What is aseptic fill-finish manufacturing?
What is aseptic manufacturing?
Aseptic manufacturing covers processes, activities, and procedures undertaken in a sterile environment. The sterile manufacturing environment (aseptic environment) is maintained through specialized equipment that prevents microbial material from technicians, raw materials, or machinery from contaminating medical devices or products.
The terms aseptic and sterile are not synonymous, even though product labels utilize sterile and aseptic interchangeably. While both sterile and aseptic manufacturing will prevent microbial contamination following product use, the processes by which microbial contamination is prevented are different. Sterile is a broader term and encompasses microbial contamination prevention through a complete absence of viable microorganisms or the death of microbes that have the potential to reproduce. In contrast, aseptic manufacturing only prevents microbial contamination by ensuring the absence of microbes during processing, not by killing viable microbes.
Thus, sterile products are often manufactured in non-aseptic environments and then chemically or heat sterilized after being filled or placed into their final packaging. The chemical or heat sterilization process ensures that any microorganisms inside the products (obtained during manufacturing and packaging) are no longer viable. In contrast, aseptic manufacturing prevents contamination by the exclusion of microorganisms. For microorganisms to be excluded, an aseptic healthcare product’s manufacturing and packaging processes happen with sterilized materials in a controlled environment designed to prevent microbial contamination of the product.
What are examples of products manufactured in aseptic environments?
- Pharmaceutical sterile products
- Bulk sterile drug substances
- Sterile intermediates
- Excipients
- Medical devices
- Biologics
What are fill-finish manufacturing processes?
Fill and finish operations enable a product to be filled and sealed into end-use containers with appropriate sterility and precision. Fill and finish operations are essential for filled vials, syringes, cartridges, and other medical-grade products so that the correct quantity of sterile and contaminant-free products are added and sealed consistently.
Why are aseptic fill-finish manufacturing processes important?
Aseptic filling and finishing processes are used for packaging drugs and other essential healthcare products. For drugs and other products to work safely and effectively, accurate amounts of the product must be added to containers and filled such that no contamination occurs. Otherwise, lifesaving treatments can cause further illness and disease.
Thus, aseptic fill-finish manufacturing processes are essential for microbe and contaminant-free products filled into vials, syringes, cartridges, and the like.
How are aseptic filling and finishing manufacturing processes performed?
Filling and finishing processes are complex due to the number of activities that must be coordinated to prevent microbial contamination of products and fill containers accurately. Below is a list of some activities that must be coordinated for aseptic fill-finish processes to be successful.
Activities that contribute to aseptic filling success include:
- Primary packaging container qualification
- Extractable and leachable studies
- Equipment qualification
- Filter validation
- Environmental monitoring performance and qualification
- Personnel training and qualification
- Robust manufacturing procedure and batch record development
- Utility qualification
- Cleaning validation
- Cleanroom validation
- Sterilization cycle validation
Filling and finishing processes vary based on the type of product and the container being filled.
Sterile products can be aseptically filled into multiple containers. The most common containers for filling are vials, prefilled syringes, cartridges, and ampoules. Aseptic exposure risk varies based on each product container’s shape and opening size. Thus, general process steps of filling equipment washing, sterilization, depyrogenation, product loading, container loading, and product filling do not vary. However, the complexity of these steps differs by the product and container being filled. Product containers such as vials and stoppers are either ready-to-use sterile products or ready-to-sterilize non-sterile products. Ready-to-sterilize products require sterilization steps before aseptic product filling. Additionally, filling and finishing complexity varies based on the filling line type utilized (e.g., open Grade A, restricted access barrier system -RABS-, or isolator).
Activities that support product sterility during the aseptic filling and finishing process:
- Full cleaning and sanitization program
- Area clearances to reduce product mix-up risk
- Equipment setup checklists
- Equipment maintenance and calibration
- Automated environmental monitoring systems
- Automated clean-in-place and steam-in-place systems for filling lines
- Strong, aseptic technique training and intervention programs for operators
- Communication frameworks between personnel, sterilized product, filling systems, cleanroom, support facilities, and sterilized filling components
How do you control contamination risk for aseptic fill-finish processes?
Aseptic filling operations rely heavily on process protocols, personnel training and qualification practices, appropriate automated equipment, facility design, and controls for product fill-finish success. Doing one filing operations component well is not sufficient to prevent product contamination. For risk management and control, each process step is assessed to identify potential risks and eliminate or mitigate them to maintain product quality by design.
Aseptic process simulations (also called media fill studies) are used to test filling and finishing operations before the actual product is filled. Media fill studies ensure equipment, protocols, and personnel are suitable for the aseptic fill-finish task. Any weaknesses with beginning-to-end process design, personnel, facility, equipment, etc., will be identified during aseptic process simulations that simulate “worst-case “scenarios, including possible contamination. Additionally, fill weights are periodically assessed during media fill studies to ensure a product’s volume per container meets the requirements. Aseptic process simulations are run twice per year per filling line to ensure consistency is met, and accidental contamination is avoided.
Critical components to consider for aseptic fill simulations include:
- Frequency of media fills
- Type of filtration used
- Number of aseptic connections
- Interventions used
- Personnel qualification
- Allowable rejects
- Incubation temperatures and durations
- Who is completing the inspection
- When samples are taken for growth promotion
- Accountability for filled units,
- Processing hold times
- Environmental monitoring
Environmental monitoring during filling execution is a critical element of risk control for aseptic filling and finishing processes. Below is a list of routine environmental monitoring practices. In some cases, air and surface sampling is used to identify the root cause of product contamination.
Important environmental monitoring activities for contamination risk control include:
- Personnel training, scheduling, and facility access
- Viable and non-viable air sampling
- Manufacturing surface sampling (contact plate and swabbing)
- Evaluations of process air and water for injection
Adopting the approaches detailed above leads to fewer fill defects, failures, and investigations, lowering filling costs and increasing filled product yields.
What are the most common modes of failure for aseptic fill-finish processes?
The most common aseptic fill-finish process failure is product contamination via human-borne microbes or particles. Often contamination occurs on manufacturing surfaces before or during filling. The best way to prevent product contamination from human-borne contaminants is to invest in personnel training, automated processes, calibration programs, and facility maintenance.
Summary
Overall, aseptic filling and finishing operations enable a product to be filled and sealed into end-use containers with appropriate sterility and precision. Aseptic fill and finish operations are essential for filled vials, syringes, cartridges, and other medical-grade products so that the correct quantity of sterile and contaminant-free products are added and sealed consistently. Filling and finishing processes vary based on the type of product and the container being filled. The most common containers for product filling are vials, prefilled syringes, cartridges, and ampoules. Aseptic exposure risk varies based on each product container’s shape and opening size. Thus, general process steps of filling equipment washing, sterilization, depyrogenation, product loading, container loading, and product filling do not vary. However, the complexity of these steps differs by the product and container being filled. Additionally, filling and finishing complexity varies based on the filling line type utilized (e.g., open Grade A, restricted access barrier system -RABS-, or isolator). Aseptic filling operations rely heavily on process protocols, personnel practices, automated equipment, facility design, and controls for product fill-finish success. Doing one component of filing operations well is not sufficient to overcome product contamination risks. All in all, if you are outsourcing your filling and finishing processes, ensure you choose a contract manufacturing organization that can support you with your unique filling and finishing needs.
MycoScience is a contract manufacturing organization specializing in sterile syringe and vial filling cosmetic products or for products used in animal studies. In addition, MycoScience offers testing services, including Preservative Efficacy Testing, Cytotoxicity Testing, Bioburden Testing, Cleaning Validations, Microbial Aerosol Challenge Testing, Accelerated Aging, Microbiology Testing, EO Residual Testing, Bacterial Endotoxin Testing, Package Integrity Testing, Sterilization Validations & Environmental Monitoring services medical devices and allied industries. MycoScience is an ISO 13485 certified facility.
References
2020. Challener, “Prepping Fill/Finish Systems to Ensure Quality Output,” BioPharm International, 33 (12) 2020.
2020. Langer, “Fill/Finish Outsourcing,” BioPharm International 29 (10) 2016.
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
United States Pharmacopeial Convention. <1116> Microbiological Control & Monitoring of Aseptic Processing Environments. Rockville, MD, USA. 2021. (USPC <1116>).
