In any economy, Biopharmaceutical companies need to lower costs associated with manufacturing processes. However, in today's economic debacle and super regulated atmosphere, it is of utmost importance to look for new cost saving, repeatable methodology, and regulatory compliant manufacturing systems that eliminate waste and the possibility for self-induced contamination. Although disposables have been a growing trend, and typically associated to bag systems replacing tanks, there are also many new products and capabilities to disposables in other areas within the manufacturing process for targeting various cost reduction programs.

How are things done today?

In manufacturing settings, firms historically produce Fluid Transfer Tubing Assemblies for their internal manufacturing operations which utilize silicone tubing and stainless steel fittings. This involves the labor to clean stainless valves and components, cut tubing, assemble systems and sterilization methods and using an autoclave sterilizer on in-house assembled tubing sets used in the connection of other flexible or stainless containers. The assemblies are produced to fit the specific applications pertaining to each unique production set up. Use of internal engineers for assembly and autoclave is expensive and inefficient; Autoclaving, while common in regard to tubing set manufacturing, has inherent limitations: Autoclaved assemblies typically have a short shelf life of a few weeks at best. The process generally limits the maximum length a tube can be cut, and still be effectively sterilized with the autoclave process. This presents validation problems in many applications, or many small lengths coupled to assure sterility through the validation, further complicating the issue to maintain sterility through additional connection points during the manufacturing process.

Opportunities for new components in disposables

With recent development in disposable valves, disposable sanitary ends, and filtration available in a capsule format, most stainless applications for sterile fluid transfer can be replaced by disposable components and assemblies. And although the recent history has seen major growth in disposable bags being used for anywhere from Bioreactors, mixers, transport, transfer, harvest, it is only the beginning of the opportunities for the integration into disposables manufacturing components and assemblies.

Today you can also integrate disposable aseptic connector assemblies. Aseptic connectors attached to stainless tanks, bag systems or tubing assemblies allow you to make sterile connections in a non sterile environment. The use of Aseptic connectors allow for less need to hookup or transfer under a laminar flow hood or class 100 clean environment, as they allow you to make a sterile fluid path connection in a non sterile environment.. Further adoption of tubing assemblies with aseptic connectors and including disposable capsule filters, disposable valves, sanitary ends, allow the consumer (manufacturer) to develop the complete fluid path in a disposable format.

While silicone tubing has a long history of use, many thermoplastic elastomer tubing alternatives are available, such as CFlex ™, which has better physical characteristics, lower gas permeability, low particulate, and good for use in peristaltic pump for manufacturing applications. Additionally thermoplastic Elastomer tubing can be used in conjunction with tubing sealers which allows one to seal closed the tube, or tubing welders that allow the fusing of two sterile tubing paths. The options of sealing or welding are not a capability of silicone tubing, and add great manufacture flexibility.

Disposable valves are available from Millipore and Colder Connector (as there are other sources), which allow the replacement of stainless valves throughout the production facilities. The valves are available in SIP as well as to steam trap configurations. A sanitary connectors typically in stainless can be replaced in plastic for one time use sterile product.

Additionally, there are many OEM disposables manufacturers with interest to develop just about any format of interest requested by the Pharma manufacturing consumer for fluid movement within the facility.

Using new disposable components then internally assembled and autoclaved

Obviously the components can be purchased and simply allow for the internal assembly of tubing assemblies, changing to remove the need of cleaning stainless connections prior to assembly of the tubing assemblies. Most companies are integrating some disposable components into their Fluid Path tubing assemblies and continuing to assemble and autoclave tubing assemblies. This should be done cautiously as many of the components such as disposable valves have been developed closed to being opened at point of use in the manufacturing process.

The autoclave process cannot always kill the bacteria burden on disposable valves that are in the closed position. The OEM manufactures have developed the valves from the thought that they would be used at point of use or in association with a pre-irradiated tubing system, which adds another level of savings opportunities. Pre-planning production to use disposables such as pre-irradiated tubing assemblies can improve sterility assurances during connections in the fluid path.

Irradiation over autoclave opportunities and risk

Utilizing a contract manufacturer to assemble fluid path tubing assemblies, package, and irradiation sterilization is a huge labor and cost savings opportunity for the Pharmaceutical manufacturer. The pharmaceutical manufacturer has the option to re-direct production personnel to direct production responsibilities rather than as support or indirect labor. The cost reductions from kitting or purchased disposable of the fluid path assembly begin with the use of prepackaged, sterile tube sets that attach to disposable bags or stainless systems. The irradiated disposables have established shelf life of 3 years and will maintain sterility until opened. However, although utilizing a manufacturer for supply of sterile tubing assemblies can be a great internal labor and cost savings, it also adds another level of management for these purchased assemblies. By either coordinated efforts or maintaining a safety inventory of sterile fluid path assemblies, one needs to establish a supply partner relationship with an OEM of the designed configuration for continuous supply of long lead-time components used in the product design. Therefore it is extremely important that the inventories are managed well. I promote looking at yearly production needs placing blanket orders to assure product availability at the desired production moment. It is always easier to adjust downward order requirements, than attempt to have one's manufacturer respond to extremely short deliveries that utilize long lead-time componentry.

Although there are many manufacturers eager to supply disposable irradiated tubing assemblies it is the responsibility for the Pharma customer to assure the manufacturer meets the need from a quality and control perspective. In other words, Buyer beware, as there are OEM firms that can supply fluid path assemblies but DON'T really understand the function and process requirements of said product design. In the bag supply there is a large focus towards the manufacturer via, film leachables /extractible, Cgmp manufacturing traceability and process control, Cleanroom conduct, irradiation validation compliance, etc. From my view this same due diligence is not taken when auditing the tubing and tube set suppliers. Although the cGmp, and cleanroom conduct may not be viewed as critical on tubing assemblies with in the user facilities, the sterility assurance of an irradiation sterile product used in a sterile environment should be. To this point do not assume the manufacturer knows all needed to assure sterile fluid path irradiation directives. The customer is ultimately responsible to audit and be certain the manufacturing integrator is meeting the required control.

Radiation sterilization is a very accepted and common means of sterilization applied to bag systems or tubing assemblies (single-use systems). Many Biopharmaceutical companies mistakenly believe due to the infinite number of component and design options available, that management of radiation sterilization is too complex and not financially feasible for complex designs or small order quantities of bioprocess systems. The AAMI TIR33:2005 radiation guidelines specifically address large and complex bioprocess components and systems. Commonly, manufacturers of multiple bioprocess products develop one or more product families with the intent that a single bioprocess product can represent a wide range of a family of bioprocess products.

This single bioprocess product used to represent a product family may be designated as a "master product". A master product is not necessarily representative of similar materials and components or the largest bioprocess product in a family. A master product may be one that possesses the most component types, the greatest combination of materials, the highest filter area, the most handling during manufacture and assembly, or a combination of those factors. Ultimately, the master product is the one deemed most challenging to a sterilization process. By utilizing a master product approach, a manufacturer can easily and inexpensively manage the radiation sterilization of a large range of component and design options of bioprocess products to ensure product sterility.

Most manufacturers of single use bioprocess systems employ the VDmax methods to substantiate a radiation sterilization dose to achieve an SAL (Sterility Assurance Level) of 10?6. A Sterility Assurance Level is derived mathematically and it defines the probability of a non-sterile product unit. For instance, a SAL of 10?6 means the theoretical probability of not more than one viable microorganism being present in or on a product is equal to or less than one in 1,000,000. The AAMI TIR33:2005 guidelines provide the flexibility of using nine sterilization doses based on the product's bioburden level. For instance, a minimum sterilization dose of 15 kGy is required for bioburden levels up to 1.5 cfu, whereby a minimum sterilization dose of 25 kGy is required for bioburden levels up to 1,000 cfu.

The approach utilized by manufacturers when using the VDmax method comprises the following steps:

1. Obtain product units from three production lots of the master product

2. Experimentally determine the average bioburden. The bioburden estimate must meet the criteria for the selected VDmax dose.

3. Determine the verification irradiation dose appropriate for the average bioburden.

4. Perform a dose verification study (irradiation and sterility testing).

5. Interpret results – accept or reject the study.

6. Accept or reject the predetermined irradiation dose as the minimum dose for sterilization.

7. Institute periodic dose audit testing for continued effectiveness.

These steps are routinely performed by the manufacturer when developing a radiation sterilization program for a master product. Additionally, most new products usually fall into a pre-established product family, and thus there is no delay in time and no additional costs are incurred.

Single use bioprocess systems represent a substantial benefit to biopharmaceutical process development and manufacturing. Utilizing a contract manufacturer to manufacture single use bioprocess systems can represent a huge labor and cost savings opportunity for the Pharmaceutical manufacturer. Likewise, contract manufacturers of single use bioprocess systems must possess the knowledge and skill to provide a myriad of customized products with the assurance that the product will be received sterile by the pharmaceutical manufacturer each and every time. The Pharmaceutical consumer must evaluate the manufacturer of choice to assure they understand and meet the requirements of a high quality and sterile product supply.

Reasons for growth and savings opportunities:

a) Disposables can eliminate the cleaning process and cleaning validation associated with stainless vessels,

b) Use of custom pre-irradiated fluid transfer Tubing Assemblies negates the need to carry internal overhead of production and sterilization,

c) Use of disposables reduces the total investment in facilities and tank and piping costs, resulting in lower capital outlay.

d) Disposable designs offer "faster to production" build-outs. And allows the technicians to stay focused on higher production turns.

e) A well developed disposable will assure lower risk of contamination probability in manufacturing.