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Post Aseptic Fill Sterilization and Lethal Treatment
CHAPTER
13
Post Aseptic Fill Sterilization and Lethal Treatment Michael J. Sadowski Lead Scientist, Sterility Assurance, Baxter Healthcare Corporation, IL, United States
Introduction Due to inherently lower risks of nonsterility, terminal sterilization processes are universally considered to be superior to aseptic processes and thus preferred by regulators. However some parental drug product formulations are not stable and may degrade due to processing by terminal sterilization processes that utilize exposure to moist heat. Accordingly these products necessitate the ongoing need for aseptic processing. With aseptic processing, there is a very low probability that any filled unit might contain a microorganism due to the robust process design and associated environmental microbial controls. Any microorganisms present are low in number and most likely from human origin (i.e., primarily Gram-positive cocci) and are expected to demonstrate relatively low resistance levels to moist heat sterilization processes. To further reduce the risk of nonsterility with an aseptic product that can tolerate some of level of heat, a post aseptic fill lethal treatment process could be employed. For this situation, the product is aseptically filled and sealed in containers followed by exposure to a validated microorganism inactivation process that delivers a low level of heat history as the terminal step of the overall manufacturing process. Based on the heat sensitivity of the product, the low heat history treatment step can be performed at conventional moist heat sterilization temperatures or at lower temperatures. It is important to note that the application of a post aseptic fill lethal treatment process is not to be considered mandatory. Based on the documented, successful, safe application of aseptic processing for many years, there is a Principles of Parenteral Solution Validation. DOI: https://doi.org/10.1016/B978-0-12-809412-9.00013-7 © 2020 Elsevier Inc. All rights reserved.
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lack of scientific and risk-based evidence to support the absolute need for the application of terminal sterilization or other lethal treatment processes for product produced via well designed, properly controlled and operated aseptic processes. Accordingly, aseptic manufacture in these cases can provide products of suitable quality and there is no scientific justification to support the expectation that products produced through aseptic manufacture would necessarily require the addition of some moderated ‘terminal sterilization’ or other lethal treatment conditions.1
The implementation of a post aseptic processing sterilization or lethal treatment process step yields a reduced risk for nonsterility. Therefore optimization of the sterility assurance program should be one of the benefits derived from this enhanced focus on proactive measures to support product sterility. This chapter will discuss lethal treatment approaches, considerations, and potential benefits that can be derived from applying a terminal microbial inactivation process on product that has been previously filled using an aseptic process.
Sterilization and Lethal Treatment The term “sterilization” is a well-known term that is very precisely defined in global regulatory standards and guidance documents while the term “lethal treatment” is a much broader term that is not as precisely defined nor widely understood. Accordingly the author prefers to recognize the terms “post aseptic fill sterilization” and “post aseptic fill lethal treatment” in a distinctive and exclusive fashion much in the way that traditional sterilization is not commonly referred to as lethal treatment.
Post Aseptic Fill Sterilization The following definition and clarifying notation for the term sterilization can be found in ISO111392 (2018): Sterilization: Validated process used to render product free from viable microorganisms. Note: In a sterilization process, the nature of microbial inactivation is described as exponential and thus the survival of a microorganism on an individual item can be expressed in terms of probability. Adapted from PDA Comments Submitted to EMA on “Guideline on the sterilization of the medicinal product, active substance, excipient and primary container,” October 2016. 2 ISO11139 (2018). Sterilization of healthcare productsVocabularyTerms used in sterilization and related equipment and process standards. 1
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While this probability can be reduced to a very low number, it can never be reduced to zero. Aseptic processes provide a high level of bioburden control based on the robust and successful design, development and qualification (e.g., Aseptic Process Simulation, Environmental Monitoring Performance Qualification, etc.) of the process. The resulting low product bioburden levels support the use of the Product Specific Design Approach and an associated reduced physical lethality (F0) for moist heat sterilization processes for any products that can tolerate a relatively low heat history at recognized sterilization temperatures. Since the presence of product bioburden in this situation should be at a low probability, reduced assumptions for the product bioburden population level and resistance level may be considered in the determination of the Probability of a Nonsterile Unite (PNSU) for these products. Additionally, the use of the Product Specific Design Approach could provide for a PNSU of # 1026 which represents a significant reduction of the risk of nonsterility when compared to traditional aseptic processing. The use of the Semilog Survivor Curve Equation adapted from PDA Technical Report No. 1 Eq. (13.1)3 can be used to calculate the resulting PNSU for product with exposure to a low heat history sterilization including the product bioburden assumptions listed below: Log NF 5 2 F0 =D121 C 1 Log N0
(13.1)
where, NF is the number of product bioburden microorganisms surviving after exposure to a specific F0. NF is also the PNSU. The target for a terminal moist heat sterilization process is a PNSU # 1026. F0 is the equivalent lethality of a cycle calculated as minutes at a reference temperature of 121 C, using a defined temperature coefficient or z-value of 10 C. F0 should be calculated from heat penetration temperature readings in the slowest to heat location in the product. Assume an F0 value of 2.4 minutes for this example. D121 C is the D121 C value—thermal resistance value, in minutes, of a product bioburden microorganism at 121 C. Assume a product bioburden resistance of 0.4 minutes for this example. N0 is the number of product bioburden microorganisms prior to exposure. Assume 1 heat resistant spore for product bioburden for this example. 3 PDA Technical Report No. 1 (2007). Validation of Moist Heat Sterilization Processes: Cycle Design, Development, Qualification and Ongoing Control.
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Then, Log NF 5 2 F0 =D121 C 1 Log N0 Log NF 5 2 2:4=0:4 minutes 1 Log ð1Þ 5 2 6 1 0 Log NF 5 2 6 NF 5 1026 Note: An additional safety factor can be added by increasing the F0 value to 3 minutes or more to further reduce (enhance) the resulting PNSU for the post aseptic fill moist heat sterilization process. In order to support the achievement of a corresponding moist heat sterilization process biological lethality (FBIO), biological indicators (BI’s) with D121 C values in the range of 0.20.6 minutes (e.g., Bacillus subtilis 5230) are available from various BI manufacturers. FBIO is calculated as follows: FBIO 5 D121 C ðSLRÞ
(13.2)
where, FBIO is the biological lethality for the sterilization process; D121 C is the D121 C value of the BI; SLR is the Spore Log Reduction (SLR) achieved for the BI after exposure to the sterilization process. SLR 5 LogðN0 Þ 2 LogðNF Þ
(13.3)
where, N0 is the starting spore population of the BI prior to exposure to the sterilization process and NF is the surviving spore population of the BI after exposure to the sterilization process. An SLR value of 6.0 will be used for this example with the assumption of complete inactivation of a BI with a starting population of 106 spores per unit. In this case, an NF of 1 must be assumed since it is not mathematically valid to calculate the logarithm of 0. Then SLR 5 Log (106) 2 Log (1) 5 6.0 2 0 SLR 5 6:0 Then, FBIO 5 D121 C value (SLR) FBIO 5 0.4 minutes (6.0)
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FBIO 5 2.4 minutes which can be included in place of F0 in Eq. 13.1 above to also support a PNSU # 1026. In addition to or as an alternate to moist heat sterilization, other modalities of terminal sterilization such as radiation (gamma or e-beam) may also be used to enhance the PNSU/product sterility after completion of aseptic processing.
Post Aseptic Fill Lethal Treatment Post aseptic lethal treatment can be defined as the application of a terminal treatment process designed to inactivate microorganisms present after completion of an aseptic process. As stated above and due to the extensive environmental controls and the prevalence of microorganisms from human origin that are vegetative microorganisms and not spore-formers, the number and resistance of any microorganisms present in product from aseptic processing is expected to be very low. In order to inactivate vegetative organisms to obtain a count that is exclusively from spores in the Spore Count Test, a heat shock at 60 C80 C for 1530 minutes is often employed on the samples prior to plating and incubation. Therefore these temperatures and exposure ranges can also be considered for use with post aseptic fill lethal treatment for those products that are not negatively affected by exposure to these levels of heat history. Based on this author’s experience, 80 C for 15 minutes seems to be a widely used heat history for sanitization which could be suitably adapted for post aseptic fill lethal treatment. However the temperature set point should be based on the heat sensitivity of the product while the overall target heat history should be based on the resistance of the microflora at the aseptic processing facility. This could lead to potential higher or lower temperature set points with shorter or longer exposure times, respectively. The simplest heat processing option for the post aseptic fill lethal treatment would be heat exposure in an appropriately sized water bath in a batch type of process although it would also be possible also utilize a continuous process with appropriate equipment. The process heat history could be set and demonstrated by monitoring time at temperature (i.e., 15 minutes at 80 C) or with integration of time and temperature similar to the approach with F0 but with an alternate reference temperature (Tref) corresponding to the target exposure temperature. For temperature monitoring, the temperature could be
266
Principles of Parenteral Solution Validation
monitored in the slowest to heat location of product for each batch or the time needed at the minimum exposure temperature could be developed and qualified. Although this section discussed the application of moist heat with a water bath, other sterilization technologies (e.g., radiation) could be similarly utilized based upon the sensitivity of the product to these technologies.
Parametric Release As stated previously, the implementation of proactive measures such as post aseptic fill sterilization and lethal treatment should result in an optimized sterility assurance program. The application of parametric release aligns well with the implementation of proactive and validated microbiological inactivation processes which far exceed the risk mitigation potential of highly intensive product testing strategies such as the finished product sterility test. It is well known that the product sterility test is statistically flawed with very limited capability to support that a batch of moist heat terminally sterility product is sterile. It is important to note that these same limitations also exist with the finished product sterility test used with aseptically filled products. PDA Technical Report No. 304 defines parametric release as: “A sterility release program that is based on effective control, monitoring and documentation of a validated sterile-product manufacturing process where sterility release is based on demonstrated achievement of critical operational parameters in lieu of end-product sterility testing.” FDA has stated that a firm will be approved for parametric release based on how well the firm has mitigated all risks related to product sterility.5 Accordingly, it could be possible in the future for a parenteral product that utilizes a validated post aseptic fill lethal treatment process to reduce the risk of nonsterility to be a be a potential candidate for parametric release. Post aseptic fill lethal treatment has a critical role to play in the pursuit of Aseptic Parametric Release. As stated above, it is well 4
PDA Technical Report No. 30 (2012). Parametric Release of Pharmaceutical and Medical Device Products Terminally Sterilized By Moist Heat. 5 FDA Submission Guidance Document (2010). Submission of Documentation in Applications or Parametric Release Of Human and Veterinary Drug Products Terminally Sterilized with Moist Heat Processes.
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established that the sterility test is limited in its ability to reliably and accurately confirm that aseptic products are sterile. In consideration of the proposition of parametric release with an aseptic product exposed to a post aseptic fill lethal treatment, the role of the sterility test could potentially be eliminated and replaced by the adoption of relevant traditional parametric release practices (i.e., comprehensive risk assessment to identify and mitigate all risks to sterility, etc.) including the critical parameters of the lethal treatment process. In comparison to conventional aseptic processing with sterile product release supported by a finished product sterility test, it is clear that an aseptic product subjected to a validated post aseptic fill lethal treatment and administered by a parametric release sterility assurance program represents a superior proposition.
Summary The implementation of a post aseptic fill sterilization or lethal treatment process drives an enhanced product PNSU and a superior sterility assurance program when compared to conventional aseptically filled sterile products. With the application of post aseptic fill sterilization or lethal treatment as a terminal step to further reduce process and product nonsterility risk, other potential benefits that could be considered including reduction in environmental monitoring, the need for fewer media-fills and even the possibility for the adoption of parametric release.
13
Post Aseptic Fill Sterilization and Lethal Treatment Michael J. Sadowski Lead Scientist, Sterility Assurance, Baxter Healthcare Corporation, IL, United States
Introduction Due to inherently lower risks of nonsterility, terminal sterilization processes are universally considered to be superior to aseptic processes and thus preferred by regulators. However some parental drug product formulations are not stable and may degrade due to processing by terminal sterilization processes that utilize exposure to moist heat. Accordingly these products necessitate the ongoing need for aseptic processing. With aseptic processing, there is a very low probability that any filled unit might contain a microorganism due to the robust process design and associated environmental microbial controls. Any microorganisms present are low in number and most likely from human origin (i.e., primarily Gram-positive cocci) and are expected to demonstrate relatively low resistance levels to moist heat sterilization processes. To further reduce the risk of nonsterility with an aseptic product that can tolerate some of level of heat, a post aseptic fill lethal treatment process could be employed. For this situation, the product is aseptically filled and sealed in containers followed by exposure to a validated microorganism inactivation process that delivers a low level of heat history as the terminal step of the overall manufacturing process. Based on the heat sensitivity of the product, the low heat history treatment step can be performed at conventional moist heat sterilization temperatures or at lower temperatures. It is important to note that the application of a post aseptic fill lethal treatment process is not to be considered mandatory. Based on the documented, successful, safe application of aseptic processing for many years, there is a Principles of Parenteral Solution Validation. DOI: https://doi.org/10.1016/B978-0-12-809412-9.00013-7 © 2020 Elsevier Inc. All rights reserved.
262
Principles of Parenteral Solution Validation
lack of scientific and risk-based evidence to support the absolute need for the application of terminal sterilization or other lethal treatment processes for product produced via well designed, properly controlled and operated aseptic processes. Accordingly, aseptic manufacture in these cases can provide products of suitable quality and there is no scientific justification to support the expectation that products produced through aseptic manufacture would necessarily require the addition of some moderated ‘terminal sterilization’ or other lethal treatment conditions.1
The implementation of a post aseptic processing sterilization or lethal treatment process step yields a reduced risk for nonsterility. Therefore optimization of the sterility assurance program should be one of the benefits derived from this enhanced focus on proactive measures to support product sterility. This chapter will discuss lethal treatment approaches, considerations, and potential benefits that can be derived from applying a terminal microbial inactivation process on product that has been previously filled using an aseptic process.
Sterilization and Lethal Treatment The term “sterilization” is a well-known term that is very precisely defined in global regulatory standards and guidance documents while the term “lethal treatment” is a much broader term that is not as precisely defined nor widely understood. Accordingly the author prefers to recognize the terms “post aseptic fill sterilization” and “post aseptic fill lethal treatment” in a distinctive and exclusive fashion much in the way that traditional sterilization is not commonly referred to as lethal treatment.
Post Aseptic Fill Sterilization The following definition and clarifying notation for the term sterilization can be found in ISO111392 (2018): Sterilization: Validated process used to render product free from viable microorganisms. Note: In a sterilization process, the nature of microbial inactivation is described as exponential and thus the survival of a microorganism on an individual item can be expressed in terms of probability. Adapted from PDA Comments Submitted to EMA on “Guideline on the sterilization of the medicinal product, active substance, excipient and primary container,” October 2016. 2 ISO11139 (2018). Sterilization of healthcare productsVocabularyTerms used in sterilization and related equipment and process standards. 1
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While this probability can be reduced to a very low number, it can never be reduced to zero. Aseptic processes provide a high level of bioburden control based on the robust and successful design, development and qualification (e.g., Aseptic Process Simulation, Environmental Monitoring Performance Qualification, etc.) of the process. The resulting low product bioburden levels support the use of the Product Specific Design Approach and an associated reduced physical lethality (F0) for moist heat sterilization processes for any products that can tolerate a relatively low heat history at recognized sterilization temperatures. Since the presence of product bioburden in this situation should be at a low probability, reduced assumptions for the product bioburden population level and resistance level may be considered in the determination of the Probability of a Nonsterile Unite (PNSU) for these products. Additionally, the use of the Product Specific Design Approach could provide for a PNSU of # 1026 which represents a significant reduction of the risk of nonsterility when compared to traditional aseptic processing. The use of the Semilog Survivor Curve Equation adapted from PDA Technical Report No. 1 Eq. (13.1)3 can be used to calculate the resulting PNSU for product with exposure to a low heat history sterilization including the product bioburden assumptions listed below: Log NF 5 2 F0 =D121 C 1 Log N0
(13.1)
where, NF is the number of product bioburden microorganisms surviving after exposure to a specific F0. NF is also the PNSU. The target for a terminal moist heat sterilization process is a PNSU # 1026. F0 is the equivalent lethality of a cycle calculated as minutes at a reference temperature of 121 C, using a defined temperature coefficient or z-value of 10 C. F0 should be calculated from heat penetration temperature readings in the slowest to heat location in the product. Assume an F0 value of 2.4 minutes for this example. D121 C is the D121 C value—thermal resistance value, in minutes, of a product bioburden microorganism at 121 C. Assume a product bioburden resistance of 0.4 minutes for this example. N0 is the number of product bioburden microorganisms prior to exposure. Assume 1 heat resistant spore for product bioburden for this example. 3 PDA Technical Report No. 1 (2007). Validation of Moist Heat Sterilization Processes: Cycle Design, Development, Qualification and Ongoing Control.
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Principles of Parenteral Solution Validation
Then, Log NF 5 2 F0 =D121 C 1 Log N0 Log NF 5 2 2:4=0:4 minutes 1 Log ð1Þ 5 2 6 1 0 Log NF 5 2 6 NF 5 1026 Note: An additional safety factor can be added by increasing the F0 value to 3 minutes or more to further reduce (enhance) the resulting PNSU for the post aseptic fill moist heat sterilization process. In order to support the achievement of a corresponding moist heat sterilization process biological lethality (FBIO), biological indicators (BI’s) with D121 C values in the range of 0.20.6 minutes (e.g., Bacillus subtilis 5230) are available from various BI manufacturers. FBIO is calculated as follows: FBIO 5 D121 C ðSLRÞ
(13.2)
where, FBIO is the biological lethality for the sterilization process; D121 C is the D121 C value of the BI; SLR is the Spore Log Reduction (SLR) achieved for the BI after exposure to the sterilization process. SLR 5 LogðN0 Þ 2 LogðNF Þ
(13.3)
where, N0 is the starting spore population of the BI prior to exposure to the sterilization process and NF is the surviving spore population of the BI after exposure to the sterilization process. An SLR value of 6.0 will be used for this example with the assumption of complete inactivation of a BI with a starting population of 106 spores per unit. In this case, an NF of 1 must be assumed since it is not mathematically valid to calculate the logarithm of 0. Then SLR 5 Log (106) 2 Log (1) 5 6.0 2 0 SLR 5 6:0 Then, FBIO 5 D121 C value (SLR) FBIO 5 0.4 minutes (6.0)
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FBIO 5 2.4 minutes which can be included in place of F0 in Eq. 13.1 above to also support a PNSU # 1026. In addition to or as an alternate to moist heat sterilization, other modalities of terminal sterilization such as radiation (gamma or e-beam) may also be used to enhance the PNSU/product sterility after completion of aseptic processing.
Post Aseptic Fill Lethal Treatment Post aseptic lethal treatment can be defined as the application of a terminal treatment process designed to inactivate microorganisms present after completion of an aseptic process. As stated above and due to the extensive environmental controls and the prevalence of microorganisms from human origin that are vegetative microorganisms and not spore-formers, the number and resistance of any microorganisms present in product from aseptic processing is expected to be very low. In order to inactivate vegetative organisms to obtain a count that is exclusively from spores in the Spore Count Test, a heat shock at 60 C80 C for 1530 minutes is often employed on the samples prior to plating and incubation. Therefore these temperatures and exposure ranges can also be considered for use with post aseptic fill lethal treatment for those products that are not negatively affected by exposure to these levels of heat history. Based on this author’s experience, 80 C for 15 minutes seems to be a widely used heat history for sanitization which could be suitably adapted for post aseptic fill lethal treatment. However the temperature set point should be based on the heat sensitivity of the product while the overall target heat history should be based on the resistance of the microflora at the aseptic processing facility. This could lead to potential higher or lower temperature set points with shorter or longer exposure times, respectively. The simplest heat processing option for the post aseptic fill lethal treatment would be heat exposure in an appropriately sized water bath in a batch type of process although it would also be possible also utilize a continuous process with appropriate equipment. The process heat history could be set and demonstrated by monitoring time at temperature (i.e., 15 minutes at 80 C) or with integration of time and temperature similar to the approach with F0 but with an alternate reference temperature (Tref) corresponding to the target exposure temperature. For temperature monitoring, the temperature could be
266
Principles of Parenteral Solution Validation
monitored in the slowest to heat location of product for each batch or the time needed at the minimum exposure temperature could be developed and qualified. Although this section discussed the application of moist heat with a water bath, other sterilization technologies (e.g., radiation) could be similarly utilized based upon the sensitivity of the product to these technologies.
Parametric Release As stated previously, the implementation of proactive measures such as post aseptic fill sterilization and lethal treatment should result in an optimized sterility assurance program. The application of parametric release aligns well with the implementation of proactive and validated microbiological inactivation processes which far exceed the risk mitigation potential of highly intensive product testing strategies such as the finished product sterility test. It is well known that the product sterility test is statistically flawed with very limited capability to support that a batch of moist heat terminally sterility product is sterile. It is important to note that these same limitations also exist with the finished product sterility test used with aseptically filled products. PDA Technical Report No. 304 defines parametric release as: “A sterility release program that is based on effective control, monitoring and documentation of a validated sterile-product manufacturing process where sterility release is based on demonstrated achievement of critical operational parameters in lieu of end-product sterility testing.” FDA has stated that a firm will be approved for parametric release based on how well the firm has mitigated all risks related to product sterility.5 Accordingly, it could be possible in the future for a parenteral product that utilizes a validated post aseptic fill lethal treatment process to reduce the risk of nonsterility to be a be a potential candidate for parametric release. Post aseptic fill lethal treatment has a critical role to play in the pursuit of Aseptic Parametric Release. As stated above, it is well 4
PDA Technical Report No. 30 (2012). Parametric Release of Pharmaceutical and Medical Device Products Terminally Sterilized By Moist Heat. 5 FDA Submission Guidance Document (2010). Submission of Documentation in Applications or Parametric Release Of Human and Veterinary Drug Products Terminally Sterilized with Moist Heat Processes.
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established that the sterility test is limited in its ability to reliably and accurately confirm that aseptic products are sterile. In consideration of the proposition of parametric release with an aseptic product exposed to a post aseptic fill lethal treatment, the role of the sterility test could potentially be eliminated and replaced by the adoption of relevant traditional parametric release practices (i.e., comprehensive risk assessment to identify and mitigate all risks to sterility, etc.) including the critical parameters of the lethal treatment process. In comparison to conventional aseptic processing with sterile product release supported by a finished product sterility test, it is clear that an aseptic product subjected to a validated post aseptic fill lethal treatment and administered by a parametric release sterility assurance program represents a superior proposition.
Summary The implementation of a post aseptic fill sterilization or lethal treatment process drives an enhanced product PNSU and a superior sterility assurance program when compared to conventional aseptically filled sterile products. With the application of post aseptic fill sterilization or lethal treatment as a terminal step to further reduce process and product nonsterility risk, other potential benefits that could be considered including reduction in environmental monitoring, the need for fewer media-fills and even the possibility for the adoption of parametric release.