces allows collection of particles for quantitative microscopic analysis. While most single use manufacturers claim compliance with the USP 788 particles standard, USP 788 applies only to sub-visible particles in final injectable drug products, and does not describe particle extraction and counting methods for single use systems. This presentation addresses the scientific and technical challenges found in the development of reliable methods for particulates contamination measurement in single use systems. Automated microscopy measurement of particles collected on filter membranes, or counting of particles dispersed in liquid are imperfect but widely accepted methods. The main challenge resides in development of robust extraction methods, especially for complex single use components. The highly developed “technical cleanliness” standards (ISO 16232) for automotive components provide some guidance. Studies comparing rinsing methods with agitation methods, and studies comparing different extraction fluids (solvents vs. aqueous media) highlight the challenges in the development of methods for measuring particulate contamination in single use systems

Protection of Animals and Animal Experimentation: A Survey of Scientific Experts

This article summarizes information from a survey of biomedical scientists, specifically pharmacologists and toxicologists, on the use of laboratory animals and the potential for replacing their use with alternative methods for the development and evaluation of pharmaceutical substances. The majority of those surveyed felt that the alternatives could supplement or complement animal tests, but not replace the tests altogether. However, most favored the use of nonsentient material in safety tests

Protection of Animals and Animal Experimentation: A Survey of Scientific Experts

This article summarizes information from a survey of biomedical scientists. The survey focuses on pharmacologists and toxicologists, their use of laboratory animals, and the potential for replacing their use with alternative methods for developing and evaluating pharmaceutical substances. Most surveyed felt the alternatives could supplement or complement animal tests but not replace the tests altogether. However, most favored the use of non-sentient material in safety tests

Manual visual inspection for particulates in single-use systems: Method development and validation

Single-use systems (SUS) are used not only in upstream and downstream processing of biopharmaceuticals, but also in critical applications such as final fill and finish, aseptic processing of vaccines, and cell and gene therapies. Typically, SUS are not rinsed prior to application. Especially for applications of SUS downstream of final filters, SUS cleanliness with respect to particulate matter is of high importance since particulates on the fluid-contacting surfaces could detach and directly end up in the final drug product. Manufacturing of SUS occurs in a “clean-build” process within clean rooms. However, current SUS manufacturing technologies using cutting, welding and assembly processes often use manual labor and are not usually free of particulates. For the SUS supplier, an important part of the SUS manufacturing process is the final visual inspection of SUS for particulate matter and other defects. In addition, SUS end-users typically visually inspect SUS prior to implementation in biopharmaceutical processes. Currently, most SUS manufacturers manually inspect components and assemblies for visible particle matter without a deep understanding of all the factors which may impact the probability of detection. Significant challenges arise in visual inspection due to the often large dimensions of assemblies, and due to challenges with translucent and turbid plastic materials. Visualization of particles on the interior fluid-contacting surfaces remains a significant challenge. This presentation will show the results of the development and validation of a manual visual inspection method for loose particulates inside SUS. Carefully characterized test particles were seeded into single-use bag and tubing assemblies, and the probabilities of detection determined under controlled inspection conditions. The effect of particle size and particle type (black, clear, fiber), assembly type (bag, tubing), assembly size, lighting conditions and inspection timing were determined in designed experiments. The particle size visible in an inspection of a small vial of final drug product is typically around 100 microns. However, we find that for the visual inspection of SUS under optimized conditions with well-trained inspectors, good detectability of black particles starts at around 500-1000 microns in size, whereas fibers are not reliably detected at 2000 microns in length

Particulate contamination in single-use systems: real versus perceived risk

Certainly final drug products must be “essentially free” of visible particulate contamination and visual inspection systems must meet USP 790 criteria. In addition, final drug products must meet USP 788 limits for sub-visible particles. It is however important to distinguish final drug product standards from requirements for single-use process containers and equipment, even though it is common to claim single-use systems (SUS) “meet USP 788 requirements”. USP 788 does not describe a method for determination of particulate counts in SUS process containers and equipment (1). Visible particles are “visible” and thus a visual indicator of SUS quality, and consequently sometimes lead to visceral reactions and the perception of major or even critical risk to product safety. However, guidance from PDA TR66 (2), ASME BPE-2016 (3) and the BPSA (4) published in the last few years provide valuable information on assessment of particulate risk in SUS processes. In most situations where SUS are currently applied, filtration and purification steps occur downstream, which essentially reduces the risk to zero for transfer of particulate contamination from SUS to the final drug product. However, any applications of SUS after final filtration (such as in ascetic processes or final filling operations) present significant risk to drug substance or drug product. So is risk to final drug product from SUS an essentially a binary situation: Prior to final filtration low risk, and after final filtration high risk? While assembly of SUS is a “clean build” process usually done in ISO 7 classified cleanrooms, incoming components and cleanroom processes such as cutting, welding and human assembly are unfortunately not particulate-free with current SUS manufacturing technologies. In addition, visual inspection of SUS components and assemblies is nowhere near 100% effective at detecting visible particles, especially for large complex assemblies or stirred tank reactor systems. Sartorius is currently implementing a “Visible Particle Test” (VPT: liquid extraction and microscopy) for process monitoring and continuous improvement efforts. Thus while most SUS manufactures strive to minimize particulate contamination, absence of particulates remains a goal but is not a currently feasible SUS specification. Particle contaminants may lie within the interior surfaces of SUS (in the fluid contact path), may be embedded within bag films or plastic components, or lie on the exterior surfaces of SUS. Particulates fall into two general categories: intrinsic (particles from SUS manufacturing process and component materials) and extrinsic (particles from human operators or the environment). Extrinsic particles potentially contain microbiological or viral contamination. These classifications of location and particle type lead to different assessments of risk. One concern are potential “secondary effects” of particulate contamination. Particle contamination could potentially nucleate protein aggregation. Particles embedded in SUS films or plastic components, or on the interior surfaces of the SUS assemblies could potentially leach out chemicals or release microbiological or viral contamination into the bioprocess fluids. In this presentation, the topic of particulate contamination risk is approached holistically and scientifically using literature data along with calculations. The goal of the presentation is to gain feedback from end users, and to facilitate the discussion between suppliers and end users based upon real rather than perceived risks. (1) Particulate Contamination in Single-Use Systems, J. D. Vogel and K. Wormuth, Bioprocess International, 15(9) 2017 (2) Application of Single-Use Systems in Pharmaceutical Manufacturing, PDA Technical Report No. 66, 2014 (3) Bioprocessing Equipment, ASME BPE-2016, American Society of Mechanical Engineers, 2016 Recommendations for Testing, Evaluation and Control of Particulates from Single-Use Process Equipment, Bio Process Systems Alliance, 201