Abstract
Annex 1 of the EudraLex includes recommendations for filter integrity testing (FIT) of filters used for sterile filtration of sterile drug products. Manufacturers of low bioburden drug substances (DS) are seeking guidance on the appropriate strategy for integrity testing of filters used in bioprocessing. The BioPhorum Closed Systems in CNC Spaces workstream developed a risk-based (and value-driven) approach for FIT testing of sterilizing grade filters used in the manufacture of low bioburden drug substances. This study yielded key criteria which served as the basis of a decision tree model for when and where FIT should be implemented to mitigate the risk of contamination. The findings of the study and the decision tree model were compared to current industry practice. Strong alignment was evident, suggesting the model could be used by DS manufacturers to develop a robust strategy for FIT which is congruent with regulatory guidance - specifically EudraLex Annexes 1 and 2. The risk-based approach is recommended to avoid dilution of effort on unnecessary FIT controls and target critical FIT use-cases that increase process reliability and patient safety outcomes.
Abstract
This paper introduces scientific and technical perspectives and recommendations from industry peers including cell banking technical experts and regulatory representatives from across the globe, representing over 15 pharmaceutical companies. The paper proposes a risk-based scientific approach to qualifying replenishment working cell banks (WCBs) when they are manufactured with, and without, changes. A consistent technical approach to the qualification of replenishment WCBs by incorporating risk-based analysis enables appropriate planning, nimble operations and de-risks product supply for patients by preventing possible delays when replenishing WCBs.
Abstract
In this paper, a BioPhorum member team of experts in biologics and vaccines have summarized the current challenges linked to the registration of global products in Russian Federation. This paper describes some of the challenges faced by the industry in relation to current pharmacopoeial requirements for biologics and vaccines and presents a framework of options and activities that would lead to greater alignment with the ICH and the expectations of other regulatory agencies.
Abstract
This paper outlines the application of human performance principles to document design and provides guidance for how to implement this in a biopharmaceutical manufacturing environment, with proven results. A more effective system for creating and revising documents—specifically, one that is aligned with human performance principles—leads to reduced time spent revising documents, improved training and performance, and fewer deviations and CAPAs. By investing the time to understand how work is done and creating documents that align with the needs of the end-user and the realities of how work is performed, we can harness the reliability and promise of a learning organization that is steeped in the principles of human performance.
Abstract
This paper summarizes some of the approaches taken by the biopharmaceutical industry to optimize and/or minimize the number of post-approval regulatory notifications and/ or the variation categories associated with product lifecycle changes. It offers a summary of the systematic approach used in the industry for the demonstration of product and process knowledge and the definition of the appropriate process controls that will also allow future flexibility. This approach can mitigate supply issues that are prevalent in the industry by allowing easier transfers between sites, leading to significant benefits for the patients. There are no novel approaches described in the paper, instead this is a summary of current industry practice. It is intended that this paper is used to review current regulatory practices in existing organizations, and as a reference for new regulatory professionals and organizations.
Abstract
This papers propose a pragmatic, simple and regulatory-acceptable solution to the supply shortage challenges it currently faces. It explores the diversity of registration practices for innovative and complex materials and illustrates this through a survey of the current state. The paper then offers a simplified harmonized approach for registration of materials, through a mature definition of product quality approach. This third case study in the series looking at increasing flexibility by a change in radiation for sterilization. However, the same mature approach to the definition of product quality that was used in the previous two papers is also used here. By reviewing the attributes of a material that are critical to product quality and assessing the potential risks linked to the change of sterilization method, the team was able to propose a consensual industry view on the change from gamma to x-ray sterilization for this family of products.
Abstract
BioPhorum has defined a best practice approach to the registration of innovative and complex raw materials. The approach is based on quality by design(QBD) principles. It is applicable to different families of non-compendial raw materials in the manufacture of biologics. The approach has already been used by BioPhorum member organizations and accepted by national health authorities.
Abstract
The BioPhorum approach to the registration of innovative raw materials using quality by design principles, explored the diversity of registration practices for innovative and complex materials and illustrated this through a survey of the current state. This appendix consists of an introduction to Protein A, the process followed for identifying critical material attributes, and controls and principles for registration that would offer future flexibility of supply.
Abstract
This group supports the Environmental Protection Agency’s (EPA) efforts to protect public health and the environment through the Residual Risk and Technology Review (RTR) process and recognizes the need to develop stringent emissions standards to mitigate any potential hazards posed by Ethylene Oxide (EtO) emissions. However, they are also cautious of the impact these changes may have on the availability and timely delivery of biotherapeutics to patients who rely on them. Biotherapeutics, including vaccines, therapeutics, and other life-saving medications, play a crucial role in improving patient health outcomes and saving lives. For the biopharmaceutical industry, EtO sterilization is a critical process used to ensure product safety and efficacy. The EtO Response team raised several concerns regarding the potential impact of the proposed rule changes on the biotherapeutics market. This document discusses the concerns.
Abstract
Climate change and global warming resulting from greenhouse gas emissions are widely recognized as the biggest threats to global health. The healthcare sector is responsible for 4–5% of global emissions, more than 70% of which are driven by supply chains.
Abstract
Colombia decree consolidated feedback from the BioPhorum Post Approval Change Management workstream, Colombia sub-team. This content is only available to BioPhorum members.
Abstract
BioPhorum’s in-depth feedback includes 70 line-by-line, detailed comments, including the rationale for the points and any proposed changes/recommendations that are deemed necessary by the team to ensure a harmonized implementation across industry and regulatory agencies.
Abstract
The BioPhorum response to the Annex XV Report on the proposal for universal PFAS restrictions. It is considered by the BioPhorum collaboration that unless ECHA provide the biopharmaceutical manufacturing industry with appropriate exemptions or derogations to find, test and validate alternatives and execute a transition out of these materials (where alternatives are available), there will be a real threat to the global availability of critical vaccines and biotherapeutics.
Abstract
This paper is intended to be an all-inclusive manual (a one-stop shop) on change notification best practices for single-use biomanufacturing systems. A summary of previous publications is also provided. This includes improvement updates to the decision tree and supporting table based on user feedback. This paper delineates the main attributes of an effective supplier change notification program. The team’s vision for this toolkit is to facilitate adoption of these practices by the majority of end-users and suppliers in the single-use supply chain. In time, it is hoped that these practices will become reflected in quality management practices and in formal business agreements.
Abstract
Since 2017, it has been mandatory for suppliers of APIs, excipients and packaging materials to register their material in China on the DMF registration platform. While many agencies ask for details of a component’s quality and its impact on products, the Chinese requirements for 'high risk' materials, such as those used in biopharmaceuticals, also ask for historical information that is typically proprietary which many suppliers are reluctant to share. This paper summarizes the requirements for raw materials in other ICH countries and compares these to the Chinese approach. The paper also lists all of the details needed for the Chinese registration of biopharmaceutical products' raw materials in a single place, to help suppliers register their products into this vast market.
Abstract
The control of the environment around biologics manufacturing has historically been a key consideration for the design and operation of bioprocessing facilities to ensure product quality and safety. Facility design and control considerations for commercial biopharmaceutical manufacturing processes include environmental controls (e.g., temperature, humidity, and pressure), air quality (e.g., particulate and microbiological), facility finishes, gowning and flow procedures, equipment containment, system integrity, and cleaning procedures. This paper written in 2011 argues that advances in process technologies and analytics enables manufacturers to close, contain and monitor more of their process steps and operate effectively with closed systems. This paper was the precursor to studies to prove the principles that ultimately lead to the gude 'Data driven equipment and facility design case study' that is available here
Abstract
Moving low bioburden drug substance manufacture from inflexible operations in a grade C environment to a modern, flexible multi-product facility in a CNC environment will result in significant reduction in costs for the industry. Such designs provide superior benefits like energy conservation, reduced facility capital and operating cost, shorter facility construction and qualification times, enhanced facility throughput and operational flexibility, reduced cost of goods and speed to market; all while maintaining the highest product quality standards. Capital costs may reduce by 45 per cent and operational costs by between 50 per cent (energy) to 100 per cent (Environmental Monitoring). This document reports on the learnings from bioburden reduction studies on hybrid (stainless steel and disposable) functionally closed bioprocessing systems developed over three years in collaboration with the Biomanufacturing Training and Education Center (BTEC) at NC State University that support these developments. The study concluded that measures as simple as flushing with WFI may be successfully employed to effectively mitigate the risk of assembling and operating a modern hybrid closed bioprocessing system in a controlled, non-classified environment, and are more effective at preventing bioburden contamination than making an open connection in a classified cleanroom without a subsequent cleaning step.
Abstract
This paper discusses a systematic approach to assessing virus segregation measures, which can help biopharmaceutical developers achieve sufficient segregation for the low-pH inactivation steps in their downstream processes. It covers a process description, mathematical modeling, failure modes and the effects on viral clearance, and the importance of proper design.
Abstract
The existing model of locating biopharmaceutical manufacturing in classified cleanrooms is being re-examined as the biopharmaceutical industry aims to improve patients’ access to products by reducing costs, while maintaining assurance of product quality and patient safety. The evolution of verifiably closed-manufacturing technologies is replacing open systems, thus removing the need for the extensive use of costly, classified environments as a risk-mitigation measure. This article considers the potential additional risks that concurrent multi-product manufacturing in a common/shared ballroom facility introduces. The premise is that the concepts discussed in the prior publication and extensive use of closed processing in a CNC environmental are successfully applied. It also seeks to meet industry regulations for formal risk-management approaches (QRM) to the design of facilities, especially because the updated EU Annex 2 mentions risk early on and extensively. The focus of this paper envisages typical combinations of biological product classes within the same CNC ballroom facility.
Abstract
This paper is an interpretive response to Annex 2 of Eudralex—Volume 4; the European Union (EU) guidelines for good manufacturing practice (GMP) of medicinal products for human and veterinary use. The purpose of this paper is to share an interpretation of key areas of Annex 2, providing enhanced clarity for the industry. This paper supports a scientific and risk-based approach that identifies the biological active substance manufacturing requirements, and the types of control that meet those requirements. Its focus is around use of a QRM approach to assess environmental control requirements for a low bioburden drug substance process, and that use of closed systems is an effective way to reduce risk and this minimize need for environmental controls. Use of closed systems in reduced area classification enables a significant reduction in costs for the industry.
Abstract
This paper describes the tools, steps, and documents required to assess risk and qualify biomanufacturing facilities that use closed-system technologies. It sets the scene for closed systems and discusses the right approach, tools, and methods of implementing them in appropriately operated and non-classified zones. This is the first chapter in a series to be published over Q4 2023 and throughout 2024. Subsequent chapters will include the general philosophy of closed systems, standard terminology, and how to apply the risk assessment model.
Abstract
This 100 page guide and case study is a response to US Food and Drug Administration (FDA) 2011 process validation guidance on Stage 3, ‘Process Validation: General Principles and Practices’. It describes the approach commonly referred to as ‘Continued Process Verification’ (CPV). The paper provides guidance on what is CPV, why it is important, and how might it be implemented. It offers specific recommendations on the content of a CPV Plan, along with associated rationale. Produced through a large collaborative industry effort, these recommendations are modeled around a typical cell culture production process for making a fictitious monoclonal antibody product, described in the ‘A-Mab Case Study’. The paper is a key foundational document which introduces important topics such as an approach to legacy products and the validation of IT systems and their design. These important topics are then addressed in the following documents available from BioPhorum
Abstract
Continued process verification (CPV) provides ongoing verification of the performance of a manufacturing process and as such entails the processing of large amounts of data. This paper draws on the experiences of multiple biopharmaceutical manufacturing companies in validating the informatics components of their CPV programs. It sheds light on common issues and provides recommendations and best practices. Computer systems validation is relevant across the lifecycle of a CPV informatics solution. As such the papers scope includes the initial and ongoing activities and deliverables to determine that the solution meets its intended uses and other requirements, for example, data integrity and performance requirements.
Abstract
This guide to the implementation of continued process verification (CPV) across a portfolio of legacy products complements the foundational document 'Continued process verification (CPV): An industry position paper with an example plan' published in 2014. The guide helps biomanufacturers understand how to build efficient and effective plans for legacy products and links to QA systems, provides guidance on implementations across multiple sites and advises on discovery, disclosure and regulatory reporting.
Abstract
This paper describes how signals can be developed and evaluated in support of CPV in the biopharmaceutical industry. Implementation of CPV, in addition to meeting regulatory expectations, can also provide a basis for continuous improvement of production processes and hence greater consistency of product quality and assurance of supply. CPV involves gathering data related to CQAs and CPPs, as well as analyses that reveal any statistical signals that become evident over time. It is designed to detect variation within specifications. Thus, CPV is about maintaining control within specification and so does not normally lead to a formal investigation. This paper provides several examples of signal response and escalation within the quality system where necessary as a model of a risk-based approach to CPV.
Abstract
In 2014, the members of BioPhorum produced a 100-page continued process verification case study, entitled “Continued process verification (CPV): An industry position paper with an example plan”. This case study captures the thought processes involved in creating a continued process verification plan for a new product in response to the U.S. Food and Drug Administration’s guidance on the subject introduced in 2011. In doing so, it provided the specific example of a plan developed for a new molecular antibody product based on the “A MAb Case Study” that preceded it in 2009. This document provides a roadmap that draws on the content of the continued process verification case study to provide a step-by-step guide in a more accessible form, with reference to a process map of the product life cycle. It could be used as a basis for continued process verification implementation in a number of different scenarios, for a single product and process, a single site, to assist in the sharing of data monitoring responsibilities among sites, and to assist in establishing data monitoring agreements between a customer company and a contract manufacturing organization.
Abstract
This paper draws on the experiences of more than 20 biopharmaceutical manufacturing companies in creating CPV reports and integrating them with their APR processes to propose an approach that significantly improves efficiency while still complying with regulations and achieving the business benefits of a robust CPV program
Abstract
This article looks at the role of technology in the workplace and specifically how the Senior BioPhorum Connect group is addressing issues such as the use of remote working technologies, cyber security and digitizing the cGMP space.
Abstract
BioPhorum has developed a risk-based deviation management system (DMS). 13 member companies have implemented this approach, and summary data from these companies shows improved quality performance plus an average time saving of 22,200 work hours per site per year, which is equivalent to a $888k cost saving. This guide outlines the work of the BioPhorum DMS Workstream in defining and creating a simplified and effective risk-based deviation management system with advanced RCA methodologies, and a track-and-trending process of low-risk events. It includes everything required to build a risk-based approach to DMS, including the business case for change, the new process, risk-based tools, and a detailed sharing of post-implementation benefit.
Abstract
Conventional methodologies which conduct check-the-box “investigations” for every minor deviation, can lead to companies unintentionally instilling an over reliance on basic tools and running the risk of losing the point as to why deviation management is performed — to find and fix problems. They do little to help companies understand minor slips/lapses, nor do they enhance product quality or assure patient safety. This article published in the BioProcess International, proposed this risk based approach and provides guidance on how to make track and trend work in away that is consistent with other companies involved in the program. This risk based approach is based on dropping the investigation of each minor, low-risk events but effectively track and trending them, to free up significant resources to work on prevention, and driving improvement of quality at source. This has been implemented successfully by early adopters and they have had successful inspections from multiple authorities.
Abstract
This revised extractables protocol for polymeric single-use components in biopharmaceutical manufacturing is based on an extensive scientific review and represents the combined opinion of the biopharmaceutical manufacturers and, crucially, the supply chain. It will reduce costs and focus people on the important data points. The protocol provides guidance on the suggested methods for extractables studies, including sample preparation, extraction conditions, recording test-article sampling conditions, and reporting data from the analysis of extracts. Flexibility is built-in, allowing suppliers to alter many study parameters due to restrictions based on the use of SUS, physical form factor, chemical compatibilities, etc. The new protocol includes significant changes to the 2014 version, including the removal of 5M sodium chloride and 1% Polysorbate 80 as extraction solvents, the elimination of the time-point zero interval, and the elimination of elemental analysis of 50% Ethanol extracts.
Abstract
This toolkit gives users a set of tools to respond to problems and materials to include in their communications and operator training.It will help reduce product losses, investigations, manufacturing disruptions and the number of leaks. It equips industry with tools to help standardize the vocabulary around SUS anatomy and processes and expand its understanding of SUS abnormalities.
Abstract
This paper provides practical considerations and strategies for protecting cleaned equipment. It provides a justification and rationale for the acceptability of residual moisture following cleaning for routine reuse of equipment while promoting a post-cleaning condition of ‘drained’ after cleaning or ‘dry’ for process equipment intended for long-term storage. It also discusses the factors that contribute to residual water post-cleaning and the considerations, supporting rationale, and justifications to rationalize and justify what levels of residual water may be acceptable.
Abstract
Extractable and leachable (E&L) compounds associated with the use of polymeric single-use systems (SUS) are of primary concern due to their direct impact on product and patient safety. The 2014 Biophorum extractables protocol provided a standardized framework to conduct E&L testing and has been widely used by SUS suppliers as well as the end-user biomanufacturing companies. Since its implementation, several concerns associated with the testing methods proposed in the protocol have been raised by testing laboratories. A comprehensive review of the data generated using the 2014 BioPhorum extractables protocol was initiated by Biophorum’s Extractables and Leachables workstream to mitigate these concerns. This document aims to summarize the findings of the data review and make scientific, data-driven recommendations to address specific concerns about extraction solvents and testing timepoints. This review established that certain extraction solvents (5M Sodium Chloride and 1% Polysorbate 80) and timepoints (Time 0) proposed in the testing matrix of the 2014 protocol added limited value to determination of the full extractables profile. Such trends were observed for organic and elemental extractables alike. Based on these findings, specific recommendations about elimination of these solvents and timepoints are outlined in this document.
Abstract
Consistent reporting and presentation of extractable data by suppliers is critical to the fast and reliable assessment of single use systems by users for new solutions. The BioPhorum approach to reporting and presenting extractable data is now the industry standard and adoption of this approach enables all single use suppliers to fit together in an industry ecosystem that effectively supports the continued growth of adoption of single use technologies in biopharmaceutical manufacturing. This pack contains a guide and documents to help single use suppliers and integrators set up their webpages papers and present their extractable data in a way that aligns with the industry standard and extends the ecosystem. Once implemented this approach enables integrators and biomanufacturers to build an extractables profile for a system without needing to transcribe the data, saving time on new designs and minimising the need for expensive custom extractable studies.
Abstract
This guidance document and the accompanying XI risk evaluation tool define the BioPhorum approach to risk evaluation of X-ray irradiation for sterilization of single-use systems (SUS) and is a flexible resource for incorporation of supporting tools into end-user quality system documents. End-users are responsible for critically reviewing this content prior to application and selecting the aspects that are most aligned with internal procedures, as well as making refinements as needed to meet local requirements.
Abstract
The standardized extractables testing protocol provides suppliers with a set of procedures agreed upon as representative of a comprehensive range of conditions by a broad group of companies. Suppliers can use this to prepare standardized extractables test reports for single-use systems (SUS) components including, but not limited to, films, tubing, tubing connectors and disconnectors, aseptic connectors and disconnectors, sterilizing-grade and process filters, tangential-flow filter cassettes, sensors, valves, chromatography columns, impellers, and filling needles. This template supports the completion of the extractables test report.
Abstract
A standard process map providing industry with a set of simple tools containing a structured approach for materials introduction across the supply chain. This paper summarizes a stepwise process that can be used as a guideline for introducing a material to support new drug substance manufacture and can be used in conjunction with detailed, company-specific NPI procedures. In addition it is relevant best practice for cell and gene therapy manufacturers.
Abstract
One of the dilemmas companies face when driving down failures and near misses to 'zero' is what to measure. Conventional approaches often fail to support ambitious 'zero' performance levels and can discourage the right type of debates and discussions. This guide from the Human Performance (HuP) team explains how biopharma operations can understand and measure performance in the most meaningful way and how to capture risks and enable sustainable learning and improvement through the 'Family II' mindset. Piloted by four companies the guide explains how to measure success rates and encourage employee reporting, how to implement such reports, and management the communication around the program to help everyone get closer to the target of zero failures.
Abstract
In 2015 when the BioPhorum Human Performance team started to understand how the industry could reduce error rates many were seeing a plateau of performance. Industry data showed 50% of deviations were attributable to human error and that the error rate has been constant over several years. Comparing us to other high-risk industries with unparalleled levels of reliability, such as nuclear power and aviation, the team saw that changes that could be made with the integration of HuP into our operations. This article utilizes the experience of two large, global biotech companies, at the time to illustrate the pathways to integrate HuP and the benefits realized not just in human error reduction, but also to quality, safety, compliance, and on-time delivery—the critical measures that will make or break a biotech company’s performance.
Abstract
A well established Human Performance program will significantly reduce failures and deviations in any biomanufacturer's operation. Critical to this is the creation of a culture where leaders partner with workers to learn about what enables success and what creates challenges. This learning is most effectively done through first-hand observation, active listening and ensuring candid discussions about systems’ issues related to risk. Written by BioPhorum’s Human Performance Workstream, this guide details how to implement and maintain a leader observation and coaching program, what such a program entails, the expected benefits, the expectations for leaders and a suggested implementation plan.
Abstract
The Human Performance Assessment (HPA) tool is designed to enable a biopharmaceutical organization to assess its maturity in implementing a human performance operating philosophy, as well as plan next steps toward the biopharmaceutical blue-sky for human performance. The maturity profile describes a number of stages towards blue-sky performance in seven dimensions, each containing multiple lever attributes. This members only pack contains the, Human Performance Assessment too, a facilitator's guide to running the assessment and a full set of blinded member industry assessment results covering 2014, 15, 16, 17 and 19 when the overall score for existing companies moved from a level of understanding to one of competence. The workstream goal of reaching competence by 2020 was reached in a year early
Abstract
Errors are a part of life. With human errors accounting for approximately 50% of quality incidents and related problems within the pharmaceutical industry, the need to improve human performance in manufacturing operations is obvious. The purpose of this article is to describe error-proofing ways of structuring and writing knowledge documents, procedures, batch records, as well as practices for structuring, conducting, and documenting training to assure competence. These practices are recommended for adoption to shift the current 'training for compliance' paradigm to a 'training for competence' paradigm. It will also be demonstrated that a training for competence focus achieves GMP compliance. Results at Lonza have been encouraging, with human error-related quality deviations and non-conformities reduced by more than 40% across 13 sites globally within the first two years of the implementation of its Error Prevention System.
Abstract
For decades, the biopharmaceutical industry has trained its workforce with a ‘read and understand’ approach. This approach is outdated and ineffective at delivering effective learning and competent staff. This ‘Training for competence’ guidance enables companies to understand how their organisation compares to their peers, and to identify what ‘best in class’ looks like for operator training, and will help to identify how to implement this approach across their networks
Abstract
In 2016 BioPhorum members came together to consider how to improve the efficacy of their investigation and root cause analysis approaches. Considerable scope for improvement existed in the industry from improving training of investigators and better tools to analyses complex problems. This article this written by Clifford Berry and published in BioPharm International socialized the recommendations to a wider audience.
Abstract
In any industry, quality is the building block of everything. People are relied on to deliver the services and products customers expect and need. This is especially so in biopharmaceuticals. But what happens when things go wrong? And what makes them go wrong in the first place? The reasons are myriad but ‘human error’ is often cited as the cause of problems such as accidents, product recalls and patient safety issues. Unfortunately, a human error is not seen as an opportunity to learn, but as something that drains time, money and resources. Changing this mindset is crucial to a better understanding of how success and failure happen within an organization, and how to improve its potential to anticipate, monitor, respond and learn – the cornerstones of resilience. This paper sets out to accelerate industry’s maturity by building a greater understanding of what is desired and explaining how to get there. It provides proven guidance and a case study of why one company’s standard approaches to root cause analysis were ineffective at reducing repeat events – both minor events but also significant ones that caused a loss of product and production time, such as contaminations. It discusses how the culture of the company changed from one of ‘it only happened once’ with weak corrective and preventive actions, to one where ‘human errors’ were only considered symptoms of wider system-level problems in the organization.
Abstract
This members only toolkit provides all the guidance, tools, assessments and case studies from across the industry to enable a site or biopharma corporation to implement the best human performance best practices. Developed through the collaboration of more than 20 corporations, the efforts of innumerable practitioners, over more that six years. This body of work, that grew from benchmarking established practices in the nuclear and aerospace industries. Going deeper and wider then published guides. This material has enabled member companies to realise reductions in deviations, growth in real capacity and reductions in lead-times from improve right first time rates in operations.
Abstract
The Human Performance Workstream recognized the importance of effective investigation techniques during their collaborative work in 2016. The team conducted a survey of member companies and shared within the workstream a report with 14 recommendations, and 11 best practice company case studies. These recommendations and case studies were used to create an investigator training package for the industry, and to inform the contents of the human performance assessment tool, which the group uses to benchmark and improve human performance.
Abstract
A comprehensive response to ICH Continuous manufacturing of drug substances and drug products Q13 draft version. The BioPhorum team overall think the draft reads well and believes the concepts and ideas are aligned with BioPhorum thinking on continuous manufacturing for biologic drug substance and drug product.
Abstract
The aim of ICH Q12 is clearly stated as a framework to facilitate the management of post-approval CMC changes. This document in the industry response to an agency consultation on draft guidance on ICH Q12. The biopharmaceutical industry through these comments commends the agency on leading the way to the implementation of ICH Q12. The BioPhorum comments are heavily influenced by the principle of simplification, which is why our views sometimes differ from the draft guideline.
Abstract
This paper proposes a solution, applicable to all innovative and complex raw materials, to the challenges the biopharmaceutical industry faces with the registration of complex and innovative raw materials in Europe. The biopharmaceutical industry has designed a direct solution to the issue and identified a way to higher quality regulatory submissions, enhanced knowledge, understanding, control and robustness of its products and processes.
Abstract
Independent industry surveys have shown that concerns about extractables and leachables are the number one barrier to implementing disposables technologies. There is clear regulatory guidance around what is required by regulatory authorities such as the EMA, yet to date there has been limited or no information (consensus or best practice) on how companies should do this.
Abstract
The regulatory-intensive nature of the biopharmaceutical industry means that companies spend a significant amount of time and effort demonstrating to inspectors that what they set out to do is what they actually did – and equipment and facilities are no exception. However, the variable adoption across the industry of a risk-based approach has resulted in many inefficiencies, which prove both time-consuming and expensive. The first guide – Change Management for System Lifecycle – was born out of a flowchart depicting a proposed change control management strategy, with the idea being to stimulate discussion within member companies, confirm where accountabilities and responsibilities lie within their own organizations and also identify any changes that need to be made.
Abstract
This paper discusses the issues around trace elements and gives a suggested approach for developing a method for analyzing trace elements in cell culture media and hydrolysates. The approach is based on a ground breaking BioPhorum collaboration that shared blinded data and compared analytical methods between biopharmaceutical and media manufacturers.
Abstract
This paper gives a best practice recommendation for fingerprinting cell culture media. It includes a standardized analytical test method suite, a three-tier testing approach and flowcharts that guide the reader to choose a suitable media fingerprinting method based on their goals and the raw material properties.
Abstract
This peer-reviewed paper outlines the risk of aerotolerant anaerobic bacterial contamination during the manufacture of biologic drug substance and the challenges of detection. It examines the issues that manufacturers may consider regarding anaerobic bioburden testing during mammalian cell culture biologics processing, focusing on the detection of aerotolerant anaerobes. It also contains case studies from multiple biopharmaceutical companies, which detected Cutibacterium acnes (C. acnes), the primary anaerobe of concern. A survey of the BioPhorum Microbial Control Workstream found that more than half of the participants reported contamination events with C. acnes. This survey reported variability in the ability of the compendial microbial enumeration tests to detect C. acnes, thus presenting a challenge for bulk biologics manufacturers. This paper recommends testing conditions designed to increase the likelihood of detecting aerotolerant anaerobe contaminations.
Abstract
This paper provides general guidance on how to perform disinfectant efficacy validation and implementation. It includes how to ensure the concepts of disinfectant efficacy are understood, how to interpret facility data and use it to demonstrate control awareness for your facilities, and how to leverage the data to reduce redundancies in validation or verification. It also details an efficient way to qualify disinfectants without impacting the quality of the study. The recommended program could be more robust than any individual approach developed in any one site. As regulators now require thorough validation studies, the paper is not about why you need to do disinfectant efficacy, but how you do it so you can meet that regulatory challenge for study data and will help build a business case for change.
Abstract
The purpose of this paper is to provide guidance and drive consistency in regards to microbial control for manufacturers of low-bioburden bulk biologics. This paper provides recommendations based on biologics produced using cell cultures such as monoclonal antibody(mAb)-based products and recombinant protein manufacturing process. These recommendations, from the members of the BioPhorum Bioburden Working Group, are intended to assist biopharmaceutical manufacturers develop microbial monitor-ing strategies and product safety assessments. Each manufacturer is unique, therefore, alternative strategies maybe justified and/or qualified.
Abstract
Due to the potential for microbial colonization, affinity capture chromatography requires robust microbiological control. In this paper the BioPhorum Microbial Control team addresses the microbial risks and controls associated with affinity capture chromatography. Further the paper sets out an approach to improve understanding of the risks for bioburden, and manage these risks through effective controls during the chromatography process so that bioburden issues will be reduced.
Abstract
Mold impacts every biopharma company and the prevalence of mold events can be costly. This guidance recommends how biological manufacturers can refine their mold control strategy and develop control strategies for new facilities, processes and products. By putting the paper into practise, companies can be assured they are following best practice in isolating mold events, monitoring mold, and will see a reduction in the instances of mold and ultimately save significant drug substance costs.
Abstract
Unlike most analytical chemistry tests relying on validated automatic instrument systems from which the test is automatically performed, data are electronically recorded and archived; traditional microbiological tests are performed manually, and the results are generally obtained by visual examination and transcribed by hand. Ensuring data integrity in microbiological test data is fundamental and significant to drug product quality and patient safety. The soundness of traditional culture-based microbiological test data is largely determined by multiple factors including effective sampling, valid testing and appropriate result reading and interpretation. In this paper, the fundamentals ensuring microbiological test data integrity are discussed and qualitative risk assessment is performed for the traditional culture-based quality control (QC) microbiological tests requiring contemporaneous verification by the second person.
Abstract
Historically, the biopharmaceutical industry has relied on traditional pharmaceutical manufacturing practices to make and release products. This publication examines the future of biopharmaceutical manufacturing by presenting the vision of fully implemented in-line monitoring (ILM) and real-time release. This aspirational vision includes full ILM, predictive analytics and advanced process controls (APC) enabling release of product in real time, with concomitant predictive and preventative alerts and resolution of process, equipment and other production issues.
Abstract
Drawing on their real-world experiences, a group of experts drawn from 28 BioPhorum member companies has provided guidance on the detailed working methods that support a successful remote inspection or audit; for example, how to manage information flows between the inspectors and the site subject matter experts’ team. With the impact of Covid-19 likely to be seen for the foreseeable future, virtual inspections may be required for some time. This guidance will help all stakeholders prepare and to avoid the potential problems of remote inspections and audits.
Abstract
Chemistry, manufacturing, and control post approval changes are an intrinsic part of the life cycle of pharmaceutical products. In this paper, the authors examined the potential impact of such changes on the product quality, safety, and efficacy of biologics. Comparability studies and more specifically analytical comparability are introduced as one of the tools that can support both biomanufacturers and health agencies in ensuring that patient safety and product safety and efficacy is maintained through the proposed changes. Together with a scientific risk-based review approach based on product and process knowledge and the definition of acceptance criteria that will ensure that the product is “essentially similar”, what constitutes a holistic comparability study is detailed. ICH Guidelines principles and definitions are used throughout the paper to aid the reader with other appropriate references. Finally, two case studies are presented: change to the manufacturing facility of the drug substance, and change to the manufacturing process of a drug substance intermediate and manufacturing facility.
Abstract
As the first regulatory authority in Latin America to gain full membership of the International Council for Harmonization (ICH), the Brazilian Health Regulatory Agency (ANVISA) asked BioPhorum to support review of its Post-Approval Change regulation to bring it in line with ICH, but also global WHO guidelines . Brazil’s stability and manufacturing data requirements typically delayed submission of post-approval changes by several months to years. The paper demonstrates how to align the national regulation with international standards, resulting in quicker submissions as well as a more efficient review process for the agency.
Abstract
For multi-product biopharmaceutical facilities, setting the acceptable level of process residues following equipment cleaning is an important regulatory, business, product quality, and patient safety consideration. Conventional approaches for setting an acceptance limit for process residues have been based on the assumption that the active pharmaceutical ingredient (API) is chemically or functionally intact following the cleaning process. These approaches include Maximum Allowable Carryover (MAC) Health Based Exposure Limits and other “dose” or Permissible Daily Exposure (PDE)-based limits. The concept for cleaning acceptance limits based on intact product originated from the manufacturing of small molecule pharmaceuticals. In contrast biopharmaceutical products are large molecules that are likely to degrade and become inactive when exposed to cleaning conditions. Therefore, an alternative approach to setting cleaning acceptance limits for biopharmaceutical products based on the actual process residues that could potentially be present on production equipment should be considered. This paper, describes the methodology to assess and verify API inactivation during cleaning
Abstract
The EMA guidance, 'Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities' goes against current best practice for product changeovers (PCO) in the biomanufacturing industry, This paper is a response that sets out the currently accepted practices and controls in an evidence-based justification to help companies validate and continue working towards their implementation. The paper promotes: limited or no sampling at PCO, supported by cleaning validation, the use of alternative methods for calculating limits, eliminating the need for a health based exposure limit (HBEL) calculation, the necessary use of additional programs (e.g. eye-sight testing) and the generation of a robust risk assessment that align with industry practices.
Abstract
Product changeover is a process that prepares and configures the facility and equipment for the next manufacturing process, and includes actions taken to protect the subsequent process against contamination from the previous process. Historically, the change-over between two products within a multi-product facility has created a great deal of operational inefficiency. This paper shows how with the use of risk-based tools and supporting data, the changeover activities of multi-product facilities can be significantly reduced and, under well-controlled and characterized operations, concurrent manufacturing may be achieved. Specifically, the change-out of small parts and elastomers as well as the collection of changeover cleaning samples may be significantly reduced or eliminated. This article is primarily intended for the manufacture of bulk biologic drug substance; however, the principles may be applied to finished drug product as well.
Abstract
The primary objective of any biopharmaceutical product changeover (PCO) program is to employ control strategies before, during, and after the manufacturing process which will minimize the opportunity for cross- contamination when switching between products. Evaluation of the need for an elastomer change out (ECO) should be considered as a segment of an overall changeover assessment. By understanding the actual value of ECO in terms of the overall PCO program, and the other systems and procedures that are in place that protect against cross contamination, the need for ECO for every product changeover is not necessary. The purpose of this paper is to review the practice of ECO at product changeover, evaluate the need for an ECO using a risk based approach, and provide rationale for justifying the reduction or elimination of ECO at product changeover. Based on the experience in six companies and the use of elastomers in over 10 manufacturing sites. It outlines that using a risk-based approach to outline the rationale for reducing elastomer change-out at the biopharmaceutical change over.
Abstract
For multi-product biopharmaceutical facilities, setting the acceptable level of process residues following equipment cleaning is an important regulatory, business, product quality, and patient safety consideration. Conventional approaches for setting an acceptance limit for process residues have been based on the assumption that the active pharmaceutical ingredient (API) is chemically or functionally intact following the cleaning process. These approaches include Maximum Allowable Carryover (MAC) Health Based Exposure Limits and other “dose” or Permissible Daily Exposure (PDE)-based limits. The concept for cleaning acceptance limits based on intact product originated from the manufacturing of small molecule pharmaceuticals (1). In contrast biopharmaceutical products are large molecules that are likely to degrade and become inactive when exposed to cleaning conditions. Therefore, an alternative approach to setting cleaning acceptance limits for biopharmaceutical products based on the actual process residues that could potentially be present on production equipment should be considered. In this paper alternative approaches for setting acceptable levels of process residue are described building upon the basis that API inactivation by the cleaning process has been demonstrated.
Abstract
QC labs in biomanufacturing facilities are complex high throughput operations, that the manufacturing facility is totally dependant on for analysis and release of batches. In many ways QC labs and their support services are more like conventional 'factories' than the operations that they support in terms of processing volumes flows and human interventions. As such an optimized stable and effective lab operation can only really be achieve with the application of appropriate manufacturing best practices practices. But once developed it will deliver significant improvements for the entire manufacturing operation. This 'Members Only' navigation tool guides you to a comprehensive range of operational best practices that have been proven and validated in the industry to deliver highly lean and effective QC lab operations.
Abstract
It is impossible to define the raw materials used in the biopharmaceutical industry with a single set of regulatory or compliance criteria. What is considered fit-for-function changes depending on the product attributes and the intended customer. This tool standardizes and structures the risk assessment process, addressing three fundamental questions when determining raw material fit-for-function: What user requirement is the raw material designated to perform? What material attributes are essential to the designated function and what might have unintended consequences? This paper helps improve communication between – and within – manufacturers and suppliers and enables users to make uniform, evidence-based decisions on risks and priorities concerning raw materials. An industry-wide methodology for the resolution of high-impact raw material variability issues.
Abstract
This document communicates a strategic framework for solving technical problems relating to managing raw materials in the biopharmaceutical industry and encourages biopharmaceutical end-users and suppliers to work together to address specific raw material and end-user process needs. It highlights the importance of implementing industry solutions and sign-posts a range BioPhorum raw materials publications. These establish standard definitions, a common understanding of raw material requirements, and the importance of regulatory, quality, and supply chain links.
Abstract
The purpose of this best practice guide is to provide key information and best practices for media supplier partners and companies in the biopharmaceutical industry on the design, development and controls for manufacturing of media and medium solutions to minimize potential variation that may impact product quality, process performance and operational efficiency and costs. It is intended that it can be used to support a proactive approach to evaluation and self-audit of internal processes.
Abstract
Raw material variability and control in the supply chain are important matters for the biopharmaceutical industry. The industry is still working to align the supply performance with biopharma's needs. More still needs to be done to understand, monitor and control of raw materials. Patient well-being is best assured by reducing or eliminating variability of the finished drug product, and this can be achieved, in part by targeted reduction and/or elimination of variation in raw materials. This paper identifies ten areas of practice endorsed by leading global biopharmaceutical manufacturers to start to address and reduce raw material variation through our supply chains.
Abstract
This guidance document identifies the relevant change areas, and for each area, exemplifies the type of changes which the biopharmaceutical industry needs to be informed about. It also lists the required information, in terms of supporting data and documentation, to support notification of changes. This guidance is relevant to all raw materials used to produce biopharmaceutical products, including but not limited to cell culture media, fermentation broth components, column resin, buffers, solvents, and excipients. By highlighting the changes biopharmaceutical industry end-users need to know about and specifying the information required, the intention of this industry-aligned guidance is to reduce the quantity of rework required and the time taken to process change requests. In turn, this will reduce variability in demand patterns as end-users refrain from building extensive inventories to mitigate against the perceived risks which arise from proposed changes. While complete alignment and standardization on the information which should be provided for changes is not possible, a more robust alignment on the typical information required, as set on in this guidance, will significantly improve the current state.
Abstract
It is important for biomanufacturers to understand trace element variation within soy hydrolysates (by knowing the minimum, maximum and average concentrations), so they can determine if the degree of variation has an impact on their process. The knowledge gained through process characterization across the maximum variation found in soy hydrolysates can be evaluated to determine if it has an impact on the biomanufacturers’ process or product on a product-byproduct basis. This is the first in a series of proposed hydrolysate white papers. The purpose is to educate users of hydrolysates of the various characteristics that they should be aware of to manage their processes. There are many parameters to consider within a hydrolysate. The intention is to start with data that can be collected on as many different hydrolysates used in the biopharmaceutical industry.
Abstract
This guidance developed by BioPhorum's Reliability workstream enables biopharmaceutical companies to optimize their maintenance and calibration frequencies by assigning the correct ‘trigger’ for these activities. The intent is for the industry to move away from simply relying on time based maintenance routines. The guidance describes the various tools and processes available, as well as methods to implement change, illustrated by case studies. The Return on Investment (RoI) for optimization of maintenance frequencies is clear: direct reduction of maintenance man-hours and planned downtime, thus increasing plant availability. This translates to financial savings as well as increased production capacity.
Abstract
Run a Google search on ‘Maintenance Excellence and Reliability Engineering’ will get an indication how prominent the subject has become within the corporate agenda. This is particularly true of the biopharmaceutical industry where such concepts are becoming more widely adopted in attempts to reduce risk and costs. While leaders are pressing for wider adoption, organizations are often slow to adopt because many of the concepts are counter-cultural. Reliability Engineers spearheading the change find themselves constantly challenging existing mindsets, having to educate the non-believers by introducing sound reliability concepts. Across a large organization this becomes a difficult and time-consuming task. This brief Survival Guide, goes back to basics, focuses on common misconceptions and introduces the key concepts behind Reliability Engineering.
Abstract
The biopharmaceutical industry has for a long time suffered inconsistent reliability performance of valves and diaphragms. The cost of a single batch failure can run into the millions of dollars while unplanned production stoppage and contamination investigations consume vast amounts of resources. One cause can be poor maintenance practices by the user, but as lessons are learned and practices improved, the spotlight is shifted. End users increasingly expect valve and diaphragms to deliver more consistent reliability performance through better product design, reliability testing, and improved change control. To enable this much needed transition, the time is right for the biopharmaceutical industry and valve and diaphragm suppliers to change the way they do business with each other.
Abstract
This paper describes risk-based alternative strategies for defending the suitability of equipment and facilities requiring revalidation. These robust and risk-assessed approaches include real-time review, routine monitoring and in-/at-line alarms and measurements to help identify what data and testing are critical to assure the continued validated state of the equipment.
Abstract
In 2020 the Russian agency adopted a new testing regimen for biological imports, that moves from testing all batches to testing the first imported batches and then potentially only annually. While the changes are intended to support industry and align with procedures in other regions there is concern that some parts of the approach and unintended consequences may worsen the supply of biological products to patients. This paper makes a series of proposals and recommendations to mitigate these concerns and help alignment between the Russian Federation requirements and those of other prominent agencies.
Abstract
This paper discusses design challenges such as how biomanufacturers often use extreme measures to segregate a post-nanofiltration operation from a cell-culture operation – but use a common glass washer or clean-in-place (CIP) skid for cleaning and sanitizing components from the two operations. The article looks at this apparent contradiction by using a mathematical model to evaluate the potential carryover/crossover risk.It aims to simplify production facilities so that a manufacturer doesn’t have multiple systems performing the same task. This means lower costs and complexity and facilities that are quicker to build and operate.
Abstract
The single-use audit guide has been designed to help the auditor and auditee understand the areas of focus in SUS audits, referencing relevant requirements and SUS manufacturing ‘elements’. It is also designed to assist the auditor in reporting their assessment of SUS manufacturers to the end-user. It includes sections on general quality management system areas and products and production processes to consider. It is designed to be applicable to audits of single-use system manufacturers.
Abstract
Single-use technology is growing fast in the biopharmaceutical industry, but designing new single-use systems involves a long, iterative process between end-user and supplier to ensure quality, regulatory, and technical requirements are met. Wouldn’t it be convenient if all these requirements were captured in a toolkit? BioPhorum and BPSA have created templates aligned with industry standards (i.e. ASTM E3051) which will simplify the single-use design process. The Single-Use User Requirement (SUUR) Template helps end users to communicate process/application details and SU requirements to suppliers, who in return can affirm or describe their capabilities to meet these requirements. The Technical Diligence Templates are pre-populated with end-user requests for detailed information that describes how suppliers may fulfil specific user requirements. Supplier responses allow end users and suppliers to make informed decisions and reduce gaps in understanding. The Supply Chain Template allows end users to request supply chain-related information and gives suppliers with a dedicated document to respond to this request. These templates combine to provide the industry with a set of common user requirements, clarity on criteria for fulfilling these requirements, and a mechanism for transmitting supply chain-related information. Adoption of these templates will yield distinct advantages to both end-users and suppliers in terms of compliance, time, and efficiency. Quality and compliance is improved by documenting and aligning expectations. Further, the tools enable clear and consistent communication, fostering a right-first-time approach to the design of single-use components.
Abstract
The biopharmaceutical industry is increasingly dependent on the use of single use systems to enable manufacturing. These systems are often customised and built from many parts, from a range of component suppliers. Change notification and change management in this complex ecosystem is very difficult unless all suppliers, integrators and users follow the same system and standards for change notification. This guide provides guidance on the classification of changes, helping those implement the best practice establish consistency in their teams and thereby helping them adopt the change notification practices more effectively. Adoption of these practices enables your company to connect more effectively with the global supply chain and avoid the impact and delay from misunderstood change notifications
Abstract
For change notification practices to realize value the team recognized it is important that a critical mass of biomanufacturer and supply partner companies commit to and implement the same practices as others in the single-use ecosystem. The target was for 15 biomanufacturer companies and seven supply partner companies to implement these practices by the end of 2019, to create critical mass and a working system. The annual scorecard survey is a tool used to monitor the overall effectiveness of change notification for single use systems within the bioprocessing industry. The results from 2018 can be viewed here.
Abstract
The biopharmaceutical industry is increasing dependant on the use of single use systems to enable manufacturing. These systems are often customized and built from many parts, from a range of component suppliers. Change notification and change management it this complex ecosystem is very difficult unless all suppliers, integrators and users follow the same system and standards for change notification. This guide provides a definition of best practices that once adopted across the ecosystem will deliver an effective and harmonized change notification system between companies. Specifically it provides an understanding that all companies should categorize changes,standardizes content of a pre-notification and a notification and provides a reporting template, and workflow
Abstract
Technology transfer is a key foundational component in product commercialization. It is more than just the transfer of documents; it relates to all aspects of the transfer of knowledge and experience to the commercial manufacturing unit to ensure consistent, safe, and high-quality product. This is the first in a series of articles from the BioPhorum member companies discussing best practices and benchmarking of biopharmaceutical technology transfer. In this article, we provide the common terminology developed by BioPhorum to accommodate both transferring and receiving organizations. We also review the key elements of a robust technology transfer business process, including critical milestones. Finally, we provide a brief overview of the articles in this series.
Abstract
The technology transfer of biological products is a complex process requiring control of multiple unit operations and parameters to ensure product quality and process performance. To achieve product commercialization, the technology transfer sending unit must successfully transfer knowledge about both the product and the process to the receiving unit. A key strategy for maximizing successful scale-up and transfer efforts is the effective use of engineering and shake-down runs to confirm operational performance and product quality prior to embarking on good manufacturing practice runs such as process performance qualification runs. We consider key factors to consider in making the decision to perform shake-down or engineering runs. We also present industry benchmarking results of how engineering runs are used in drug substance technology transfers alongside the main themes and best practices that have emerged. Our goal is to provide companies with a framework for ensuring the “right first time” technology transfers with effective deployment of resources within increasingly aggressive timeline constraints
Abstract
The purpose of this paper is to stimulate debate in the biopharmaceutical industry and to work toward industry-wide alignment on the creation and use of optimized and lean user requirement specifications (URSs) for equipment, facilities, utilities and systems qualification.
Abstract
A proactive risk-based approach to understanding key factors that can introduce product variability is necessary to avoid delays. One such factor identified is elemental impurity variability introduced by cell culture media. Though the impact of the variability will differ, it is important that both manufacturers and supply partners understand the sources of elemental impurities and perform risk assessments to identify mitigation strategies. Such assessments will allow an understanding of the level of risk, and what steps may be taken to dissipate it. This paper is an effort to drive regulatory bodies, drug manufacturers, supply partners and N-1 suppliers toward a common understanding of the problem and possible solutions that can be taken towards risk mitigation. Though there may not be a single or ideal solution for this issue, a common rational approach can be taken by all parties to understand the impact on their processes and products, to drive identification of mitigation strategies.
Abstract
Shipping lane validation or qualification of thermal protection systems is not a simple task. Each pharmaceutical company and regulatory body use different standards leading to inconsistency. Vendors also do not have a standard for the specific tests that customers require. This absorbs huge amounts of resources for qualification testing, where work is unnecessarily repeated and existing data is not leveraged. To address this, the guidance details a best practice for standardized shipping lane validation that can deliver an annual saving of between $0.5m and $1m per shipping solution, a 50% reduction in resource requirements, and a reduction in product submission timelines by as much as 6-12 months.
