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.
The BioPhorum Report 2020 consists of industry views and opinions, and includes more than 50 interviews with industry leaders and subject matter experts. It highlights examples of how participating in BioPhorum, and applying best practices and learnings, have resulted in benefits for members, the industry and, ultimately, the patient.
As we find ourselves amid a global pandemic, BioPhorum’s collaborations and technical documents explore, propose and define industry best practices. The Report looks at how applying these guidelines can scale-up operations and get products to market faster, as well as delivering efficiency and cost benefits.
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.
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.
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
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.
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.
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
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
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.
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.
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
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
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.
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.
As the product in company pipelines increase in number and reduce in expected patient numbers there is a need to move from large batch, high-speed lines, to agile units that can rapidly switch between products. These changes are leading to innovation and creativity from equipment suppliers, but in addition customers need more standardization and fewer proprietary systems to aid with interchangeability, reliability and unit cost reduction. To make this happen in good order users need to ask for similar capabilities, using the same language to create necessary pull to influence equipment suppliers. This URS establishes an industry benchmark of flexible filling needs and serves to streamline the acquisition and approval of new equipment by pharma company leadership. It will enable the industry to bring products to patients faster and reduced costs through use of standard components and processes. Ultimately, enabling organizations to develop small-batch capabilities in preparation for the future of personalized medicines.