PDA Poster Presentation - Particle Reduction_R01
- 1. Particle Reduction Guidance From Industry (West Pharmaceutical Services): Background: Maintaining a high level of quality for all primary product contact surfaces is critical, specifically for the final container and closure for injectable drug products. The container and closure must meet GMP requirements for sterility, endotoxin and particulate limits. Case Study: This case study focuses on developing a component (closure) processing cycle that effectively reduces endotoxin and sterilizes the components, while minimizing particulate generation during the process. Developing an efficient processing cycle was especially challenging given the sometimes aggressive nature of the processing steps. Nevertheless, these components are required to be endotoxin and particulate free, sterile and must function smoothly on the filling line. Processing steps, such as washing, sterilization and drying, had to be carefully designed in order to meet the GMP requirements, while avoiding over processing which resulted in particle generation, damage to the components and potential improper function on the filling line. Particle Reduction During Component / Closure ProcessingParticle Reduction During Component / Closure Processing Lifting Device: • Automated lift system • Programmable paths for vessel docking to filling line • Compatible with different vessel sizes and isolator configurations • Ergonomic Process / Transfer Vessel: • Perforated diffusion plate • Variable sizes (10-300 liter volumes) • Sealed upon process completion • Compatible with lift system • Butterfly valve for transfer to isolator • Beta port flange for RTP connection at filling line GMP Requirements for Components: • Endotoxin free – validated for > 3-log reduction of bacterial endotoxin • Sterile – validated for a Sterility Assurance Level of > 10-6 , Spore Log Reduction > 12 Replicate cycles including: • Vessel filling with WFI • WFI overflow • WFI / pharmaceutical air flow • Vessel draining Critical Parameters: • WFI Temperature • WFI flow rate • Pharm air bubbling pressure • Time Challenges: • Meeting GMP requirements for endotoxin reduction and sterility without generating particles • Defining the requirements for particle reduction Solution: Using a detachable vessel component processor, a cycle was developed for the components which included slow vessel rotation and gentle pharmaceutical air bubbling during the wash process, thus preventing damage to the components. Slow vessel rotation and pulsed vacuum / pressure helped to minimize particle generation during the drying and cooling process steps. Cycle development using specialized component processing equipment was critical, given the requirements and risks involved. Unique parameters for washing, sterilization, siliconization, drying and cooling were 100% configurable, allowing for optimizatioin of the cycle during development. These configurable parameters include filling under vacuum, rotation speed / angle / frequency, pharmaceutical air flow (bubbling pressure) and pulsed drying pressure / temperature. Wash / Rinse Sterilization • Pre-vacuum pulses • 123oC steam • 30 minutes steam exposure Critical Parameters: • Pressure • Temperature • Time • Rotation speed / frequency Drying Alternating pulses including: • Vacuum • Pressure • Continuous addition of hot, dry, sterile filtered air Critical Parameters: • Air removal • Steam quality • Time • Temperature Critical Parameters: • Temperature • Time • Rotation speed / frequency Cooling Alternating pulses including: • Continuous addition of cool, dry, sterile filtered air Process Trend Unclassified Cleanroom Grade C or D Vessel Process Station Transfer Lift at Filling Line Loading Station Component Processing Equipment Features Process Station: • Clean utilities (WFI, clean steam, pharmaceutical air) • Rotates process vessel • Detergent and silicone capabilities • PLC with customizable programs Reporting Category Enhanced Specification (particles / 10cm2) PCI < 2.5 > 25µm but ≤ 50µm < 13 > 50µm but ≤ 100µm < 3.5 > 100µm < 0.9 Proved Clean Index Particle Count Component Flow: Remove Foreign Particles and Minimize Particle Generation Stopper Inoculation: • Artificially inoculate stoppers with particles of known quantity and size (rubber, plastic, aluminum, hair) • Process stoppers • Recover inoculated stoppers • Inspect for particulate material • Recover 100% particulate material in drain filter Particle Counting (Rinse Water): • Liquid particle counter installed in processor drain piping, recording in real time • Overflow water – smaller, lower density particles are removed • Drain water – larger, higher density particles are removed • Information used to develop cycle parameters (overflow time and replicate filling/draining cycles) Particle Counting (Processed Stopper): • Conducted in laboratory under laminar air flow with validated methodology • Standard Operating Procedures • Sample stoppers after processing and recover particles • Count particles by filtering and viewing filter under a microscope or with a liquid particle counter Inoculated Components Example: 0.5 mm aluminum particle 2.5 mm hair 25-50 µm 50-100 µm >100 µm PCI Total Particles 83 17 4 NA Particles per 10cm2 8.3 1.7 0.4 1.6 Specification ≤ 13 ≤ 3.5 ≤ 0.9 ≤ 2.5 Particle Load Assessment Example: