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Making use of a biological safety evaluation plan
Making use of a biological safety evaluation plan
2
D. Parente Ecolab, St. Paul, MN, United States
2.1 Introduction ISO 10993-1:2018, Biological Evaluation of Medical Devices—Part 1: Evaluation and Testing within a Risk Management Process states that this “document is to serve as a framework in which to plan a biological evaluation.” The standard is just a framework, and the tables in A.1 in the annex of the document are a tool used to develop biological safety evaluation plans. They are not checklists of what must be done, because no checklist can satisfy the requirement of the standard. Unique to the checklists in this 2018 revision is a list of rationale for each test selected in the table. One can utilize the rationale in preparing your plan. In addition, Annex B provides guidance on completion of the Biological Safety Evaluation Plan. Years ago, my boss at the time told me that one “doesn’t want to complete paperwork, rather one wants to use working paper.” How does one make sure the Biological Safety Evaluation Plan is indeed working paper?
2.2 The fundamentals of safety evaluation planning ISO 10993-1 stresses the fact that animal testing should not be used to uncover information that is already known. The document also states that biological safety evaluations “shall be planned, carried out, and documented by knowledgeable and experienced professionals.” Most importantly, the biological safety evaluation plan defines how the firm will assure the safety of its product. An effective plan starts with material selection. The objective is to pick materials whose properties are most suitable for the performance of the device. Given those requirements, materials are characterized and qualified, so that the risk of an adverse biological effect arising from the use of that material is negligible. After qualifying the material, the component is qualified. We then examine the molding process—specifications such as molding cycle time, generations of regrind permitted, melt flow range and other parameters that could influence the material and whether the processed material could change the safety profile of the material. Once completed, we have a tremendous amount of confidence in the safety of that component and material. We can now apply that information across a range of devices and uses. Combining the information from the raw material supplier and final product test results assured device safety by mitigating the biological risk previously identified. This is exactly what the FDA desires. Biocompatibility and Performance of Medical Devices. https://doi.org/10.1016/B978-0-08-102643-4.00003-3 © 2020 Elsevier Ltd. All rights reserved.
18
Biocompatibility and Performance of Medical Devices
Communication of the biological safety plan to team members is key to maximizing its usability as the driving force in the execution of the necessary steps required to assure biological safety. The definition of tasks, milestones and key events in the schedule are essential in bringing this device to market or in advancing the project schedule. Gantt charts and timelines drive schedules. Yet most companies wait to communicate with the regulatory agencies, such as the FDA, until late in the process and, when they do, they are less than clear. This plan therefore serves an additional function of explaining the steps necessary, and why such steps were taken, to assure safety. The plan also can be used in preliminary discussions with these agencies, so they can better understand the firm’s thought process. If the firm wants to work closely with FDA, they can use the test plan as an effective communication tool with the agency. Even if the company declines the opportunity to work with FDA early on, this evaluation plan is the perfect instrument for proper communication of the firm’s rationale for assuring safety. In addition, the plan acts as documentation of prevalent thought within the firm, its vendors and consultants, much like a validation master plan does when dealing with validation work. Planning is a documented process. Any plan breaks down into subsections which then breaks down into action steps. The process is of extreme importance, since the document is the end product of hours of research, deliberation, discussion and decision making—all culminating into a series of action steps used to guide a cross functional team. These action steps allow us to complete our preclinical evaluation. The evaluation, however, is never quite complete but rather extends onto both the clinical stage of the product and during postmarket activities. Those postmarket activities include product changes, all of which must be addressed within the context of the original plan. This method is far more comprehensive than selecting from a checklist of suggested tests. The biological safety process is a continual process that is dependent upon information.
2.3 Safety evaluation planning for biomaterials In order to assure safety, one has to address risk. The checklist approach assumes that, given a list of discrete categories of body contact and duration, the risk to the patient never changes. That is like saying that the risk of safely driving from New York to Tampa is identical each time I do it. It does not take into account my vehicle, the time of day I am driving, the weather conditions, traffic, etc. Of course, this is absurd but this is what occurs when you truncate an incredible variety of medical devices into a handful of categories. The plan addresses the uniqueness of each device so that the safety team can implement a customized list of action items that defines the risk of device intended use. Despite its drawbacks, the checklist approach is easy to use, easy to teach and does not require much thinking. While knowledge of materials and the process by which they are assembled, coupled with risk assessment, gives rise to information that is needed to construct the biological safety evaluation plan.
Biological safety evaluation planning of biomaterials
19
In order for a biological safety evaluation plan to be just as effective, it needs to convince the reader that the steps being taken to ensure safety adequately address the biological risks of product use, so that successful completion of these actions steps will give us the confidence that the product is biocompatible and that this biocompatibility can be confirmed clinically. The purpose of the plan is to describe how a company will utilize limited resources (because indeed all resources are limited) to perform the best possible evaluation to assure biological safety. Members of the team use the plan to carry out the action steps required to assure a safe device. For example, a manufacturer makes an IV Catheter. The catheter material is the same material that the manufacturer uses to produce another short-term blood contact device, a guide wire. The production processes for both are similar in that neither impacts on biocompatibility. In order for the plan to be effective, it would have to deal with the pragmatic approach of leveraging testing and other information for the material as a guide wire. Merely to state that certain tests will be completed when indeed they were conducted as part of another device is both confusing and misleading and will indeed lead to more regulatory questions. Stating very clearly what exactly will be accomplished is much more effective and better understood—both good reasons for initiating the plan to begin with. It should be authored by someone who has the necessary education and/or training/experience to have knowledge of how the ISO 10993 series should be applied and used. In addition, that person should have a firm knowledge of the device in question, its materials of construction, the manufacturing process and manufacturing materials, and studies that have already been conducted providing information about potential toxicological risk. Furthermore, the plan clearly communicates to the team that previous testing will be leveraged and no additional testing will be planned. This allows for finishing the project without a need to fund further testing and allows the project manager to report that any planned budget for testing can be used for other potential projects. The timeline is also further refined, and the schedule can be updated.
2.4 Developing and documenting plans Prior to initiating a biological safety evaluation plan, a risk assessment should be conducted. In Annex I of ANSI/AAMI/ISO 14971:2012, Medical devices—Application of risk management to medical devices, it is stated that applying risk assessment to biological hazards involves an examination of a range of effects of potential biological hazards. These hazards could include short-term effects such as acute toxicity, irritation to the skin, eye and mucosal surfaces, hemolysis and thrombogenicity, as well as long-term or specific toxic effects such as subchronic and chronic toxic effects, sensitization, genotoxicity, carcinogenicity (tumorigenicity) and effects on reproduction including teratogenicity. These possible effects are evaluated in conjunction with intended use. Intended use drives the perception of device risk and also provides us with limitations as to where and how biological safety might be impacted.
20
Biocompatibility and Performance of Medical Devices
Since the initial edition of this book/chapter was authored, risk assessment has grown to be a more common part of the medical device manufacturers’ life, and indeed with respect to biocompatibility there has been a slow shift toward risk assessment as the driving force for devising the biological safety evaluation plan. The assessment begins by analyzing all potential biological hazards given the intended use of the product and the materials of composition. In reviewing the materials of composition, one should remember also to consider materials that are used during manufacturing but do not constitute part of the bill of materials of the device. Such “manufacturing materials” may remain on the device in the form of small quantities of residuals. The assessment begins with a collection of information regarding the product and the conduct of a literature search, in order to determine what is known about the device and what remains unknown. A prescribed plan for literature search must be documented. Appendix C of ISO 10993-1 gives us excellent guidance on how literature must be studied and how to assure that an unbiased assessment is conducted. If there is insufficient information to address a specific biological endpoint, then obtaining this unknown information should be targeted in the plan. This would be likely to result in conducting tests so that data can be generated and the evaluation can be completed. We must consider all research in literature but some literature is more valuable than others. Human data are often most applicable, but if these data are occupational inhalation data, they may be less valuable than IV data on a rat when investigating a blood contact device such as an IV catheter. If we are looking for slight behavioral or adverse effects induced by a repeated dose study (these effects are generally reflected by a NOEL or NOAEL value), then a short-term LD50 value would be of little use. This process is a cyclic one because the evaluation of biological safety is continual. Action is taken in an effort to reduce risk. The results of that action lead to reevaluation. Changes in the product lead to reevaluation, and finally the acquisition of new information can lead to further assessment. In reality, all three of these occur. The plan documents the balance between known and unknown information and how such information impacts on the ultimate goal of demonstrating adequate safety when compared to the benefit of device use. What the plan should not be is a regurgitation of Annex A in ISO 10993-1. In order to understand this, one must understand that biological safety cannot be completely assured by the testing of one sample replicate. Consistency of materials and consistency of processing are mandatory prerequisites to evaluating biological safety. Without proven process validation and material qualification, it becomes impossible to evaluate the safety of a device because one cannot establish what the device truly is. Validation is documented proof that the device can be made as per documented specifications in a reproducible manner. Once reproducibility of product and process is established, then we can evaluate the product and be assured that our evaluation will impact all validated products. A full understanding of the impact on biological safety is required. The purpose of the plan is to sort out the information that is needed to make such a judgment and acquire it.
Biological safety evaluation planning of biomaterials
21
2.5 Using safety evaluations “Paperwork” is often a bureaucratic exercise that has little value. A “working document” on the other hand has lasting value. The biological safety evaluation plan is the quintessential working document. It establishes the who, what, when, where and how of the evaluation sequence and documents it for historical reference so that future evaluations are consistently applied. It is a working document of execution. It should document what is to be done and why. It should also address when it is to be done. Essentially, biological safety can be divided into four categories: 1. 2. 3. 4.
systemic toxicity, local toxicity, carcinogenicity, special considerations, that is, blood contact, central nervous system (CNS) contact, etc.
Each of these is handled quite differently during planning. The plan hinges on risk assessment. The assessment hinges on known information. There is typically a large amount of information in the areas of systemic toxicity and carcinogenicity. There is often quite a bit documented on irritation as well, but there is less information on sensitization and histopathology upon implantation. Special considerations are even rarer. Even if information is available, one has to consider the impact of the manufacturing process. This applies to both converting the material to the polymer you purchased, and processing and assembling the materials and components into the finished device. The risk assessment examines this information and more. The document characterizes the risk so that it is clearly understood what is already known and understood, as against that which is unknown. The more information that is not well understood, the greater the risk to the safety of the patient. Thus the overall value of the biological safety evaluation plan is that it defines the evaluation of the unknown so that a sufficient amount of information can be evaluated and risk can clearly be understood and characterized. It documents the thought process behind the choices made in conducting testing, in choosing the way the test is conducted, and in waiving the conduct of certain tests that may be expected otherwise. For example, a polylactic acid (PLA) implant that has been well characterized with regard to both short-term and long-term toxicity may have little information with regard to skin or tissue contact. The easiest way to uncover this type of information is to perform an implant study to demonstrate that the device is safe with regard to local tissue contact. The length of the study would depend on the type of information that is discovered either through literature or other testing. The plan also tends to limit any regulatory deficiencies to those that essentially disagree with your assessment rather than those that seem quite unordinary in terms of scope and magnitude. I like to look at this using the sports expression “home field advantage.” This is to say that it is to your advantage to set the subject matter on which the regulatory debate will ensue. Your preparation of the assessment and the plan will have made you quite comfortable and knowledgeable in this area.
22
Biocompatibility and Performance of Medical Devices
2.6 Conclusion It is clear that the benefits of documenting a biological safety evaluation plan is worth the time and effort. It is a valuable communication document. It keeps the project moving forward by communicating approach and expectations to the project team. There is no doubt that this process is far superior to checking off a list of tests and submitting them to your reviewer. These test methods have withstood the test of time. There is a great deal of comfort and trust in the reliability of these tests. However, they are probably the most inadequate means of evaluation. In conclusion, the next time your needs turn to biological safety do not initiate testing until you have documented a plan for ensuring biological safety.
2.7 Sources of further information and advice ISO 10993-1:2009, Biological safety of medical devices—Part 1: Evaluation and testing within a risk management process.
2
D. Parente Ecolab, St. Paul, MN, United States
2.1 Introduction ISO 10993-1:2018, Biological Evaluation of Medical Devices—Part 1: Evaluation and Testing within a Risk Management Process states that this “document is to serve as a framework in which to plan a biological evaluation.” The standard is just a framework, and the tables in A.1 in the annex of the document are a tool used to develop biological safety evaluation plans. They are not checklists of what must be done, because no checklist can satisfy the requirement of the standard. Unique to the checklists in this 2018 revision is a list of rationale for each test selected in the table. One can utilize the rationale in preparing your plan. In addition, Annex B provides guidance on completion of the Biological Safety Evaluation Plan. Years ago, my boss at the time told me that one “doesn’t want to complete paperwork, rather one wants to use working paper.” How does one make sure the Biological Safety Evaluation Plan is indeed working paper?
2.2 The fundamentals of safety evaluation planning ISO 10993-1 stresses the fact that animal testing should not be used to uncover information that is already known. The document also states that biological safety evaluations “shall be planned, carried out, and documented by knowledgeable and experienced professionals.” Most importantly, the biological safety evaluation plan defines how the firm will assure the safety of its product. An effective plan starts with material selection. The objective is to pick materials whose properties are most suitable for the performance of the device. Given those requirements, materials are characterized and qualified, so that the risk of an adverse biological effect arising from the use of that material is negligible. After qualifying the material, the component is qualified. We then examine the molding process—specifications such as molding cycle time, generations of regrind permitted, melt flow range and other parameters that could influence the material and whether the processed material could change the safety profile of the material. Once completed, we have a tremendous amount of confidence in the safety of that component and material. We can now apply that information across a range of devices and uses. Combining the information from the raw material supplier and final product test results assured device safety by mitigating the biological risk previously identified. This is exactly what the FDA desires. Biocompatibility and Performance of Medical Devices. https://doi.org/10.1016/B978-0-08-102643-4.00003-3 © 2020 Elsevier Ltd. All rights reserved.
18
Biocompatibility and Performance of Medical Devices
Communication of the biological safety plan to team members is key to maximizing its usability as the driving force in the execution of the necessary steps required to assure biological safety. The definition of tasks, milestones and key events in the schedule are essential in bringing this device to market or in advancing the project schedule. Gantt charts and timelines drive schedules. Yet most companies wait to communicate with the regulatory agencies, such as the FDA, until late in the process and, when they do, they are less than clear. This plan therefore serves an additional function of explaining the steps necessary, and why such steps were taken, to assure safety. The plan also can be used in preliminary discussions with these agencies, so they can better understand the firm’s thought process. If the firm wants to work closely with FDA, they can use the test plan as an effective communication tool with the agency. Even if the company declines the opportunity to work with FDA early on, this evaluation plan is the perfect instrument for proper communication of the firm’s rationale for assuring safety. In addition, the plan acts as documentation of prevalent thought within the firm, its vendors and consultants, much like a validation master plan does when dealing with validation work. Planning is a documented process. Any plan breaks down into subsections which then breaks down into action steps. The process is of extreme importance, since the document is the end product of hours of research, deliberation, discussion and decision making—all culminating into a series of action steps used to guide a cross functional team. These action steps allow us to complete our preclinical evaluation. The evaluation, however, is never quite complete but rather extends onto both the clinical stage of the product and during postmarket activities. Those postmarket activities include product changes, all of which must be addressed within the context of the original plan. This method is far more comprehensive than selecting from a checklist of suggested tests. The biological safety process is a continual process that is dependent upon information.
2.3 Safety evaluation planning for biomaterials In order to assure safety, one has to address risk. The checklist approach assumes that, given a list of discrete categories of body contact and duration, the risk to the patient never changes. That is like saying that the risk of safely driving from New York to Tampa is identical each time I do it. It does not take into account my vehicle, the time of day I am driving, the weather conditions, traffic, etc. Of course, this is absurd but this is what occurs when you truncate an incredible variety of medical devices into a handful of categories. The plan addresses the uniqueness of each device so that the safety team can implement a customized list of action items that defines the risk of device intended use. Despite its drawbacks, the checklist approach is easy to use, easy to teach and does not require much thinking. While knowledge of materials and the process by which they are assembled, coupled with risk assessment, gives rise to information that is needed to construct the biological safety evaluation plan.
Biological safety evaluation planning of biomaterials
19
In order for a biological safety evaluation plan to be just as effective, it needs to convince the reader that the steps being taken to ensure safety adequately address the biological risks of product use, so that successful completion of these actions steps will give us the confidence that the product is biocompatible and that this biocompatibility can be confirmed clinically. The purpose of the plan is to describe how a company will utilize limited resources (because indeed all resources are limited) to perform the best possible evaluation to assure biological safety. Members of the team use the plan to carry out the action steps required to assure a safe device. For example, a manufacturer makes an IV Catheter. The catheter material is the same material that the manufacturer uses to produce another short-term blood contact device, a guide wire. The production processes for both are similar in that neither impacts on biocompatibility. In order for the plan to be effective, it would have to deal with the pragmatic approach of leveraging testing and other information for the material as a guide wire. Merely to state that certain tests will be completed when indeed they were conducted as part of another device is both confusing and misleading and will indeed lead to more regulatory questions. Stating very clearly what exactly will be accomplished is much more effective and better understood—both good reasons for initiating the plan to begin with. It should be authored by someone who has the necessary education and/or training/experience to have knowledge of how the ISO 10993 series should be applied and used. In addition, that person should have a firm knowledge of the device in question, its materials of construction, the manufacturing process and manufacturing materials, and studies that have already been conducted providing information about potential toxicological risk. Furthermore, the plan clearly communicates to the team that previous testing will be leveraged and no additional testing will be planned. This allows for finishing the project without a need to fund further testing and allows the project manager to report that any planned budget for testing can be used for other potential projects. The timeline is also further refined, and the schedule can be updated.
2.4 Developing and documenting plans Prior to initiating a biological safety evaluation plan, a risk assessment should be conducted. In Annex I of ANSI/AAMI/ISO 14971:2012, Medical devices—Application of risk management to medical devices, it is stated that applying risk assessment to biological hazards involves an examination of a range of effects of potential biological hazards. These hazards could include short-term effects such as acute toxicity, irritation to the skin, eye and mucosal surfaces, hemolysis and thrombogenicity, as well as long-term or specific toxic effects such as subchronic and chronic toxic effects, sensitization, genotoxicity, carcinogenicity (tumorigenicity) and effects on reproduction including teratogenicity. These possible effects are evaluated in conjunction with intended use. Intended use drives the perception of device risk and also provides us with limitations as to where and how biological safety might be impacted.
20
Biocompatibility and Performance of Medical Devices
Since the initial edition of this book/chapter was authored, risk assessment has grown to be a more common part of the medical device manufacturers’ life, and indeed with respect to biocompatibility there has been a slow shift toward risk assessment as the driving force for devising the biological safety evaluation plan. The assessment begins by analyzing all potential biological hazards given the intended use of the product and the materials of composition. In reviewing the materials of composition, one should remember also to consider materials that are used during manufacturing but do not constitute part of the bill of materials of the device. Such “manufacturing materials” may remain on the device in the form of small quantities of residuals. The assessment begins with a collection of information regarding the product and the conduct of a literature search, in order to determine what is known about the device and what remains unknown. A prescribed plan for literature search must be documented. Appendix C of ISO 10993-1 gives us excellent guidance on how literature must be studied and how to assure that an unbiased assessment is conducted. If there is insufficient information to address a specific biological endpoint, then obtaining this unknown information should be targeted in the plan. This would be likely to result in conducting tests so that data can be generated and the evaluation can be completed. We must consider all research in literature but some literature is more valuable than others. Human data are often most applicable, but if these data are occupational inhalation data, they may be less valuable than IV data on a rat when investigating a blood contact device such as an IV catheter. If we are looking for slight behavioral or adverse effects induced by a repeated dose study (these effects are generally reflected by a NOEL or NOAEL value), then a short-term LD50 value would be of little use. This process is a cyclic one because the evaluation of biological safety is continual. Action is taken in an effort to reduce risk. The results of that action lead to reevaluation. Changes in the product lead to reevaluation, and finally the acquisition of new information can lead to further assessment. In reality, all three of these occur. The plan documents the balance between known and unknown information and how such information impacts on the ultimate goal of demonstrating adequate safety when compared to the benefit of device use. What the plan should not be is a regurgitation of Annex A in ISO 10993-1. In order to understand this, one must understand that biological safety cannot be completely assured by the testing of one sample replicate. Consistency of materials and consistency of processing are mandatory prerequisites to evaluating biological safety. Without proven process validation and material qualification, it becomes impossible to evaluate the safety of a device because one cannot establish what the device truly is. Validation is documented proof that the device can be made as per documented specifications in a reproducible manner. Once reproducibility of product and process is established, then we can evaluate the product and be assured that our evaluation will impact all validated products. A full understanding of the impact on biological safety is required. The purpose of the plan is to sort out the information that is needed to make such a judgment and acquire it.
Biological safety evaluation planning of biomaterials
21
2.5 Using safety evaluations “Paperwork” is often a bureaucratic exercise that has little value. A “working document” on the other hand has lasting value. The biological safety evaluation plan is the quintessential working document. It establishes the who, what, when, where and how of the evaluation sequence and documents it for historical reference so that future evaluations are consistently applied. It is a working document of execution. It should document what is to be done and why. It should also address when it is to be done. Essentially, biological safety can be divided into four categories: 1. 2. 3. 4.
systemic toxicity, local toxicity, carcinogenicity, special considerations, that is, blood contact, central nervous system (CNS) contact, etc.
Each of these is handled quite differently during planning. The plan hinges on risk assessment. The assessment hinges on known information. There is typically a large amount of information in the areas of systemic toxicity and carcinogenicity. There is often quite a bit documented on irritation as well, but there is less information on sensitization and histopathology upon implantation. Special considerations are even rarer. Even if information is available, one has to consider the impact of the manufacturing process. This applies to both converting the material to the polymer you purchased, and processing and assembling the materials and components into the finished device. The risk assessment examines this information and more. The document characterizes the risk so that it is clearly understood what is already known and understood, as against that which is unknown. The more information that is not well understood, the greater the risk to the safety of the patient. Thus the overall value of the biological safety evaluation plan is that it defines the evaluation of the unknown so that a sufficient amount of information can be evaluated and risk can clearly be understood and characterized. It documents the thought process behind the choices made in conducting testing, in choosing the way the test is conducted, and in waiving the conduct of certain tests that may be expected otherwise. For example, a polylactic acid (PLA) implant that has been well characterized with regard to both short-term and long-term toxicity may have little information with regard to skin or tissue contact. The easiest way to uncover this type of information is to perform an implant study to demonstrate that the device is safe with regard to local tissue contact. The length of the study would depend on the type of information that is discovered either through literature or other testing. The plan also tends to limit any regulatory deficiencies to those that essentially disagree with your assessment rather than those that seem quite unordinary in terms of scope and magnitude. I like to look at this using the sports expression “home field advantage.” This is to say that it is to your advantage to set the subject matter on which the regulatory debate will ensue. Your preparation of the assessment and the plan will have made you quite comfortable and knowledgeable in this area.
22
Biocompatibility and Performance of Medical Devices
2.6 Conclusion It is clear that the benefits of documenting a biological safety evaluation plan is worth the time and effort. It is a valuable communication document. It keeps the project moving forward by communicating approach and expectations to the project team. There is no doubt that this process is far superior to checking off a list of tests and submitting them to your reviewer. These test methods have withstood the test of time. There is a great deal of comfort and trust in the reliability of these tests. However, they are probably the most inadequate means of evaluation. In conclusion, the next time your needs turn to biological safety do not initiate testing until you have documented a plan for ensuring biological safety.
2.7 Sources of further information and advice ISO 10993-1:2009, Biological safety of medical devices—Part 1: Evaluation and testing within a risk management process.