Aseptic Vaccine Manufacturing with the Powerfuge Separation System

By Neil Policow, CARR Separations

Overview

Liquid/solid process separations during the production of human and animal vaccines pose difficult challenges to their manufacturers. Not only is an efficient and reliable separation required, but equally important are full process containment, complete cleanability and sterilization, and precise temperature control. Until now, older, "traditional" separation technologies such as tubular bowl centrifuges, vacuum and pressure filters, or disc stack centrifuges were the only option for vaccine process separations. All of these designs required additional process steps and expensive handling procedures in order to provide an acceptable separation. The Powerfuge system from CARR Separations (Franklin, MA) is the first solution that provides:

• Controllable yield-enhancing product separation.
  
• Completely contained, aseptic process.
  
• Automated, validatable clean-in-place (CIP) capability.
  
• Automated, validatable steam-in-place (SIP) capability.
  
• Temperature control of ±1°C.

Efficient, Reliable Separation

Powerfuge is a novel imperforate basket, solid bowl centrifuge that provides 20,000 XG of separating force (13,333 XG at the pool surface versus 6,500 XG at the pool surface of a similarly rated tubular bowl). This "high G" operation allows maximum separation efficiency of the liquid and solid phases by producing the driest compacted cake available while achieving excellent liquid clarity. This advantage creates higher yields per batch, whether the product is the liquid or solid phase. The fully automated, semi-continuous operation is controlled and monitored by an integrated Allen Bradley PLC. Solids removal from the bowl is also automatic (via an internal scraper), eliminating any operator exposure during product recovery.

Contained Operation

Contained operation, which eliminates the risk of product contamination, is the key to ensuring the purity of biological products for human or animal use. Powerfuge systems provide complete aseptic operation, thereby mitigating any concerns over breaches in the equipment boundary. The automated solids removal maintains the aseptic operation even during product recovery, whereas some alternate separation devices require manual removal of the solid phase.

In addition to protecting the product, fully contained operation also means that the operator is protected. A proprietary double mechanical seal design effectively eliminates seal leakage and aerosol production as encountered in previous separation technologies, thereby maximizing operator safety. The operator does not need to physically interact with the equipment during either process or cleaning operations. The entire sequence may be fully automated, thereby permitting true "hands off" operation.

"True" Clean-In-Place Capabilities

Clean-in-Place (CIP) capability is a highly desirable attribute for the aseptic manufacturing of vaccines and other injectables. Some separation technologies have erroneously claimed that they have attained this level of operation, based on a test commonly referred to as a "final rinse" test. This involves testing the equipment rinse fluid after cleaning and comparing it to an acceptable baseline. However, there will be areas that are difficult, if not impossible, to reach, and that will escape detection in this type of test.

For this reason producers of vaccines and other biologicals who consider themselves "true" clean operators disassemble all separation equipment for individual component cleaning (filter cartridges are even discarded after each run as they are considered uncleanable). This task of individual component cleaning, however, is a formidable one in a cGMP environment requiring validation of the cleaning process. It is also an expensive one, requiring as much as ten times the costs of a validatable CIP procedure. A heavy mechanical burden is also placed on the equipment with frequent disassembly, in addition to the risks of improper reassembly leading to a lost batch of product.

Steam in Place Sterilization

Following the cleaning step, vaccine manufacturers must be able to maintain sterile conditions throughout the process. Whereas the standard Powerfuge design has a 1 bar pressure rating for all boundary components, the vaccine design is full 2 bar ASME rated per Section VIII of the Pressure Vessel Code. Steaming in place will generate a validatable 141° C internal temperature within the boundary components, which is sufficient for complete pathogen kill. Coupled with the innovative double mechanical seals at all rotary joint connections, this insures that the sterile conditions, once attained, can be maintained during the process cycle. Temperature mapping tests have verified the attainment of the targeted temperature levels throughout the system.

Temperature Control

Powerfuge also provides a significant advantage for processes that require strict temperature control through the separation cycle. In addition to indirect temperature control via system jacketing, Powerfuge provides direct control by operating under vacuum. The nearly complete vacuum attainable with the integrated closed loop system eliminates the heat friction produced by the spinning bowl and dramatically improves temperature control of both phases. Temperature variations from feed to product have been commonly kept below ±1°C. Coupled with the cooling capacity of the case jacket, product temperatures can actually be controlled below the incoming feed if desired. The contained design of the Powerfuge technology permits operation from -40° C to more than 135° C. Vacuum operation can also reduce process foaming which has been shown to enhance the process separation and minimize product degradation.

Market Acceptance

Several of the world's leading pharmaceutical manufacturers are currently developing vaccine processes using the Powerfuge aseptic system. One manufacturer plans to present a paper on its breakthrough process in early 1999.

For more information: Neil Policow, Carr Separations, Inc., 10 Forge Park, Franklin, MA 02038. Tel: 508-553-2400. Fax: 508-553-2401.