- Email: [email protected]
Path forward
CHAPTER 10
Path forward Byron J. Lamberta, Joyce M. Hansenb a
Assurance of Sterility Task Force, ASTF, Abbott, Temecula, CA, United States J&J Sterility Assurance, Johnson & Johnson, Raritan, NJ, United States
b
Contents 10.1 What is next with combination products? 10.2 Sterility assurance landscape in the 2020s 10.3 Pan-industry sterility assurance risk framework 10.3.1 Sterility assurance risks in health-care facilities 10.3.2 Sterility assurance risks related to single-use products 10.4 What is next for sterility assurance professionals? 10.4.1 End-to-end sterility assurance 10.4.2 Bringing it all together in a risk management framework 10.5 What is next for the patient? References
239 240 240 241 241 242 242 243 243 244
10.1 What is next with combination products? Chapter 2 highlighted that combination products and biologics for regenerative medicine are bringing increased value to patients and increased need for creative sterility assurance solutions. In broader context, combination products, pharmaceuticals, and biologics are key for finding innovative solutions to the most challenging and pervasive unmet clinical patient needs in neuroscience, oncology, cardiology, and pulmonary disease. These four areas alone represent untold human suffering and a &45T economic burden to society [1]. Combination product opportunities for meeting patient needs and related challenges for assuring sterility are further elevated with bioabsorbables, microelectronics, and multiple active agents. Sterility assurance professionals need to facilitate these innovative products with timely solutions for sterility assurance challenges so that the pipeline of new products for needy patients is not unnecessarily restricted.
Assurance of Sterility for Sensitive Combination Products and Materials https://doi.org/10.1016/B978-0-12-805082-8.00010-4
© 2020 Elsevier Inc. All rights reserved.
239
240
Assurance of sterility for sensitive combination products and materials
10.2 Sterility assurance landscape in the 2020s Sterility assurance has many challenges; ongoing and new solutions are required for • high volume sterile commodity products that keep health-care facilities meeting the needs of patients worldwide; • now common combination products such as Drug Eluting Stents (DES) and prefilled syringes; • innovative and complex combination products with development time scales of 5–15 years that do not have simple sterility assurance solutions; and • all forms of personalized regenerative biologics and cell therapy products that may require transformative approaches to sterility assurance. This picture is complicated by current and future realities of the terminal sterilization technology landscape. Moist heat, radiation, and ethylene oxide sterilization have been the workhorses of the industry for decades, with the latter two dominating the market for heat-sensitive health-care products. Both radiation and ethylene oxide technologies are experiencing market pressure; 80% of the radiation sterilization market uses gamma radiation sterilization utilizing the isotope cobalt 60. There continues to be manufacturing, transportation, disposal, and terror threats related to this technology. Electron beam and x-ray radiation sterilization are alternative technologies but often include cost concerns, especially with commodity products [2]. Ethylene oxide sterilization is increasingly under pressure from environmental health and safety perspectives [3]. Although alternative gas technologies are available, they are still in the early stages of the development to meet supply chain needs. Innovation and new sterility assurance paradigms are required on many fronts. Required sterility assurance focus areas include new sterility assurance technologies (Chapters 3 and 4), a pan-industry risk framework (Section 10.3), and highly competent sterility assurance professionals (Section 10.4).
10.3 Pan-industry sterility assurance risk framework To meet the needs of patients for innovative new products, sterility assurance professionals need to see beyond the boundaries of their industry segment. The first step toward this broader patient-focused sterility assurance approach is seeing what the patient cares about: receiving valuable new products in a timely manner while reducing the risk of infection.
Path forward
241
10.3.1 Sterility assurance risks in health-care facilities To reduce the risk of infection around the world, the greatest need for patients is increased focus on and innovation in reducing health-care associated infections (HAI). As highlighted in Chapter 6, the realities of 2%–30% infection rates in health-care facilities is a staggering risk to patients and families and financial burden to health-care systems. Ongoing focus on basic controls related to hygiene, good hospital practices, and consistent long-term wound care continue to be critical. Discerning analysis and collaborative solutions are required. Directly related to HAI is sterilization within the health-care facilities in central sterilization departments, and in particular, sterilization of reprocessed devices. Reusable devices such as endoscopes can be challenging to disassemble, clean, and sterilize with tragic results when operational pressures lead to poor practices (e.g., insufficiently trained sterility assurance staff succumbing to time pressures from overbooked operating theaters).There has been significant focus and progress related to device design and process standardization in this area [4], and ongoing diligence in this complex area is critical. These compelling concerns need to get framed appropriately in order to pave the way for what could be a new wave of very valuable products for patients that could be manufactured directly in health-care facilities— regenerative medicinal biologic products. This opportunity also frames the need for innovation in the broader product development and regulatory paradigms being developed. There is a compelling need for clarity and thoughtfulness for sterility assurance professionals.
10.3.2 Sterility assurance risks related to single-use products Moving out of the health-care facility, the sterility assurance professional needs to put the risks related to terminal sterilization and aseptic processing into broad perspective. When validated and controlled appropriately, terminal sterilization provides reproducible and validated logarithmic reduction of product microbial load while being contained in sterile barrier systems that prevent further contamination. This provides very high confidence in robust sterility assurance. It is the preferred approach to provide sterile product [5]. As discussed in Chapter 3, established moist heat, ethylene oxide, and radiation sterilization technologies have served the terminal sterilization industry well for decades. The industry has significant innovation within these established options as well as a growing array of technology options for terminal sterilization [6].
242
Assurance of sterility for sensitive combination products and materials
When terminal sterilization at a sterility assurance level of 10−6 is not possible, the well-traveled option that has also served the industry well for decades is aseptic processing (Chapter 4).When validated and controlled appropriately, aseptic processing maintains the sterility of sterile components and produces sterile finished goods within sterile barrier systems/container closure systems that do not allow further contamination. Innovation in this industry segment is providing technologies and environments in which it is increasingly simple and robust to combine sterile components into sterile products. In addition to aseptic processing for product that cannot be terminally sterilized at an SAL of 10−6, the less well-traveled option is the use of alternative SALs. As discussed in Chapter 9, this option was recently framed within ISO [7] and has been available longer through Association for the Advancement of Medical Instrumentation (AAMI). The increased clarity in this option of providing reliable and acceptable sterility assurance for needed products should well serve the industry as well as the patients. Chapter 7 enhances this clarity by providing a unique and broad perspective on how validation sample sizes for packaging, aseptic processing, and terminal sterilization fit into, but are not the whole story, for assuring sterility.
10.4 What is next for sterility assurance professionals? The final area of sterility assurance focus to support innovation in meeting patient needs is highly competent sterility assurance professionals. Within health-care facilities, professionals experience enormous challenges under the pressure of immediate care for patients. This requires great competence and is likely the most important point of focus for patients from an infection risk mitigation perspective.
10.4.1 End-to-end sterility assurance Sterility assurance professionals in industry providing single-use products are well served by a broad understanding of all industry segments. This can be understood in a framework of the entire product life cycle or ‘end-toend sterility assurance.’ In the product R&D planning phase, knowing the innovation within established terminal sterilization technologies as well as innovation in novel sterilization technologies optimizes the opportunity to find a sterility assurance solution with a sterility assurance level of 10−6. When this is not possible, knowing the innovation within aseptic processing and the clarified alternative SAL approach optimizes the chance of delivering valuable new products to meet patient needs.
Path forward
243
Patients do not benefit from an R&D solution, however. They benefit when that solution is implemented to bring them an innovative sterile product. The sterility assurance professional needs to source the solution and then develop a robustly validated process. (S)he also needs to implement a robust supply chain with contingency since sterilization is a single point of supply chain failure. In addition, the SA (sterility assurance) professional needs to understand the process and the business deeply in order to appropriately address process and product exceptions that challenge the supply chain. Coupled with all of this is the reality that all sterile products require robust sterile barrier systems to maintain sterility over time. Interfacing with the design of robust and sterilization compatible packaging for the shelf life of the product is critical (see Chapter 5).
10.4.2 Bringing it all together in a risk management framework Bringing innovative product to market with robust sterility assurance will never be easy. The sterility assurance professional needs to pull all the above factors into a deep understanding of the product development process and risk management (see Chapter 8). As highlighted in Chapter 7, a simplistic approach will not be sufficient. All the inputs and risks need to be assessed in a risk-based framework that allows patient needs to be prioritized. This requires well-rounded, experienced, and collaborative sterility assurance professionals to seize the opportunities being provided for the patient. This is being made possible with increasing pan-industry forums provided in the industry. For example, Johnson and Johnson resurrected the Kilmer conference in 2016 to bring together thought leaders from the regulatory agencies, industry, and academia. In addition, they donated the proceedings of the Kilmer conference from 1974 to 2003 to AAMI to provide resources to the sterilization community [8].
10.5 What is next for the patient? Confidence in a flow of valuable and innovative products facilitated by sterility assurance professionals minimizing the risk of infection is the key. Advances in biologics, personalized medicine, and new sensitive combination products will open new products and treatments to patients.A thorough understanding of the balance of risks to benefits and the options available to the sterility assurance professional is necessary. Nothing else will suffice!
244
Assurance of sterility for sensitive combination products and materials
References [1] John Capek, IMRP 2016 presentation, referencing WHO, McKinsey 2012-02-27 ABT Newport Global Growth Presentation. [2] J.W. Chou, M. Skornicki, J.T. Cohen, Unintended consequences of the potential phase-out of gamma irradiation, F1000 Research 7 (2018) 348. [3] Guideline for Disinfection and Sterilization in Healthcare Facilities (2008) Center for Disease Control and Prevention. https://www.cdc.gov/infectioncontrol/guidelines/ disinfection/sterilization/etheylene-oxide.html. Accessed: August 2, 2019. [4] Food and Drug Administration (FDA), Reprocessing Medical Devices in Health Care Settings:Validation Methods and Labeling. Accessed: August 2, 2019. [5] ANSI/AAMI/ISO 13408-1:2008 (R2017)/A1:2013 “Aseptic Processing of Health Care Products Package”. [6] Food and Drug Administration (FDA), January 21, 2016, Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile: Guidance for Industry and Food and Drug Administration Staff. [7] International Organization for Standards, ISO/TS 19930:2017 “Guidance on aspects of a risk-based approach to assuring sterility of terminally sterilized, single-use health care product that is unable to withstand processing to achieve maximally a sterility assurance level of 10−6”. [8] Kilmer Conference Proceedings, http://www.aami.org/productspublications/content. aspx?ItemNumber=2594. Accessed August 2, 2019.
Path forward Byron J. Lamberta, Joyce M. Hansenb a
Assurance of Sterility Task Force, ASTF, Abbott, Temecula, CA, United States J&J Sterility Assurance, Johnson & Johnson, Raritan, NJ, United States
b
Contents 10.1 What is next with combination products? 10.2 Sterility assurance landscape in the 2020s 10.3 Pan-industry sterility assurance risk framework 10.3.1 Sterility assurance risks in health-care facilities 10.3.2 Sterility assurance risks related to single-use products 10.4 What is next for sterility assurance professionals? 10.4.1 End-to-end sterility assurance 10.4.2 Bringing it all together in a risk management framework 10.5 What is next for the patient? References
239 240 240 241 241 242 242 243 243 244
10.1 What is next with combination products? Chapter 2 highlighted that combination products and biologics for regenerative medicine are bringing increased value to patients and increased need for creative sterility assurance solutions. In broader context, combination products, pharmaceuticals, and biologics are key for finding innovative solutions to the most challenging and pervasive unmet clinical patient needs in neuroscience, oncology, cardiology, and pulmonary disease. These four areas alone represent untold human suffering and a &45T economic burden to society [1]. Combination product opportunities for meeting patient needs and related challenges for assuring sterility are further elevated with bioabsorbables, microelectronics, and multiple active agents. Sterility assurance professionals need to facilitate these innovative products with timely solutions for sterility assurance challenges so that the pipeline of new products for needy patients is not unnecessarily restricted.
Assurance of Sterility for Sensitive Combination Products and Materials https://doi.org/10.1016/B978-0-12-805082-8.00010-4
© 2020 Elsevier Inc. All rights reserved.
239
240
Assurance of sterility for sensitive combination products and materials
10.2 Sterility assurance landscape in the 2020s Sterility assurance has many challenges; ongoing and new solutions are required for • high volume sterile commodity products that keep health-care facilities meeting the needs of patients worldwide; • now common combination products such as Drug Eluting Stents (DES) and prefilled syringes; • innovative and complex combination products with development time scales of 5–15 years that do not have simple sterility assurance solutions; and • all forms of personalized regenerative biologics and cell therapy products that may require transformative approaches to sterility assurance. This picture is complicated by current and future realities of the terminal sterilization technology landscape. Moist heat, radiation, and ethylene oxide sterilization have been the workhorses of the industry for decades, with the latter two dominating the market for heat-sensitive health-care products. Both radiation and ethylene oxide technologies are experiencing market pressure; 80% of the radiation sterilization market uses gamma radiation sterilization utilizing the isotope cobalt 60. There continues to be manufacturing, transportation, disposal, and terror threats related to this technology. Electron beam and x-ray radiation sterilization are alternative technologies but often include cost concerns, especially with commodity products [2]. Ethylene oxide sterilization is increasingly under pressure from environmental health and safety perspectives [3]. Although alternative gas technologies are available, they are still in the early stages of the development to meet supply chain needs. Innovation and new sterility assurance paradigms are required on many fronts. Required sterility assurance focus areas include new sterility assurance technologies (Chapters 3 and 4), a pan-industry risk framework (Section 10.3), and highly competent sterility assurance professionals (Section 10.4).
10.3 Pan-industry sterility assurance risk framework To meet the needs of patients for innovative new products, sterility assurance professionals need to see beyond the boundaries of their industry segment. The first step toward this broader patient-focused sterility assurance approach is seeing what the patient cares about: receiving valuable new products in a timely manner while reducing the risk of infection.
Path forward
241
10.3.1 Sterility assurance risks in health-care facilities To reduce the risk of infection around the world, the greatest need for patients is increased focus on and innovation in reducing health-care associated infections (HAI). As highlighted in Chapter 6, the realities of 2%–30% infection rates in health-care facilities is a staggering risk to patients and families and financial burden to health-care systems. Ongoing focus on basic controls related to hygiene, good hospital practices, and consistent long-term wound care continue to be critical. Discerning analysis and collaborative solutions are required. Directly related to HAI is sterilization within the health-care facilities in central sterilization departments, and in particular, sterilization of reprocessed devices. Reusable devices such as endoscopes can be challenging to disassemble, clean, and sterilize with tragic results when operational pressures lead to poor practices (e.g., insufficiently trained sterility assurance staff succumbing to time pressures from overbooked operating theaters).There has been significant focus and progress related to device design and process standardization in this area [4], and ongoing diligence in this complex area is critical. These compelling concerns need to get framed appropriately in order to pave the way for what could be a new wave of very valuable products for patients that could be manufactured directly in health-care facilities— regenerative medicinal biologic products. This opportunity also frames the need for innovation in the broader product development and regulatory paradigms being developed. There is a compelling need for clarity and thoughtfulness for sterility assurance professionals.
10.3.2 Sterility assurance risks related to single-use products Moving out of the health-care facility, the sterility assurance professional needs to put the risks related to terminal sterilization and aseptic processing into broad perspective. When validated and controlled appropriately, terminal sterilization provides reproducible and validated logarithmic reduction of product microbial load while being contained in sterile barrier systems that prevent further contamination. This provides very high confidence in robust sterility assurance. It is the preferred approach to provide sterile product [5]. As discussed in Chapter 3, established moist heat, ethylene oxide, and radiation sterilization technologies have served the terminal sterilization industry well for decades. The industry has significant innovation within these established options as well as a growing array of technology options for terminal sterilization [6].
242
Assurance of sterility for sensitive combination products and materials
When terminal sterilization at a sterility assurance level of 10−6 is not possible, the well-traveled option that has also served the industry well for decades is aseptic processing (Chapter 4).When validated and controlled appropriately, aseptic processing maintains the sterility of sterile components and produces sterile finished goods within sterile barrier systems/container closure systems that do not allow further contamination. Innovation in this industry segment is providing technologies and environments in which it is increasingly simple and robust to combine sterile components into sterile products. In addition to aseptic processing for product that cannot be terminally sterilized at an SAL of 10−6, the less well-traveled option is the use of alternative SALs. As discussed in Chapter 9, this option was recently framed within ISO [7] and has been available longer through Association for the Advancement of Medical Instrumentation (AAMI). The increased clarity in this option of providing reliable and acceptable sterility assurance for needed products should well serve the industry as well as the patients. Chapter 7 enhances this clarity by providing a unique and broad perspective on how validation sample sizes for packaging, aseptic processing, and terminal sterilization fit into, but are not the whole story, for assuring sterility.
10.4 What is next for sterility assurance professionals? The final area of sterility assurance focus to support innovation in meeting patient needs is highly competent sterility assurance professionals. Within health-care facilities, professionals experience enormous challenges under the pressure of immediate care for patients. This requires great competence and is likely the most important point of focus for patients from an infection risk mitigation perspective.
10.4.1 End-to-end sterility assurance Sterility assurance professionals in industry providing single-use products are well served by a broad understanding of all industry segments. This can be understood in a framework of the entire product life cycle or ‘end-toend sterility assurance.’ In the product R&D planning phase, knowing the innovation within established terminal sterilization technologies as well as innovation in novel sterilization technologies optimizes the opportunity to find a sterility assurance solution with a sterility assurance level of 10−6. When this is not possible, knowing the innovation within aseptic processing and the clarified alternative SAL approach optimizes the chance of delivering valuable new products to meet patient needs.
Path forward
243
Patients do not benefit from an R&D solution, however. They benefit when that solution is implemented to bring them an innovative sterile product. The sterility assurance professional needs to source the solution and then develop a robustly validated process. (S)he also needs to implement a robust supply chain with contingency since sterilization is a single point of supply chain failure. In addition, the SA (sterility assurance) professional needs to understand the process and the business deeply in order to appropriately address process and product exceptions that challenge the supply chain. Coupled with all of this is the reality that all sterile products require robust sterile barrier systems to maintain sterility over time. Interfacing with the design of robust and sterilization compatible packaging for the shelf life of the product is critical (see Chapter 5).
10.4.2 Bringing it all together in a risk management framework Bringing innovative product to market with robust sterility assurance will never be easy. The sterility assurance professional needs to pull all the above factors into a deep understanding of the product development process and risk management (see Chapter 8). As highlighted in Chapter 7, a simplistic approach will not be sufficient. All the inputs and risks need to be assessed in a risk-based framework that allows patient needs to be prioritized. This requires well-rounded, experienced, and collaborative sterility assurance professionals to seize the opportunities being provided for the patient. This is being made possible with increasing pan-industry forums provided in the industry. For example, Johnson and Johnson resurrected the Kilmer conference in 2016 to bring together thought leaders from the regulatory agencies, industry, and academia. In addition, they donated the proceedings of the Kilmer conference from 1974 to 2003 to AAMI to provide resources to the sterilization community [8].
10.5 What is next for the patient? Confidence in a flow of valuable and innovative products facilitated by sterility assurance professionals minimizing the risk of infection is the key. Advances in biologics, personalized medicine, and new sensitive combination products will open new products and treatments to patients.A thorough understanding of the balance of risks to benefits and the options available to the sterility assurance professional is necessary. Nothing else will suffice!
244
Assurance of sterility for sensitive combination products and materials
References [1] John Capek, IMRP 2016 presentation, referencing WHO, McKinsey 2012-02-27 ABT Newport Global Growth Presentation. [2] J.W. Chou, M. Skornicki, J.T. Cohen, Unintended consequences of the potential phase-out of gamma irradiation, F1000 Research 7 (2018) 348. [3] Guideline for Disinfection and Sterilization in Healthcare Facilities (2008) Center for Disease Control and Prevention. https://www.cdc.gov/infectioncontrol/guidelines/ disinfection/sterilization/etheylene-oxide.html. Accessed: August 2, 2019. [4] Food and Drug Administration (FDA), Reprocessing Medical Devices in Health Care Settings:Validation Methods and Labeling. Accessed: August 2, 2019. [5] ANSI/AAMI/ISO 13408-1:2008 (R2017)/A1:2013 “Aseptic Processing of Health Care Products Package”. [6] Food and Drug Administration (FDA), January 21, 2016, Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile: Guidance for Industry and Food and Drug Administration Staff. [7] International Organization for Standards, ISO/TS 19930:2017 “Guidance on aspects of a risk-based approach to assuring sterility of terminally sterilized, single-use health care product that is unable to withstand processing to achieve maximally a sterility assurance level of 10−6”. [8] Kilmer Conference Proceedings, http://www.aami.org/productspublications/content. aspx?ItemNumber=2594. Accessed August 2, 2019.