Development of Large-Scale Bulk Freezing Systems

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The biopharmaceutical industry is under pressure to generate value for shareholders and find innovative therapies while driving down development and manufacturing costs. As the industry considers more flexible and scalable production solutions for patients, new therapies will continue to be developed faster than ever before. These products will need to rely on robust and reliable manufacturing solutions. To deliver on that challenge, streamlining manufacturing processes will be necessary so that many lots of drug substances can be manufactured, stored, and/or processed rapidly and safely. That allows for faster turnaround times between products.

Single-use freeze systems are a sound investment in current unit operations and support future capital returns capable of handling rapidly changing bioprocessing requirements. Single-use technologies (SUTs) have been implemented mainly in upstream biomanufacturing but also some downstream processing and drug-product handling operations (1, 2). SUTs offer increased flexibility while significantly reducing the risk of contamination and the need for cleaning and validation (3). Major applications include filtration, hold bags for storage of simple solutions, and mixing. Recent uses for SUTs have been in bioreactors, ultrafiltration/diafiltration, and membrane chromatography for downstream processing.

Bulk Freeze Advisory Board
Problem Statement: Existing systems such as legacy stainless steel or current single-use technologies have limitations of scalability, logistics, and safety.
Business Case: Due to the advantages of single-use systems relative to stainless steel in cost, flexibility, and speed, an improved single-use platform is preferred by the industry. This advisory board seeks to align efforts toward a new single-use industry platform and influence the development of new and versatile solutions meeting the growing needs for pharmaceutical companies.
Objective: The objective is to develop a flexible user requirement specification brief that can be used for the design of a new single-use bulk freeze platform that may be used at any of the participating companies without significant customization.

Key challenges have been the development of disposable storage containers for bulk frozen drug substances. Compared with stainless steel alternatives, disposable storage containers offer several well-characterized advantages (4). A few key drivers for replacing large stainless steel tanks with single-use containers are listed in the “Disposables or Steel?” box.

Disposables or Steel?
Single-use systems offer several advantages over steel systems.
Cost

  • Reduced capital spending on steel tanks, steam-in-place (SIP) and clean-in-place (CIP) skids
  • Reduced use of cleaning materials, water, energy, and labor
  • Significant reduction in tank management logistics and global planning
  • Low cost of container and recyclability, enabling one-way logistics
Quality

  • No reprocessing (rouge, debris, scratches, repairs)
  • No foreign objects or contamination introduced into bulk container by handling
  • No losses due to particulates, leaks from gaskets, valves, or other operator-error assemblies
  • Easy maintenance of aseptic environment with gamma irradiation
Time

  • Elimination of fabrication and qualification enables flexible capacity management
  • Elimination of cleaning validation enables faster development cycles
  • Consistent material of construction enables seamless transition to large-volume production

However, most applications of single-use drug-substance storage containers have been at 2–20-L volumes. This creates significant inefficiencies for scale up to commercial production, which requires either a return to large-scale steel storage containers or use of new larger single-use drug-substance storage containers. Implementing steel technologies requires complex cleaning validation and managing a fleet of capital equipment. But large-scale single-use drug-substance storage containers bring specific challenges related to robustness and usability in manufacturing environments, with designs that are not directly scalable.

Here we discuss aspects that must be evaluated before using large, disposable storage containers at clinical or commercial scales in a biopharmaceutical manufacturing
environment, including technical and procurement evaluation activities.

Technical User Requirements
Using bulk drug-substance storage containers may appear to be simple, but it can become technically challenging as more capabilities are required of such containers. For single-use solutions to be viable as alternatives to current steel (or Hastelloy) storage containers, they would be required to support the same chain of operations, potentially including fill, freeze, storage, transportation, mixing, and depletion. Disposal of a single-use bulk system also must be considered.

As with anything in biomanufacturing, costs and potential points of failure increase with complexity, so it is important to define carefully the minimum requirements that single-use freeze systems must meet. For example, if a bulk-drug substance does not need to be frozen, then its containers can be simplified significantly and should be less expensive than those designed to support freezing and thawing. Requirements can be unique for each manufacturer, but a collection of standard and agreed-upon characteristics was written by the new Bulk Freeze Advisory Board. They include material quality attributes, design characteristics, operational requirements, and disposal considerations. As an example, the “Technical User Requirements” box above provides a list of requirements.

Examples of Technical User Requirements (Simplified)
Material Requirements

  • Use appropriate material that meets food-grade, sterile, biocompatible, endotoxin and particle free, no animal-derived requirements.
  • Enable cleaning with standard agents.
  • Provide clean extractable and leachable report.
  • Demonstrate material robustness at cold temperatures.
  • Support shelf life of multiple years.
  • Demonstrate chemical compatibility.
  • Provide light protection.
Design Requirements

  • Enable scalability of design: Volume range should be from small to large using the same material of construction.
  • Fit with standard pallet dimensions
  • Limit height to fit in air-cargo containers.
  • Enable aseptic connection and disconnection.
  • Demonstrate pressure robustness.
  • Provide certificate of conformity.
  • Provide access to qualification/validation guides.
  • Provide adequate labeling.
  • Fit on standard pallet dimensions.
  • Enable tamper evident closure.
Operational Requirements: Filling

  • Allow partial filling or fill to capacity.
  • Limit filling duration.
  • Support filling of containers in series or in parallel.
  • Support fill monitoring (e.g., by mass).
Operational Requirements: Freezing and Thawing

  • Limit freezing or thawing duration.
  • Support different freezing or thawing methods.
  • Support freezing and thawing cycle validation.
  • Enable temperature monitoring during freezing or thawing.
  • Support mixing of thawed materials.
Operational Requirements: Storage

  • Limit water vapor transmission rate.
  • Limit gas permeability (e.g., oxygen, carbon dioxide).
  • Ensure pH stability with representative formulations.
Operational Requirements: Transportation

  • Demonstrate robustness through simulated handling and distribution.
Operational Requirements: Depletion

  • Enable connection for depletion.
  • Support different depletion methods.
  • Minimize residual loss.
  • Demonstrate integrity of container was maintained through full sequence of operations.
Operational Requirements: Disposition

  • Enable separation of components with different disposition requirements (e.g., container and pallet).
  • Minimize the quantity of single-use materials.
  • Identify appropriate disposition mode for each material.
Reference
1
International Safe Transit Association. Guidelines for Selecting and Using ISTA Test Procedures and Projects; http://www.ista.org/ forms/ISTAGuidelines.pdf.

Procurement Requirements
Creating common and detailed technical user requirements is the first step toward the development of new technologies that suit the needs of a global manufacturing network. To bring new large-scale single-use storage containers to fruition, container manufacturers should survey the market and tap into the brilliant and innovative talent of their suppliers.

Development and implementation of new technologies is a long-term commitment for both their developers and their adopters, with significant financial risks and burden. Significant investment is shared by both sides: Developers invest in research and development without firm commitments from clients to implement, and adopters implement new technologies without exhausting all failure possibilities and without jeopardizing the launch of new molecules. Hence, only a strong build and strategic partnership with suppliers of single-use materials can enable a successful development and launch of such disruptive technologies.

Given the complexity and risk associated with this effort, the Bulk Freeze Advisory Board was created across multiple biopharmaceutical companies. Its objective is to harmonize technical requirements of large-scale, single-use drug-substance storage containers and maximize interest of manufacturers by highlighting an industrywide need for such technologies.

Through those harmonization efforts, the board’s objective is to challenge suppliers to develop solutions that meet the needs of all pharmaceutical companies involved, without legal or intellectual property limitations. In that effort, the board is not discussing specific solutions. Each pharmaceutical company is free to engage in its own sourcing exercise, choosing the right industrial partner with the right combination of interests and business alignments, technical capability, supply chain control, manufacturing capacity, and quality systems for its own needs.

Partnerships are Key
Sourcing of new large-scale, single-use drug-substance containers is a partnership between the biopharmaceutical industry and single-use equipment manufacturers. This requires close collaboration to ensure that procurement and technical requirements are both met. Another challenge of this activity (not discussed in detail here) is that the addition of new disposable components requires new capital equipment to support single-use designs and new logistic support to distribute these components safely. A total cost-of-ownership model is required when evaluating potential solutions, although the business case might not be profitable in all scenarios (5).

Despite those challenges, single-use technologies such as large-scale storage containers provide real opportunities to improve current manufacturing processes for biopharmaceutical molecules, increasing agility, flexibility, speed, and quality while reducing costs. Implementation of new single-use bulk freezing containers is a significant change that must be managed with care. But with a clear list of user requirements and engaged biopharmaceutical companies and single-use manufacturing experts working together, the benefits will be realized.

References
1
Goldstein A. Freeze Bulk Bags: A Case Study in Disposables Implementation. BioPharm Int. November 2009.

2 Sinclair A, Monge M. Disposables Cost Contributions: A Sensitivity Analysis. BioPharm Int. April 2009: 28-32.

3 Singh SK. Storage Considerations As Part of the Formulation Development Program for Biologics. Amer. Pharm. Rev. 10 (3–4) 2007.

4 Bieger B. Development and Implementation of Disposable Bags with a Freeze/Thaw Unit for Fast and Controlled Freezing/Thawing of Drug Substances. 8th BioProcess International Conference, 18–19 April 2012, Prague.

5 Sinclair A, Monge M. Quantitative Economic Evaluation of Single-Use Disposables in Bioprocessing. Pharm. Engin. 22(3) 2002: 20–34.

Corresponding author Adam Goldstein is senior scientist, Pharma Tech Innovation, at Roche Genentech, 1 Antibody Way, Oceanside, CA, 92056; 1-760-207-5995. Justin Bourret is senior engineer, Global Packaging Development, at Roche/Genentech. Loic Barbedette is principal engineer, Container Science and Engineering, at Amgen. David Kolwyck is director materials science at Biogen. Bill Scott is scientist II, Materials Science, at Biogen. Atul Mohindra, PhD, is R&D director at Lonza. Diego Schmidhalter is director, Global Single-use Systems Definition, at Lonza. Sally Kline is director, Pharma Tech Innovation, Material Sciences, at Roche/Genentech. Marion Glenn is global senior category manager, Single Use, at Roche/Genentech. Paola Ramirez is technical lead at CRB Inc.

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