What are the top challenges with aseptic filling and finishing manufacturing operations?
What is aseptic manufacturing?
Aseptic fill finish 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. Sterile injectables fill finish, aseptic fill finish processes, top challenges with aseptic fill finish, and aseptic fill products are further explored below.
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?
Sterile injectables fill finish and other fill 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.
What are the top challenges with aseptic fill-finish manufacturing?
Sterile injectables fill finish processes are the last manufacturing stage before a product is secondarily packaged, shipped, and given to a patient. The main goal during aseptic processing is to keep the final product from collecting microbes, particulates, or pyrogens (e.g., endotoxins). Many components of filling and finishing processes, such as supplier quality management, facility design, cleaning, and environmental monitoring, are part of the quality and risk control (and management) process. Dependable filling and finishing contract manufacturers must overcome the following three challenges to provide safe, high-quality products efficiently.
#1: Ensuring sterility
Product sterility is critical for ensuring patient safety during use. Any minor breach in sterility during aseptic fill-finish manufacturing of sterile injectables can result in microbial contamination and impact the purity of the entire product batch. Further, contamination can harm the patient and elicit embarrassing product recalls if contamination is not found before a product is released to the market. Thus, each process during fill/finish manufacturing must pass extensive inspection and meet stringent acceptance criteria to ensure the sterility and regulatory compliance of the entire batch. Further, specialized, automated equipment is utilized to eliminate unnecessary contamination risks during processes like equipment cleaning and raw material loading.
#2: Assuring accurate filling
Mis-dispensing is always a risk and must be addressed in the filling process. High-end systems have inline process controls that monitor the product fill weight within each container. While inline weight controls keep the final fill within acceptance criteria, it does not account for unnecessary product loss due to splashing or sloshing during high-speed filling. Indeed, solutions easily splash when added to a container at a high velocity. Further, filling needle drips can result in product liquid accidentally painting vial or syringe exteriors if the filling needle isn’t centered properly. Splashing and needle drips can result in product loss and contamination of the fill line, as microbes love to make homes in wet places. Sterility breaches can be of concern if a product residual is left on a vial neck. Microbes contaminating the neck of a product can migrate to the sterile interior and contaminate the entire product. Thus, modern high-speed filling systems must be programmed to operate with precise product-specific volume and speed to avoid unnecessary splashing, resulting in product loss or contamination. Sensors on automated systems ensure nozzle position is correct to prevent needle drips. Additional fine-tuning can be accomplished with specialty nozzles for filling equipment.
#3: Ensuring rapid containment of contaminants and regulatory compliance
Fill-finish manufacturing is held to strict regulatory standards, defined, and inspected by the Food and Drug Administration (FDA). These standards cannot be met without meeting process monitoring criteria and fill-finish production safeguards. The monitoring processes and safeguards apply to all fill-finish processes, regardless of the batch size to be filled. Fill-finish safeguards minimize contamination, maximize efficiency and accuracy, generate electronically auditable data, and identify contaminations early so that time and financial costs of batch rejection can be minimized or avoided altogether. Many of the safeguards for fill-finish processes are inline process-controlled instrumentation. These inline process-controls are automated and support sterility since they are closed systems where human contact is eliminated. Additional safeguards include environmental monitoring systems to ensure that surfaces, air supply, and other areas of the filling and finishing process are free of contaminants throughout fill-finish manufacturing. Further, the number of personnel on the manufacturing line for processes that aren’t automated is minimized to reduce contamination. All of these control and monitoring factors keep contamination monitored and ensure GMP and certified cleanroom criteria are met during filling.
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 particularly important 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. Aseptic filling and finishing activities and operations must overcome three primary challenges: 1) ensuring sterility, 2) assuring accurate filling, 3) ensuring rapid containment of contaminants and regulatory compliance. Overcoming these three fill-finish manufacturing challenges leads to dependable product filling and finishing. 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.
2016. Langer, “Fill/Finish Outsourcing,” BioPharm International 29 (10) 2016.
John Erdner. Putting fill-finish customization into your line of sight: Tackling the challenges of small-batch manufacturing in fill-finish programs. Biopharma Group. 2020.
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>).
