Adoption of Single-use Disposable Technology in Biopharma Industries – Manufacturing, Economic and Regulatory Issues to Consider

Single-Use Disposable Bioprocessing products have gained rapid acceptance by biopharmaceutical manufacturers worldwide. Single-use disposable devices and systems have reduced overall contamination rates, enhanced production throughput efficiency resulting in decreased manufacturing operation and maintenance costs. Recent collaborations between leading filtration, container /closure, mixing and fermentation / cell culture suppliers has resulted in fully integrated Single-Use Disposable Bioprocessing Platforms and Systems (SUS.) Implementing these SUS into legacy and new processes requires examining many process parameters and cost / benefit factors. This article will provide an overview into these issues.

Key Factors Encouraging Implementation of Single-use Systems (SUS)

The biopharm manufacturing industry has been flooded with writings from SUS end-user, suppliers and consultants discussing the benefits of these disposable single-use products. Between the numerous articles there are a continual stream of forums and meetings bringing together the principal decisions makers that influence the future developments and applications of these SUS products.

The following is a review of the key factors that not only encourage implementing single-use systems technology, but actually oblige the end-users to consider using these disposable devices. The article will assist and facilitate the decision-making process as well as spotlighting those critical operations that significantly impact productivity of the drug manufacturing process with regard to;

       •   Product Development and Process Timelines and Mileposts
       •   Labor / Material / Utility Costs and Cost Controls
       •   Process Efficiency and Productivity
       •   Contamination and Process Risk
       •   Regulatory Compliance and Industry Standards.

Product Development and Process Timelines and Mileposts

Once a compound has shown some therapeutic value in R&D and animal studies, the next steps in process development focus on the scale-up process development. These concerted efforts then begin to demand large investments in time and materials. Any meaningful reductions in the time and development of a drug product through to the regulatory approval will contribute to a successful and profitable market introduction.

Having a good estimate of the process development to production scale-up timelines and mileposts can offer insight into the probability of a successful program. Implementing single-use polymeric devices and systems can appreciably reduce process change lead times in qualification and commissioning of the manufacturing systems. These SUS can also provide greater design flexibility and expedited delivery, when process and device changes are required, than the comparable stainless steel hardware components. Lastly, another key factor for the implementation and ready acceptance of single-use technology is the reduction of change control documentation costs and time that are achieved by using polymeric materials with known qualification, e.g., leachables, and risk factor (toxicology) evaluations.

Labor / Material / Utility Costs and Cost Controls

One major advantage of employing Single-Use Technology in pilot plants and full scale manufacturing is the direct savings in general overhead costs in labor and materials. When examining the direct cost of labor for assembly, sterilization steaming-in-place (SIP) disassembly, cleaning (chemicals and high purity PW / WFI) as well as the cost of the chemicals and water, the saving achievable through SUS is significant when compared to the equivalent stainless steel hardware systems. In many instances, the use of SUS can completely eliminate the need for these chemicals and utilities, thereby contributing even more to the lowering of the cost of goods sold (COGS).

The question of waste management streams can be difficult to show comparable measures, however the cost of chemical disposal can be more than the cost of the chemicals themselves. While SUS do contribute to solid waste disposal volumes, alternate methods for disposable other than landfill may offer some cost and volume relief, e.g. incineration (steam and power co-generation) and recycling

An Overview of Labor and Material Cost Control and Reductions

SUS storage bags, which may require reusable/collapsible containment pallets, can replace SS tanks and plastic tubing can replace hard plumbed piping, providing for lower overall capital costs.

The footprint of SU storage containers (stackable design) greatly reduces the floor space requirement than equivalent sized hardware tanks and vessels. Stainless steel hardware, e.g. pressure vessels, storage tanks and interconnecting piping may be minimized, thereby reducing initial capital investments and longer lead times for design and commissioning. Single-use device manufacturers and suppliers must provide the qualification and validation information for their products, e.g., qualify attributes, which include cleanliness, sterility claims and durability. These requirements shift the burden to meet regulatory compliance and industry standards to the suppliers, thereby reducing costs and time constraint from the end-users. SUS have lower maintenance and downtime than hardware systems that contribute to reducing the COGS. Plant utility capacity for WFI and Steam can be a limiting bottleneck thereby resulting in supply shortages for key production lines. By eliminating or greatly reducing the water needs for CIP / SIP in cleaning, sterilizing and preparation operations, overall production throughput can realize increased capacity. Cost per liter ($/L) measures of overall production costs provide a truer calculation of the COGS, not just the cost of individual components. SUS, which are considered an on-going production cost, may prove more costly in the longer term expenses than equivalent amortized hardware, however the increased efficiencies and capacity more than compensate for these higher SUS outlays.

Process Efficiency and Productivity

The disassembly, cleaning and reassembly labor and time between production runs (turn-around or cycles) may increase the number of batch runs possible by eliminating or reducing the need for clean-in-place and Steam-in place operations, (see Labor / Material / Utility Costs section.) Although SUS may reduce the overall need for operator manipulations, these system can result in multiple connections amongst the various single-use components, e.g., tubing, connectors, bags, filters, etc. when compared to similar stainless steel systems. Overall, single-use systems are supplied gamma irradiated sterilized, with all connections made-up (hosebarb-tie or manifold) and factory shipped as a ‘ready-to-use’ systems. In order to achieve ‘out-of-the-box’ usage, the complete SUS does require initial engineering design configuration and ordering commitment by the end-users.

The smaller footprint of SUS reduces the production space needed over equivalently sized hard plumbed systems. More productivity coupled with more batch turnovers would result in greater output in same manufacturing floor space. Since bags/chambers are shipped in a collapsed state, the storage of bag inventory is less than that of similar volume sized stainless steel storage tanks.

Maintaining the same materials of construction, process parameters and conditions, a simple tank or fermenter/bioreactor upsizing may be considered a minor or moderate change for regulatory filing, thereby cutting back on the documentation and time needed to qualify these scale-up changes. Therefore, as new product demands grow after initial market introduction or through process optimization, the need for change control and regulatory filing documents can be ‘scaled-down’ by keeping the materials, and process conditions the same.

Contamination and Process Risk

Every single-use device and system must meet stringent cleanliness and sterility as well as durability requirements. And as each is discarded after its single use, the risk of batch cross contamination is practically eliminated. Compared to the higher risk associated with improper practice or human error when performing clean-in place or steam-in-place operations, the clear advantage of disposable SUS become readily apparent. The same concerns can be analogous to risks of microbial contamination. Either upstream and/or downstream process manipulations can result in accidental or advantageous microbial invasions. Thus, the observed batch contamination rates in all operations have demonstrated significant reductions when using SUS.

Regulatory guidance compliance requires that all new drug entities and processes have been examined for extractables and leachables and meet test study standards. Various industry groups, professional societies and standards organizations have published white papers, articles and monographs about testing, toxicology and testing limits and specification. In general, most SU suppliers have well qualified the materials of construction in regards to extractables and leachables from polymers and additives used in their devices/systems. Operator safety concerns and the needs for personal protection equipment, (OHSA regulations) may be met when using disposable bags and containers systems. SUS lessen the concerns for bio-hazardous materials exposure to operators and for disposal since in essence they are containment vessels.

Lastly, the reduction and /or elimination of cleaning solutions, microbialcides, and harsh base/acid chemicals will improve the associated risks of contaminating residues or excessive exposure to operators

Regulatory Requirements and Industry Standards

Most significantly is the drive by FDA for manufacturing efficiency changes and improved Quality Management Systems in the biopharmaceutical production. The overarching goal is that of lowering drug costs and reducing drug shortage, which have become endemic in recent years. One telling paper is by Dr. John Finkbohner, Deputy Director, Div. of Manufacturing and Quality, CBER, who presented the CBER Perspectives on using disposables in biopharma production. His observations, although from 2005, are even more compelling today. The FDA’s stated mission is primarily patient and drug safety, secondarily supply and lastly costs. However with this paper, Dr. Finkbohner elevates the production processes for not only the ‘safety’ issues but highlights the need for SUS technologies to provides even greater safety while providing for ‘…Cost Savings’ and ‘Speed to Market.’

He writes:

‘The most common elastomeric (polymeric) issues noted during …PAIs (Pre-Approval Inspections) are related to;
       •   Equipment –related failures in processing
       •   Documentation of extractable profile characterization
       •   Vendor qualification and/or fitness-for-use criteria definitions’

He concludes his presentation with:
Careful consideration during the process design state can be very beneficial and contribute to successful implemen-tation of a well-controlled and reliable production system.

We see enforcement as well as general encouragement from global regulatory agencies helps to promote the adoption and realization of single-use technology. Although, new drug process systems will lend themselves more readily to implementing these SUS than legacy production processes, there are non-critical applications in which these older processes could adopt SUS. There are many guidance documents that will assist in the implementation of single-use systems that will require change control fillings;

•  Change Control Fillings Simplified:

         •   Significant Change requires ANDA
         •   Moderate Change may require CBE 30s
         •   Minor Change may require an Annual Report

Examples:

• Upstream Non-critical Applications: Annual / CBE 30

         •   Buffer & Media preparation: filters, tubing, mix tanks and bags.
         •   Storage and Transport containers

•  Downstream Critical Applications: ANDA / CBE 30

         •   Purification / Separation qualified processes; TFF/ Chromat./Filtration
         •   Long Contact Duration ( hold tanks)
         •   Filtration / Final Sterile-filling

•   Comparability / Compatibility Guidance:

         •   Scalability from Bench to Pilot to Production
         •   Validation and Qualification Documentation

Regulatory and Industry References

The listing below is for easy reference and focuses primarily on extractables and leachables concerns of global regulatory bodies. There are several other major concerns expressed by FDA as the burst strength and microbial and vapor integrity of the bag layers or skins. These issues are usually addressed in the SU supplier’s validation and qualification documents. As there are many guidance and regulatory documents from the FDA, EMEA, ICH, ISO, etc., with differing regulations and guidance for SU technology and considering that many are vague and even contradictory, herein are the more reliable references; FDA Title 21Code of Federal Regulations;

         •   CFR 211.65 Equipment Construction
         •   CFR 211.94 Drug Product Containers and Closures
         •   CFR 177 for cGMPs
         •   ICH Q7A Guidance for Industry

Compendia tests: USP <87, 88, 381, 661, 1031>

         •   The biological tests <87, 88> Bioreactivity tests, acceptable predictors of toxicological activity but do not identify extractables or leachables.
         •   USP <381> Elastomeric Closures for Injectables: physicochemical tests are typically done in water, drug product or solvent vehicle. Test is gravimetric NVRs and is nonspecifi c.
         •   USP <661> Container Performance Testing, leaching polymers with PW, analyze for NVRs, residue on ignition, heavy metals. Do not identify specifi c leachables.
         •   USP <1031> Biocompatibility Materials in Drug Containers, Medical devices and implants: extracted polymers do not alter stability of product or exhibit toxicity.

Conclusion

Global regulatory authorities are one more driving force to the adoption and realization of the use of these innovative single-use disposable technologies. The overarching goal is to achieve increased patient safety, increased drug supply (reduce drug shortages) and to lowering risks and drug costs. Biopharmaceutical manufacturers seek increasing productivity, faster time to market, greater profi tability. SUS suppliers are compelled to provide newer innovative products, cleaner and stronger polymeric materials while providing suffi cient capacity to meet the rapidly growing demand for SUS products. All are part of the major market drivers that further product development, while promoting the approval and implementation of SUS in the biopharmaceutical development and manufacturing industry.

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