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]
621 FILTER DRYER CRYSTALLIZER i CENTRIFUGE BLENDER BULK CONTAINER SPRAY DRYER Figure 2. Typical isolation process for a filter/dryer or spray dryer 8.0 SPRAY DRYING an be batch or production needs and the stability of the solutions to be spray dried. Because of reduced product manipulation, microbial and particulate burden can be educed. Normally there is a solution vessel, a filtration system with prefilters and sterile filters, a pressure vessel to feed the spray dryer at a controlled rate, spray dryer itself, and bulk containers The air used for product drying should be HEPA filtered. Whe esigned with silicone gaskets, the system will withstand sterilization peratures. The atomizing device can be either a spray nozzle or a high centrifugal device Spray dried products are typically temperature sensitive, therefore, air temperature should be controlled and as low as possible. Design of the atomizing device should ensure that product will not adhere to vessel walls Surface drying and depyrogenation can be done in a continuous operated tunnel or batch oven. The former method is preferred since it minimizes the potential of particulate contamination during loading
Sterile Formulation 621 Figure 2. Typical isolation process for a filter/dryer or spray dryer 8.0 SPRAY DRYING Spray drying processes can be batch or continuous depending on production needs and the stability of the solutions to be spray dried. Because of reduced product manipulation, microbial and particulate burden can be reduced. Normally there is a solution vessel, a filtration system with prefilters and sterile filters, apressure vessel to feed the spray dryer at a controlled rate, the spray dryer itself, and bulk containers. The air used for product drying should be HEPA filtered. When designed with silicone gaskets, the system will withstand sterilization temperatures. The atomizing device can be either a spray nozzle or a high speed centrifhgal device. Spray dried products are typically temperature sensitive, therefore, air temperature should be controlled and as low as possible. Design of the atomizing device should ensure that product will not adhere to vessel walls. Surface drying and depyrogenation can be done in a continuous operated tunnel or batch oven. The former method is preferred since it minimizes the potential of particulate contamination during loading
622 Fermentation and Biochemical Engineering Handbook The spray dryer is normally dry heat sterilized by a hot air system that is used for drying the product. All lines entering the spray dryer must be sterilizable. The selection of spray dryer size and solution atomizing device is best determined by trial runs on sized pilot equipment. As with freez drying, operational expense may limit spray drying operations to specific product applications. a flow diagram illustrating the spray drying process is shown in Fig 3 PRODUCT FEED AIR PRE- BLOWER/ HEPA FILTER HEATER FILTER ATOMIZER AIR FILTER DRYER CYCLONE PRODUCT COOLER PRODUCT OUT Figure 3. Spray drying process 9.0 EQUIPMENT PREPARATION All portable equipment and tools used in a sterile area must be thoroughly pre-washed with proper cleaning agents, final rinsed with WFl, and wrapped if required. These items are usually passed into the sterile are through a double door autoclave. Elimination of all particulate matter fre any object entering the sterile area should be a major design consideration
622 Fermentation and Biochemical Engineering Handbook FILTER The spray dryer is normally dry heat sterilized by a hot air system that is used for drying the product. All lines entering the spray dryer must be sterilizable. The selection of spray dryer size and solution atomizing device is best determined by trial runs on sized pilot equipment. As with freeze drymg, operational expense may limit spray dyng operations to specific product applications. A flow diagram illustrating the spray drying process is shown in Fig. 3 DRYER CYCLONE PRODUCT FEEC b-21 Figure 3. Spray drying process 9.0 EQUIPMENT PREPARATION All portable equipment and tools used in a sterile area must be thoroughly pre-washed with proper cleaning agents, final rinsed with WFI, and wrapped if required. These items are usually passed into the sterile area through a double door autoclave. Elimination of all particulate matter from any object entering the sterile area should be a major design consideration
Sterile Formulation 623 All product-contact equipment, especially large mixers, should be electropolished. When stability is a concern, product should be cooled as soon as possible after leaving the cyclone separator Materials that cannot be sterilized should be transferred into the sterile area through an isolated area in which an outer wrapping is removed. The object is then wiped down with a sanitizing agent such as isopropanol or hydrogen peroxide Stationary equipment such as conveyors and filling equipment must be sanitized at some specified frequency. This can be accomplished by wiping down with a sanitizing agent or fogging the sterile area with formaldehyde All product contact parts such as powder hoppers, filling wheels, and stopper bowls are removed from the sterile area, cleaned and sterilized as previously described Freeze dryers are usually steam sterilized or sterilized using VPHP (vapor phase hydrogen peroxide). Trays used in a freeze dryer are usually cleaned and sterilized separately. 10.0 VALIDATION Procedures must be developed and staffing provided for the collection of data that proves that the processes and equipment meet all parameters claimed(12) Systems should be in place for equipment qualifications, validation, changes, and replacement. The manufacturing process validation could be invalidated without proper documentation of equipment mainte nance. A minimum of three consecutive manufacturing lots should be evaluated for process validation. Parameters involved in process validation include in-process and final bulk product test, deviation analysis of the process, stability testing of final product and equipment qualification and validation. Other validation requirements are discussed by S 11.0 FILLING VIALS WITH STERILE BULK MATERIALS 11.1 Vial and Stopper Preparation Vials must be thoroughly washed, dried, sterilized, and depyrogenated They should be handled in a clean room to minimize contamination by Washing is normally done in au d vial washe using purified water, filtered oil-free air, and a final rinse of WFI
Sterile Formulation 623 All product-contact equipment, especially large mixers, should be electropolished. When stability is a concern, product should be cooled as soon as possible after leaving the cyclone separator. Materials that cannot be sterilized should be transferred into the sterile area through an isolated area in which an outer wrapping is removed. The object is then wiped down with a sanitizing agent such as isopropanol or hydrogen peroxide. Stationary equipment such as conveyors and filling equipment must be sanitized at some specified frequency. This can be accomplished by wiping down with a sanitizing agent or fogging the sterile area with formaldehyde. All product contact parts such as powder hoppers, filling wheels, and stopper bowls are removed from the sterile area, cleaned and sterilized as previously described. Freeze dryers are usually steam sterilized or sterilized using VPHP (vapor phase hydrogen peroxide). Trays used in a freeze dryer are usually cleaned and sterilized separately. 10.0 VALIDATION Procedures must be developed and staffing provided for the collection of data that proves that the processes and equipment meet all parameters claimed.~'*] Systems should be in place for equipment qualifications, validation, changes, and replacement. The manufacturing process validation could be invalidated without proper documentation of equipment maintenance. A minimum of three consecutive manufacturing lots should be evaluated for process validation. Parameters involved in process validation include in-process and final bulk product test, deviation analysis of the process, stability testing of final product and equipment qualification and validation. Other validation requirements are discussed by Sawyer and stats .[I3] 11.0 FILLING VIALS WITH STERILE BULK MATERIALS 11.1 Vial and Stopper Preparation Vials must be thoroughly washed, dried, sterilized, and depyrogenated. They should be handled in a clean room to minimize contamination by particulate matter. Washing is normally done in automated vial washers using purified water, filtered oil-free air, and a final rinse of WFI
624 Fermentation and Biochemical Engineering handbook Rubber closures for vials are also washed and depyrogenated in an automatic washer. The final rinse of the stoppers should be wFl. The use of detergent is optional. These operations should occur in a clean room to minimize contamination. After washing, stoppers are batched and auto- clawed prior to entering the sterile area Depending on stoppering equipment and tendency of stoppers to clump during sterilization, a silicone lubricant may be added to the stoppers prior to sterilization. Several manufacturers offer equipment which is capable of all these operations-washing, silicone addition, and sterilization Vial and stopper washers are available that will allow processing from the clean room area into the sterile area in one operation. This equipment eliminates the transfer of vials and stoppers into the sterile area through ovens or autoclaves, thereby minimizing the potential for viable or nonviable particulate contamination. A typical flow sheet for the handling of vials, stoppers, and miscellaneous equipment is shown in Fig. 4 STERILE NON STERILE EQUIP MENT AREA AREA EANING VIAL WASHER/ STERILIZER CON V CLAVE WASHER Figure 4. Sterile vial preparation 11.2 Filling of vials Vials used in a filling operation are fed into the system automatically by a conveyor from a vial sterilizer or manually from trays that have been
624 Fermentation and Biochemical Engineering Handbook Rubber closures for vials are also washed and depyrogenated in an automatic washer. The final rinse of the stoppers should be WFI. The use of detergent is optional. These operations should occur in a clean room to minimize contamination. After washing, stoppers are batched and autoclaved prior to entering the sterile area. Depending on stoppering equipment and tendency of stoppers to clump during sterilization, a silicone lubricant may be added to the stoppers prior to sterilization. Several manufacturers offer equipment which is capable of all these operations-washing, silicone addition, and sterilization. Vial and stopper washers are available that will allow processing from the clean room area into the sterile area in one operation. This equipment eliminates the transfer of vials and stoppers into the sterile area through ovens or autoclaves, thereby minimizing the potential for viable or nonviable particulate contamination. A typical flow sheet for the handling of vials, stoppers, and miscellaneous equipment is shown in Fig. 4. EQUIPMENT NONSTERILE WASHER Figure 4. Sterile vial preparation 11.2 Filling of Vials Vials used in a filling operation are fed into the system automatically by a conveyor from a vial sterilizer or manually from trays that have been
Sterile formulation 625 processed through a batch oven. Because of the increased risk of contami- tion, the former method is preferred Powder fills are made by aseptically transferring the sterile bulk powder from its containers into the hopper ofthe filling machine. Thetransfer is usually done from a container that is mechanically positioned over the hopper with a solid aseptic connection to the hopper The type of filling machine to be used is best determined from trial runs of various supplier machines. All filling lines and equipment should be designed to prevent contamination by people and particulate matter. A typical vial filling operation is shown in Fig. 5. More recent designs barrier technology to accomplish this objective. 4) NONSTERILE STERILE AREA STERILE AREA AREA ACCUMULATOR FCONVEYOR CAPPER <FILLER INSERTER SWING AWAY CON VEYOR Once a vial has been filled with powder, it is stoppered and transported out of the sterile area, and is capped The current regulatory trend is to perform the capping operation in a sterile area using sterilized caps. After capping, vials are usually visually inspected, labeled, and packaged A liquid fill operation is delivered to a pump through lines that have been sterilized in place or sterilized and assembled aseptically
Sterile Formulation 625 processed through a batch oven. Because of the increased risk of contamination, the former method is preferred. Powder fills are made by aseptically transferring the sterile bulk powder from its containers into the hopper ofthe filling machine. The transfer is usually done from a container that is mechanically positioned over the hopper with a solid aseptic connection to the hopper. The type of filling machine to be used is best determined from trial runs of various supplier machines. All filling lines and equipment should be designed to prevent contamination by people and particulate matter. A typical vial filling operation is shown in Fig. 5. More recent designs incorporate barrier technology to accomplish this objective.[l41 NO NSTER 1 LE STERILE AREA STE w ILE - AREA ARElP Figure 5. Sterile filling line Once a vial has been filled with powder, it is stoppered and transported out of the sterile area, and is capped. The current regulatory trend is to perform the capping operation in a sterile area using sterilized caps. After capping, vials are usually visually inspected, labeled, and packaged. A liquid fill operation is delivered to a pump through lines that have been sterilized in place or sterilized and assembled aseptically
