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Mike Marciniak is senior product manager for freeze-thaw technologies with Sartorius Stedim Biotech, USA.
CÃ©dric Gentile is field marketing manager with Sartorius Stedim Biotech in Aubagne, France.
As more companies decouple drug substance from finished drug manufacturing operations, an integrated approach can ensure safe, reliable logistics for frozen storage and shipping.
Biopharmaceutical companies are expanding their global manufacturing networks to bring more medicines to a greater number of patients, more quickly. They are building final drug production sites in local markets, to meet a growing number of legal mandates to invest in local facilities rather than importing materials. This general trend of decoupling global drug substance from final drug product manufacturing sites increases the need for safe, reliable, and well-qualified product transfers throughout the world.
This article introduces a method that might be used to achieve successful drug substance transfers using an integrated single-use freeze-and-thaw solution. The drug substance is first frozen in robust single-use containers, and then shipped in purpose-designed shippers to ensure transport integrity. This complete logistical chain safeguards and preserves the integrity of drug substances throughout their entire lifecycles: freeze, store, ship, and thaw.
Achieving successful implementation of a freeze-and-thaw process requires a focus on transportation logistics, and an emphasis on physical and thermal qualification, in order to assure that the product is adequately protected throughout its lifecycle. Normalized methods such as the American Society for Testing Materials’ (ASTM) D4169 Standard Practice for Performance Testing of Shipping Containers and Systems (1) and requirements set by the International Safe Transit Association (ISTA) (2,3) are used to show transport integrity and packaging robustness.
Finally, the article explores the possibility offered by single-use freeze and thaw technologies for one-way logistics to simplify global biopharmaceutical supply chains, increase process efficiency and flexibility, and reduce operating costs.
As biopharmaceutical companies continue to expand their global distribution of bulk drug substances, networks are becoming increasingly complex, including not only traditional production centers but contract manufacturing organizations’ (CMOs) production sites, offshore facilities, and greenfield facilities.
Legislators in countries around the world have published new directives that grant market access only to companies with local manufacturing capacity. This has driven a trend for biopharmaceutical companies to localize production of final drug product in target markets they wish to serve.
As a result, many companies are decoupling drug substance from drug product manufacturing. This means that valuable drug substances and/or APIs must move through these networks at a furious pace, and must be stored and shipped to remote locations around the world.
Any handoff between sites can be complex, especially since drug substances are worth millions of dollars. At this point, the industry has not yet developed standardized methods for meeting the challenges associated with product transfers. Thus, it is up to the manufacturers to create safe, reliable, and adaptive operations to serve their expanding networks.
In order to meet this challenge, closed-system processing, packaging integrity, and simplified logistics are necessary. Single-use technologies are already being used to reduce the risk of cross-contamination, improve process robustness, and speed implementation (4).
At low temperatures, long-term product stability is better maintained when bulk drug substances are transported in a frozen, rather than a liquid, state. Shipping frozen drug substances in single-use containers to final drug product manufacturing sites throughout the world can help biopharmaceutical manufacturers meet their mandate to maintain their products’ safety and quality throughout their lifecycles (5).
The industry increasingly prefers to perform freezing operations to maintain the stability and quality of proteins during the development and production of biopharmaceutical products (6). The production of biologics is expensive and, to optimize efficiency, manufacturers often decouple production of the bulk from that of the final drug product and then store the bulk solution in frozen form.
Freezing drug substance maximizes productivity and reduces overall production costs (7). It enhances operational flexibility and allows for cost savings by enabling batch processing. Frozen storage also provides a much longer product shelf life by decelerating chemical and physical degradation reactions and reducing the risk of microbial growth. When the drug substance and drug product sites are decoupled, product transportation in a frozen state promotes easier temperature-control requirements and limits interactions between the product and the container (8).
Figure 1: Freezing and thawing operations are commonly used along the entire downstream purification process, from biomolecules processing toward finished biopharmaceutical manufacturing, as outlined here.
Application of freeze-and-thaw processes may also be extended to product intermediates from harvesting and purification steps to allow longer hold periods between manufacturing unit operations (see Figure 1).
Frozen drug substances are usually stored at temperatures ranging from -20 °C to -80 °C (9). Established during stability testing studies, frozen storage, shipping, and handling temperatures should be chosen that maintain the product in the glassy phase, unless the protein is robust enough to tolerate higher temperatures (5). Operational infrastructure and logistics for storage and product shipment are favorable at higher temperatures in the range; hence, the objective is to develop a drug substance formulation that is stable between -20 °C to -80 °C (9).
Stability studies that consider the distribution of the product throughout a manufacturing network are a relatively new concept for biopharmaceuticals. Such studies can stress the product in either “real-world” shipment or simulated settings.
However, this approach may increase the allowed temperature range of the temperature-controlled network, thereby reducing costs, improving the level of service, and diminishing non-conformances (10).
Developing robust formulations and applying process knowledge are critical aspects for process owners to know how to transfer precious frozen product from well-controlled facilities to foreign countries safely and reliably. They must review these aspects along with available technical options for further scale-up activities.
The selection of the freeze and thaw system, as well as the associated logistics platform to transport frozen drug substances worldwide, must primarily ensure product integrity and preserve the product’s quality throughout its lifecycle. Process owners must demonstrate excellent mechanical and thermal performance so that this information can be leveraged during process development activities and stability studies.
Careful consideration of biophysical, engineering principles, cold chain management, and process scaling are essential to link drug substances to drug product sites worldwide. Robust, complete, and scalable single-use solutions are required to design successful frozen transfers.
When frozen drug substances involving single-use technologies are poorly designed, results can be devastating. Unprotected frozen single-use bags fail when dropped or bumped, and frozen tubing breaks when mishandled. Any breach may cost dearly in lost revenues and, often worse, may cause a two-month time wait in manufacturing its replacement, disrupting the supply chain.
Securing high-value frozen drug substances requires purpose-designed solutions to mitigate constraints linked to low-temperature environments. When using single-use technologies, plastic material tends to become brittle at low temperatures, and therefore, must be properly protected from the mechanical stresses that can occur during typical handling and shipping operations.
The best approach combines the use of robust single-use bags with protective shells or frames (i.e., primary containers), secondary packaging (i.e., insulated shipper), and proven system performance through extensive testing (see Figure 2). This approach allows manufacturers to be confident that a single-use solution will safeguard frozen drug substances throughout their lifecycles
Material science, film extrusion expertise, and assurance of supply should be carefully evaluated when selecting suppliers of single-use technologies. These are the critical attributes that will ensure consistent film and single-use assembly performance with the required level of quality.
The primary container and its associated insulated shippers must show the ability to protect pro-duct from mechanical failure (i.e., container closure integrity ensured within conditions set during stability studies) and from temperature excursions (i.e., exposure to a temperature range outside the recommended conditions established during stability studies).
The end-use mechanical properties of single-use assemblies are complex. They depend not only on the materials of construction (i.e., film, tubing, and connector) but also on the design and configuration of the single-use bag supported by the integral shell or frame. Therefore, it is important that the robustness and failure modes of the final configuration be evaluated under typical and extreme handling and shipping conditions.
Understanding the product lifecycle and associated risks are prerequisites for establishing a suitable qualification testing approach. Connections tests, freeze-and-thaw cycles, and liquid and frozen robustness tests (i.e., rotate, lift, and drop tests) address mechanical stresses that occur during liquid and frozen bag handling, frozen storage, and transfer across campuses or manufacturing sites. Shipping tests are required to confirm protection against loss of container closure due to mechanical shocks and vibrations, or damage to drug substances due to thermal inputs during the international transport of frozen containers within a shipper.
Because multitudes of shipping lanes exist, and each shipping lane may be specific, evaluating packaging against well-defined industry standards provides a strong basis from which to predict performances in real conditions. Selecting the distribution cycle (the types of mechanical tests and sequences of procedures, to recreate what the shipper can experience during transport) and ambient profile (temperature expected to be experienced by the shipper during transport) is crucial to qualify a shipping system that brackets real process conditions, and to offer a solution supported with robust data.
ASTM’s D4169 at Assurance Level 1-Standard Practice for Performance Testing of Shipping Containers and ISTA’s 7D (2) or 7E thermal profiles (3) are suitable stress testing methods for primary packaging plus the shipper, and can demonstrate mechanical and thermal performance levels under severe conditions.
Selecting proven and robust single-use solutions provides manufacturers with safe and easy-to-use handling containers to minimize risk of product loss. It ensures both the long-term maintenance of product integrity and safe international shipments without temperature excursions.
Definition of process flow and process requirements is the foundation for defining the testing plan for qualifying and validating drug substance frozen transfers. The validation master plan concept can be applied for this purpose (10) (see Figure 3).
Figure 3: The distribution validation master plan (dVMP).
The transport qualification process must bring together information on the shipper’s physical qualification, thermal stress testing, and design qualification (min/max load). Design qualification (DQ) and operational qualification (OQ) must be performed in a laboratory environment.
During the performance qualification (PQ), however, mock payloads with data loggers are sent for live shipments to a set of destinations. These are representative of the distribution lanes to which manufacturers will send the drug substances. It is recommended that shipments during seasonal extreme temperatures be included in the qualification process in order to obtain the most robust data from these experiments.
It is also crucial that biopharmaceutical manufacturers choose thermal profiles and mechanical shock and vibration profiles carefully. These data will be vital in order to qualify the insulated shippers during DQ and OQ.
This information is also required in order to complete validation and achieve project success. Failure to select these profiles correctly could lead to the PQ failing, resulting in the need for reworking during DQ and OQ phases.
Companies should map and monitor their distribution lanes for temperature data and other relevant environmental hazards (i.e., humidity, light, vibration) prior to developing transport packaging. Indeed, the development process for new shippers is complex and lengthy, and can involve considerable associated costs. Testing occurs in environmental chambers against simulated shipping conditions. Further testing under accelerated mechanical conditions follows before a company can move on to live shipment tests. Altogether, the development of a new shipper should be expected to take up to nine months.
To overcome these challenges, vendor pre-qualified shippers and associated single-use bags have been validated against the relevant mechanical and thermal industry standard shipping tests. They can offer great value to manufacturers, allowing them to move, confidently, to PQ with shipping tests in real conditions, bypassing the DQ and OQ phases for which data are already available.
Considerations for successful frozen transfer, often limited through the performances of the distribution process itself, must be broadened throughout the entire drug substance lifecycle, from product filling to draining. The lifecycle includes several process steps requiring equipment and accessories, especially for large volume manufacturing batches.
Complete solutions (i.e., single-use bags, freeze-and-thaw systems, logistic accessories, and pre-qualified shippers) from only one supplier create the most reliable platform logistics for consistent operations. This consistency helps manufacturers build stronger cold chain operations, improves output, and allows them to benefit from efficient application support and accountability when needed.
The frozen transfer of drug substance may be required at different stages of the development process, from clinical trials through commercial manufacturing. Technical solutions retained to decouple product manufacturing from fill-and-finish activities must often be adapted for different batch sizes, process requirements, or regulatory expectations that can vary throughout these phases. Considerations such as single-use bag volume, validation efforts, logistics, process control, speed to clinic or market, and costs are then essential for the selection of the most suitable platform (see Figure 4).
Figure 4: Scalable solutions for single-use freeze-and-thaw: Design and process requirements.
Product stability data will define the critical process parameters during frozen drug substance transfer at production-scale. Scale-down models that replicate large-scale systems are needed for development and regulatory stability studies. The execution of lab-scale studies has traditionally been limited to the assessment of container construction materials for the presence of extractables and leachables, and for product compatibility or product adsorption (11).
Manufacturers should carefully select single-use technologies that allow them to scale up and scale down their operations, depending on the product development stage. They should also choose systems that can be changed, in response to modifications in process requirements , without their having to repeat such studies.
Lab-scale studies done from a process perspective may also be required to obtain similar time- temperature profiles throughout all process scales, and manage the impact of the freeze and thaw rates on drug substances. In this case, scalable solutions based on heat- and mass-transfer dimensions, become critical, and controlled-rate freeze-and-thaw processes are required. Certain protein formulations are robust enough to be processed at slow rates. Freezing and thawing methods, using existing infrastructure, are then the easiest, quickest, and least costly.
However, slow freeze-and-thaw rates can cause degradation of the active ingredient due to cryo-concentration in other protein solutions (12). Heat transfer must be maximized and system design optimized to deliver fast and reproducible thermal cycling. This type of platform preserves product stability and may allow the monitoring of freeze and thaw critical process parameters and full process control for a perfect match into GMP manufacturing processes.
Scalable solutions from laboratory to production-scale and from clinical to commercial GMP manufacturing ensure the easy adoption today by manufacturers and create opportunity for tomorrow’s frozen transfers. It gives the flexibility to expand production and while maintaining consistent quality to ensure business continuity. Stability assessments can be performed to develop frozen transfers with confidence for earlier and smarter process decisions.
The advantages provided by freeze-and-thaw in single-use bags versus traditional freezing and thawing methods (i.e., use of stainless steel tanks, single-use bottles) have been well described in the literature (8, 9, 11, 13, 14, 15). Disposable technology improves operational flexibility and reduces capital requirements as well as validation, operating, and maintenance costs. Pre-sterilized, enclosed single-use assemblies reduce the risk of cross- contamination. Single-use technologies also reduce complexity during dispensing, and the manual interventions often needed during freezing, thawing, handling, and shipping, thus optimizing the ergonomic and safety aspects of drug substance processing.
Frozen bags may be stored in various types of freezers (i.e., chest, upright, walk-in or blast freezers). They can be designed to provide a shorter freezing path length distance per volume than commercially available rigid containers, thereby reducing resistance to heat transfer significantly. Shorter freezing path length and sufficiently higher heat transfer rates can overcome the diffusion of the protein to preserve drug substance stability, which is the design basis for efficient single-use controlled-rate freeze and thaw systems.
Dividing products among several disposable single-use bags allows manufacturers at the drug product site the flexibility to thaw and use only what is needed without subjecting a whole batch to a new freeze-and-thaw cycle. This feature is especially relevant to real-time commercial campaigns or clinical trials, in which the demand may not be predictable; for product with short shelf-life; or for manufacturing processes in which the drug substance concentration may vary.
Flexibility in single-use bag configuration improves process efficiency with multi-fill operation, allowed when assembled into manifolds. It also addresses the differences in practices found between the drug substance and drug product sites, whose connection and disconnection technologies may be different. The wide range of single-use bags that have been integrated into pre-designed solutions facilitates the implementation of disposables into drug substance frozen transfer. Finally, the use of freeze-and-thaw single-use bags reduces storage requirements in the warehouse or during process in the freezers compared to the use of stainless steel vessels or other rigid containers.
Figure 5: One-way logistics applied to drug substance frozen transfer.
Coupled with single-use shippers, single-use freeze-and-thaw bags significantly decreases the supply chain complexity through one-way logistics (see Figure 5) (16). One-way logistics means that there is no substantive return of shipping materials from the destination site back to the originating facility. The supply chain can be easier to predict because the single-use consumables are delivered directly to the drug substance manufacturers, and are then filled and shipped to the drug product site.
Once the drug substance is dispensed at the destination site, the single-use containers and shippers are disposed of or collected for local recycling. This approach not only simplifies the drug substance supply chain, but reduces operating costs and creates manufacturing efficiencies.
Supply chain risk mitigations for inventory and both cycle and safety stock can be managed by the vendor, in contrast to the management of reusable stainless steel vessels. Designing a complete disposable supply chain for drug substance frozen transfer with single-use bags prevents the complex process and extensive costs of reverse logistics with primary container or shipper return, cleaning, sterilization, and refurbishment services. Manufacturers should dispose of waste according to good environmental practices, and vendors of single-use technology should offer recycling options.
Frozen storage and shipment of high value bulk drug substances is becoming increasingly important for today’s global manufacturing networks, as more drug substance manufacturing sites are decoupled from the drug product sites. Single-use bags already provide significant benefits to biopharmaceutical manufacturers by reducing the risk of contamination and improving packaging robustness and operating efficiency. Freezing in single-use bags can provide additional benefits by ensuring product stability, extending drug substance shelf life, and simplifying logistics.
Well-qualified, complete solutions based on single-use bags ensure that the platform is well-integrated and that its components have been tested together before it reaches the market. Single-use bags must be protected by a secondary container or frame, then fitted to a purpose-designed shipper and tested extensively to meet this objective. The result is maximum product security, excellent process reliability and flexibility. Considerable savings also result from one-way logistics that eliminates the reprocessing of materials and ensures a strong, consistent supply chain.
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Volume 30, Number 6
When referring to this article, please cite it as C. Gentile and M. Marciniak, "Storing and Shipping Frozen APIs in Single-Use Containers," BioPharm International 30 (6) 2017.