Moist Heat Terminal Sterilization for Controlled Release Materials

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1 Moist Heat Terminal Sterilization for Controlled Release Materials James Agalloco Agalloco & Associates

2 Presentation Overview Terminal Sterilization Fundamentals Steam Radiation Current Best Practices TS processes and approaches that everyone, including regulators can agree on. Current processes with a modest twist. Those may that create will likely create some angst. Expected Future Developments Thinking outside the current box that might be a part of our future.

3 Terminal Sterilization Aseptic Processing Relies on a lethal treatment to microorganisms Safer Preferred by regulatory bodies Method of choice Degradation of materials always a concern Easily reproducible process Relatively easy to validate Not for all materials Assumed more expensive Relies on removal / separation of microorganisms More risky Closely scrutinized by regulators More widely used Material quality / stability largely unaffected More variable process Much harder to control No material issues Presumed less expensive

4 Why TS is preferable to AP Component 1 Component 2 Formulation Component 1 Component 2 Formulation Assembly Sterilize Sterilize Sterilize Assembly Sterilize No post sterilization handling Extensive handling is usually necessary

5 Why is there a preference? Patient safety concerns Recalls for lack of sterility are predominantly associated with aseptically processed materials. Terminal processes are destructive of microorganisms in the container and fewer variables can impact the process. Aseptic processing requires careful control of many more variables and is therefore more prone to contamination.

6 Which process to choose? Regulators require firms to evaluate TS processes before accepting an aseptic processing solution. FDA Sterile Product Submission Guidance FDA Aseptic Processing Guidance EMEA 1999 Decision Trees for the Selection of Sterilization CPMP/QWP/054/98 But are these guidance documents sufficiently clear and flexible to be of real value?

7 EMEA Decision Tree Can the product be sterilised by: Moist heat at 121 C for 15 minutes yes no Moist heat with F 0 = 8 minutes achieving SAL of 10-6 no yes Can the formulation be filtered through a microbial retentive filter yes no Use pre-sterilised individual components and aseptic compounding and filling Use a combination of aseptic filtration and aseptic processing

8 Sterilization / Sterilisation The America s PNSU of 10-6 LVP s Part 212 Regulation 1976 PDA TM# & 2007 Microbiology Based Validation Practice FDA Sterilization Guidance 1994 Cycle parameters vary substantially Adapt cycle to product / load requirements Europe 121 C / 15 minutes Hospital Problems HTM Engineering Based Validation Practice HTM , EN 285 & EN 554, Eur. Ph., CPMP Decision Tree 1998 Strong preference for standard cycle Adapt product / process to standard cycle

9 Some Basic Perspectives Some products should always be TS WFI, saline, LVP s (D5W, Ringer s, etc.) Some products are incompatible w/ TS (at least by steam) and should be aseptically filled. Freeze-dried, dry powder, water free products, etc. The focus of the effort should be on those which fall between these extremes. Controlled release products are a greater concern because of their unique product delivery concerns.

10 Terminal Sterilization A balance must be achieved between the need to maintain a safe, stable and efficacious product while providing sufficient heat input to attain a minimum level of sterility assurance.

11 Material Perspectives Sterilizing processes should be a compromise between the degradation effect on the materials and destruction of microorganisms. A sterilization process that destroys all microorganisms, but renders the item being sterilized unfit for use is of no value. The sterilization process and the specific product formulation and container must be suited to each other. There are few universal answers, and some of those that appear to be broadly applicable may be wrong.

12 Sterilization Validation Methods Overkill Method For items that can tolerate substantial heat or radiation. Can be used for some very stable products. Bioburden / Biological Indicator Method Balance of lethality and stability concerns. Common option for moist heat TS processes. Bioburden Method Lowest possible adverse effect Basis for most radiation sterilization validation.

13 Heat or Radiation Input Terminal Sterilization Concerns Terminal sterilization processes require consideration of the effects of maximum treatment conditions for their potential deleterious effect on the materials being processed. Sterile Non-Stable Sterile Stable Non-Sterile Stable

14 Validation Methods Compared Demonstrated PNSU Expected Shelf Life Information Needed For Validation Heat / Radiation Input to Materials Bioburden Method Bioburden / BI Method Overkill Method

15 Products & Containers - Steam Solutions, suspensions, and emulsions can all be terminally steam sterilized. A minimum water content of approximately 5% is considered necessary, but this must be evaluated. Glass and plastic pre-formed vials, BFS, glass and plastic syringes have all been successfully processed. Interpolation of container sizes, formulation strength, etc. is possible.

16 Remember the Real Target The most common error associated with terminal sterilization (and perhaps sterilization in general) is forgetting that the intent is destruction of the bioburden to low levels (a Probability of a Non- Sterile Unit [PNSU] of not more than 1 in 10 6 units). What happens to the biological indicator (if there is one) is largely irrelevant outside of the context of the validation exercise.

17 BI & Bioburden Relative Resistance Population Biological Indicator Death Curve Bioburden Death Curve Time

18 Bioindicator F 0 = 8.0 minutes Bioburden F 0 = 8.0 minutes D 121 of BI = 0.5 minutes D 121 of bioburden = minutes N 0 of BI = 10 6 N 0 of bioburden = 100 ( or 10 2 ) PNSU for BI = PNSU for Bioburden = 10-1,598 log N u F D log N Where, N u = Probability of Non-sterile Unit (PNSU also known as SAL) D= natural resistance of bioburden F= Fvalue or lethality of process N o = bioburden count per container 0

19 Contamination Rate How not to test TS products N/A Cleanroom N/A TS Sterility Testing EM Testing

20 Contamination Rate How to test TS products N/A Isolator N/A TS Sterility Testing EM Testing

21 Contemporary TS Processes using Moist Heat

22 Terminal / Non-Porous Loads Air over-pressure of the load may be required to maintain container integrity. Steam quality testing is irrelevant. Materials sensitive to excess heat can be processed. Minimum and maximum time-temperature or F 0 requirements are needed. Container-closure interface sterilization can be a concern if components aren t sterile.

23 Terminal Sterilization Cycles The common autoclave cycles can be used, as well as some others. Gravity Displacement Single Pre-Vacuum Multiple Pre-vacuum Steam-Air Steam-Water-Air (Raining Water) Immersion Continuous Sterilizer

24 Temperature Gravity Displacement Cycle Steam Inlet Heat-up Exposure Cool-down Time Steam Trap

25 Multiple Pre-vacuum Cycle Pre-vac Come-up Exposure Exhaust Drying Atmospheric Break Pressure Temperature

26 Steam-Air Sterilizer Courtesy of Fedegari Autoclavi, SPA

27 Steam-Air-Water Sterilizer Courtesy of Fedegari Autoclavi, SPA

28 Advanced Steam Designs

29 Continuous Sterilizer

30 Internal Pressures During Cycles T = 100 C P = 2 Bar T = 122 C P = 3.1 Bar T = 80 C P = 1.5 Bar T = 80 C P = 1.8 Bar T = 122 C P = 3.7 Bar T = 100 C P = 2.4 Bar Heating Steady State Cooling

31 Air Overpressure Cycle Container internal Pressure Chamber Pressure TEMPERATURE / PRESSURE Temperature Setpoint Chamber / Drain Temperature Equilibration Time Exposure Time Temperature Setpoint Dead Band Load Come-up Time Load Cool-Down Time Chamber Cool-Down Time Load Temperature Chamber Come-up Time Cycle Start Chamber Temperature TIME

32 Sterilization Cycle Development Screen formulation for terminal sterilization. Selection the correct equipment / process. Determining the slowest / fastest to location in filled product containers. Determining the slowest / fastest to heat zone of load. Define how much lethality is enough based upon bioburden. Define load sizes and patterns. Product stability evaluation.

33 Mapping Studies Container mapping Probe position in container Load mapping Position of load in chamber Both hot and cold spot determination Load sizes & patterns Minimum, maximum loads Use of dummy load components (fixed loads) Container Sizes / Fill Volumes Minimum and maximum container sizes Multiple fill volumes in single container

34 Container Mapping - Vertical

35 Container Mapping - Horizontal - HEAT MAPPING STUDY AVERAGE HEAT INPUT (F ) AT VARIOUS LOCATIONS Fill Level

36 Key Validation Concerns Minimum / maximum F0 criteria are required. Tight temperature range at steady state is preferred. Hot and cold spot determination in load (may be a region rather than a single point). Temperature & BI challenge performed together. Need to define routine probe locations. Cold spots are rarely monitored in commercial processes Correlation developed between control location and cold / hot spot to regulate process. Bioburden monitoring instituted as routine measure if not an aseptic fill.

37 Maximum and Minimum Loads Maximum loads are typically all that will fit in a chamber in a normal loading pattern. Minimum loads are arbitrary minimums which a firm might process. Some of the minimums used are a single tray, or single box. The utility of maximum and minimum loads depends to a large extent on the range of lot sizes produced. There are firms which have chosen to validate only maximum loads, and any load smaller than maximum is made up to maximum with dummy units. More widespread is the validation of maximum and minimum loads, which affords greater flexibility in batch size.

38 Bottles of Convenience Monitoring of sterilizer cold spot is not required for process control. Correlation between the cold (and hot spot) with the monitored location should be established during cycle development / validation. A fixed monitoring location can be used provided its process requirements are defined to assure conditions at the points of interest are know in relation to the monitored location.

39 Biological Indicator Choices Geobacillus stearothermophilus (rarely) ATCC 7953 or Clostridium sporogenes ATCC Bacillus coagulans Bacillus subtilis ATCC 5230 Bioburden organisms Must know D-value in product or product substitute

40 Test Fluids (Product Surrogates) Water for Injection, normal saline, salt solutions, SCDM, other microbiological medias and buffers, match product viscosity & solids content? Advantages Reduce the amount of product required for validation purposes, Widely used for preliminary mapping studies, etc. If a growth medium is used, may simplify microbial challenge studies. Disadvantages - If used for microbiological challenges, additional D-values must be obtained. Must be shown to resemble product. Selection Criteria - Cost, safety, resemblance to product, ease of testing, use as physical and/or biological model for product Consider use of SCDM for microbiological challenge units to simplify testing.

41 Use of D & z Values D-values - of critical importance Never use a biological indicator without knowledge of the D-value on the substrate or in the product. Supplier data is normally from a paper strip. Requires internal resources - Biological Indicator Evaluation Retort {BIER} vessel, detailed microbiological methods z-values - of less importance Their measurement by manufacturers and users is nonroutine. In most cases the values given in the literature are utilized without difficulty. Varies only slightly over the temperature range of most interest.

42 Bioburden Information #, amount, quantity Kind, type, species, genus, origin? Seasonal variation Positive & Negative controls on methods Kinds of products growth supportive highly contaminated Filtration method as adapted from sterility test USP microbial methods adapted Need for periodic monitoring Establishment of action / alert levels

43 Container-Closure Integrity It is important to ensure that the initial and long term microbial barrier properties of the container-closure system are not compromised by the sterilization cycle. Initial development and validation of a sterilization cycle should include an assessment of the package integrity, when sterilized at the maximum exposure time and temperature.

44 Closure-Container Interface All LVP manufacturers (and some others) inoculate the seal area of the stopper / glass with B. atrophaeus to confirm lethality where steam might not easily penetrate. A 1x10 6 CFU challenge might be excessive at this location, given the minimal potential for bioburden. If both container and stopper are sterilized prior to filling, this evaluation isn t necessary.

45 Stopper Vial Interface Inoculation VIAL Stopper Stopper 1 2 VIAL 3 4 Inoculum

46 Some TS Experience Minimum F 0 requirements ranging from 2 to 38 minutes Glass / plastic containers 0.5 to 500 ml BI s used G. stearothermophilus, B. subtilis 5230, B. atrophaeus Product D 121 values minutes Containers vials, ampules, syringes Aseptic & non-aseptic fills

47 Parametric Release From a risk and science perspective there is no value in performing a sterility test on terminally sterilized products. The only thing that a sterility test could potentially detect would be a failure to run the cycle, and depending upon the product characteristics even this detection is not assured. There is the impression that a laboratory test is required, however thermal or dosimetry data is more likely to indicate process failure than a lab test. The real obstacles with respect to parametric release are regulatory and compendial, not scientific.

48 TS Processes / Practices on the Horizon

49 Breaking out of the Box Post-aseptic filling lethal treatments at temperatures that kill spores have been used for decades. While this is not in the strictest sense terminal sterilization it is a means by which microbial risk can be mitigated. Many pathogenic organisms are killed very efficiently at temperatures in the o C range or at lower radiation doses. We shouldn t think of aseptic processing or terminal sterilization as an either/or proposition. Post-aseptic filling treatments should be more broadly applied.

50 Dr. Sasaki s Suggestion Dr. Sasaki suggested at the USP Open Conf. in 2002 that parametric release could be considered for processes that deliver as little as F o =2 minutes. To those convinced that only overkill processes are suitable for use in moist heat sterilization this idea may seem preposterous. Environmental endospores do not have a D 121 higher than 0.2 minutes, vegetative cells would have D 121 values in some cases >100,000X less. So, a process yielding a F 0 of 2 minutes would provide a ten log spore reduction against the most resistant pre-sterilization bioburden. With that in mind Dr. Sasaki s suggestion doesn t seem preposterous at all, in fact it seems downright logical.

51 Aseptic Processing & Terminal Sterilization Aseptic Processing Percentage of Contaminated Units (not an SAL) Implied Estimate of Sterility Assurance Terminal Sterilization Probability of a Non-sterile Unit (PNSU) Quantitative Assessment of Sterility Assurance Assumes known F 0, D and bioburden N 0 Terms cannot be added to determine an overall SAL for a combined process.

52 What if? Is there a benefit to a terminal treatments (moist heat or radiation) following aseptic processing? Absolutely, but we have been fixated on processes that kill highly resistant spores. Almost everyone agrees that this type of process would risk to the patient. Almost no one agrees on what type of post aseptic fill lethal process should be used.

53 TS and AP Component 1 Component 2 Formulation Sterilize Sterilize Sterilize This process could be either moist heat or radiation Assemble Sterilize

54 Post Aseptic Fill Heat Treatment Sterile Non-Stable Sterile Stable Non-Sterile Stable Conventional TS Heat Input Sterile Non-Stable Sterile Stable Post-aseptic fill Treatment

55 A New Perspective Decision Tree Can the product be sterilized by moist heat, using 121 C for 15 minutes? Yes Sterilize by moist heat, using standard cycle Yes Sterilize by moist heat to minimum PNSU of 10-6 No Can the product be sterilized by moist heat, achieving a minimum PNSU of 10-6? No Can the product be sterilized by moist heat, achieving a PNSU of ? No Can the formulation be sterilized by filtration? Yes Is the product stable at 100 C No Is the product stable at 80 C No No Yes Yes Yes Yes Sterilize by moist heat, to a PNSU of Use pre-sterilized product, components, aseptic compounding and filling Validate destruction using B. megaterium D100 = ~1 minute Validate destruction using >>106 of nonsporeformer Sterile filter, aseptically process and fill Downloaded from sterilize.it

56 Possible Post A/P Heat Treatments Reduced F 0 and/or time-temperature - F 0 of 2,4,6, or 8 - No standards exist Processing at less than 121 C 100 C for X minutes lethal for most spores and all non-spore formers 80 C for X minutes lethal for some spores and all non-spore formers 60 C for X minutes - lethal for nearly all non-spore formers

57 ISO The A 0 Concept This standard developed for hospital disinfection equipment evaluates thermal processes in the 80 C range in a manner identical to F 0 with the time expressed in seconds due to the susceptibility of vegetative cells to destruction by moist heat. Minimally acceptable A to disinfect (destroy vegetative cells) are 600 seconds for medical devices in contact with intact skin and 3000 seconds for critical medical devices. The use of this system may be well suited for post-aseptic fill heat treatments. ( T 80) A t

58 What these changes might mean Movement away from the black or white view of aseptic processing or terminal sterilization Approaches that visit the gray area in between the extremes are desirable. If not aseptic processing & terminal sterilization, then perhaps aseptic processing and supplementary lethal treatment. The end result is less risk to the patient, improved stability over classical TS processing and substantially fewer issues in aseptic processing control.

59 Future Processes If we recognize that the concern is risk to the patient, then postaseptic fill processes make perfect sense. We shouldn t thing in terms of current PNSU or even F 0 targets, but in slightly different terms. The A 0 model or something like it makes sense below 121 C for moist heat.

60 Conclusion In the future we can make our products safer, we just have to be willing to re-think some of our traditional goals for patient safety. With more and more biological products coming to market, new thinking is necessary to provide greater assurance than our current practices allow.

61 PostScript Walter Kelly, 1971