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Fill and Finish Biologics

The final step in the downstream process is sterile fill and finish operations. With stringent regulations requiring the biologic product quality being controlled throughout biomanufacturing, the sterile fill and finish phase requires special processes and equipment to ensure product integrity during storage, transportation and delivery to patients.

Aseptic Fill and Finish Processing: The Final Biomanufacturing Phase

During final fill and finish manufacturing, the sterile (aseptic) product is packaged in a sterile container in a clean, controlled environment using methods and technologies that maintain sterility. Aseptic filling of sterile drugs, sometimes called sterile filling, is a critical process in biopharmaceutical manufacturing. It requires strict adherence to processes since it has potential safety impacts on the end user, usually an already compromised patient.  

Techniques Used During Fill and Finish Include:

  • Freezing and thawing of a bulk substance
  • Lyophilization (freeze-drying) used for products with stability problems or when providing an exact dosage is challenging
  • Dilution of purified substance to a target concentration
  • Filtration
  • Filling into a selected container-closure system
  • Inspection, packaging, storage, transport, and delivery

CPC’s Focus on Fluid Connection Technology Benefits Sterile Fill and Finish Process Design

CPC understands it takes a well-designed sterile fill and finish system and system components to ensure frozen biologic materials retain their sterility and integrity. Matter of fact, CPC’s focuses on innovative fluid connection technology important to single-use assemblies used in upstream and downstream applications including the freeze-thaw and sterile fill and finish processes. Collaborating with biomanufacturing scientists and engineers, CPC’s team of product engineers, application engineers and film extrusion and plastic molding specialists design robust, single-use, fluid connection solutions for use in fill and finish operations.

CPC Aseptic Connectors for Fill and Finish Workflows

  • Compatibility with sterile plastic containment bags used in freeze-thaw processing
  • Innovative seal design that functions without failure after freeze thaw operation
  • Aseptic connection in cotrolled and uncontrolled environments
  • Technical package that includes freeze thaw data -80°C
     

Freezing Helps Expand Fill and Finish Biologic Product Reach

Freezing is used for long-term storage and shipping of biologic substances. It maintains biological integrity while allowing manufacturers to implement the best logistical operations for delivering the product to the patient. In addition, freeze-thaw applications are used phases to extend hold times between intermediate processing steps. Implementation of a freeze-thaw process requires careful testing of the physical and thermal properties of the single-use system, as well as the integrity and quality of the drug substance.

Why Freeze Biologic Products?

  • Maintain temperature control requirements is easier in a frozen state
  • Fewer interactions between the bulk drug and the container
  • Reduce product degradation, especially with large molecule drugs which are particularly susceptible to degradation
  • Mitigate risks associated with mechanical stresses that come from relocating containers from room to room of a manufacturing facility, or country to country within an international manufacturing network

Single-Use Systems Now Standard for Fill and Finish Biologics Operations

The logistics of decoupling drug substance manufacturing from final drug product formulation is now possible using integrated single-use freeze-thaw assemblies that incorporate reliable components. Single-use technology integrates storage containers, filters, tubing, sterile connectors and disposable filling manifolds to minimize contamination risk and reduce operational downtime during fill and finish manufacturing.

CPC Aseptic Connectors Effectively Block Contaminants

CPC aseptic connectors have a protective barrier―usually a membrane―in each half, which prevents bacteria and contaminants from entering the fluid pathway while the barrier is in place. A sterile fluid pathway opens once the two halves of the connector are together.

To ensure a single-use assembly functions without failure during storage, transportation and manipulations before and after, CPC has perfected its seal designs and offers robust connectors that are easy to use. CPC aseptic connectors are tested for their intended use, as well as unattended abuse.

Contract Manufacturers Traditionally Perform Sterile Fill and Finish Steps

In many cases, fill-finish operations are typically performed by contract manufacturers. Biopharmaceutical companies, including outsourced manufacturers, must consider both large-scale production and increasingly smaller-footprint operations used by some products, such as cell- and tissue-culture biologics. Smaller operations require increased attention to reducing waste and ensuring desired profits as well as special packaging and shipping needs.

Single-Use Freeze Thaw Systems for Cell Therapy

Autologous cell therapies use a patient’s own cells collected in a hospital or clinic, then sent to a lab to be manipulated, concentrated and then returned to the clinic to be injected into the patient as therapy. Because the patient’s cells are the active pharmaceutical ingredient, there is less margin for error due to container failures and logistic errors. Freezing the cells make transportation easier and extends the time available for getting the drug back to the patient.

Benefits of Single-Use Technology in Freeze-Thaw Applications

  • Reduce risk of cross-contamination
  • Diminish complexity of manual interventions during freezing, thawing, handling and shipping
  • Increase process flexibility and efficiency
  • Cut capital requirements
  • Decrease operating costs by enabling batch processing
  • Eliminate cleaning or sterilization with pre-sterilized single use systems
  • Shrink maintenance and validation times
  • Decrease staff training requirements
  • Serve more patients in a shorter time

 

Single-Use Transfer Lines and Connectors

Final fill tanks are designed to transfer formulated product from formulation suites to storage areas and ultimately to filling suites. To allow sterile connection to and from these vessels, designers replace heavy three-way assemblies with single-use transfer lines and CPC sterile connectors―eliminating cleaning validation and maintenance while reducing mobile vessel weight by tens of kilograms.

Effective Sterile Fill and Finish Operations Leads to Increased Efficiency

Fill-finish systems with single-use transfer lines help reduce sterilization time and lower costs. Using pre-sterilized, single use freeze thaw systems with shorter freeze-paths allow more uniform heat transfer between different areas within the total volume of drug material and lead to a more homogeneous mix of biological components and a more stable product. An added advantage is single-use bags can be conveniently stored in freezers of different styles and dimensions.

CPC Steam-Thru® Connections and Single Use Transfer Lines in the Fill and Finish Operation

Single-use transfer lines can be attached before vessel SIP sterilization with CPC Steam-Thru Connections (used as either steam access or condensate drainage sites) or can be steamed separately before fluid transfer line can create a robust system to ensure product safety.

Use Example

Outlet transfer lines could incorporate a single-use CPC Steam-Thru Connector to attach to the sterile holding tank. In this case, a "through-the-wall" fluid transfer system brings a portion of the transfer line into an isolator where filling occurs. Next, a CPC quick-connect HFC39 fitting or AseptiQuik® Connector attaches the transfer line to the filling machine. Finally, transfer lines using a valved CPC HFC39 quick-disconnect coupling aseptically disconnect the processor from the filling equipment.

CPC's Robust Testing under Extreme Conditions is Critical

Freezing single-use assemblies puts added stress on connectors. CPC performs a variety of tests on its connectors against mechanical stress under freezing and thawing operations within the temperature range of -20° C to -80° C.

Examples of CPC Testing

  • Seal design testing to make sure the seal functions as it should and withstands mechanical side-loading, flexing and tensile forces without compromising the integrity of the seal after the freeze thaw process
  • Testing and validation of all raw materials used for CPC connectors
  • Complete, reliable and relevant extractable testing
  • Bacterial ingress testing to ensure a sterile connection is made and maintained during use under extreme conditions

Versatility and Flexibility

CPC aseptic connectors and SIP connections provide flexibility necessary for sterile fill and finish operations to easily combine multiple components including process containers, tubing manifolds, single-use and metal transfer lines, and freeze thaw equipment. When changeovers need to occur, genderless CPC aseptic connectors make it easy to connect and disconnect fill and finish components and processes. Multiple termination options meet today’s mounting and flow requirements.

Innovative Design

Sterile fill and finish processes and techniques differ widely. CPC’s comprehensive portfolio of aseptic connectors and SIP connections meet the need for a wide variety of sizes, configurations, termination options and materials. Our team of biopharma design and application engineers develop innovative, high-quality products that make sterile media transfer safe and easy, even in harsh conditions. Innovative connection methods help eliminate contamination risk and provide connection assurance.

Trusted Reliability

CPC aseptic connectors and Steam-Thru Connections are engineered for upstream and downstream applications including fill and finish operations and freeze thaw processes. To help maintain sterile filling integrity, CPC connection solutions are rigorously tested―including materials testing, product testing and torture tested to failure―to meet product specifications. CPC offers reliable, reproducible performance and provides validation and extractable reports that support the performance attributes.

Overall Robustness

CPC aseptic connectors and Steam-Thru Connections deliver optimized flowrates with excellent flow to size ratio for superior performance to manage media transfer required during fill and finish processes. CPC purpose-built connectors are designed to be compatible with a wide variety of chemicals to meet the needs of fill and finish systems and freeze thaw applications. We provide a unique combination of industry expertise with the broadest portfolio of products including sterile connects, sterile disconnects, SIP connections and quick connects.

Sterility Assurance

Lack of sterility assurance is a major reason for drug recalls. Robust and easy-to-use, single-use, aseptic connectors and SIP connections from CPC maintain flow path sterility and integrity while enabling biopharmaceutical manufacturers to use the necessary fill and finish processes and systems that meet their timing and cost targets.

Assurance of Supply

CPC has a proven track record of providing products consistently under their stated specifications and quality requirements through having a strong supply assurance program. The program includes control of the manufacturing process from raw materials to final product manufacturing. Investments in extra capacity and redundant manufacturing ensure capacity when it’s needed. Biopharma customers have confidence in CPC’s ability to fulfill demand acquired by a track record of accurate lead times, identifying and communicating potential delays and, most importantly, by sound supply chain management.


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