Sterile Formulation Michael. akers. Curtis S Strother mark r Walden 1.0 INTRODUCTION Historically, sterile bulk pharmaceutical manufacturing processes prior to filling operations, have followed general bulk pharmaceutical guidelines. As technology and equipment have improved, the requirements for aseptic manufacture have increased. It is important to understand that product quality often is realized in the manufacturing phase and should be maintained throughout the remaining filling/packaging processes. It is the Food and Drug Administrations current opinion that Current Good Manu facturing Practice for Finished Pharmaceuticals apply to sterile bulk operations. 2 Adherence to the Guideline on Sterile Drug Products Produced by Aseptic Processingl3I is considered essential for non-terminally sterilized products as is the case for sterile bulk pharmaceutical dry powders. The facility design and manufacturing process should be integrated with current regulatory guidelines, the interpretation and application of which can be found in several publications- (4j-9J This chapter focuses on the preparing and filling of injectable solid bulk pharmaceutical formulations. The material presented is general in nature but with references to direct the reader to more in-depth treatment of the subject matter. Coverage includes sterile bulk product preparation, 66
14 Sterile Formulation MichaelJ. Akers, CurtisS. Strother, MarkR. Walden 1.0 INTRODUCTION Historically, sterile bulk pharmaceutical manufacturing processes, prior to filling operations, have followed general bulk pharmaceutical guidelines. As technology and equipment have improved, the requirements for aseptic manufacture have increased. It is important to understand that product quality often is realized in the manufacturing phase and should be maintained throughout the remaining filling/packaging processes. It is the Food and Drug Administration's current opinion that Current Good Manufacturing Practice for Finished Pharmaceuticals['] apply to sterile bulk operations .L21 Adherence to the Guideline on Sterile Drug Products Produced by Aseptic is considered essential for non-terminally sterilized products as is the case for sterile bulk pharmaceutical dry powders. The facility design and manufacturing process should be integrated with current regulatory guidelines, the interpretation and application of which can be found in several publi~ations.[~1-[~1 This chapter focuses on the preparing and filling of injectable solid bulk pharmaceutical formulations. The material presented is general in nature but with references to direct the reader to more in-depth treatment of the subject matter. Coverage includes sterile bulk product preparation, 61 6
Sterile formulation 617 filtration, isolation, filling, and environmental conditions required for asep tic processing 2.0 STERILE BULK PREPARATION The solutions used for the dissolution of injectable products are prepared by using Water for Injection (WFI USP that has been made as described in Ch 13 of this handbook. In some cases, solutions are prepared using organic solvents(e.g, acetone, methanol, ethanol, isopropanol) alone or in combination with WFI. The potential for preventing microbial contamination should dominate the delivery and storage systems for water and solvents a typical solution system will consist of a dissolution vessel, a sterile filtration transfer line, and a vessel to hold the sterile filtered solution prior to further processing. Dissolution areas tend to have Class 100,000* air quality with smooth, easy-to-clean surfaces. The sterile side of the system should have the capability of being cleaned and steam sterilized in place or easily dismantled for cleaning and sterilization. [o normally, type 316 stainless steel can be used throughout the facility unless process condition dictate otherwise. Passivation of welds will minimize the potential for microbial growth at rough edges. Metal particulates should be a concern when welding into the processing system. Computer automated systems tend to be the method of choice for validated cleaning and sterilizing operations The solution filtration system should have a prefilter and final steril- ization filter. The selection of filters is dependent on the type of solutions to be filtered. The sterile filters should be validated for the intended use with the product/solution systems. Sterile filters for gases(air or nitrogen)need to be discussed with filter manufacturers to ensure that pressure ratings are appropriate with the intended use. Appropriate pressure regulation of ancillary systems should always be a design consideration. vent filters will be needed in the processing system to maintain sterility during transfe operations. Filter integrity testing(e.g, bubble point or diffusion testing)is quired to ensure that filters remain functional after their usage. Redundan cy of filters will provide a greater safety factor for product during manufac- turing operations. Sterilization of diaphragm valves tends to present fewer concerns with microbial penetration compared to ball type valves. The number of connections should be kept to a minimum. Thread-fitted piping Class 100,000 means no more than 100,000 particles per cubic foot greater than or equal to 0.5 micrometers
Sterile Formulation 61 7 filtration, isolation, filling, and environmental conditions required for aseptic processing. 2.0 STERILE BULK PREPARATION The solutions used for the dissolution of injectable products are prepared by using Water for Injection (WFI) USP that has been made as described in Ch. 13 of this handbook. In some cases, solutions are prepared using organic solvents (e.g., acetone, methanol, ethanol, isopropanol) alone or in combination with WFI. The potential for preventing microbial contamination should dominate the delivery and storage systems for water and solvents. A typical solution system will consist of a dissolution vessel, a sterile filtration transfer line, and a vessel to hold the sterile filtered solution prior to fbrther processing. Dissolution areas tend to have Class 100,000* air quality with smooth, easy-to-clean surfaces. The sterile side of the system should have the capability of being cleaned and steam sterilized in place or easily dismantled for cleaning and sterilization.[l01 Normally, type 316 stainless steel can be used throughout the facility unless process conditions dictate otherwise. Passivation of welds will minimize the potential for microbial growth at rough edges. Metal particulates should be a concern when welding into the processing system. Computer automated systems tend to be the method of choice for validated cleaning and sterilizing operations. The solution filtration system should have a prefilter and final sterilization filter. The selection of filters is dependent on the type of solutions to be filtered. The sterile filters should be validated for the intended use with the productholution systems. Sterile filters for gases (air or nitrogen) need to be discussed with filter manufacturers to ensure that pressure ratings are appropriate with the intended use. Appropriate pressure regulation of ancillary systems should always be a design consideration. Vent filters will be needed in the processing system to maintain sterility during transfer operations. Filter integrity testing (e.g., bubble point or diffision testing) is required to ensure that filters remain fbnctional after their usage. Redundancy of filters will provide a greater safety factor for product during manufacturing operations. Sterilization of diaphragm valves tends to present fewer concerns with microbial penetration compared to ball type valves. The number of connections should be kept to a minimum. Thread-fitted piping * Class 100,000 means no more than 100,000 particles per cubic foot greater than or equal to 0.5 micrometers
618 Fermentation and Biochemical Engineering Handbook connections are not recommended and should be replaced with soldered passivated or sanitary clamp connections. The transport ofliquid streams can be accomplished using either pressure or pumps. For pressure transfer with organic solvent, nitrogen is preferred due to its noncombustible properties however, appropriate safety precautions need to be considered in the system design. A flow diagram illustrating solution preparation is shown in Fig. 1 The location of the sterile filter traditionally has been on the non-sterile side primarily for ease of changing and to minimize contamination of sterile area if leakages occur. However, new designs have the filter on the sterile side NONSTERILE AREA STERILE AREA ( CLASS100,000) (CLASS 100 PRE-FILTER STERILE FILTER CRYSTALLIZER DISSOLUTION Figure 1. Bulk solution preparation 30 ISOLATION OF STERILE BULK PRODUCT 3.1 General Considerations All equipment should be easy to clean and steam sterilizable and have a sanitary finish. If the facility is not dedicated to one product, computer automated"recipes"provide the greatest control and flexibility for process ing. The overall operation must be designed so as to minimize the personnel required to operate the equipment and thus minimize the exposure of product
61 8 Fermentation and Biochemical Engineering Handbook connections are not recommended and should be replaced with soldered, passivated or sanitary clamp connections. The transport of liquid streams can be accomplished using either pressure or pumps. For pressure transfer with organic solvent, nitrogen is preferred due to its noncombustible properties; however, appropriate safety precautions need to be considered in the system design. A flow diagram illustrating solution preparation is shown in Fig. 1. The location of the sterile filter traditionally has been on the non-sterile side primarily for ease of changing and to minimize contamination of sterile area if leakages occur. However, new designs have the filter on the sterile side. NONSTERILE AREA STERILE AREA (CLASS 100,000) Figure 1. Bulk solution preparation 3.0 ISOLATION OF STERILE BULK PRODUCT 3.1 General Considerations All equipment should be easy to clean and steam sterilizable and have a sanitary finish. If the facility is not dedicated to one product, computer automated “recipes” provide the greatest control and flexibility for processing. The overall operation must be designed so as to minimize the personnel required to operate the equipment and thus minimize the exposure of product
Sterile formulation 619 to people. One of the most important facility design factors is in the isolation of product from its surrounding environment. Within the constraints of product quality, prevention of bacterial and particulate matter contamination should dominate the design concept and selection of equipment When product is exposed, air quality should be Class 100* or better which can be achieved by High Efficiency Particulate Air(HEPa)filtration Documentation of initial HEPA certification and periodic test results should be available at all times. Air pressure balancing should provide air flow from clean to less clean areas. Temperature and humidity are properties important to control in order to minimize the potential for microbial growth within the constraints of impact on product. Frequent rotation of sanitizing agents reduces the potential development of resistant organisms. Environmental monitoring is required to verify that product protection systems are working as expected. Environmental and safety concerns have reduced the practical ity of ethylene oxide sterilization while other methods such as peracetic acid and VPHP (vapor pressure hydrogen peroxide)are currently being explored as sterilant 4.0 CRYSTALLIZATION Crystallizers should have variable speed agitators, temperature con- trol, and sterilizable vent filters. As many controls as possible should be located outside of the sterile area. The crystallization vessel should be located as close to the filtration unit as possible. Time, temperature, and agitation speed are critical variables that may need strict control during the crystalli zation process. The crystallization vessel should be part of a closed system and often is jacketed for glycol temperature control 5.0 FILTERING/DRYING The filtration unit can be a centrifuge or closed filter that is either a pressure or vacuum unit. Some processes may require solution washing of the crystalline product. Facility design should therefore be optimized for flexibility. Recent pressure/vacuum filtration units can perform several functions such as collection washing with appropriate solvents, solution washing, and drying of a crystalline product. These filter/dryer units offer the advantage of a closed system that protects product from people and vice *Class 100 means no more than 100 particles per cubic foot greater than or equal to 0.5 micrometers
Sterile Formulation 61 9 to people. One ofthe most important facility design factors is in the isolation of product from its surrounding environment. Within the constraints of product quality, prevention of bacterial and particulate matter contamination should dominate the design concept and selection of equipment. When product is exposed, air quality should be Class 100* or better, which can be achieved by High Efficiency Particulate Air (HEPA) filtration. Documentation of initial HEPA certification and periodic test results should be available at all times. Air pressure balancing should provide air flow from clean to less clean areas. Temperature and humidity are properties important to control in order to minimize the potential for microbial growth within the constraints of impact on product. Frequent rotation of sanitizing agents reduces the potential development of resistant organisms. Environmental monitoring is required to verify that product protection systems are working as expected. Environmental and safety concerns have reduced the practicality of ethylene oxide sterilization while other methods such as peracetic acid and VPHP (vapor pressure hydrogen peroxide) are currently being explored as sterilants. 4.0 CRYSTALLIZATION Crystallizers should have variable speed agitators, temperature control, and sterilizable vent filters. As many controls as possible should be located outside ofthe sterile area. The crystallization vessel should be located as close to the filtration unit as possible. Time, temperature, and agitation speed are critical variables that may need strict control during the crystallization process. The crystallization vessel should be part of a closed system and often is jacketed for glycol temperature control. 5.0 FILTERING/DRYING The filtration unit can be a centrifuge or closed filter that is either a pressure or vacuum unit. Some processes may require solution washing of the crystalline product. Facility design should therefore be optimized for flexibility. Recent pressurehacuum filtration units can perform several functions such as collection washing with appropriate solvents, solution washing, and drying of a crystalline product. These filteddryer units offer the advantage of a closed system that protects product from people and vice *Class 100 means no more than 100 particles per cubic foot greater than or equal to 0.5 micrometers
620 Fermentation and Biochemical Engineering Handbook versa. The unit's agitator can resuspend and smooth product cake. After washing the product cake, the filter/dryer can be rotated to facilitate drying The filter dryer should be readily sterilizable and allow continuous flow of product to the next operation. Drying can be done in vacuum dryers, fluid bed ryers, continuous or manual tray dryers; the latter is least preferable Solvent emissions and recovery will be an important consideration for any solvent drying system 6.0 MILLING/BLENDING The dried product is aseptically discharged into suitable bulk contain ers or, alternately, to the milling unit. Bulk containers need to be designed for cleanability/sterilization. Milling and blending can be done as separate steps or in series by feeding the milled product directly to a blender. Mill parts are generally sterilized in place and blenders must be capable of cleaning and terilizing in place. The working size of the blender should dictate batch size for the crystallization process. Blending is normally achieved in a tumbler type blender such as drum, double cone, twin, oracube, or in a stationary shell type blender such as a ribbon or vertical screw mixer. Aseptic filling and sampling of the final bulk container should be part of the design consider ations in order to minimize product exposure. If possible, the final bulk product should be filled into its final marketed container at the same facility as manufactured. However, if the final bulk container must be transported the container must be designed and tested for container-closure integrity and product compatibility. A flow diagram illustrating a typical isolation process for a filter/dryer or spray dryer process is shown in Fig. 2 7.0 BULK FREEZE DRYING A suitably sized solution preparation system similar to that mentioned under the previous sections can be used to provide material for bulk freeze drying. ( Since product solutions can be sterile-filtered directly into the final container, microbial and particulate exposure will be minimized. ) The sterile solution is subdivided into trays and placed into a sterilized freeze dryer Aseptic transfer of sterile product in trays to the freeze dryer must be validated. After tray drying, the sterile product is aseptically transferred through a mill into suitably designed sterile containers. the preparation of sterile bulk material is usually reserved for those cases where the product cannot be isolated by more common and relatively less expensive crystalli zation methods. due to recent advances in this field, a freeze drying process should be considered as a viable option. 11
620 Fermentation and Biochemical Engineering Handbook versa. The unit’s agitator can resuspend and smooth product cake. After washing the product cake, the filteddryer can be rotated to facilitate drying. The filter dryer should be readily sterilizable and allow continuous flow of product to the next operation. Drying can be done invacuum dryers, fluid bed dryers, continuous or manual tray dryers; the latter is least preferable. Solvent emissions and recovery will be an important consideration for any solvent drylng system. 6.0 MILLING/BLENDING The dried product is aseptically discharged into suitable bulk containers or, alternately, to the milling unit. Bulk containers need to be designed for cleanability/sterilization. Milling and blending can be done as separate steps or in series by feeding the milled product directly to a blender. Mill parts are generally sterilized in place and blenders must be capable of cleaning and sterilizing in place. The working size of the blender should dictate batch size for the crystallization process. Blending is normally achieved in a tumbler type blender such as drum, double cone, twin, or a cube, or in a stationary shell type blender such as a ribbon or vertical screw mixer. Aseptic filling and sampling of the final bulk container should be part of the design considerations in order to minimize product exposure. If possible, the final bulk product should be filled into its final marketed container at the same facility as manufactured. However, if the final bulk container must be transported, the container must be designed and tested for container-closure integrity and product compatibility. A flow diagram illustrating atypical isolation process for a filteddryer or spray dryer process is shown in Fig. 2. 7.0 BULK FREEZE DRYING A suitably sized solution preparation system similar to that mentioned under the previous sections can be used to provide material for bulk freeze drying. (Since product solutions can be sterile-filtered directly into the final container, microbial and particulate exposure will be minimized.) The sterile solution is subdivided into trays and placed into a sterilized freeze dryer. Aseptic transfer of sterile product in trays to the freeze dryer must be validated. After tray drying, the sterile product is aseptically transferred through a mill into suitably designed sterile containers. The preparation of sterile bulk material is usually reserved for those cases where the product cannot be isolated by more common and relatively less expensive crystallization methods. Due to recent advances in this field, a freeze drying process should be considered as a viable option.[’l]