Category: Temperature-Controlled Logistics

Gene therapy is a promising approach to altering the genetic composition of cells as a way to correct disease-causing mutations or to introduce proteins or RNA molecules that have potential therapeutic benefits. On a high level, gene therapy seeks to deliver nucleic acids to target cells to change their function in a favorable manner. While gene therapy is the introduction, removal or change in the content of a person’s genetic code with the goal of treating or curing a disease, cell therapy, while closely related, is the transfer of intact, live cells into a patient to help lessen or cure a disease ¹.

The importance of these breakthrough medical approaches cannot be understated, and, as of September of 2019, the U.S. Food and Drug Administration (FDA) has approved a total of 17 gene and cellular therapy products² aimed at treating a wide array of medical conditions, with that number expected to grow rapidly in the coming years. Although global research and clinical trials that utilize genetic and cellular therapeutic approaches abound, of paramount importance is seamlessly mitigating challenges associated with the supply chain of these biological materials. Maintaining the integrity and transparency of these autologous and allogeneic cells throughout extraction, storage, transportation, delivery and administration of surgical procedures can present a myriad of logistical challenges, requiring close and cooperative collaboration among industry, academic, regulatory, clinical and patient communities.

A Holistic Approach to Transport and Delivery

Before delving into the challenges associated with the gene and cell therapy supply chain, early considerations need to be evaluated and tested to determine the best methodology for cell delivery. A primary consideration is whether to deliver cells fresh or frozen, which often is determined by necessity rather than an understanding of how preservation impacts cell function.³ While freezing cells is commonplace for research purposes, clinical administration of gene and cell therapy requires a more specified and calculated approach to understanding the impact of preservation methods for their specific product, both in the short and long term, to better predict whether the cells will perform differently when fresh or frozen. This understanding is crucial early in the clinical research process to reduce bottlenecks that can delay approval and go-to-market viability. Another challenge is quality control — ensuring that there are sufficient surrogate markers of quality and/or function that are quick and easy to test.³ Compared with pharmaceutical products that are easily controlled, variability abounds in autologous therapies, specifically as it pertains to variables that exist within patients and donors, making it difficult to achieve consistency in processing. Methods need to be continually tested and improved to ensure the highest levels of quality control.

Preparation, Packaging and Shipping

Medical technology companies are developing a range of packaging products that aim to preserve cells and maintain their integrity throughout transport and delivery. Cells are most often shipped under cryopreservation, a process that involves deep freezing cells with dimethyl sulfoxide (DMSO), which acts as an antifreeze.⁴ The DMSO inhibits the formation of ice crystals, which can cause cells to expand and become damaged. However, DMSO is toxic to cells and must be thoroughly washed out to prevent contamination. Once frozen, cryopreserved cells have traditionally been stored using either liquid nitrogen for aircraft travel or dry ice for ground transportation, which fall under passive (static) or semi-active packaging models. High-tech solutions are becoming more common, such as active (dynamic) packaging, which requires an external power source to maintain a constant temperature.⁵ In semi-active solutions, a static cold source, such as a phase-change material (PCM), is placed in an isolated compartment, and heat exchange between the biological material and the cold source is regulated using a system that operates without a power source.⁵ Passive packaging comprises eutectic plates of a PCM within an insulating material.⁵ All three of these approaches ultimately aim to provide environments for cells to maintain their viability throughout transport.

Other Logistical Concerns Affecting Delivery and Use

There is a crucial need for a high level of synchronicity among various stakeholders and processes to ensure successful delivery of biological materials. Real-time monitoring and tracking of packages are necessary to ensure that they are handled properly, maintained at precise temperatures and successfully delivered to the correct destination at the right time. Providing transparent visibility during the shipping process is also crucial for maintaining a chain of custody and identity to establish accountability among all parties involved in the process. Other factors, including comprehensive understanding of local, national and international transport regulations, as well as the use of quality management systems, aid to increase the probability that cells are delivered on time and in usable condition.⁵

Upon arrival at their destination, cells need to be thawed and then require time to acclimatize and grow. Once fully thawed, an entirely different set of challenges emerges. Cells typically must be used within one to two hours, requiring surgeons, nurses and patients to coordinate very tight windows to execute the administration of treatment. Any delays in transportation can complicate or even terminate the viability of the cells, increasing costs required to restart the supply chain cycle. Another concern stems from the behavior of the cells post-thawing, as they may differ genetically and behaviorally as a result of the cryopreservation and shipping process.⁴

Decentralization and Scalability

As more gene and cell therapy products gain U.S. FDA approval and their clinical administration becomes more common, manufacturers will have to decide how to best navigate challenges that arise from production from a centralized location. Due to the transportation sensitivities and limited shelf life of the cells themselves, the fastest route from laboratory to patient is most desirable. There are cases where it may be concluded that there are no viable routes to guarantee delivery of materials within an acceptable time frame. While this issue can theoretically be overcome by collecting patient samples sooner or requiring manufacturers to offer more flexibility in accepting or dispatching material to make it possible to align with available transportation schedules, a decentralized approach for collection and delivery may prove most sustainable as the industry grows and expands. Another possible solution is having patients travel to within closer proximity to manufacturing sites, but this approach is not as scalable or sustainable as decentralization, which should prove to become more feasible as the field continues to grow. Although the field is essentially still in its infancy, gene and cell therapy products offer hope to potentially billions of people around the globe. If the range of curable conditions through gene and cell therapy continues to increase, thereby creating higher patient demand, researchers, manufacturers, medical technology companies and medical practitioners will undoubtedly continue to collaborate to increase efficiency, consistency and quality control in the supply chain process.

References

1. “Gene and Cell Therapy FAQ’s. American Society of Gene & Cell Therapy.” Sep. 2019. Web.
2. “Approved Cellular and Gene Therapy Products.” U.S. Food and Drug Administration. Sep 2019. Web.
3. Coopman, Karen. “Logistical Considerations of the Cell Therapy Supply Chain at the Point of Care” Bioinsights. Jul. 2018. Web.
4. Brown, Alan. Industry Confronts Challenge of Shipping Cells for Therapy. Alliance of Advanced BioMedical Engineering. 16 Jan. 2018.
5. Jaffer, Gulam. Keys to Successful Storage, Management and Transport of Biological Materials. Pharma’s Almanac. 24 May 2019.

Originally published on PharmasAlmanac.com on December 6, 2019.

Life science organizations invest heavily in quality and product integrity within the confines of their own facilities and the facilities of their contract manufacturing organizations (CMOs) and contract packaging organizations (CPOs). However, those investments are for naught if drug makers fail to apply similar standards to the soft underbelly of their supply chain — transportation and logistics.

Need for Rigorous Quality Controls

It has been estimated that 20% of drug products and more than 33% of vaccines experience temperature excursions en route to their final destinations,¹ at enormous monetary cost and — more importantly — at the risk of patient adverse reaction or reduced efficacy. This issue is particularly stark for vaccines, as patients who believe that they have been vaccinated with a compromised vaccine may be at greater risk of contracting the relevant disease than patients who know that they have not been immunized.

Whereas the European Union promulgates regulations for transportation quality in the form of “Good Distribution Practices,” no such prescriptive regulation exists in North America. Rather, a combination of government and industry groups establishes and disseminates recommended standards and best practices, such as USP <1079>.² Therefore, it is incumbent upon life science organizations to ensure that service providers apply rigorous quality controls when transporting their products.
The layperson is often shocked when he or she peels back the onion of logistics. Many North American providers use business models with labels like “non-asset/asset light/intermediary/3PL/4PL.” There has been an explosion of entities that happily insert themselves between you and the actual transporter of your product. The intermediary provider brokers the shipment to a carrier, who, in turn, may subcontract to an independent truck owner, who may then hire drivers to accomplish the delivery. This model works well for e-commerce and lower-value commodities that do not require much in the way of quality, safety or security. However, this multi-tiered “game of telephone” is typically not a good fit for pharmaceutical and biologic shipping, where accountability and execution of protocols are paramount.

Given the value of pharmaceutical and biologic shipments, it is imperative that life science organizations have representation from their quality, security and logistics groups when engaging a transportation provider. Shipping can either pose a huge risk or it can serve as an extension of the quality management practices found within the shipper’s walls. Pharmaceutical logisticians charged only with cost control often bemoan this dynamic. A common complaint goes something like this: “We spend billions making this drug, and now we’re supposed to hand it over to the cheapest carrier?” The risk of forfeiting control over a drug is an obvious concern.

In contrast to the multi-tiered subcontracting model described above, our company operates a closed-loop system — our fleet of vehicles is company-owned, and our professional drivers are highly qualified, vetted, trained and uniformed employees (not independent subcontractors). There are no handoffs to a third party. As a result, we are able to apply rigorous quality, safety and security protocols. Our history is rooted in the transportation of sensitive cargo for the U.S. military, so we have applied that disciplined expertise to life science commodities for the past 12 years.

Given the value of pharmaceutical and biologic shipments, it is imperative that life science organizations have representation from their quality, security and logistics groups when engaging a transportation provider.

Think Inside the Box

We use tractor-trailers to transport pharmaceuticals and biologics within the United States and into/out of Canada. One might think that, after buying a $95,000 temperature-controlled trailer outfitted with premium specifications and technologies, we’d be able to start transporting such products, right? Though this would seem reasonable, several steps are still required. Before ever putting such equipment into service at Boyle Transportation, we perform both validation and calibration, all in accordance with USP <1079>.

The thermal mapping/validation study follows a comprehensive protocol established in cooperation with our partners at Sensitech. Thirty data loggers are placed throughout the trailer to record temperature performance for more than 24 hours at the prescribed set point. An exhaustive analysis (and a 30-page report) reveals whether all cargo spaces in the trailer are conditioned within the established tolerance. When we began this process more than 10 years ago, one study resulted in a failure. Embracing the credo that “failure is an opportunity to improve,” we adjusted the specification of our trailers to increase thermal performance. In essence, the validation process proves the efficacy of the trailer’s temperature control.

The calibration process involves proving that the temperature sensors within a trailer are accurate. Our protocol mandates that we use a reference thermometer that itself must be calibrated to National Institute of Standards and Technology (NIST) standards annually. By comparing the reference thermometer to the trailer’s sensors, we can document that the temperature we report to shippers is accurate.

Some transportation service providers perform mapping and calibration on only a portion or “representative sample” of their fleet. As someone who has witnessed the extremely manual job shop of a trailer manufacturing process, I would not be comfortable representing to a pharmaceutical shipper that 10% of a batch of trailers accurately depicts the temperature performance of an entire lot. As one of our valued customers experienced during a recall, the U.S. Food and Drug Administration (FDA) does not want to hear that “the particular trailer that’s bringing the product back for analysis has not been validated, but there’s a similar one that has.”

Our company chooses to perform both thermal mapping/validation and calibration before even putting a trailer into service, and we revalidate and recalibrate at regularly scheduled intervals thereafter, for 100% of our fleet. By proving the temperature efficacy of all of our containers, to use a football analogy we can say, “they are who we thought they were.”

In-Transit Visibility

Some transporters may furnish a printed temperature history receipt at the end of a trip, or the receiver may download a temperature data logger that had accompanied the product on its voyage. While such methods are nice to have, they serve as an ex post facto record. If a temperature malfunction had occurred in transit, it is now too late to do anything about it. You won’t ever hear: “Your product suffered an excursion. Here’s your receipt. Have a nice day.”

Instead, we apply real-time communication technology to view a vehicle’s location, route and estimated time of arrival (ETA), as well as its temperature throughout transportation. If we incur a mechanical issue, or if the temperature veers outside the predetermined tolerance, an alert is communicated both to the professional drivers and our 24/7 operations center. That way, we can take action immediately and mitigate the risk of any effect on the product.

We also provide complete visibility to customers, via a web or email interface that allows them to see their shipment moving across a map, along with the temperature and ETA to destination. The temperature and location history is downloadable as a PDF in case the customer needs to retain it for quality or security purposes. It also remains accessible at any later date from our system.

Our company chooses to perform both thermal mapping/validation and calibration before even putting a trailer into service, and we revalidate and recalibrate at regularly scheduled intervals thereafter, for 100% of our fleet.

Advanced Safety and Risk Management

Your product is subject to substantial risk once it leaves your facility — in the form of temperature, product integrity or motor vehicle accidents. While that will never get to zero, it is crucially important to have a partner that manages that risk as close to zero as possible.

We have always been an early adopter of onboard safety technologies. All of the trucks in the Boyle Transportation fleet are equipped with radar-based automatic emergency braking and adaptive cruise control, speed limiters, roll-stability control, and lane-departure warning. These systems were designed and implemented to arm our people with the tools necessary to do their job as safely as possible.

Furthermore, our fleet is outfitted with video cameras. The purpose of the camera system is twofold: to exonerate us from false claims and to continuously improve driving habits. The system generates weekly safety scores for each professional driver and helps to determine whether anyone is exhibiting unsafe or suboptimal habits. If so, we can proactively train the drivers. A significant portion of their incentive compensation is linked to this score, and we have achieved substantial improvement. Through such advanced management, we reduce risk for customers. This commitment to managing and reducing risk was validated as evidenced by our being awarded the Grand Prize in the National Fleet Safety Awards.

People — Our Most Important Assets

We invest heavily in our most important assets — our people. Most North American carriers compensate drivers on a “per mile” basis, which incentivizes people to go over on their allowable hours or drive fast and erratically in order to make a decent paycheck. Our clients entrust us with precious cargo, so our salary-based package is predicated on drivers executing quality, safety, and security protocols — thereby aligning the incentives of our professional drivers with the goals of our customers. By ensuring predictable earnings and predictable schedules, we achieve significant retention of the drivers in our fleet, with a turnover rate of 18%, while the industry averages ~90% turnover. Furthermore, 37% of our professional drivers are women. Each truck is staffed by a team of two professional drivers, which ensures continuous movement and attendance to the loaded vehicle.

Our drivers undergo a robust training and credentialing process, including an extensive background check, a hazardous materials handling course and certification, Transportation Worker Identification Credential (TWIC), Smith System defensive driving course, pharmaceutical protocol training, security awareness training, quarterly safety training and Truckers Against Trafficking instruction. At Boyle Transportation, we view our operation as a “virtuous circle” — the company invests in its people, the people, in turn, take care of the customer, and, therefore, the customer wants to continue doing business with the company. By focusing on a high touch customer experience, Boyle Transportation has achieved a Net Promoter Score of 85.7 for 1H2019 (i.e. 92% of customers rated us either 9 or 10 out of 10). We’re delighted to say that we’ve been named one of the “20 Best Fleets to Drive For” in North America for 5 years running!

If a product’s quality and temperature has been controlled throughout the entire supply, manufacturing, and distribution chain, it can almost be considered to be a small miracle. But given the amount of risk that exists in the transportation and logistics component of that chain, life science organizations are wise to engage service providers as strategic partners rather than counting on divine intervention. Mitigating those risks requires a comprehensive approach that includes processes, technology, and most importantly — people.

About Boyle Transportation

Boyle Transportation is a specialized trucking firm providing exceptional quality, safety, and security to select clients in life sciences and defense. By combining expertise in highly regulated and valuable military cargo with rigorous quality and temperature protocols, Boyle Transportation is now widely regarded as the premier provider of end-to-end, secure cool and cold chain truckload services for pharmaceutical shippers in the U.S. and into/out of Canada.

References

1. Hanson, Celina M. et al. “Is Freezing in the vaccine cold chain an ongoing issue? A literature review.” Vaccine. 17: 2127–2133 (2017).
2. <1079> Good Storage and Distribution Practices for Drug Products. U.S. Pharmacopeia. 2019. Web.

Originally published on PharmasAlmanac.com on October 28, 2019.

The process for manufacturing messenger RNA (mRNA) vaccines and therapeutics comprises two main steps: production of the mRNA payload, which is translated inside the body into proteins that produce antibodies or impact disease mechanisms in some way; and production of the lipid nanoparticles (LNPs) encapsulating the mRNA to provide protection and facilitate delivery into cells. The unique nuances of mRNA production — which can impact safety, efficacy, quality, and manufacturability — and the inherent fragility of mRNA molecules drive the need for a host of specialized capabilities and expertise. Strict ultra-cold chain processes and protocols are necessary to maintain material viability and quality. An outsourcing partner like Samsung Biologics that can provide true end-to-end manufacturing support combined with effective material sourcing and distribution management strategies can accelerate project timelines while reducing risks.

Challenges to mRNA Production and Supply

Unlike most typical recombinant protein and antibody drug substances, mRNA is inherently fragile and prone to degradation. The phosphodiester bonds in the backbones of single-stranded mRNA molecules are cleaved via transesterification by 2′-hydroxyl groups, a reaction that can be catalyzed by water. Ribonucleases (RNases), enzymes widely present in the environment, and other ribozymes also catalyze phosphodiester bond cleavage.

During manufacturing, RNase contamination control is crucial to ensure the manufacture of high-quality mRNA products. Gamma-irradiated, single-use equipment is strongly preferred to avoid possible contact with problematic enzymes. Samples and mRNA products must be stored at low temperature (–20 to –70 °C) to suppress degradation reactivity.

Encapsulated mRNA payloads are also typically unstable at room temperature. The temperature during LNP manufacturing must be closely monitored and controlled. In addition, carefully controlled and dedicated processes for freezing and thawing must be developed, as the timeline for both can affect the final particle size and encapsulation efficiency. The temperature-dependent sensitivity of mRNA–LNPs must also be addressed via controlled low-temperature storage and handling.

Sourcing of raw materials and single-use consumables, meanwhile, requires careful approaches and strategic relationships with suppliers. Specialty lipids and tailor-made plasmid DNA are high-value raw materials; suppliers must be selected under strict quality standards, and business transactions must be handled appropriately. Unit price, delivery, and quality dispute terms should be closely evaluated when establishing supplier agreements.

Some critical raw materials also require strict storage and handling conditions to ensure that their high quality is preserved. As a result, flexible temperature-controlled storage areas covering a range of temperatures are required to ensure that not only mRNA drug substances and mRNA–LNP drug products, but also other key raw materials, can be securely stored while maintaining their quality.

The COVID-19 pandemic created additional supply challenges. Soaring demand for both plasmid DNA and other raw materials (e.g., lipids, capping reagents, etc.) required for mRNA production, as well as components for single-use systems, led to shortages that persist today. For instance, when the pandemic emerged, only few suppliers produced GMP-grade plasmids at large scale. Consumables were, meanwhile, increasingly used at manufacturing scale not just for mRNA vaccines but also for COVID-19 therapeutics and many non-COVID biologics.

In the face of this skyrocketing demand, vendors responded quickly to expand existing production capacity and build new manufacturing facilities, albeit not quickly enough to meet demand and avoid inevitable delays for drug manufacturers. Much of that new capacity has recently come onstream or will in 2023, and supply issues are therefore somewhat alleviated today and should continue to improve going forward.

Global Supply Chain Shifts

COVID-19 impacted all aspects of the global pharmaceutical supply chain due to lockdowns, raw material supply shortages, lower shipping container availability, route closures, reduced personnel, less frequent commercial air traffic, and many other factors. Prioritization (out of necessity) of the COVID-19 therapeutics and vaccines ahead of existing APIs and drug products made it even more challenging for biopharma companies and their outsourcing partners to secure inventory, even for raw materials. Enhanced collaboration, proactive monitoring technologies, and implementation of innovative supply chain management strategies helped streamline sourcing and reduce risks.

The effects of this supply chain crisis continue to linger. Production scheduling remains challenging because there is often no assurance as to when raw materials will be available. With few qualified raw material suppliers offering products suitable for GMP manufacturing, demand for GMP-grade, mRNA-specific raw materials has increased dramatically, as have lead times. A lack of specific raw materials can force the use of substitutes/alternatives, but the risks of doing so — when possible — must be clearly understood before manufacturing is initiated. Use of unqualified raw materials can cause risks of degradation if appropriate low-temperature storage space is insufficient.

Difficulty accessing single-use consumables owing to high demand and limited supply also continues to affect production scheduling. Lead times for these materials have increased more than twofold in some cases. The heavy reliance of mRNA manufacturing on single-use equipment for contamination control may well expand the need for localized production of single-use technologies to minimize supply shortages and to enable suppliers to maximize business opportunities.

Cold chain management has become strategically imperative for the industry in general, with mRNA-specific logistic route management becoming truly essential for mRNA manufacturers. Effective management of cold-chain logistics for mRNA vaccines and therapeutics requires precise coordination from start to finish, including temperature monitoring, real-time tracking for traceability, and well-trained and skilled logistics personnel, to ensure retention of efficacy.

Supporting Continued mRNA Production

Manufacturers of conventional biologics (recombinant proteins and monoclonal antibodies) have cold chain capabilities, but they are not typically set up to support the extreme temperatures often required for mRNA–LNP products. In order to adapt to global supply chain shifts, contract development and manufacturing organizations (CDMOs) have thus expanded their cold chain and fill/finish offerings to address the additional requirements for new modalities, such as mRNA.

Multiple types of storage capabilities, each with appropriate standard operating procedures, have become essential. Notably, mRNA–LNP products must be carefully frozen and thawed in blast freezers that provide storage at temperatures from –20 to –70 °C, a process typically achieved using control-rate freezers, which require management and operational resources to be effective.

Flexibility in primary packaging is also important for mRNA product developers, as is validation of drug products. If all handling of the mRNA–LNP product takes place on site with little likelihood of temperature variations that, if they do occur, can be more easily controlled, static validations are suitable. Off-site drug product–handling activities (e.g., transport) require dynamic validations, because greater variation in conditions, including temperature shifts, are expected.

End-to-End CDMOs Offer the Best Solution

CDMOs that offer end-to-end support for the entire mRNA workflow can more easily overcome some of these challenges due to their experience across the entire spectrum (from sourcing raw materials, reagents, and single-use equipment to implementing and monitoring temperature controls across each phase of development and distribution). The supply chain is also greatly streamlined by eliminating the need to work with numerous vendors, saving both time and cost.

Equally important, risks are significantly reduced. Having mRNA drug substance manufactured at one site, then transferred to another for encapsulation, and a third for fill/finish introduces opportunities for product loss given the fragile nature of mRNA. Every time the material experiences high-temperature excursions, it is possible that quality, efficacy, and safety can be negatively impacted.

Ideally, mRNA drug substance should be either transferred directly to the LNP formulation step or used immediately after thawing and stabilization to achieve maximum yield and purity of the encapsulated payload. With mRNA drug substance manufacturing, mRNA–LNP drug product production, and final fill/finish operations located within the same facility and supported by on-site analytical services — as is the case at Samsung Biologics — drug and vaccine companies can have much greater confidence that their products will be safely and securely manufactured with the highest quality and efficacy while avoiding common supply chain challenges.

Samsung Biologics’ clients also benefit from its ability to achieve biologic product approvals from global regulatory agencies including the U.S. FDA and the EMA, among others. The company has also repeatedly demonstrated capabilities with respect to validated processes for the manufacturing, packaging, and shipping of products that require cold-chain distribution within a wide range of temperature-controlled environments, as well as storage and handling of raw materials that require cold chain management. The depth of knowledge and expertise gained from this experience has direct applicability to mRNA–LNP product shipping and supply.

End-to-end support also facilitates scale-up of mRNA drug substance and drug product manufacturing, which will become increasingly important as the many candidate vaccines and therapeutics in the clinical pipeline advance to later development stages and ultimately to commercialization. The ability to perform all activities from lab to commercial scale at one facility eliminates unnecessary time loss, cost, and risks associated with the transfer of materials from one site to another.

Agile and Transparent Communication Simplify Sourcing

Samsung Biologics and its clients have benefited from an approach to sourcing that emphasizes ongoing open communications with both suppliers and customers. For all activities, including sourcing, client satisfaction is a constant driver.

Each client works with a dedicated team of technical experts that includes representatives from procurement. At weekly supply meetings, project updates are shared, followed by a brainstorming session to lead to the best-case scenario and establish specific action items. In addition, client product forecasts are converted to raw material forecasts, which are then quickly shared with vendors to enable sufficient supply at the right time.

Samsung Biologics also applies a concurrent engineering concept to tech-transfer projects, with dedicated experts remaining engaged with a project throughout its lifetime. This approach ensures that the people with the most knowledge about the process are involved in technical discussions with the client and can help to ensure on-time delivery by resolving any quality or other issues that arise. In addition, the supply chain management team communicates directly with the technical and manufacturing teams in order to overcome challenging supply issues. The end result: tech-transfer projects (both conventional biologics and mRNA) are typically completed within six months, faster than the industry average.

 In the case of mRNA production, Samsung experts focus on eliminating bottlenecks involving single-use components from customized equipment assemblies by working closely with technical experts at external vendors. Early-stage joint communication also accelerates the forecast and ordering process, enabling the completion of tech transfer within six months. Combined, these efforts result in significantly increased raw material readiness.

As a top-10 global CDMO with extensive mAb manufacturing experience, Samsung Biologics has also established close relationships and strong ties with many global suppliers. These relationships have been leveraged to expedite access to important raw materials and single-use components for mRNA production.

Building Local Supply Chains to Enhance Security of Raw Material Supply

In addition to a team approach that emphasizes continuous, transparent communication within Samsung Biologics and between suppliers and customers, multi-sourcing has become an important and successful strategy for addressing supply chain challenges. Sourcing raw materials from multiple suppliers helps ensure access to key ingredients. If some of those different suppliers are local, the security of the supply chain is even greater.

This philosophy has led Samsung Biologics to attract major biopharma raw material manufacturers into Songdo, the city in South Korea in which Samsung’s manufacturing site is presently located. This area is rapidly becoming a key hub for the production of important raw materials and single-use components used in biologics manufacturing, including mRNA–LNP products. Sourcing materials coming from manufacturers in Songdo, Samsung Biologics’ headquarters, helps to minimize lead times. As additional raw material producers establish nearby manufacturing sites, stability of supply will be further enhanced, and Samsung Biologics’ internal efficiency will increase even further.

Established Cold Chain Processes

With today’s distribution network becoming increasingly complex at a time when biopharma companies face new challenges, Samsung Biologics ensures on-time delivery of high-quality mRNA–LNP products leveraging effective sourcing strategies and cold chain capabilities.

Strong and deep relationships with raw material suppliers ensure consistent supply of mRNA-specific raw materials and single-use components. Investment in local supply chain infrastructure facilitates collaboration with not just local suppliers but also global partners and regulators. Dedicated manufacturing capacity ensures the production of high-quality mRNA drug substances and mRNA–LNP drug products, and extensive infrastructure for cold chain supply enables storage and handling of mRNA drug substances and mRNA–LNP drug products at temperatures ranging from –20 to –70 °C. Products and samples are packaged with precision for distribution and stored within temperature-regulated and highly controlled areas in compliance with strict quality standards before being released.

Prepared to Manage Future Uncertainties with Newer Modalities Beyond mRNA

Biopharma companies developing new modalities, such as mRNA therapeutics and vaccines, face uncertainties from two directions. On one end, predicting demand for new classes of drugs is difficult. On the other, for mRNA-based candidates in particular, accessing large quantities of high-quality, GMP-grade plasmids and fit-for-purpose, and single-use assemblies is even more difficult. Added to these uncertainties is the general lack of industry knowledge about producing novel drug substances and drug products at large scale.

Samsung Biologics is tackling these uncertainties head on. The company’s development and manufacturing systems have built-in flexibility and agility, enabling rapid responses to changing market dynamics that influence both supply of key raw materials and quality for final drug products. The localized supply approach provides an ecosystem better equipped to respond to sudden crises. As an end-to-end CDMO, Samsung Biologics also integrates typically segmented production operations into consistent processes — all at one site — that allows for greater control and affords high-quality products. The company is also applying its knowledge and expertise of mAb manufacturing where appropriate, to address challenges to the production of new modalities, such as mRNA.

Originally published on PharmasAlmanac.com on March 9, 2023.

Temperature-Controlled Needs for Advanced Therapies

Emerging cell and gene therapies (CGTs) are showing enormous potential for treating cancer, neurodegenerative diseases, and a wide range of other conditions. The CGT industry is expected to grow 30% between 2019 and 2025, and the transition from clinical trials to commercial-scale production is now seen as inevitable.¹

Pharmaceutical companies are addressing the challenges that CGTs present for temperature-controlled logistics. Unlike traditional biological therapies requiring temperature control, CGTs (as well as some biological samples) require ultra-cold temperatures, ranging from –4°C and –20°C to –80°C, –120°C, –150°C, and beyond.

Despite this, investment in the CGT market is strong. Between January and June 2020, CGT developers raised $10.7 billion from IPOs, venture capital, and other sources.² This is a 120% increase from the first half of 2019. Noting the upswing, the U.S. Food and Drug Administration (FDA) released a statement in January 2019 stating that it expects more than 200 investigational new drug (IND) applications a year through 2025.³

Because of their potential to cure disease, CGTs are seen as potentially disruptive to traditional therapies. Thus, pharmaceutical companies are making CGT an important part of their growth strategy. Amid the continued growth of these markets, temperature-controlled logistics account for nearly 18% of all biopharma logistics spending, according to the 2020 Biopharma Cold Chain Sourcebook published by Pharmaceutical Commerce.⁴

The ultra-cold storage requirements of these products, their personalized nature, their direct patient involvement in a circular supply chain (“vein-to-vein”), and limited industrial capacity are challenges to achieving an efficient supply chain. Pharmaceutical companies are having to outsource ultra-cold-chain services to third-party companies, including outsourcing temperature-controlled storage to biorepositories. Biorepositories are primarily collections of human specimens and associated data, but their functions have expanded to include specimen processing, information management system, storage, and preparation for distribution.

This article will focus on the current purposes of biorepositories for CGT and outsourcing to biorepositories as one solution to transitioning to commercial-scale production.

CGT biorepositories have become not just storage facilities but information management systems that coordinate closely with manufacturers, providers, and distributors to ensure that therapies are in good shape and are delivered to the right patients. The chain of identity must be maintained and verified throughout the entire supply chain.

Biorepositories Maintain the Chain of Identity

With today’s CGT products, other biologic therapies, and several COVID-19 vaccine candidates currently in clinical trials, there is increasing demand for storing product at deep frozen temperatures (on the order of –40°C to –80°C), and cryogenic for living cells (requiring liquid nitrogen; –160°C to –196°C).²

In contrast to traditional medications, the patient is part of the manufacturing process in the CGT supply chain, donating and/or receiving a live therapy. This vein-to-vein supply chain means that biorepositories need to create logistics platforms that will connect therapies to the correct patients.

As a result, CGT biorepositories have become not just storage facilities but information management systems that coordinate closely with manufacturers, providers, and distributors to ensure that therapies are in good shape and are delivered to the right patients. The chain of identity must be maintained and verified throughout the entire supply chain.

All the relevant information, as well as data concerning the study participant and laboratory analyses, must be properly stored in a biorepository’s interoperable information management system. With this patient identity information also comes the responsibility of protecting personal health information.⁵ A biorepository must be compliant with Health Insurance Portability and Accountability Act (HIPAA) and General Data Protection Regulation (GDPR) health privacy regulations in the United States and the European Union, respectively.^{6, 7}

Unlike conventional, large-batch drugs, each CGT patient requires his/her own manufacturing batch. The patient is literally the first step of the supply chain. Few manufacturers have the systems in place to track the condition of the cells from the moment of apheresis until re-infusion of the therapy. Data tracking and verification capabilities must preserve the chain of identity. This is more complex and nuanced than simply tracking a consumer. This demands an infrastructure that can track and verify that CGTs get to patients efficiently and compliantly to drive the best possible outcomes and potentially save lives.

Multiple Storage Sites

Multiple storage sites at dispersed locations becomes an expensive but often necessary reality. This is partly due to the ongoing impacts of the COVID-19 pandemic, which has led to even further decentralization of the vein-to-vein supply chain. Fear of infection forced apheresis centers and facilities to close or decentralize and collect specimens closer to or at patients’ homes.

Biorepositories — and outsourced providers that offer such services — must now coordinate with a wider network of apheresis centers, clinical sites, patients, logistics vendors like distributors, and biopharmaceutical partners. This decentralization will likely last after the pandemic. Patients have come to enjoy less commute time to collection sites and the added comfort associated with the increased patent-centric practices resulted from the decentralization of clinical services.

Multiple storage sites become even more important when one considers remote locations or developing countries. It is not always possible to have access to liquid nitrogen, ultra-cold freezers, or even electricity in some situations. In situations where freezer systems may not be available, lower-cost options include saliva filter cards, certain branded collection tubes, and tissues fixed in formalin and embedded in paraffin blocks.⁸ Biorepositories can work with pharma companies to assess the best collection and storage options.

Experiences in the industry with spoiled product have led biorepositories to rely heavily on the use of data-collection tools, such as advanced monitoring systems and telemetry, to reduce the frequency and likelihood of delays and temperature excursions.

Temperature-Sensitive Packaging

Temperature-sensitive packaging is essential for the preservation of CGT products. Along their journeys through production, storage, and shipping, specimens are exposed to extreme temperature that can fluctuate anywhere from –190°C to 37°C. Biorepositories need to supply appropriate packaging for storage (primary) and shipping (secondary).

Packaging also needs compliant chain-of-identity labelling, unique National Drug Code codes for various dosing kits, and additional labeling text statements, which may impact label size and placement. Adding country-specific requirements in multiple languages can further complicate the development of product labeling. Biorepositories and integrated logistics providers must have excellent information management systems and knowledge of country regulations to make sure no labeling errors are made.

With so many variables to consider, it’s no surprise that pharmaceutical companies are increasingly outsourcing their temperature-controlled — including ultracold — storage needs to providers with biorepository capabilities.

Outsourcing Temperature-Controlled Storage

With so many variables to consider, it’s no surprise that pharmaceutical companies are increasingly outsourcing their temperature-controlled — including ultra-cold — storage needs to providers with biorepository capabilities. Outsourcing to third party temperature-controlled services occurs at every development phase, especially phase II.⁹

Pharma companies would rather focus on research and development. They know that logistics companies tend to be more experienced at engineering solutions that reduce costs, such as creating warehouse space by building giant freezer farms, holding temperature-controlled inventory, providing CGT on a just-in-time basis, expanding use of preconditioned shippers, reducing the multi-step process to just two or three steps, and tightening process integration.²

As the number of approved CGT products continues to grow, there is more demand for cryogenic storage systems that can maintain internal temperatures between –150°C and –180°C for extended periods of time. Biotech companies need to grow their cryogenic storage infrastructure, especially liquid nitrogen cryogenic storage (–180°C).

This is especially difficult for small biotech companies that lack hard assets like cryostorage but are conducting clinical trials. They need CGT-experienced biorepositories that use a logistics-by-design approach to tackle temperature-controlled storage and provide other services.¹⁰ For example, some biorepositories can go beyond informatics, storage, and packaging by taking on tasks like aliquoting (dividing) specimens for further analysis.

Yourway Biopharma Services offers the storage needed to service the CGT temperature-controlled chain no matter how complex a project and its needs may be. With a robust and advanced temperature-controlled global GMP deport network, Yourway provides storage at 21 depots around the world, as well as integrated primary and secondary packaging services. Yourway can store material within hours or even minutes of its destination.

Yourway also provides clients with the ability to seamlessly manage inventory through our easy-to-use customer portal. Our warehousing and logistics services are fully automated, allowing you to monitor your inventory 24 hours a day, seven days a week. Simply call in your orders and they will be immediately dispatched by next-flight-out (NFO) or ground transport. Partnering with Yourway means minimized overhead, field inventory levels, and — most importantly — faster turnaround time, enhanced quality/compliance, and reduced costs. 

References

1. Biggins, Jay. “The Rise Of Gene & Cell Therapy And The Resulting Need For In-House Production Facilities: A Guide.” Cell & Gene. 9 Sep. 2020. https://www.cellandgene.com/doc/the-rise-of-gene-cell-therapy-and-the-resulting-need-for-in-house-production-facilities-a-guide-0001, 9/29/2020.
2. Shelley, Suzanne. “Today’s pharma cold chain is going cryogenic.” Pharmaceutical Commerce. 9 Sep. 2020. https://www.pharmaceuticalcommerce.com/view/todays-pharma-cold-chain-is-going-cryogenic.
3. Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. U.S. Food and Drug Administration. 15 Jan. 2019. https://www.fda.gov/news-events/press-announcevments/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics.
4. Basta, Nicholas and Mark Lipowicz. “2020 Biopharma Cold Chain Sourcebook, 11th Edition.” Pharmaceutical Commerce. 2021. https://www.pharmaceuticalcommerce.com/view/sourcebook.
5. “Best Practices.” National Cancer Institute. 17 Dec. 2018., https://biospecimens.cancer.gov/bestpractices/.
6. Health Insurance Portability and Accountability Act (HIPAA). 1996. https://www.hhs.gov/hipaa/index.html. 
7. General Data Protection Regulation (GDPR), https://gdpr-info.eu/.
8. Vaught, J.B. and M. Henderson. “Biological sample collection, processing, storage and information management.” IARC Sci. Publ. 23–42 (2011).
9. Branch, Emilie, Steve Kuehn, Carrie Cao, and Cynthia Challener. “Keeping the Chain Going,” Pharma’s Almanac. 8 Mar. 2017. https://www.pharmasalmanac.com/articles/keeping-the-chain-going.
10. Harris, Erin. “Sneak Peek: The Unique Challenges Of Cell And Gene Supply Chains.” Cell and Gene. 22 Jan. 2019. https://www.cellandgene.com/doc/sneak-peek-the-unique-challenges-of-cell-and-gene-supply-chains-0001.

Originally published on PharmasAlmanac.com on December 14, 2021