The Evolution from Fixed to Single-Use Systems

For many years, "blockbuster" drugs have made fixed systems the most pragmatic choice for manufacturing high volumes to meet high demand. Fixed systems rely heavily on stainless steel for piping, valves, tanks, and fittings because the parts needed are rigid and fixed in nature. Steel components can be manufactured with a variety of surface finishes, are sterilizable using most sanitizing medium, and can withstand high temperature. Production runs in fixed systems tend to be long with infrequent changeover. For the above reasons, and because of the riskadverse culture that is synonymous with drug manufacturing and engineering, stainless steel has been the predominant material in biopharmaceutical manufacturing.

Image courtesy of the authors

This thinking began to evolve with the advent of single-use systems (SUS), most commonly referred to as "disposables." A new mindset and technical platform was introduced to meet the changing industry needs presented by "personalized" large-molecule drugs. Initial SUS processes were deployed by manufacturers in response to the need for the low-volume production of vaccines in high concentration (Merck) and to meet hormone medication commercialization (Amgen) in a relatively short period of time (1). Fixed stainless-steel systems require extensive downtime because the process needs to be revalidated and sterilized after each use. Disposable process technology, on the other hand, utilizes fewer parts and eliminates the costly need to revalidate; the system can be used once before the prevalidated components are replaced for a fast changeover to a new vaccine or drug.

Factors favoring the fundamental shift to SUS are:

• Reduced R&D costs compared with using a high volume fixed system as part of the research line.

• Decreased time to market for a specific medicine, which can be tailored for smaller volume use.

• Rapid setup and regional deployment to meet drug needs worldwide.

• Ability to manufacture many products in the same facility with no risk of cross-contamination.

• Minimal expansion cost through drug development and scale up.

• Lower utility costs in cleaning and system revalidation.

PLASTIC COMPONENTS AND SINGLE-USE SYSTEM RESEARCH

Many questions were raised over initial plastic designs. These issues were exacerbated by the general lack of polymer knowledge after years of metal use.

The list of candidate plastics for single-use pharmaceutical processing includes those currently used in industry designs (see Table I). One of the strengths of these plastic components is the diversity of properties and designs presented. However, this also represents one of the main challenges as biopharm engineers struggled with how to incorporate a number of material components into a system and industry designed to minimize risk.

Table I: Chemical, brand name, and application of common plastics.

Membrane and filtration

The longest running polymer components used in biopharmaceutical applications are filter membranes and cartridges. These components have been used in fixed systems for many years. Membrane filtering applications have primarily used polytetrafluoroethylene (PTFE), polyvinyldene fluoride (PVDF), polypropylene (PP), and polyethersulfone (PES) (2). PVDF has been the resin of choice for over 20 years in protein synthesis and separation for biopharm applications. The large surface to volume ratios required in filter membranes exceeds that of other common components including tubing and containers. Therefore, this fluoropolymer resin has been long vetted and provides biopharmaceutical process engineers with a track record and history of successful performance in industry processes.

Piping

Polymer materials, especially PP and PVDF, have experienced success supplanting stainless steel in some fixed industry piping designs as the materials could be used in various water service criteria, including United States Pharmacopeia (USP) purified water for both plastic resins. Additionally, PVDF piping lends itself to use in ultra high purity water, laboratory reagent grade water Type 1, as well as Semiconductor UHPW ASTM Type 1 service criteria. One advantage of polymer components to stainless steel is the latter's capacity to rust or rouge in high-purity water causing system contamination. Chemical passivation is frequently required to remove free ions from the surface and restore the oxide film that gives stainless steel its corrosion resistance (4).

Tubing and fittings

Tubing is the most highly utilized component within a disposable system because large fluid transfer is required with the single-use system design. Multiple materials have been used ranging from silicone, EVA, TPE compounds, low density PE, PTFE, and PVDF copolymers.

Molded fittings are required to attach or weld to other process componetry including bags and containers. Therefore, welding and processability becomes an important design criteria. The most common industry fitting materials are PE, PP, polycarbonate (PC), silicone, and PVDF.

Bags

Film bags and containers pose possibly the most significant challenge as they are needed in numerous disposables functions starting with reaction vessels and progressing to transfer, storage and media preparation. Long dwell times are the norm, which makes purity concerns paramount despite being only one of a host of factors that affect their maximum utilization. These bags must be strong and tough, possess barrier properties and have the ability to melt bond effectively in multilayer structures. Purity, melt processability and bonding, as well as the contact layers ability to be sterilized while providing a significant barrier or permeation properties is a tall task. Common bag layers include EVA, PE, and PVDF.

FLUOROPOLYMERS MOVE TO THE FOREFRONT

As previously stated, one of the original concerns with plastics was the many varieties to meet multiple design characteristics. Biopharm engineers desired a more universal option. In other words, a polymer alternative to stainless steel. The industry hit on the idea of a more defined and singular "contact layer" to meet the diversity required in SUS. This search for a common contact material instinctively led its way to PVDF fluoropolymers (e.g., Kynar) for many reasons, as noted below (5).

Processability

PVDF is completely melt processable on conventional equipment allowing for its ability to be found in the complete range of component forms required. This melt processability attribute extends itself to not only rigid parts (pipe, filter housings and membranes, pumps) which use PVDF homopolymers, but also to parts favoring added flexibility (tubing, fittings, and film). Copolymer PVDF resin helps attain the more flexible part designs while maintaining the purity and processability aspects. Most importantly, the ease of melt processability allows for welding by various industry methods (6).

High purity

No processing aids or additives are required in PVDF fluoropolymer resin manufacturing, allowing for its compliance with USP Classification VI. There are no animal derivatives in Kynar resins.

Cholesterol binding

Fluoropolymers have low surface tension properties and as such do not have the propensity to attach to organic matter such as proteins and lipids. This promotes increased manufacturing efficiencies as proteins do not stick to the bags or vessel walls.

Sterilizable

PVDF is unique among polymer materials as it is compatible to the various sterilization methods including gamma, autoclave (steam), and chemical (EtO) (7). Gamma radiation is commonly used in disposables practices. Common industry gamma sterilization levels are 25-30 KGy. Table II contains data that shows no change in properties even after doses twice the industry level (50 KGy).

Table II: Properties of PVDF fluoropolymer (Kynar) before and after gamma sterilization at 50 kgy.

Multilayer adhesion technology

The ability to make multilayer film (bags) and tube structures was a final obstacle to overcome. As PVDF fluoropolymers have the advantage of low surface tension, this same property can make it more difficult to adhere to complementing resins when appropriate. This can often be the case in bag manufacturing. Multilayer bag structures and technology utilizing PVDF fluoropolymers as the contact layer are now readily available due to the development of new extrusion designs. Such designs allow plastics with additional barrier properties, such as EVOH, and lower cost softer resins, such as PE and copolyamides, to be incorportated in outside layers.

Chemical resistance

The appropriate selection of polymers can offer long term advantages to metals in areas where cleaning agents are used. Plastic materials are available that fully resist a broad range of chemicals and rusting or rouge is never a concern. PVDF can handle steam, chlorinated disinfectants, oxidants and acidic chemicals at varied concentrations. PVDF belongs to the fluoropolymer family of resins which contains the carbon-fluorine bond which is one of the strongest bonds in chemistry. The high energy that is required to break this bond creates its unique chemical resistance across a broad range of pH values. PVDF components are commonly used in applications where bleach, chlorine dioxide, chlorinated water, brominated water, ozone, peroxide, peracetic acid, HCl, and alcohols are used in cleaning and bacterial control processes.

CONCLUSION

Stainless steel continues to lead the way for mass-production drugs and fixed-system approaches. Disposables equipment has moved into the biotechnology–pharmaceutical mainstream. Only 3% of biopharmaceutical manufacturers use no disposables today, according to the Third Annual Report on Biopharmaceutical Manufacturing Capacity and Production, issued in June 2005 by BioPlan. Additionally, the Biopharm Miram Murge Study estimated capitol costs reduction of 40% by single use systems. This trend is expected to continue as the industry evolves into a more pragmatic approach to regionalized and smaller-dose drugs. The need for lighter and more efficient components and systems will become increasingly important as quick changeover and low costs move to the forefront. The PVDF fluoropolymer alternative has continued to gain acceptance as a single fluid contact surface as it offers biopharm engineers the advantage of reduced risk and a universal polymer-system approach.

Gary M. Dennis is market manager for highpurity fluropolymer resins, Charles Weidner is a business development manager, and Saeid Zerafati is a senior research engineer, all at Arkeme Inc., 900 First Avenue, King of Prussia, PA 19406. tel., 610.205.7535 gary.dennis@arkeme.com

REFERENCES

1. A. S. Brown, Chem. Process. (February, 2006).

2. D. R. Keer, Ultrapure Water (July/August 1993) 40–44.

3. R. Greene, Chem. Eng. Progress (July 2002) 15–17.

4. L. Shnayder, Pharm. Eng. (November/December 2001) 66-72.

5. W. J. Hartzel, Innov. Pharm. Technol. (22) 2008.

6. T. Sixsmith and B. Paul, Chem. Process. (September 1995) 86-89.

7. H. Gruen, M. Burkhart, and G. O'Brien, Ultrapure Water (October 2001) pp. 31-38.