Introduction
In the current economic environment many companies are more rapidly identifying and implementing cost cutting and cost savings measures. One method of cost savings that has gained traction is the utilization of single-use systems (SUS). Within the biotech-manufacturing sector, SUSs are available as line kits for bioreactors, the bioreactors themselves, filters, and even purification columns are available as disposable or limited use components. Although use of an SUS can be cost saving, there is a cost associated with the implementation. Managing implementation of SUSs as outlined below can lead to reduced timeline for implementation, reduced cost of implementation, and increase freedom with respect to redesigning parts and processes.
This article intends to introduce a concept for managing data collected while introducing an SUS. In short, each SUS should be defined by materials of construction (MOC). The performance of those MOC with respect to safety evaluations including extractables and leachables should be tracked in a database. Subsequent introduction of the same MOC in a new SUS should be streamlined by not repeating the original tests. Once a material with the needed properties is identified more SUSs can be developed utilizing that material. More cost savings are realized.
There are many questions to address when considering changing to an SUS. Several are addressed below.
Why use an SUS when I have a validated Clean In Place (CIP) cycle?
Manpower is often the greatest operating expense. A CIP cycle can be automated. However, automation does not eliminate the need for manpower but may simply change the requirements from an operator performing all manual tasks to an operator performing less, while an engineer is required to maintain the automation system. Frequently, the utilization of CIP cycle requires the subject equipment be disconnected and reconnected to CIP systems. While the CIP cycle is being executed, operators are on to other tasks. With an SUS replacing the subject, equipment operations are simplified. Peripheral equipment may still require cleaning but the subject equipment is disconnected and new unit connected. Depending on peripheral activities, a new process could be started in less time than having to perform a CIP cycle. The CIP cycle requires periodic revalidation. Assuming the revalidation activities demonstrate the CIP system has been performing as prescribed, no issues are foreseeable. However, if the revalidation indicates that the CIP system is not performing as validated, a considerable investigation may follow. Appropriate responses may vary from simply fixing the issue to the drastic measure of product recall.
The utilization of an SUS may save costs by reducing the complexity of a validation, but may also save the cost of routine monitoring such as bioburden, residual proteins, and Total Organic Carbon (TOC). Materials such as an SUS that are discarded after use are generally not monitored.
Is the proposed management method applicable to parts in the manufacturing process that are currently SUSs?
Yes. Parts such as polypropylene Ts, Ys, Xs, and many types of silicone tubing are essentially SUSs. The user likely gathered considerable data on the SUS parts in service in the GMP facility. How that data is warehoused is the issue at hand. Philosophically, these parts can be managed the same as larger, complex, process critical single-use systems such as filters and bioreactors that are increasingly prevalent in the biotechnology industry.
Is the proposed SUS compatible with the existing process?
This question is answered in three parts.
First, the functionality of the part needs to be evaluated. The part needs to meet the demands of the process. One method to evaluate is to use the product in simulated conditions. For an example, the reader can refer to publication [1]. If the manufacturing process requires irradiation, freezing, transportation, or storage, the material should be evaluated for performance in those conditions. Once acceptable performance of a material has been established, further actions are required to demonstrate acceptability for the manufacturing process.
Second, steps are taken to evaluate the system’s impact on the product. This includes consideration of the effects of plastic materials on the product. The new part must be acceptable with respect to the product, not having any interactions with the Active Pharmaceutical Ingredient (API) that could affect the quality attributes of the drug product. For example, if the manufacturing process requires irradiation, freezing, transportation, or long term storage, the material should be evaluated under those conditions.
The third aspect is evaluation of the part with respect to end user safety. The safety evaluation of the material may include a battery of tests for extractables and leachables. Refer to Miller et al, reference [2] for additional discussion. Extractables are compounds that extract via physical or chemical means from materials. Leachables are compounds that migrate from product-contact materials into a process stream, product intermediate and final drug product under normal processing conditions. A compound that is extractable under exaggerated conditions may not be a risk for leaching. Testing of both extractables and leachables might not be necessary and a risk-based approach should be adopted based on the utilization of a material.
SUS Management to Reduce Cost
Having considered the cost savings, and evaluated the applicability of the part to the process, the decision is made to implement an SUS. The manufacturer collects all data as required by their own procedures including testing for extractables and leachables. This implementation is successful and the potential savings through implementation of a second part is identified. At this point there is an opportunity for additional savings.
Many parts are made from the same materials. If a part is defined by materials of construction and subsequent parts are manufactured from the same MOC, the implementation of a new part may be considered a reconfiguration of the original part and should be assumed to perform the same with respect to extractables and leachables. The application to the process in other regards should still be evaluated. The cost savings is achieved by defining parts of interest by MOC and not repeating testing of previously utilized materials.
When a new part is made from exactly the same materials, at the same plant, with raw materials sourced from the same supplier as the currently approved and in-use part, the implementation of new part is limited to confirming functionality and applicability. The introduction could be as simple as a change control review with the documentation supporting manufacturer and certification of the raw materials.
If the new part is almost exactly the same as existing parts, but for example uses a different bonding agent, then the propensity for the bonding agent to be in the process stream should be evaluated. If the implementation team does not have the resources or expertise to make that determination then conferring with a subject matter expert for further evaluation or performing leachables and extractables testing may be required. However, with respect to this example, issues with bonding agents can be overcome by sourcing molded, not bonded, parts.
In addition to streamlining the introduction of a new part maintaining data on the raw material may also address changes to existing parts. One challenge many companies have encountered recently is the manufacturer of an SUS has changed supplier of their raw material. This change should trigger an evaluation of the subject SUS. Raw materials may pass through several hands before receipt at the SUS manufacturer. Consequently, a change of their supplier may be that they are buying the same raw material but from a different distributor. This change should trigger a change in documentation indicating that end user of the SUS is aware of the change, and has evaluated the need to perform typical tests, but determined that no additional testing is required. If the supplier of the SUS does source a raw material from a new supplier or from the same supplier but manufactures at a different plant or with a different method, justifying not performing the safety evaluations is more difficult. However, there is benefit to both the end user of the SUS and the supplier to ensure the evaluations of the new parts manufactured with new material are performed.
The user of the SUS must be confident that sufficient change control occurred to implement changing a raw material. The user must also confirm that this SUS made from new raw material is appropriate for the process. Assuming that this raw material is appropriate and performs equivalent to the original MOC, and is less costly than the original material one would expect this material to be utilized in an increasing variety of SUSs. Having already evaluated this new material, introduction of subsequent SUSs utilizing this new raw material will be streamlined.
To streamline the introduction of new parts to the manufacturing process, each part should be defined by their MOC. Each critical MOC should be identified by grade, whether the material has components of animal origin, presence of heavy metals, presence of colorants or additives, trade names, or any other unique components or properties.
Once a part or system is defined by MOC, each MOC can be tracked in a database with respect to performance in the various safety evaluations. This article presents justification for tracking materials that pass the safety evaluations in that new SUSs composed of the same MOC can be evaluated and introduced without the full battery of testing. However, materials that are not deemed acceptable for use in the manufacturing process should also be tracked in order to avoid repeating the evaluation and they may be appropriate for an alternative use. Raw materials suppliers who learn that their material has not been approved for use may be motivated to change their manufacturing process to address any concerns.
Many common raw materials can be sourced from multiple raw materials suppliers. The suppliers of raw materials should cooperate in supplying information to an exhaustive degree of MOC. The information should be available to both user of the SUS manufactured from the MOC, and to the end user as well. This degree of disclosure may not be readily achieved. Establishing non-disclosure agreements may be required, but ultimately the effort invested in gaining this degree of information may benefit all parties should changes to any of their processes or materials change. Once non-disclosure agreements have been established, the raw materials supplier and SUS manufacturer may have a marketing advantage with the SUS end user. The SUS end user may provide the SUS manufacturer with additional business prior to developing additional relationships with other suppliers simply because the agreements are in place. Again, timeline from development to implementation can be reduced.
Many parts are supplied in multiple sizes, for example gaskets or O-rings. In these cases, the composition of each size should be tracked. Each size, although appearing identical may be manufactured at different locations or by different companies and repackaged by distributors or made of different MOC. Each plant may source raw materials from different suppliers. The final composition of the O-rings of different sizes may vary.
Benefits and Other Considerations
If any of the attributes of the MOC change, the leachables and extractables test can be repeated or the evaluation of the change in attribute documented by a subject matter expert (SME) who will determine if additional testing is required. For example, if the raw material distributor’s name changes, the documentation should be updated to reflect the name change, though this change should not require any new testing of the material. If the parts supplier has identified a less expensive source for their raw material, this change should likely trigger an evaluation of the subject by the end user.
Once systems are tracked by their MOC, new systems can be easily evaluated. With MOC being tracked, new systems can be evaluated by their MOC. If all MOC are in the database, the system may be rejected or accepted based on previously acquired data. For example, materials of an approved-for-use T-connector are being utilized to manufacture an X-connector; the evaluation with respect to materials could be performed comparing a manufacturer’s certification of MOC with the existing information on those materials. Assuming that an electronic database is used to track the MOC, the evaluation of a system can be accomplished based on the MOC, significantly reducing the time and cost required to introduce a system relative to treating this part as new.
Considering the distance between the final product and application of the SUS can save time. For example, the evaluation of an SUS with product contact at the final API step clearly should be more stringent than the evaluation of a system that holds raw materials for an upstream process. Once a working database is established, it becomes simpler to estimate expected extractables or leachables for a given material. Using knowledge of a process’ ability to clear impurities allows a quicker evaluation of upstream materials.
Finally, it may be valuable to work with vendors that comply with the ISO 10993 standard or USP VI testing (USP chapter). Materials that meet these standards have been evaluated to have no biological effect for their specific medical application. Vendors should be able to provide specific details about the testing of their materials, which can reduce or eliminate in-house testing.
Summary
Changing the manufacturing process may require introduction of new systems constructed of materials that have not previously been evaluated for extractables and leachables. The installation of new materials in an existing process can be expensive due to the cost of performing these evaluations. Defining new parts by MOC and tracking performance of parts by MOC in a database can facilitate the introduction of new systems. A new system with known MOC from a known supplier may be approved and in use with less effort and cost because that new system could be evaluated using an existing database, rather than testing the system for extractables and leachables. The streamlining of introduction of new systems may facilitate evolution of the production process by reducing effort required to make changes.
References
- Kilburn, Malliett, Wong, Evaluating Single-Use Frozen Storage Systems, American Pharmaceutical Review, April 2010
- Miller, et al, BioPharm International, December 2002
Author Biography
Arn Malliett has worked in the biotechnology industry for more than 22 years, with the last 12 focusing on discrepancy management. The bulk of his experience is in fermentation and purification, but he has also contributed to discrepancy management in other process streams including filling, packaging, and QC testing. Arn graduated from UC Berkeley and is currently contracting in discrepancy management in the pharmacuetical industry in the San Fransico bay area, California. He can be reached at [email protected] and welcomes all comments on this article.
This article was printed in the November/December 2011 issue of American Pharmaceutical Review - Volume 14, Issue 7. Copyright rests with the publisher. For more information about American Pharmaceutical Review and to read similar articles, visit www.americanpharmaceuticalreview.com and subscribe for free.