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Cold Storage Solutions for the Drug Development Process

Maintaining Integrity at Each Phase
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Throughout the phases of the drug development process-discovery, pre-clinical, clinical, FDA review, and manufacturing/distribution- the handling of delicate biological materials necessitates meticulous refrigeration or freezing. Maintaining the integrity of these materials is vital at each stage, demanding tailored temperature control specific to the materials and the respective phase.

Tight Uniformity and Repeatability Promotes Less Variability

During the discovery phase academic and research institutions are concentrating on identifying disease areas and therapeutic targets for potential drug development. This involves identifying and validating targets and developing assays. Various biological materials such as samples, reagents, proteins, enzymes, DNA and RNA must be stored at precise temperatures to ensure the success of research efforts. Even the slightest temperature fluctuation, often caused by door openings, can jeopardize the functionality, structure, and composition of these sensitive samples, thereby compromising their integrity, millions of dollars invested and the entire research project.

Many of these samples require ultra-low temperature storage alongside uniform freezing methods. While a range of technologies can achieve a certain level of uniformity and repeatability in refrigeration and freezing, forced air convection refrigeration /freezing stands out as the clear winner in meeting the rigorous quality, reliability, and efficiency standards vital in the Life Science sector.

Cold storage solutions that offer tight uniformity with forced air convection are superior at ensuring sample integrity and reducing experimental variability-crucial for researchers seeking to replicate experimental conditions and outcomes. Forced air convection technology uses a fan to circulate and distribute air around the biological material. This helps to transfer heat away uniformly, resulting in consistent, uniform cooling which is especially effective when there are frequent door openings. The consistent and controlled environment that forced air convection produces enables repeatable, reliable experimental conditions.

Efficiency Reduces Operating Cost

Efficiency is paramount in research laboratories and holds significant importance. Given that research is often funded by grants and endowments, cost-effective practices are standard. Besides benefiting sample integrity, efficient refrigeration and freezing technologies contribute to reduced operating costs. Forced air convection technology optimizes temperature control through efficient air circulation, leading to improved energy efficiency, minimized experimental waste, and extended refrigerator/freezer lifespan.

To ensure optimal facility efficiency, investing in a refrigerator/freezer vetted through Accelerated Life Testing (ALT) is crucial for performance and longevity. ALT, supporting for example a 10-year service life, would provide ultimate assurance of durability compared to a unit that may not offer ALT testing.  Additionally, EPA-certified equipment meeting ENERGY STAR® standards is ideal for identifying the most efficient laboratory refrigerators and freezers. The ENERGY STAR® certification signifies products recognized by the EPA for reducing energy utilization and lifetime costs, aiding in reducing overall operating expenses and environmental impact.

Pre-Clinical Cooling Solutions Support Drug Formulation and Stability Studies

During the pre-clinical phase of drug development, refrigerators and freezers remain vital for storing pre-clinical research studies, assays, and reference standards, essential for creating the data required to advance drugs to clinical trials. Pre-clinical studies are not very large, but they do provide detailed information on dosing and toxicity levels.

After preclinical testing, researchers will review their findings and decide whether the drug should be tested on humans. Furthermore, studies conducted during this phase necessitate controlled rate chambers, offering uniformity and repeatability in rapid, controlled freezing and thawing applications. Forced air convection technology brings efficiencies to the pre-clinical phase.

Clinical Phase Requires Critical Cold Storage Repeatability

During the clinical trial phase of drug development, patient samples, investigative drugs, clinical trial materials, and API need cold storage. The quality and integrity of biological material directly impacts the outcomes and validity of clinical trials.  Refrigerators, freezers, ultra-low freezers, and chambers support various specimen containers and supplies.

Freeze-thaw methods are used for bioavailability and bioequivalence studies to ensure the chemical and physical stability of the pharmaceutical. A convection-based controlled freezing and thawing pro-cess can provide optimal results by allowing temperature-specific conditioning to satisfy processing and shipping protocols. By reducing the freeze-thaw time, physiological changes in biopharmaceuticals are minimized.

Regardless of the cold storage being used, it must have customizable shelving, flexible storage configurations, and comply with regulatory standards and certifications such as FDA, Good Manufacturing Practices (GMP), and Good Laboratory Practices (GLP). During this phase of drug development, it can be beneficial to acquire all cold storage equipment from a sole source who takes a consultative approach and specializes in providing a complete line of solutions, support, and industry expertise.

Supporting the Manufacturing Stage

Cold storage solutions have a remarkably diverse range of applications throughout the drug development process. During the early stages, refrigerators and freezers in various configurations, temperature ranges, and capacities are needed.

In the manufacturing and commercialization stage focus shifts to production scaling, protocol establishments and logistics including product distribution and transportation. The decision-making/influencing process for cold storage shifts from the scientist to process engineers with a strong collaboration between internal and external stakeholders. The manufacturing of biologics typically involves different steps that have unique cold storage needs.

Cell line development involves the establishment and maintenance of specific cell cultures. The cells are grown in cell cultures within bioreactors under controlled conditions. During this process, cold storage is needed to store the cell culture media and other reagents used in the process. The biologic is then harvested from the cell culture and will require freezing or refrigeration until the purification step takes place to remove impurities and other unwanted substances. The purified biologic will then go through additional chemical and enzymatic modifications to improve its efficacy and stability during the modification reaction step. Finally, the biologic is ready for the fill-finish process, the final manufacturing step. This is where the biologic is filled into its container and sealed for sterility.

Fill-Finish Process Requires Freeze-Thaw Uniformity and Repeatability

In biopharmaceutical manufacturing the cold storage needs are far more complex than manufacturing small molecule pharmaceuticals that are chemically synthesized. Biologics are significantly more expensive to develop and manufacture and require special handling, storing, and transporting to protect its sensitive structure and function.

The freeze-thaw cycles bring many advantages in biologics and hold immense importance to the protection of the biologics structure. In the fill-finish stage of biopharmaceutical manufacturing the drug product is frozen to a low temperature - usually between -20 °C to -80 °C - and then thawed to room temperature. This process is used to improve the stability of the drug product during storage and shipping.

The freezing and thawing of the product could damage the proteins stability and quality if it is not performed correctly or the equipment is not optimal. For best results with freeze-thaw for fill-finish applications equipment that can offer uniformity and repeatability in rapid, controlled freezing using forced air circulation is best. It will provide efficient pulldown from ambient to the desired temperature, which allows the rapid pulldown process to extend to the fluid core, avoiding false freezing points and optimizing the freezing process. This unique, convection-based, controlled freezing and thawing process eliminates uncertainty and allows temperature specific conditioning to satisfy processing and shipping protocols for various biologics. In addition, some biologics may require cold room storage to maintain their stability and efficacy during the manufacturing and distribution phase.

A cold room is engineered and offers an integrated, controlled environment for various needs. These rooms can be modular, semi-custom or custom. There are several types of cold rooms used in the biopharmaceutical manufacturing and distribution stage. Finished goods, stability, bulk product unfinished goods, frozen blood storage and vaccine and drug storage are standard examples of custom rooms that can be designed specifically to a manufacturer needs.

Customizable cold storage can be tailored to meet specific requirements such as controlled humidity levels, specialized shelving, and storage configurations, enabling the storage of a wide range of biopharmaceutical products under optimal conditions. These cold rooms are designed with features that enable compliance with industry standards and regulatory requirements, ensuring that biopharmaceutical products are stored in accordance with GMP guidelines.

Cold rooms also provide a stable environment for long term storage needs ensuring the preservation of the biopharmaceutical materials over an extended period without compromising quality. Most cold rooms are scalable so manufacturers can adapt storage capacity according to their needs which may change over time -this flexibility makes cold rooms ideal for both small scale and large-scale production. It is valuable to work with a cold storage solution provider who takes a consultative approach, has a large portfolio of products, and is familiar with the challenges facing the Biopharmaceutical industry.

One Provider for All Cold Storage Needs

From the early stages of discovery through clinical trials to the manufacturing and distribution phase, a versatile and specialized range of cold storage equipment contributes to research continuity, data integrity, and optimal biopharmaceutical manufacturing. Ultimately having a single trusted provider for all cold storage needs offers a streamlined approach, ensuring consistent quality, compliance, and support from early research to commercialization. Collaborating with a cold storage specialist, who is well versed in the unique cold storage demands of biopharmaceutical development and capable of offering a robust portfolio of solutions with tailored guidance can be beneficial.

For additional information on how FARRAR provides cold storage solutions for Life Science applications, visit farrarscientific.com

References

Jain, K., Salamat-Miller, N. & Taylor, K. Freeze–thaw characterization process to minimize aggregation and enable drug product manufacturing of protein-based therapeutics. Sci Rep 11, 11332 (2021). https://doi.org/10.1038/s41598-021-90772-9

Bernal-Chávez, S.A., Romero-Montero, A., Hernández-Parra, H. et al. Enhancing chemical and physical stability of pharmaceuticals using freeze-thaw method: challenges and opportunities for process optimization through quality by design approach. J Biol Eng 17, 35 (2023). https://doi.org/10.1186/s13036-023-00353-9

Singh, Satish & Kolhe, Parag & Wang, W. & Nema, Sandeep. (2009). Large-Scale Freezing of Biologics. BioProcess International. 7. 32-44.

William J. Rayfield, Sunitha Kandula, Heera Khan, Nihal Tugcu, “Impact of Freeze/Thaw Process on Drug Substance Storage of Therapeutics,” Journal of Phar-maceutical Sciences, Volume 106, Issue 8, 2017, Pages 1944-1951, https://doi.org/10.1016/j.xphs.2017.03.019.

Nikola Radmanovic, Tim Serno, Susanne Joerg, Oliver Germershaus, “Understanding the Freezing of Biopharmaceuticals: First-Principle Modeling of the Process and Evaluation of Its Effect on Product Quality,” Journal of Pharmaceutical Sciences, Vol-ume 102, Issue 8, 2013, Pages 2495-2507, https://doi.org/10.1002/jps.23642.

Rathore N, Rajan RS. Current perspectives on stability of protein drug products during formulation, fill and finish operations. Biotechnol Prog. 2008 May-Jun;24(3):504-14. Doi: 10.1021/bp070462h. Epub 2008 May 17. PMID: 18484778.

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