	Proper storage and transport temperatures for drugs, especially biologics, are essential to protect product efficacy and patient safety. “As strong growth continues across the global pharmaceutical industry, the sub-category of temperature-controlled products is surging ahead-growing at twice the rate of the industry overall,” said David Williams, president of Pelican BioThermal in a press release (1).

	Joe Cintavey, product specialist at W.L. Gore, agrees, noting, “The pipeline of biologic drugs in development are becoming more temperature-sensitive, resulting in an increase in storage 
	of bulk drug substance at frozen temperatures (-40 to -70 °C).” 

	Rory Davidson, Business Development Manager at Almac Pharma Services, adds that labeling, packing, and distributing cell and gene therapy products often requires products to be stored and processed at ultra-low temperatures (-20 to -80 °C), with the products only being defrosted immediately prior to use. “If these products are not kept in exact conditions, they become unusable. We have seen some cases of product becoming unusable within a minute of being out of frozen conditions and so we need to be able to handle and process product at these ultra-low temperatures as quickly and efficiently as possible,” notes Davidson.

	In addition to the growing number of temperature-sensitive products, three trends are driving the need for temperature-controlled packaging, according to a survey by Pelican BioThermal. First, quality demands increase as more sensitive products bring logistics complexity and greatly expanded risk. Yet, while awareness of temperature-controlled requirements is high, the survey shows temperature excursions happen frequently (1). 

	Second, the distribution range is expanding as products move further and through more climatic zones. More than half of survey respondents (51.8%) regularly ship products internationally, creating an increasingly complex web of local, regional, and international connections that require a broad range of transport modes (1). 

	The third trend identified in the survey is the need to optimize the total cost of ownership (TCO) due to relentless competition and margin pressures. A full 70% of survey respondents agree that TCO is “important” or “very important,” while 10% consider only basic packaging costs and transport rates. This exploration of TCO is spurring interest in reusable containers, with 79% of survey respondents saying reusable containers-though more expensive than single-use containers-are worth the investment. More than one-third of respondents (37.6%) are already using reusable rental programs in their cold-chain logistics operations, and 25% are actively exploring this option (1).

	As a result, validated, off-the-shelf, or customized protective packaging options continue to evolve for all temperature ranges, including controlled room temperature, refrigerated, frozen, and cryogenic. “The challenge is optimizing the design, materials, and components to minimize overall size and weight of the shipping solutions,” says Mark Barakat, general manager of Cryopak, a subsidiary of Integreon (formerly TCP Reliable). He continues, “Achieving peak performance while minimizing size, weight, and cost is typically contradictive.” Cold-chain engineering experience and tools like thermal modeling software and testing equipment play important roles in optimizing temperature-controlled packaging. 

	There is also strong demand for more sustainable designs, including re-use programs to reduce the carbon footprint. Interest in temperature-controlled packaging also is being impacted by changing regulations and standards. For example, “Temperature profiles issued by ISTA [International Safe Transit Association] have changed within the past five years,” reports Barakat. 

	“Regulations governing these types of highly sensitive products are growing stricter,” adds Adam Tetz, director of worldwide marketing at Pelican BioThermal. “For example,” he says, “China has become particularly strict and requires real-time tracking on all pharmaceutical shipments.” 

	Many local governments want to reduce or eliminate the use of expanded polystyrene foam (EPS), a common insulating material, because it is rarely recycled. “California and New York are limiting the amount of EPS foam that can be delivered into their states,” says M. Ryan Corbin, director of marketing at Kodiakooler. These requirements are forcing makers of temperature-sensitive drugs and biologics to look for alternatives. 

	In addition to insulation, temperature-controlled packaging includes single-use and reusable parcel and pallet shippers, thermal pallet covers, and phase-change materials. Sometimes, customized designs are needed, especially for products that will experience particularly hostile conditions or need to be maintained at cryogenic temperatures. Regardless of the application, optimized temperature-controlled packaging depends on the answers to three questions: Where is it being shipped? What temperature must be maintained? How long does that temperature need to be maintained? In addition, “Seasonal temperature changes can substantially affect the internal facility environment and shipping environment,” warns Joe Luke, vice president of sales and marketing for Reed-Lane, a New Jersey-based provider of contract packaging services.

	To ensure packaging will perform as specified, Cryopak tests it against extreme ambient temperature profiles in its ISTA-certified lab following protocols and internal standard operating procedures. “Our shipping systems are then qualified with repetitive testing to assure consistency and performance repeatability,” explains Barakat. “The real shipment is then monitored with temperature data loggers to prove operational performance and quality assurance,” he concludes. 

	To test the durability of reusable, passive thermal packaging systems, Pelican BioThermal is developing a mechanical test method. In addition to mimicking the real-world use environment, the test method also allows assessment of the impact of dynamic use on thermal performance. Tetz reports that results are promising. He says, “The test standard would give pharmaceutical manufacturers even more confidence in choosing reusable thermal packaging over single-use options to reduce costs and advance environmental initiatives.”

	“Current standards assess parcel thermal packaging systems during one intense shipment from point A to point B,” explained Bill Mayer, director of research and development at Pelican BioThermal. “Throughout the development of this new test method, we addressed the challenges of exposing systems to the multi-leg and multi-mode shipping route and more of an average trip with parcel thermal packaging used multiple times” (2).

	Reed-Lane recently added cold storage (2–8 °C) capabilities and a dedicated climate-controlled room for vial and ampule kitting at its packaging facility in Wayne, NJ (see 

). Temperature and humidity sensors constantly monitor the cold storage area to document conditions and ensure there are no product-damaging temperature excursions. “Most crucially, our environmental monitoring solutions are able to provide email alerts should any specified environmental conditions be exceeded,” says Luke. He explains, “Additional sensors are deployed to provide alerts pertaining to  ... power outages, which would result in an immediate onsite power generator startup to maintain specified temperature continuity.” The dedicated room for kitting temperature-sensitive products includes space for labeling vials and ampules and assembling them with other components such as printed literature. Its location adjacent to the cold storage area minimizes intra-facility travels and exposure to temperature excursions. 

	1. Pelican BioThermal, “Pelican BioThermal Reveals 2019 Biopharma Cold Chain Logistics Survey Insights Amid Surge of Temperature-Controlled Products,” Press Release, July 26, 2019. 

	2. Pelican BioThermal, “Pelican BioThermal to Present Development of Laboratory Mechanical Testing Protocol for Reusable Thermal Packaging at ISTA Forum,” Press Release, May 14, 2019. 

	Hallie Forcinio is packaging editor at 

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Consider trends for packaging that protects temperature-sensitive drugs.

Trends in Cold-Chain Packaging

	The United States is facing a national crisis of shortages of generic, sterile injectable drugs that are used in hospitals, says Martin VanTrieste, president and CEO of Civica Rx, a not-for-profit generic-drug company founded in 2018 to reduce and prevent drug shortages. “These medications play an essential role in surgeries, emergency care, and patient treatments. Over the past two decades, shortages of generic, injectable drugs critical to the lifesaving work of hospitals in the US have become commonplace,” says VanTrieste. Civica’s mission is to make quality generic medicines accessible and affordable, and many large healthcare systems representing hospitals have joined as members. 

interviewed VanTrieste and Russ Gall, chief manufacturing and supply chain officer at Civica, about the challenges of drug shortages and the company’s plan for addressing the problem by providing manufacturing capacity and ensuring quality.

What are the biggest challenges the industry faces in solving the drug shortage problem?

During the past several years, more than 200 drugs have been listed on the FDA’s and the American Society of Health System Pharmacists’ (ASHP) drug shortage lists. Drugs in short supply include older medications that are commonly prescribed and accessed by everyone. Many drugs in shortage are generic, sterile injectables. They can be challenging to manufacture and are sold at very low prices because they are not under patent. These chronic shortages are negatively affecting patient care. They can cause surgeries to be canceled or delayed and treatments to be suboptimal when providers must use a less effective drug.

	The root of the problem is an unsustainable economic model for the manufacture and sale of commonly used generic drugs. Despite their important role in hospital patient care, the fact that they are older generic medicines rather than innovative drugs creates competition to sell them at unrealistically low prices. The resulting low profit margins drive manufacturers to seek the least expensive suppliers, often from manufacturers in China and India, where quality control may not be as stringent as in the US. This can result in poor-quality products and quality-related recalls. Additionally, many US factories have not been modernized with improved quality systems, resulting in shortages at domestic facilities.

	Low margins also provide little incentive for manufacturers to enter or stay in the generics market. For those who do, low profits provide little motivation and few resources to maintain or upgrade manufacturing facilities, buy from suppliers of quality APIs, or ensure that business continuity plans, redundant manufacturing capacity, and well-stocked inventories to prevent shortages remain in place in the event of a natural disaster.

Can you summarize Civica’s manufacturing strategy, your progress so far, and next steps?

Civica’s manufacturing strategy begins with a well-vetted list of medically necessary products that have either been consistently on-and-off the FDA’s and ASHP’s drug shortage list or that have experienced predatory pricing. Civica utilizes feedback from its Drug Selection Advisory Committee (which is comprised of representatives from many Civica member hospital systems) to establish lists of target products and associated prioritization. 

	Civica’s manufacturing strategy is then to first identify abbreviated new drug application (ANDA) holders that are currently manufacturing the products and determine if there is a potential for contracting with the manufacturer (as a contract manufacturing organization [CMO]) to leverage that specific CMO’s ANDA to manufacture Civica-labeled product.  Long-term contracts with guaranteed volumes are often an incentive for the CMO.  However, final selection as a CMO partner only occurs following significant due diligence from the perspectives of reputation, regulatory compliance history, product quality, manufacturing capabilities, available capacity, and pricing.  All products subsequently manufactured and labeled for Civica must be released by the Civica quality unit prior to distribution.  Another critical part of Civica’s overall manufacturing strategy is ensuring redundancy of supply.  This includes sufficient sources for APIs, excipients, and components, as well as for finished product.  This can occur through multiple manufacturing facilities operated by a CMO, multiple CMOs for a specific product, and Civica-owned (autonomous) manufacturing facilities/capabilities.  In addition to redundancy of suppliers and/or manufacturing facilities, Civica will also ensure adequate levels of inventory as safety stock to further enable supply during potential shortages. 

	Civica is currently developing its own ANDAs through a partner CDMO for targeted products, the first of which will be in hospitals early in 2022, which will subsequently enable Civica to manufacture products from its own production facilities. An agreement was recently signed with Thermo Fisher Scientific to begin developing and subsequently manufacturing nine different generic injectable drug products for Civica.

	Finally, Civica has engaged a firm to help find a Civica-owned manufacturing facility. Civica is actively evaluating and negotiating with potential acquisitions and/or partnerships for autonomous manufacturing, which gives Civica the most control over the manufacturing of its products.

	Each aspect of Civica’s manufacturing strategy is simultaneously being developed and implemented to ensure all capacity and product availability needs are being addressed to support member and patient needs. Importantly, the intent is to continue utilizing all three parts of our manufacturing strategy indefinitely.

Can you share your perspective on refurbishing vs. new construction? What would some key considerations be?

We are actively considering both options and look forward to sharing our plans in the future. There are pros and cons associated with refurbishing an existing manufacturing facility versus building a new facility from the ground up. Depending on the extent of renovation required, refurbishing an existing facility can have financial and time to market advantages, as well as other advantages of potentially having an existing and trained staff and FDA inspectional history (if favorable). Although demolition can often add significant costs to a project, another potential advantage may be that key portions of the facility can still be used, such as critical utilities, equipment, etc. Although new construction can be a financial challenge, it has the advantage of being able to be designed for the exact company needs. Appropriate capacity, utilities, technologies, location, equipment, and personnel can all be established to best meet product quality, demand, and cost objectives. 

Do you see modular construction as useful parts of your strategy?

Civica has investigated this approach as part of its overall manufacturing strategy to create autonomous production capabilities. There are pros and cons to this approach too. Modular and prefabricated construction typically have the key advantage of being able to meet aggressive timelines. This can be a critical factor in being able to get products manufactured and to patients in need in the shortest amount of time possible. The potential downsides to this approach are: 1) modular or prefabricated cleanrooms may be limited in overall footprint for accommodating certain types of manufacturing lines or operations, and 2) the costs can be substantially higher than conventional construction. Furthermore, our observation is that, although modular systems arguably have the potential to be disassembled and moved to another location for reassembly, so far this has proven to be challenging.

Are GMP compounding facilities part of the solution for drug shortages?

These operations are typically a much smaller scale than those required for manufacture of commercial batch sizes for large-scale pharmaceutical products. Expiration dates are shorter for compounded products. Finally, compounded products are significantly more expensive. Civica members currently use compounding facilities, and since the members already have these relationships, they have asked Civica to focus on FDA-licensed manufacturing facilities. Today, compounding facilities serve a vital role reducing the impact of drug shortages; however, the question is whether compounding facilities will continue to have a role to play as drug shortages are resolved.

Civica Rx plans redundant manufacturing capacity to relieve and prevent shortages of generic, sterile injectable drugs. 

Equipment and Processing Report-04-15-2020

Trends in Cold-Chain Packaging

Addressing Drug Shortages