Securing and Qualifying Single-Use Technologies

The biopharmaceutical industry has started to look more seriously, in the past five years, at the potential that single-use technology offers for commercial manufacturing of biologic drug substances. There are major advantages to be had by the introduction of these technologies, none more so that the reduction in turnaround time for the manufacture of biological drug substances, leading to reduction of product costs.

Other tangible opportunities afforded by these technologies include reduced footprint of facility and energy reduction costs (i.e., reduction in sterilize-in-place [SIP] and clean-in-place [CIP] requirements and water usage). These opportunities have been well documented by various independent engineering and consultant firms. In addition, there are useful software models available to calculate what these opportunities provide from a cost perspective (1, 2).

Despite the reduced operating costs, companies are still hesitant to adopt single-use technologies, in part because of concerns that have been raised over the control of the raw materials used in the production of single-use components and finished products as well as the cost of qualification activities. Implementing oversight on the manufacturing of single-use technologies through the use of quality management systems (QMS) on the supply chain can significantly reduce the overall risk to the product.

Once better manufacturing controls have been introduced to minimize leachable and extractable impact on drug products, the qualification concerns may be mitigated by integrating risk-assessment principles into the qualification of single-use systems and components.

While control and management of the supply chain could be quite unwieldy, risk assessment can be performed to limit the qualification activities needed for disposable components. This article suggests techniques for mitigating risk and securing the supply chain for single-use components used for biopharmaceutical manufacturing and using the risk assessment to reduce the cost of their associated qualification activities.

SECURING A ROBUST SUPPLY CHAIN

Single-use technologies have been around for almost two decades but have become more prominent over the past few years in biopharmaceutical manufacturing facilities as business leaders see the advantages with speed to market and cost of goods for drug products. Single-use technologies in the past included single, discrete components such as filters that were used once and then discarded. The evolution from single components to more complex assemblies incorporating containers, filters, sensors, and other appurtenances provides advantages that were not readily available to the industry until recently. As these technologies evolve, more capabilities will become apparent and will lead to more streamlined manufacturing operations. To facilitate the increase in use of single-use technologies, a robust supply chain of single-use items is necessary to maintain production capabilities.

Quality systems

The use of QMS is recommended in the ICH Q10 guideline Pharmaceutical Quality System (3). A QMS paired with risk-assessment tools can be used to establish the best approach for the adoption of single-use technologies within a biopharmaceutical facility. The use of QMS tools ensures that single-use components and systems are manufactured to defined quality standards. The keys to the successful implementation of a secure supply chain for single-use disposable technologies may be accomplished by establishing contracts, qualification metrics, agreeable audit criteria, and robust supplier quality and change-control programs.

A crucial component in securing the supply chain is to establish a contract between single-use component suppliers and the end users. The contract should be explicit, clearly identifying terms, costs, service level agreements, and quality metrics that the end user expects the supplier to meet. The contract, for example, should define metrics arrived at by both parties that may be used to audit the manufacturing and delivery of single-use components to the end user.

With established metrics, both parties should address audit scope and frequencies that are mutually amenable. The measures or corrective actions that are acceptable to both parties should be anticipated for common failure modes to ensure that neither party overreacts and over commits to resolutions that will have a detrimental effect on the relationship. Consideration should also be given to define dispute arbitration and resolution pathways.

Single-use component and system manufacturers as well as suppliers are also well served to implement risk-based quality control and QMS programs to facilitate internal and external audit support and responses. Manufacturers specifically can leverage risk assessment to identify key critical process parameters (CPP) for control of single-use systems (SUS). It is imperative to establish a good working relationship between the supply chain and the end users. In effect, the contract supplier becomes an extension of the company's business model. Success or failure is dependent on this relationship.

Figure 1 depicts a product build map for the single-use assembly that can be used as a guideline during the risk-assessment phase. This map provides a framework to assist in the risk analysis of the supplier's product. Each leg or arm provides checkpoints in the manufacture process to evaluate CPPs. By following a risk-assessment process, safeguards can be established and implemented at various steps to mitigate risk. Appropriate risk-mitigation tools can be used throughout the assessment activity, for example failure modes effects analysis (FMEA) spreadsheets or fault tree analysis (FTA) flowcharts (refer to ICH Q9 Quality Risk Management available tools) as a way of identifying crucial issues with the manufacturing process of a single-use product.

Figure 1: Single-use systems, process build map.

As with many components used in the manufacture of therapeutics, a lifecycle management approach may also be adopted for single-use systems. The lifecycle management approach delineated in the ICH Q10 guideline discusses the application of various quality tools to the development, technology transfer, manufacturing, and discontinuation phases of a products lifecycle. This process is illustrated graphically in Figure 2.

Figure 2: Pharmaceutical lifecycle management.

The lifecycle management process is an iterative process with programs designed to capture changes to the product through both management review of performance data and through the quality system in which product quality is maintained through a corrective and preventive action program (CAPA). Manufacturers and suppliers should take into account the establishment of testing parameters, product transfer techniques, production parameters, and controls for GMP of sub assemblies. QMS/CAPA control schemes should be in place to review and control process. Storage and shelf-life management systems should be set up. A discontinuation program and obsolescence programming (supplying until an effective date) should also be considered. When vetting suppliers and manufacturers, these points will aid in the selection of the right source for the procurement of such critical-to-quality components.

It is imperative that the framework of manufacturing control parameters be established early in the contract development process. Sourcing should be done from approved suppliers. Quality change-management systems should be established with the supplier so that any changes arising from supplier process improvements are documented and approved early in the change process. Setting these controls in place during contract establishment will facilitate a smooth approach to manage improvements to the supply process. Mitigating risk is to be viewed as the primary driver.

Once a supplier has been established as a qualified supplier, defined by the supply change-management process, routine scheduled inspections of the supplier and subsuppliers will be required. Performance of these inspections and review of control parameters that have been established in the master contracts are important to reduce likelihood of out-of-specification components being produced.

RISK QUALIFICATION

Once the single-use supply chain has been established, it is crucial to assess what qualification activities are needed to implement a single-use system. While it is common knowledge that leachable-and-extractables testing is a necessary part of a single-use component program, it's important to realize that leachable-and-extractables testing can be costly to perform. However, testing may be reduced depending on the overall risk to the product for each single-use item. According to Destry M. Sillivan of FDA, manufacturers should "submit sufficient information to provide evidence that the product contacting material does not introduce contaminants into the product so as to alter the safety, identity, strength, etc." (5). If there is little to no relevant risk associated with the material in question, "vendor data can be cross referenced and a detailed justification for the applicability of these data and a justification for no additional testing should be submitted" (5).

Risk assessment

When assessing what qualification activities are needed for single-use component implementation, it is important to identify the product contact components that may present a higher leachable and extractable risk. A risk assessment is a valuable tool to determine what the crucial single-use materials are in a process. Those that surpass the tolerable amount of risk for an organization may then be slated for acquiring additional vendor information and further in-house testing. Multiple factors should be considered as part of the risk assessment including the nature of final product, how the process stream contacts the single-use component, the single-use component material properties, and the attributes of the process solvents. Once appropriate risk factors have been identified, a risk assessment should then be used to determine the extent of the qualification required for each component. Tools for performing a risk assessment as well as the general risk-based philosophy are outlined in ICH, Q9 Quality Risk Management (6).

It is important to recognize that a single-use item is often composed of many component parts that may or may not be made out of the same materials. Vendor documentation should be closely inspected to determine the material of construction of each component. Not all of these component parts may be manufactured at the vendor's facility. A primary reason for this is that many vendors outsource different components that comprise their single-use assemblies. Accordingly, subvendors must be contacted to obtain their validation packages for the individual parts to complete the risk assessment.

Consider, for example, a single-use bag system; there are the bag films, the connectors, the tubing, the capsule filters, and sampling connections as shown in Figure 3. As noted above, each of these items may be made out of different materials that all need to be considered for potential risk to product.

Figure 3: Single-use storage bag example risk assessment.

This example of a risk assessment performed on a storage bag illustrates how different components of a single-use bag can have different risk scores. The storage bag itself is rated at a higher risk relative to the rest of the component parts because it has a larger surface-area-to-volume ratio and the film is in contact with the storage material for an extended period of time. Where this bag is used in the production process will determine the overall outcome of the risk assessment. If the storage bag was used in upstream process the risk is low; however, if the storage bag was used in late stages of the process it becomes a much higher risk and would require leachable testing.

What the drug product is intended to treat, the intended route of administration, and where the single-use item is used within the process stream are the leading risk factors. The longer the product is in contact with the single-use item, the greater the risk that leachables will be transferred into the process stream. When considering this risk factor, it is important to recognize that the tubing on a component part may only see the process stream for a fraction of the time that a bag may see. This and the varying materials of construction are the reasons that component parts of each assembly should be considered separately. The proximity of the single-use item to final fill will increase the risk because there is less opportunity for the leachable (or particulate) to be mechanically or chemically removed via filtration or chromatography. The volume of product stream when compared with the surface area of the single-use item is also an important risk factor because the lower the volume is, the more potentially leaching surface area that it may contact. Consider the product contact area of a ultrafiltration/diafiltration (UF/DF) filter; the exceptionally high surface area as well as its proximity to the end of the process makes it a much higher risk to the product than an upstream storage bag.

The composition of the process stream will also contribute to the overall risk of leachables and extractables occurring. Because plastics are not typically compatible with all chemicals, the process stream extraction risks can be higher depending on the solvent and chemical concentration of specific components. First and foremost, the chemical compatibility of each of the single-use components must be understood to ensure that the process stream does not contain chemicals that will adversely affect the disposable item. Additionally, as the pH moves away from neutral to either alkaline or acidic, the risk increases for leachables to occur. For example, a 1N NaOH solution will pose higher risk than one of 0.1N.

In addition to concentration and material incompatibility, the temperature of the process stream can affect the risk of leachables and extractables being transferred into the product. Typically, the extractables qualification tests include elevated temperatures because, as temperature increases, the extraction risk increases as well. Conversely, lower process temperatures provide the least risk of this occurring. Additionally, the single-use item may be exposed to heat during the serilization process. If the item is heat-sterilized, there may be a greater risk of transferring extractables to the process stream.

How the drug product will be used will also play into the overall risk of leachables and extractables. Although typically how the drug product is used cannot be adjusted to reduce the risk, the qualification activities may be increased to ensure that the single-use item is safe to use for the process. The risk assessment should consider what the final dosage will be and how often the patient will receive the drug. The more of the drug product the patient receives, the greater the exposure to potential leachables and extractables; therefore, the risk is greater. Route of administration needs to be considered. If the product is an injectable then the risk is much higher than if the product is a topical agent.

What is already known about the single-use item should be used in the risk assessment. Vendor-supplied data should be analyzed for the material safety risks. Material safety risks serve to document what is currently known about the materials of construction. Again, the risk assessment needs to ensure that all component parts on the single-use item are accounted for within the vendor qualification package. Toxicity and/or biocompatibility (USP class VI classified) testing should have already been performed and documented. All components should be Animal Derived Component Free (ADCF) or EMEA 410/01 compliant. A great advantage to the risk assessment for implementing single-use items is that vendors will have their own extractable studies that can be referenced. A toxicologist should review the extracted substances to determine if they are acceptable. The conditions under which the extractable tests were performed should be observed; the manufacturing process might not get anywhere near these conditions but keep in mind that these tests are performed at worst-case conditions to see what can be extracted. Another thing to look for in the vendor qualification package is to see if the plastics are certified under Code of Federal Regulations (CFR) 21. 177. Although this certification is for food contact surfaces, it can reduce the overall risk because the plastics were derived from a more controlled process. A summary of key risk factors is illustrated in Table I.

Table I: Key risk factors for single-use components.

Qualification activities maybe reduced depending on risk to the process/product. Each qualification activity should be looked at individually with respect to how the single-use item will be used in the process and how high it scored on the risk assessment. Not every single-use item will need to undergo leachable testing if the risk score is low enough, which saves time and capital for the single-use item implementation. Keep in mind that if one component on the single-use assembly scored higher than the other component parts, it may be possible to have the suggested qualification activities performed on just that part and not the entirety of the assembly.

CONCLUSION

Single-use technologies will continue to be adopted over the next decade within the biopharmaceutical industry in an ever-expanding capacity (4). Establishing controls and processes that follow an ICH Q10 risk-based approach is one suggested methodology to help establish best practices and controls for introduction and security of these single-use technologies.

With the movement of the industry towards single-use components, many companies have started to address the impact of single-use equipment on product quality. The use of risk analysis is a powerful tool for implementing a single-use program.

KEVIN D. LEAR is a Principal Engineer, NICOLE COLLIER is Engineer III, and KEITH BADER is Sr. Director of Technology, all at Hyde Engineering + Consulting, Inc, Boulder, CO.

REFERENCES

1. BioSolve Software Modeling, BioPharm Services, Chesham, Buckingham, HP5 1DG, UK, www.biopharmservices.com.

2. Intelligen Software Services, Intelligen, Scotch Plains, NJ 07076 USA, www.intelligen.com.

3. ICH, Q10, Pharmaceutical Quality System (2008).

4. Single Use Bioreactors for Pharma; World Market 2012-2022, Vision Gain www.visiongain.com.

5. Martin, J. BioPharm Inter., 23 (11)(2010).

6. ICH, Q9 Quality Risk management (2005).