A Risk-Based Strategy for Implementing Disposables in a Commercial Manufacturing Process

Today’s single-use technology (SUT) is more than just bioprocess bags and the silicone tubing to connect them. Most companies now use SUT bags for at least one other application, usually storage of small-volume buffers or for in-process sampling. For sample handling in particular, bags provide obvious advantages over traditional sample bottle assemblies that must be steamed in place to obtain an aseptic sample of a cell-culture vessel. However, single use now reaches into many more phases of the modern biologics manufacturing process. Bags are available with internal mixing systems from several suppliers. Disposable filter capsules containing more than 2.3 m² of membrane area are available.

Aseptic connection devices in a variety of sizes and shapes allow tubing connections in seconds. Single-use formats are available for many sensors, including those that measure pH, conductivity, and dissolved oxygen. Together, these advances in SUT have enabled wide adoption of single-use bioreactors (SUBs) across the industry. Even chromatography columns up to 60 cm in diameter are now available pre-packed and fully disposable.

The author evaluated the potential to reduce operating costs by switching to largely disposable process equipment during the technology transfer of a commercial purification manufacturing process. The design considered replacing most of the steel tanks, filter housings, and transfer lines with SUT. Detailed design planning identified more than 80 SUT components that would be required, including roughly a dozen static bag designs from 1 L to 2000 L, mixing systems from 100 L to 1000 L, and more than 20 separate tubing assemblies, manifolds, and hoses. To support routine operations, more than 500 individual pieces of SUT would be required per batch. With only 20 batches a year, the number of SUT items that need to move annually through procurement, warehousing, release, use, and disposal quickly exceeds 10,000.

Selecting which SUT to use is only the beginning of the implementation process. Implementation of SUT at any stage of a commercial manufacturing process requires bringing the SUT components into GMP systems as a raw material. This means generation of new part numbers, material specification documents, manufacturing procedures, release testing procedures, supply agreements, quality technical agreements, quality audits of the supplier manufacturing sites, and assessment of potential SUT extractables and leachables (E/L). The E/L testing is one of the longer duration pre-requisite activities to GMP implementation. For process development teams supporting post-approval processes, the scope and duration of this work can be easily underestimated. This workload will grow exponentially when considering the technology transfer of processes currently being developed that heavily leverage SUT in multiple steps.

Risk assessment
The potential for polymeric components to leach unwanted chemicals into drug products must be evaluated (1, 2). E/L data are used to assess potential risks to patients from the use of SUT in manufacturing processes (3). The scope of the assessment should include everything from small surface area polymers such as valve diaphragms to large surface area materials such as chromatography resins. A process based largely on SUT will have hundreds of SUT polymeric components to be evaluated and potentially tested for E/L. It is not feasible to expose every process component to every process solution to confirm chemical compatibility in all situations. However, risk assessment tools can be used to provide thorough assessments and prioritize high-risk component solution combinations to result in a reduced E/L study scope.

The risk assessment tool used to design the E/L studies is a three-step process streamlined from the numerical method described by the Biopharmaceutical Process Extractables Core Team in 2002 (4). Quantitative evaluation criteria are first defined. The capability of extraction for each solution and component pair is then determined based on the criteria for both ease and extent of the extraction. Finally, the proximity to final product is determined. These three steps yield a risk action level for each SUT component solution combination. The ratings should be agreed upon by a cross-functional team, including members from the manufacturing users, technical experts, and quality assurance. Definitions and category criteria should be defined prior to making any rankings to ensure a precise, unbiased, data-driven ranking process.

The capability of extraction is determined by rating the ease and extent of the potential extraction. The ease of extraction is rated either as difficult, average, or easy. Use of organic solvents or operating a material at the extremes of the supplier-supported chemical compatibility conditions, for example, can be considered easy to extract, whereas an aqueous solution used within the component’s recommended temperature range can be considered difficult to extract. The extent of extraction is rated either as negligible, moderate, or significant. For example, components with small surface area or short exposure duration can be considered to have a negligible extent of extraction; whereas material exposed to steam or extended durations, such as liquid storage bags, can be considered as having a significant extent of extraction. The two ratings are applied to the extraction capability matrix shown in Figure 1, to identify an extraction capability level of L1, L2, or L3.

<b>Figure 1</b>: Extraction capability risk-assessment matrix. L1 has a higher capability of extraction than L3. The extraction capability level is applied to the proximity risk-assessment matrix in <b>Figure 2</b>.

Figure 1: Extraction capability risk-assessment matrix. L1 has a higher capability of extraction than L3. The extraction capability level is applied to the proximity risk-assessment matrix in Figure 2.

This “L” rating is applied to the y-axis of the action level matrix shown in Figure 2. The x-axis represents the proximity to finished goods and is categorized into three zones. Zone 1 represents materials used in a process step such as the final drug substance filtration or formulation step where there are no clearance steps (e.g., diafiltration step, bind and elute chromatography step) before the finished product. Zone 3 consists of component solution combinations that are substantially upstream in the process, typically separated from the drug substance by two or more clearance steps before the finished product. From this second matrix, the final risk action level is defined. SUT component solution combinations rated as risk action level 3-low risk-would not require additional E/L data to be generated. In all cases of product contact, the materials should be confirmed to meet the minimum United States Pharmacopeial Convention (USP) class VI or other compendial expectations or else additional risk mitigation steps may be appropriate. For components rated as risk action level 1-high risk-E/L data must be obtained and assessed. E/L data may not be necessary for materials rated as risk action level 2-medium risk-based on the justifications provided by the cross-functional risk assessment team. Many upstream components can typically be excluded from the E/L studies based on low-risk action levels.

<b>Figure 2</b>: Proximity risk-assessment matrix. Solution component combinations determined to be action level 1, or high risk, require extractable/leachable (E/L) data to be generated. Combinations determined to be action level 3, or low risk, would not need additional E/L data.

Figure 2: Proximity risk-assessment matrix. Solution component combinations determined to be action level 1, or high risk, require extractable/leachable (E/L) data to be generated. Combinations determined to be action level 3, or low risk, would not need additional E/L data.

Supplier selection and dual sourcing as risk mitigation
A manufacturing process that relies heavily on SUT requires the manufacturer to depend on the SUT suppliers. There are ways to reduce the risks resulting from this dependence. Supplier selections and the quality of your supplier relationships become crucial to ensuring consistent supply of the manufactured drug products. When identifying new SUT components to implement, leverage existing supplier relationships to expedite implementation by eliminating the need for new quality technical agreements (QTAs), supply agreements, or supplier audits. When a new supplier is required, the strength of the supplier’s quality system and their reputation in the industry are as important as the technical process needs. Understand the supplier’s validation program and lot-release process. Define requirements for endotoxin and sterility assurance. Risk assessment tools can also be used to determine the level of sterility assurance required for each component. The impact of potential bioburden ingress is not the same for all process steps, so not all components require the same level of sterility assurance. This may represent an opportunity to reduce the overall cost of goods (COGs).

High consumable volumes necessitate consideration of both capital investment and operational expenditure costs together over a fixed period before selecting SUT technologies or suppliers. The comparative analysis of capital costs and operational expenses will facilitate important process decisions such as technology and supplier selections. Establish business agreements for ≥3 years to lock in important assumptions that impact COGs at least through the initial phases of commercial production.

As with all raw materials, supply-chain risk can be reduced by qualifying a secondary source for SUT components. Occasionally, technology selection prevents dual sourcing. For example, several currently available disposable mixing systems utilize patented mixing technologies that are not interchangeable and require purchase of the compatible mixing bags from one supplier alone. Many SUT components, however, can be dual sourced.

There are essentially three ways to implement dual sourcing for SUT. The first is true redundancy for 100% of the SUT components, but this presents several challenges. It is simple enough to select two qualified suppliers and approve SUT design drawings with both. However, if the SUT parts are considered critical process raw materials and the fluid handling systems are qualified as part of the process validation (PV), it may not be feasible to validate equivalence for all SUT components. Each SUT component will require creation of two material specifications, one for each source. Enterprise inventory management systems and quality control material release systems will also have to manage the two source options for each process component. The warehouse may also need a strategy to segregate the two sources and determine when each option should be delivered to the manufacturing floor. In general, it will be necessary to generate twice the number of GMP documents to incorporate all of the duplicate SUT components into GMP systems.

A second option is to identify one supplier as primary and purchase all SUT components from that supplier for normal operations. The secondary supplier would only need to be engaged in the event of a supply-chain interruption or quality problem with the primary supplier. This strategy minimizes the number of items to be incorporated into GMP document systems. The secondary supplier, however, would need to build and maintain the templates and documentation required to produce these materials without receiving a commitment from the process owner for any significant volume purchases. This could lead to long start-up times when the material is requested. The lead time to satisfy a production request when demand is infrequent is a crucial consideration in this case.

The third, recommended option is to make each supplier the primary source for some materials and secondary for others. This option allows both suppliers to be engaged by a constant stream of revenue and dedicate some portion of their manufacturing capacity to supporting a process. E/L testing can be performed on both films to accelerate timelines. This provides an inherent alternative if any SUT components are found to have unacceptable leachable levels late in the schedule, because it is unlikely that both tested source materials will experience the same failure. Approve design drawings for most components with both suppliers for future use. The advantage of this option compared to 100% redundancy is the reduced number of new GMP documents required. Material specifications, QC material release documents, and inventory management systems require only single examples, not one for each supplier. Manufacturing procedures can also be specific to the expected source component and will not need to incorporate provisions for two possible components being used.

As part of the QTAs and business agreements, expectations for customer change notification and demonstration of component equivalency should be considered. An extractables study was performed by the SUT-integrator ASI comparing two platinum-cured silicone-tubing materials with similar specifications. The study found the extraction profiles were similar enough to conclude they were comparable within the variability of the analytical techniques used (5). Such data could allow the two raw materials to be deemed interchangeable so the SUT supplier could use either one without notifying the end user of a change in raw material source. This is a shift away from the traditional quality definition of supplier change notification expectations, but it may become a necessary flexibility as industry use of SUT increases. Questions around dual sourcing are being discussed by industry groups such as the BioPhorum Operations Group (BPOG) and the Bio-Process Systems Alliance (BPSA). SUT suppliers have the same interests in dual sourcing of raw materials as drug substance manufacturers, so expectations for supplier-change notification should be contractually defined to avoid future unwanted surprises.

SUT now exists to support all phases of drug substance manufacturing. Implementation of a commercial GMP manufacturing process that heavily leverages SUT components requires a large scope of work, including legal and business agreements; procurement and supply chain system designs; GMP documentation; and E/L studies. High numbers of SUT components can also mean a significant potential for in-process leachables, but good risk-assessment tools can prioritize the potential risks and reduce the scope of the E/L testing. The SUT-dependent process also means relying heavily on the quality systems of SUT suppliers. Dual sourcing and strong QTAs can mitigate some of that risk.

References
1. USP, USP <1031>, “The Biocompatibility of Materials used in Drug Containers, Medical Devices and Implants,” USP 38-NF 33, US Pharmacopeial Convention, Rockville, MD, 2015).
2. FDA, Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics (Rockville MD, May 1999).
3. W. Ding et al., Pharm. Eng. 34 (6), pp. 1-11 (2014).
4. J. Bennan et al., “Evaluation of Extractables from Product-Contact Surfaces” from the Mega Source supplement to BioPharm Int. 15, s22-34 (2002).
5. J. Briggs and N. Chandarana, Bioproc. Int. 12 (11), pp. 26-29 (2014).

Article DetailsBioPharm International
Vol. 28, No. 10
Pages: 60–63

Citation: When referring to this article, please cite it as C. Atwell, “A Risk-Based Strategy for Implementing Disposables in a Commercial Manufacturing Process,” BioPharm International 28 (10) 2015.