Disposable Components in Aseptic Processing - Pharmaceutical Technology

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Disposable Components in Aseptic Processing
The authors discuss current and future disposable technologies and outline the validation and qualification steps that would be required for a possible disposable process stream.


Pharmaceutical Technology


The laminate combinations can vary depending on the bag design, manufacturer, and application served. Currently, bag designs are manifold and vary in volume from 20 mL to 3000 L. The assemblies are not restricted to only a bag and a filter. They can be highly complex and engineered to fit specific requirements of the end-user. For example, buffer hold bag systems are commonly a manifold of multiple bags of the same volume, which can be disconnected by tube sealers. These assemblies also contain a sample bag for quality assurance purposes. The filtered volumes can be stored or transferred to individual process steps within a facility. Large-volume systems require storage with trays, tote, or pallet systems to prevent the large liquid volume from moving. The bags within such storage systems require unfolding in a very specific manner, otherwise pressure folds will occur and could damage the polymeric film. The design of the filling and connectivity of any outlet from the bag are essential because the hold-up volume of a hold bag must be minimal.

As mentioned, disposable systems are no longer restricted to a bag and a filter. Various equipment components are available that can be combined into a single-use system or process step. Such equipment components include:

  • Mixing systems (various designs and volumes)
  • Sensors (e.g., dissolved oxygen and pH)
  • Aseptic connectors and tubing
  • Fluid sampling devices
  • Bioreactors (many designs, volumes, and agitation technologies)
  • Fluid and solids transfer systems
  • Freeze–thaw bags
  • Ultra- and diafiltration
  • Membrane chromatography (e.g., ion exchange)
  • Viral clearance (e.g., filters and UV inactivation)

Other equipment solutions will soon follow as the requirements for single-use systems by the industry are more pressing and innovative. For example, work is underway to design disposable valves, pump heads, and filling systems.

Mixing

Disposable mixing systems are available from 5 to 1000 L and are most commonly used for buffer and media mixing, product compounding, or final formulation purposes. A more recent application is viral inactivation by pH shift. Such mixing bags use disposable sensor patches to determine the necessary pH levels during the inactivation period.

Mixing methods include recirculation, pulsation of the mixing bag; use of magnetic impellers, stirrer bars, or pads; and use of a levitation mixer. The latter is unique to all others because the mixer does not come in contact with the bag material, and it floats on a magnetic field. This configuration avoids any friction of the bag material and provides fast and thorough mixing results. The various mixing technologies are useful because the applications and complexities of mixing vary. Liquid–liquid mixing has easy mixing requirements, but liquid–powder mixing can be difficult and may require careful design and mixing mode observations.

Bioreactors

Current single-use bioreactor systems are divided into two main categories: rocking motion and cylindrical-tank reactors with various agitation modes. Rocking motion reactors were the first to enter the biopharmaceutical industry. In this design, the cell culture is moved back and forth by a rocking platform, which allows mixing of nutrients and gas input into the liquid phase. These systems produce excellent results for shear-sensitive cell cultures and have been especially established in seed reactor applications. Rocking systems are available as a basic system without sophisticated controls. Separate systems can be connected to a control unit to measure the dissolved oxygen and pH by means of a disposable sensor. The control system can also run the gas and feed strategies, which is important when the system is used as a perfusion reactor. The working volumes of rocking reactors range from 0.2 to 500 L. Recent bioreactor developments have focused on cylindrical tank systems, which use multiple agitation methods, including sleeved or fully polymeric stirrers, vibro-mixing, orbital shaking, or gas mixing. The agitation methods and cell culture requirements determine the design for these reactors. Typical capacity volumes of these cylindrical disposable bioreactor systems range from 10 to 2000 L. These units are most commonly used with the control tower systems of reusable fermentation systems. These control towers create appropriate feed and gassing environments for the cell culture.

Freeze – thaw

Bulk raw materials are often shipped over long distances, and production processes may require a product-hold step because of downstream equipment bottlenecks. In both instances. solutions are required to prevent any protein degradation, which may occur as a result of enzymatic attack and temperature, pH, concentration, or gas conditions within the hold or transport step. To avoid such yield losses, the industry has resolved to freeze steps to keep the product stabile over a period of time. However, commonly used blast-freeze steps are uncontrolled and can result in freeze concentration, pH shifts, aggregation, ice crystals within the frozen material, or bag damages. To avoid such damaging conditions, disposable controlled freeze–thaw devices have been established. These devices contain a hold bag within a frame and a freeze–thaw module that uses heat-exchanger plates, which ensure a unified controlled freeze and thaw process. The product hold bag with the frame is transferred into the freeze–thaw module, and the heat-exchanger plates move in position, pressing against the hold bag. The heat exchanger plates therefore do not only ensure the temperature transfer, but also the uniform distribution of the liquid over the entire bag design. These units are available as small-scale trial devices with a volume of 30 mL and process scale up to 16 L.


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