Taking disposable processing to the next level
A recent innovation extends the cost, labor and safety benefits of disposable processing to critical clarification and pre-filtration steps used in pharmaceutical manufacturing
By Holly haughney, Ph.D. & Monica Cardona
The biopharmaceutical industry has embraced disposable products since their advent in the 1970s. First introduced for small lab-scale applications, such as filtration, disposable products have since become available for almost every aspect of biopharmaceutical drug manufacturing.
Today, the impetus for adopting disposable technologies is not only driven by improved cost and safety, but also by the unique process optimization benefits that they offer. An increasing number of single-use product options have made it easier for biopharmaceutical companies to use disposable methods for a greater proportion of their processes.
While some parameters may differ, biopharmaceutical companies that follow pre-use filter integrity testing will gain a greater understanding of process conditions.
Looking at a typical monoclonal antibody production process, disposable technologies can be found throughout upstream processing, cell harvesting and downstream processing steps. This includes bioreactors, perfusion systems, venting applications, and a wide range of filtration, clarification, separation and purification steps.
The recent introduction of lenticular depth filters in an easy-to-use capsule format represents a significant advancement in disposable processing. This latest innovation extends the cost, labor and safety benefits of disposable processing to critical clarification and pre-filtration steps used to manufacture recombinant protein-based drugs, vaccines and blood products. In providing a single-use option for the first step in downstream processing of monoclonal antibodies, the new lenticular depth filter format enables continuous disposable processing across all three stages of production.
The expanding role of disposables
The benefits of disposable processing multiply when single-use products are bundled together as fully integrated systems. While disposable products were originally embraced to eliminate cleaning and cleaning validation, they are now also being adopted as bundled solutions for the steps they eliminate before use, such as sterilization and assembly.
Integrated single-use systems can be supplied pre-sterilized (by gamma irradiation) and pre-assembled for use right out of the box to avoid costly and time-consuming steam sterilization and set-up steps.
An example of a single-use system consisting of a Pall Kleenpak Nova capsule filter, tubing and a flush bag. This arrangement can be used for pre-use integrity testing.
These systems, which generally comprise disposable bags, capsule filters, tubing, clamps, adaptors, and connection devices, also simplify many biopharmaceutical processes, such as pre-use filter integrity testing.
Whether used alone or as part of a fully integrated system, disposable products avoid the capital costs associated with stainless steel, minimize opportunities for cross-contamination, and reduce operator exposure to catatonic fluids. Disposable products are especially beneficial in situations where operating parameters are likely to change, funding for capital equipment is limited, or a smaller system footprint is desired. For new facilities, disposable systems can greatly reduce the time required to start up a new facility.
Disposable systems can be designed and installed 4 to 6 months faster than hard-piped stainless steel systems.1 The price of stainless steel as well as the long lead times for steel components are a further cost savings associated with disposable systems.
Pre-use filter integrity testing
While regulatory guidelines strongly recommend pre-use filter integrity testing to enhance the safety of filtration processes, biopharmaceutical companies can benefit economically from this practice. These tests are performed to ensure that the effectiveness of sterilizing grade filters has not been compromised during shipping, operator handling, or sterilization before use.
In applications where high-value fluid products are used, pre-use filter integrity testing can prevent the loss of costly product batches by alerting operators to a failed filter before use. Pre-use filter integrity testing also lets biopharmaceutical companies monitor process conditions and provides an added measure of safety.
Pre-use filter integrity testing, while not mandatory, is an excellent cost-saving and precautionary measure; the test scheme should be efficient enough to offset the costs associated with the rare failed filter. Using disposable components and avoiding superfluous steps contribute significantly to the efficiency of pre-use filter integrity testing.
Apart from the actual filter test device, pre-use integrity tests can be performed using an entirely disposable system, including filters, bags, tubing, clamps, adaptors and connection devices. An automated filter test instrument is ideal for this test because it minimizes opportunities for operator error, speeds the test process, and generally has the capability to store data and records in compliance with 21 CFR Part 11.
Beyond integral system components like disposable filters and bags, single-use aseptic connection devices play a critical role in pre-use filter integrity testing for their ability to connect two sterilized components in seconds without using a HEPA laminar flow hood or a tubing welder. After the filter has been integrity-tested and found to be integral, a pre-sterilized aseptic connector can be used to connect the filter to the rest of the system. In this way, the sterility of the system downstream of the filter is not compromised by the performance of a pre-use filter integrity test.
This ensures that the downstream system does not need to be replaced (if disposable) or re-sterilized (if it is not disposable), saving processing time as well as cost. Time is further saved by the use of the aseptic connector, since a laminar environment is not needed and the connection can be made in less than a minute in any process environment.
Pre-use and post-use filter integrity tests can be performed by using either a buffer or the product as the wetting solution. Typically, a buffer solution, or WFI, is used to wet out the filter for pre-use filter integrity tests, and the filter is tested product-wet for the post-use test. But biopharmaceutical companies need to evaluate process conditions and the type of solution that will be used for post-use testing before determining the wetting solution that will be used for the pre-use filter integrity test.
When deciding on a wetting solution, also bear in mind that high-value products can be reprocessed after cycling through the pre-use test.
Filter integrity tests of liquid sterilizing filters are performed using Forward Flow or Bubble Point tests. With either test, it is important that steps be taken to evaluate the possible effects of filter failure because significant pressurization of any of the collection bags could result in a bag failure.
A Forward Flow test is generally preferred because it quantitatively measures the diffusive flow as well as flow through any open pores in a wetted membrane filter. This lets the operator determine maximum applied system test pressure and what filters are integral so that downstream gas volumes can be accurately predicted.
If the filters are to be tested by Bubble Point, the maximum system pressure will be unknown because, with automated testers, the test pressure will increase until the bubble point is detected. The likely volume of gas passing through an integral filter will be difficult to quantify, and under failure conditions will prove difficult to handle.
Performing the test
The following outline of pre-use filter integrity test steps, which corresponds to Figure 1 (Page 20), provides a simple and efficient method of protecting high-value products. While some parameters may differ depending on the wetting solution, biopharmaceutical companies that follow this basic concept will gain a greater understanding of process conditions, and the added safety of preliminary testing:
- Open clamp 2 to flush bag. Ensure clamp 1 is fully closed.
- Flush filter with the wetting solution. The flush volume and wetting fluid may vary depending on filter type and size. Collect used flush fluid in the flush bag.
- Attach an automated integrity test instrument to the upstream side of the filter. Perform a Forward Flow integrity test using the correct test limits for the filter. During stabilization phase, fluid remaining on the upstream side of the filter will be forced through the filter and collected in the flush bag.
- Drain any residual water in "T" connector into the flush bag.
- Close clamp 2 to the flush bag.
- Open clamp 1 to process bag. System is ready to process product. (Note: If product dilution is a concern, a small quantity of product can be directed to the flush bag before collecting product in the process bag.)
Tomorrow's cleanroom today
Documents like FDA's Sterile Drug Products Produced by Aseptic Processing are spurring biopharmaceutical companies to look more closely at their processes to see where quality improvements can be made, safety can be enhanced, and greater efficiency can be reaped. Disposable processing has emerged as a way to achieve these objectives in a cGMP environment.
Biopharmaceutical companies are also discovering unique process optimization benefits in pre-filtration and chromatography as new disposable products are introduced for these applications. Process optimization, safety, efficiency and cost benefits will continue to multiply as the industry moves closer to an entirely disposable drug manufacturing paradigm.
- "Single-use Systems Reduce Production Timelines," Holly Haughney and Justin Hutchinson, Genetic Engineering News, Vol 24, No 28, April 15, 2004.
HOLLY HAUGHNEY, Ph.D., is vice president/biopharmaceuticals marketing with Pall BioPharmaceuticals. She is responsible for direct-flow filtration systems, including disposable systems. Previously, she served seven years as a technical director in Pall Corp.'s Scientific and Laboratory Services department supporting process gas and fermentation applications and new separations technologies. She can be contacted at: Holly_Haughney@pall.com; MONICA CARDONA is product manager for Pall Life Sciences where she has Western Hemisphere responsibility for pre-filtration and sterile liquid filtration product lines. She can be contacted at: firstname.lastname@example.org
Making the transition to disposable
Conversion from stainless steel equipment to disposable filtration systems avoids the complexities normally associated with adopting new processing methods by virtue of the fact that both designs use the same filter. The point of differentiation—the filter housing—does not influence the outcome of the filtration. As such, scale-up studies conducted for stainless steel systems can be accurately applied to their disposable counterparts.
Process development is the biggest factor in scaling up stainless steel systems that have been retrofitted with disposable products. This involves outlining the processes, products, technologies and services that will be required at each stage—from development to production.
Since disposable products exist for every scale of development and production, scaling up single-use systems will be easy, provided that parameters such as filter media, materials of construction, flow rate, throughput and differential pressure have been accurately modeled for the original hard-piped systems.—HH & MC