Abstract
There are now available to the biopharmaceutical industry several alternative and rapid microbiological methods (ARMMs) for the detection and enumeration of microorganisms during testing. Regulatory authorities are encouraging the biopharmaceutical industry to adopt innovative technologies. Together these methods will lead to improved monitoring and assurance of control of biopharmaceutical processes and manufacturing environments, as well as shortened cycle times in the supply chain. This paper addresses the need for a systematic and best practice approach to the evaluation, validation and deployment of these methods. The absence of such best practice has hindered the adoption of ARMMs, resulting in slow adoption. A nine-step framework and common language is described which can be applied by biopharmaceutical companies wanting to take advantage of the numerous benefits of ARMMs.
Abstract
Investigations into environmental monitoring (EM) excursions can be prolonged and do not always result in clear root causes or CAPAs. This paper outlines how bio-fluorescent 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 − supporting root cause analysis and remedial actions. The paper 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. Abstract
The release of the expanded USP in 2016 cast doubt over the validity of so-called probabilistic analytical methods, including one the biopharmaceutical industry’s most universal tests – the dye ingress method for container closure integrity With the dye ingress method ubiquitously used without issue for decades, this paper highlights the continued value and applicability of this and other probabilistic analytical tests. In addition, this paper also describes how any method, whether probabilistic or deterministic, stands or falls on the quality of its development and validation, and not necessarily on the properties of the test itself. The most important factor is to apply a test method is not how it is labelled, but lies in its development, qualification and whether it meets the need for which it is designed. Abstract
In 2014 uncertainty around regulation for container closure and integrity testing (CCIT) fed a perceptible shift in mindset across the industry, causing some concern amongst many subject matter experts in biological manufacturers. Their concern was that gaps in guidance was enabling skewed expectations such that they would promote 100% CCIT for the release of drug product batches. This paper addresses this concern by re-stating the principles of CCI, qualification, process control and in-process testing to establish the framework within all effective container closure integrity programs. It concludes that performing 100% CCIT does not provide certainty that a process is well controlled and introduces an additional step that is not always necessary or suitable for the high processing speeds in the industry. Abstract
USP published its revised and expanded guidance, USP, in 2016 ostensibly asking as many questions as it answered. Specifically, USP implies ’probabilistic’ tests such as the ubiquitous dye ingress method are inferior and proposes a preference for so-called deterministic tests. The added assertions that deterministic methods can achieve high levels of sensitivity and accuracy do not reflect the ‘real world’ experience of the industry’s CCI experts whose work with the newer methods highlight a range of improvements that must be addressed before such claims can feature in guidance. This paper makes the distinction that any method – probabilistic or deterministic – when properly validated may be regarded as acceptable, with no one method type worthy of a preferred status
Abstract
Finish Biopharmaceutical Drug Products for a Modern Age is a formulation/fill-finish eBook containing two articles. One of these articles, written by Scott Ewan BioPhorum Fill Finish facilitator, brings together details on activity in the Container Closure Integrity workstream. Abstract
Eudralex volume 4, Annex 1, the EU GMP for sterile products, requires that ″The integrity of the sterilised filter should be verified before use · · ·″ (1). Implicit in this requirement for a pre-use, post-sterilization integrity test (PUPSIT) is the rationale that the sterilizing filter could sustain damage during sterilization or use (i.e. subsequent to any pre-use test conducted prior to sterilization), causing a defect which would not be detected by the post-use integrity test. That is, that such a defect could be ″masked″ during filtration. To assess whether a filter defect could be masked by partial filter plugging the Consortium evaluated the impact of bacterial retention testing on the bubble point (BP) of the test filters. The paper concludes that filtration processes producing bubble point changes sufficient to present a risk of masking defects are not common, and detectable during the routine BCT. Thus the BP ratios observed during routine bacterial retention testing is one means to assess the potential of a given filtration process for masking of defects and can be considered when determining whether a PUPSIT should be implemented. Abstract
Stoppers are a known source of particulate contamination. This is, in part, due to various physical and technological limitations inherent to the stopper manufacturing process. As a quantitative control measure, stopper manufacturers perform a battery of release tests to determine lot acceptability against established quality standards. Among the universally required release tests is particulate load of a representative sample. Elastomer stoppers are commonly tested under guidance provided through ISO 8871-3. During BioPhorum engagement with several stopper suppliers, it became apparent that multiple elements of this particle count method — including, but not limited to, equipment, environment, and particle classification — varied across the different suppliers. Consequently, the BioPhorum Stopper Quality team determined a need to undertake a comparative analysis of the test methods and constituent variables that are currently utilized by stopper manufacturers. This paper is intended to highlight testing inconsistencies and drive the collaborative development of a more sensitive, harmonized particle count method. Abstract
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. Abstract
Environmental monitoring (EM) is a fundamental control for the biopharmaceutical industry yet available guidance is quite general and open to significantly differing interpretation. This makes the full justification of sampling plans challenging in the face of regulatory scrutiny and it difficult for organizations to optimize and harmonize controls across plants and networks. Using the heightened requirements in and around grade A areas, a group of industry subject matter experts have written this highly detailed best practice guidance on EM risks assessments and sample location and method planning, to provide clarity on how to monitor and control our manufacturing environments. This is the first such detailed standard and will be the basis for consistent application of current best practice; thereby minimizing the risk of regulatory scrutiny and non-compliance, supporting business continuity while reducing unnecessary monitoring to a minimum
Abstract
This Excel spreadsheet tool compliments the guidance document 'Environmental monitoring: harmonized risk-based approach to selecting monitoring points and defining monitoring plans'. This allows the user to assess a room against six factors, the amenability of equipment and surfaces to cleaning and sanitization, personnel presence and flow, material flow, proximity to open product or exposed direct product contact material, the need for interventions/operations and their complexity, frequency of intervention and score them Abstract
This benchmark details the current industry operating practices on gloves testing, surface disinfection and interventions in isolators. It includes the practices from 26 biopharma drug product sites from 14 member organizations. The survey has been used to share practices and consider the opportunities for joint improvement in the industry. in more detail the survey compares glove inspection both visual and automatic integrity testing, disinfection and cleaning methods as we as the use of H2O2. Interventions, their categorization, tracking and approval, operator qualification and the handling of door seal failures. Abstract
The loss or delay of a batch for glove failure and uncertainties of glove management are perennial concerns for aseptic filling operations. Written by a team of industry practitioners who create, justify and manage glove programs, this guide defines current best practice and the actions we can all take to reduce risk. Specifically it enables users to understand glove-related risks, facilitating deviation investigations and building confidence when presenting to inspectors. Helps users understand the rationale for supplier recommendations about glove lifecycle management. Reduces the need for users to develop their own glove lifecycle management strategies and standardizes the language for collecting data in and across companies, that will support future benchmarking and improvement. Abstract
While freeze-drying modeling is well established and documented, the extent of its application to routine operations, including development and manufacture, has not yet been fully realized. A survey, conducted by BioPhorum, revealed that only a few companies use modeling for scale up and transfer. For the last year, the collaboration has been combining individual company efforts with the aim of harmonizing best practices and helping to define minimum regulatory standards. This paper outlines different applications of modeling to freeze-drying of biopharmaceutical products at commercial scale. It also signals the intent of the BioPhorum to champion a wider adoption, and realize the full potential of modeling across the industry to standardize lyophilization practices, accelerate technology transfers and optimize operational performance Abstract
While freeze-drying modeling is well established and documented, the extent of its application to routine operations, including development and manufacture, has not yet been fully realized. A survey, conducted by the BioPhorum collaboration of major pharmaceutical companies, revealed that only a few companies use modeling for scale up and transfer. To address this the Fill Finish collaboration has been combining individual company efforts with the aim of harmonizing best practices and helping to define minimum regulatory standards. As a result of this during 2016 the Lyophilization team agreed an education package that details how an operation can develop, validate and utilize a computer model for a commercial scale lyophilisation system for parenteral drugs. This pack was presented to the FDA during Sept 2016. THIS PACK IS ONLY AVAILABLE TO MEMBERS OF BIOPHORUM FILL FINISH. If your company are members of BioPhorum Fill Finish, one of you colleagues will be able to give you access. If your company are not members of BioPhorum Fill Finish but you are interested please contact us to understand more Abstract
All companies need to classify the risks various types of visible particles provide. This is not a simple task and without a well supported, scientific basis companies lay themselves open to regulatory challenges and sometimes have to commit to questionable controls. The proof of concept, developed by a large group of industry practitioners, allows companies to underpin their particle classification practices with a rational, risk-based approach. It will not change how companies classify visible particles, but will provide a framework to support their current classifications. The methodology assesses a range of patient risk factors, such as the route of administration, and applies a simple scoring system to calculate an overall risk score for a visible particle in a product or presentation. When challenged by regulators or internal QA teams, the methodology helps companies respond to demands to change particle classifications using an assessment of risk, which in turn may save batches from being destroyed if a classification is unnecessarily severe. Abstract
This is the Excel spreadsheet based tool that compliments the guidance document titled 'An industry-wide standardized methodology and risk classification tool for particle classification in biopharmaceutical parenteral products' As such it enables users to enter product information and particle details and create a risk classification score in line with the guidance. Abstract
This article presents an update on the efforts of the joint PDA and BioPhorum collaboration workstreams—masking studies, historical data mining, filter manufacturing and use risk assessments and PUPSIT risk assessment and the development of a best practice guide. Abstract
This paper is one in a series of publications that are the result of the collaboration, and these should be considered together and viewed holistically in order to determine the best course of action with regard to PUPSIT. This paper examines the test process and looks at the results of potential masking of sterilizing grade filters. Abstract
This article draws conclusions from the scientific studies, workstreams, and publications delivered by the Sterile Filtration Quality Risk Management (SFQRM) consortium formed between BioPhorum and PDA. It uses those conclusions to provide guidance to industry (sterile drug manufacturers, filter suppliers, and regulators) on the use of quality risk management principles and scientific data to prevent undetected non-integral sterilizing filters. 