A good way to get vendors involved in pharma cold-chain services and equipment looking sideways is to ask them to provide the data they collect during shipments and deliveries. In the frictionless, IoT (Internet of Things) world we are entering, everyone is supposed to know everything, all the time. The reality is that dataloggers often require manual data retrieval (as does the datalogger itself); and moreover, only some of the data (such as internal temperature of a parcel or pallet) is known. That’s like being told a partial baseball score is: home team, 2 (riffing on an old George Carlin joke here!).

More data is being collected all the time—but it comes from different sources, and there are different claims over ownership of it. A datalogger owned by a pharma manufacturer, put into a shipment and delivered back at the end of a trip is pretty clear-cut, but these days the data is often automatically transmitted to a carrier’s database. Meanwhile, the 3PLs or freight forwarders involved in managing logistics have their own data systems. More and more, packaging vendors are providing containers with some form of embedded sensors and communications, so they’re asserting their ownership of data, too.

Finally, there are independent communication and data-gathering services (many of which are listed in the “Instrumentation and Data Collection” section of the 

) who will provide as comprehensive a data service as the client is willing to pay for. The biggest pharma companies might have their own control tower that oversees shipments zooming around the world; smaller companies depend on their 3PL partners, or carriers that they have a relationship with, or simply hand it off to wholesalers (who have their own tangled relationship with data providers).

All this is heading in a good direction: more data, combined with smart analytics, will lead to more efficient supply chains and safer deliveries of temperature-sensitive products. But there are going to be some bumpy and/or costly roads to travel to get to this point, with various data collectors looking for a fee for tracking a manufacturer’s product. The latest iteration of this activity is to set up a blockchain to deliver data—and that might happen in a way that rationalizes the data-gathering process.

Meanwhile, before we all get carried away with IoT and blockchain buzz, here’s a cautionary note: in 2018, it is still a topic of lively discussion among pharmacists on how to interpret the handwritten scrips of physicians. (E-prescribing, which is in growing use throughout healthcare, is making this go away. Still…) At least one pharmacy publication still devotes a page per issue to the topic, which is usually looked on as a fun puzzle to figure out, until you realize that misinterpreted prescriptions could have deadly consequences. To quote another writer/thinker (William Gibson): “The future is already here; it’s just not very evenly distributed.”

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Ownership of supply chain data is becoming contentious

Gimme my data

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After a long tenure at Eli Lilly and Company, Rafik Bishara, PhD, entered a new phase in his career: a globally recognized authority on how the transportation, storage and distribution practices of the global pharma industry are defined and regulated. Even while at Lilly (from which he retired in 2004), he was instrumental in organizing the Pharmaceutical Cold Chain Interest Group (PCCIG), which began as an ad-hoc effort under the aegis of the Parenteral Drug Assn.

Dr. Bishara came to the US with a pharmacy degree from Cairo University in 1967, and added masters and doctorate degrees (PhD in bionucleonics from Purdue University) to that. Starting as a bench chemist, he rose through a variety of postings, eventually becoming Director of Quality, Knowledge Management and Technical Support. Along the way, he published prolifically; his c.v., which runs 23 pages, lists over 219 publications, training and conference proceedings.

For the past two decades, attendees of practically most conference involving life sciences cold-chain logistics, anywhere in the world, were accustomed to seeing Bishara, usually as the meeting chair, moderator or session leader, and certainly as a voice from the back of the room offering meaningful suggestions. (At presstime, he was scheduled to do this, again, at a new conference called FlyPharma, Miami, FL, Sept. 11-12; Pharmaceutical Commerce will also be on the agenda.) He is speaking at the 16th. Annual Cold Chain Global Forum, Philadelphia, Sept 26.

Bishara has also been an instructor and a mentor at PDA and WHO, respectively, and other organizations. He has served on several task teams of US Pharmacopeia, and maintains an active Technical Advising practice.

 sat down with Dr. Bishara recently to talk about how the field of temperature-sensitive healthcare products is evolving; here is what he had to say.

1. Tell us about the early days of PCCIG, and the state of the art in managing the cold chain at that time.

As a group leader at Lilly, and then as a manager overseeing development through manufacturing, I got to see pharma commercialization at first hand. I had become involved with quality regulations and stability studies to determine expiration dates for Lilly drugs. That led to work with the US Pharmacopeia, and led to collaboration with Robert Seevers, PhD, then an FDA reviewer, who eventually joined me at Lilly. Together, we saw how the emphasis in industry was changing from small molecule pharmaceuticals to large biomolecules, proteins and peptides. These are fragile molecules, sensitive to heat or freezing.

Colleagues in the industry and I realized that we needed to pay attention to develop standards for the storage, handling and distribution of these products, even though the industry practice had been to, in effect, develop new products and “throw them over the wall” to warehousing and distribution to worry about. Shipping practices at the time were more “tribal knowledge” than science-based practices. So, what started as a discussion group within PDA became an interest group, Pharmaceutical Cold Chain Interest Group (PCCIG), and because I was so vociferous about this topic, I was chosen as chair. This led to the publication of PDA Technical Report No. 39, Cold Chain Guidance for Medicinal Products, in 2005.* With the help from our colleagues in Europe we revised the US-centric document to include the European points of view and the updated report was published in 2007.

At this point it became apparent to me that an European PCCIG needed to be formed. Thus, with the help of the Georg Roessling, PhD, VP PDA Europe we formed the PCCIG – European Branch. The leadership was eventually taken over by a dear colleague and friend Erik van Asselt, PhD, a QA and stability specialist at MSD, The Nederlands.

2. Today, there are many business and professional organizations who have a say in pharma logistics. How did this diversity come about?

In its early days, PCCIG was an active, dynamic group of scientists, analytical chemists, quality managers and others—nearly all of whom were volunteers contributing their time and efforts to improving industry practices. Over time, other parts of the pharma supply chain—wholesalers, freight forwarders, contract packaging organizations and others became involved. There was some resistance to this among pharma industry managers who believed that they should be the only voice guiding the industry, and that outsiders didn’t “know the business.”

At the same time, some industry organizations in the logistics field simply didn’t think that a focus on pharma was necessary, since it is such a small part of the global logistics industry. I said, “Excuse me? The vaccine or medicine your family might need is less important than the bananas or electronics you might be shipping? What can you do about ensuring that these life-saving healthcare products do not get frozen or overheated while being transported?”

You might say that PCCIG led the charge, but soon enough, other parts of the supply chain recognized the importance of handling, storage and distribution practices for healthcare products. A good example is the International Air Transport Assn. (IATA), where we began to hold meetings in the mid-2000s, eventually to develop the Time and Temperature Work Group, and the publication of 7th edition of the Perishable Cargo Regulations in 2007. That, in turn, led to the development of the Center of Excellence for Independent Validators – Pharma (CEIV Pharma), which is being widely adopted in air cargo.

A similar story can be told about ISTA, the International Safe Transit Association: Working with PCCIG, they updated their testing procedure for insulated shipping containers in 2011, now known as ISTA Reference Standard 7E.

Perhaps the biggest change in recent years was the development of the Good Distribution Practices guidelines in the European Union; these came out in 2013 and set up quality standards that are now followed in much of the world. I used to tell people, “Before you go to bed, say your prayers, and then pull out the EU GDP standards for a brief reading,” because they are so important to the industry. Now, however, the latest standard from the US Pharmacopeia, Chapters <659>, <1079>, and the proper use of Mean Kinetic Temperature (MKT) deserves your attention. May I recommend that you check the USP Pharmacopeial Forum published in July Volume 44 (4) and note that the comments should be sent to the USP before the end of September 2018. It was published this summer, and comments on it are being received by USP even now. It is scheduled to become final next year.

I am very humbled about all the efforts that many, many people have made over the years to make all this possible. I like the saying, “A trumpeter never stops moving his/her fingers”—that’s how I feel about advancing industry practices in pharma logistics. It is so important, because it involves life-saving products, and should be an ongoing process.

3. Is the industry “done”? Are all the standards and practices now in place, and are they being followed adequately?

In the past 15 or 20 years, the industry has moved from having ‘compartments’ that handle research, manufacturing and distribution. It used to be that R&D would hand off a product to manufacturing, and they would do the same for distribution. Now there is recognition that developers need to be involved with logistics from the very beginning of drug development. I have seen the needle move at the big pharma houses, making sure that the efficacy of products is not compromised in the supply chain. Is everyone complying? No, but the majority are following best practices. And this doesn’t mean that newcomers to the industry are ready—they need to be educated about the ‘why’ and the ‘what’ of good distribution practices (GDP). With that, the ‘how’ becomes easy.

Today, there are two schools of thought about monitoring shipments. One school is, I monitor every shipment, and I have data for that shipment; the other school is, I have studied my trade lanes, performed summer and winter condition studies, and qualified my processes. But for that latter school of thought, a risk is being assumed that an inspector may ask for specific data of a shipment on a specific date.

Another important issue is the ‘last mile’ in distribution—what happens when a drug is handed off to the members of the supply chain between the manufacturer and the patient. The farther away you are from the point of manufacture, the less control you have over what is going on with your medicines. In this regard, the factors such as quality agreements, contingency planning and real-time data become quite important to manage a secure, temperature-controlled supply chain.

Also, we have studied temperature and humidity and how it affects medicines for many years. Now, with new therapies such as personalized genetically engineered pharmaceuticals appearing, additional factors such as shock, drop, shake, vibration and pressure should be investigated. If you shake a protein compound in solution, it often may aggregate, which denatures the drug or vaccine and makes it lose efficacy. Now we’re hearing about using airborne drones to deliver medicines—what effects from differential pressure and vibration might occur there? These factors need to be studied.

The subject of logistics security is more important today. Theft, counterfeiting, tampering and diversion have recently increased. While this has always been occurring in the industry, the high value of new medicines attracts more illicit activities. At the same time, the internet has made it so easy to order medicines from anywhere in the world—but I worry that many consumers are looking only at the price of the medicines they buy, and not worried about the quality. Here I would recommend following another group, the Pharmaceutical Cargo Security Coalition, led by my good friend Chuck Forsaith. Familiarize yourself with the valuable work by the Rx-360 group, and know the standards that are developed by the TAPA organization.

In the past, prior to the current Good Distribution Practices (GDPs) such as PDA Technical Report No. 52, the EU GDP, the revised USP Chapters and proper use of the MKT mentioned above, incidents of mishandling, due to human errors and improper training, resulted in compromising the quality, integrity, potency and efficacy of the medicines and vaccines due to temperature excursions as an example. The use of these degraded products did not help the patients and have caused serious side effects including death. Currently, with these new regulatory and pharmacopeial standards, I have some peace of mind that we are all working together to provide the end user patient with safe and efficacious medicines.

I’ve been blessed to work with wonderful colleagues over the years. It’s important to keep positive attitude, invite people in to share their experience, and to continue to educate oneself. I try to share my knowledge with anyone who asks me—and this is important now in other parts of the world where industrialized-nations practices are not well established. A Caution I always share with my colleagues in the pharma supply chain is that the quality standards should be global because the patient in the USA, Europe, or Japan is as important to me as the patient in Africa, Asia, Latin America or any other part of the world. However, while we in the western hemisphere have the proper infrastructures many of the developing countries lack them. This then requires us to be creative and innovate proper packaging, monitoring, transporting and delivering the vaccines as an example in a way that will help the child or patient. The WHO has many documents and standards that should help all of us as experienced or new commers to the field of secure temperature-controlled pharma supply chain.

I would like to ask the readers and colleagues to reflect on “what have you done to one of those least of your brothers and sisters?” I challenge myself on a daily basis to answer this question.

Last but no least I am always remembering a saying we had at Lilly: “Take what you have today and make it better for tomorrow.”

*The PDA PCCIG was a prolific generator of fundamental reports for the industry in the following years: PDA Technical Report No. 39 was followed by TR 46, Last Mile: Guidance for Good Distribution Practices for Pharma Products to the End User (2009); TR 52, Guidance for GDP Practices: GDPs for the Pharmaceutical Supply Chain (2011); TR 53, Guidance for Industry: Stability Testing to Support Distribution of New Products (2011); TR 58, Risk Management for Temperature Controlled Distribution (2012); TR 72, Passive Thermal Protection Systems for Global Distribution: Qualification and Use Guidance (2015). Some of these reports have been revised and updated since original publication.

Known as the “King of Cold Chain,” Bishara looks both back and ahead at progress in upgrading pharma’s logistics practices

A Conversation with Rafik Bishara

Pharma manufacturers have been able to deliver refrigerated products to patients almost since the time when mechanical refrigeration was invented—the 

 cites instructions from Parke, Davis & Co. in 1919 to keep smallpox vaccine refrigerated. Over the past decade or so, however, the pharma cold chain has become a focus of most industry supply chain managers and—equally significantly—product and service developers in packaging, logistics and transportation. Now, after waves of (packaging) product innovation, investment by logistics service providers, and a thorough effort by pharma brand owners to rationalize their delivery practices, a new pharma cold chain is emerging. Its features:

The most worry-free form of long-distance (international) shipping remains air freight and the active (powered) unit load devices (ULDs). As the most expensive form of high-volume delivery, supply chain managers are continually evaluating new containers and alternative modes of transport like ocean shipping.

Airports, air carriers and many third-party logistics providers (3PLs) have substantially upgraded and expanded their refrigeration storage capacity, so much so that shipments can depend more on moving from one temperature-controlled storage facility to another in the supply chain, rather than express deliveries from the manufacturer to a dispensing endpoint.

Reuse of parcel and pallet shipping containers is more of a reality today, meeting some of the sustainability goals of manufacturers that have been talked about for years. At the same time, the reuse “loop” is transforming the business of temperature-sensitive packaging from the purchase of single-use packaging, to the pay-per-use rental or leasing model.

Innovation continues both at the “upper end” of temperature-controlled shipping—managing controlled room-temperature products in the 5-30°C regime—and at the “lower end” of temperature-controlled shipping—cryogenic containers and delivery services for the introduction of cellular and genetic therapies (CGTs) to the market.

More attention is being paid to the front end of the biopharma supply chain—laboratories and manufacturing facilities—and the back end or last mile—including delivery of individual dosages to patients’ homes.

CGTs, in that some of them involve the patient’s own cells being extracted, transported to a pharma facility and manipulated, then returned to the patient for infusion, represents both the crowning achievement of personalized medicine, and a radically different supply chain. Commercial delivery to patients is very similar to clinical trial logistics, and in fact, the clinical trial logistics leaders are moving aggressively into managing this on behalf of pharma clients.

Finally, data—of the shipment’s condition in transit, and of the overall logistics process—is becoming a more sought-after element of supply chain management. Geolocation of the shipment is a reality; the “internet of things” (IoT) philosophy is taking hold via smart devices that automatically report their status in real time. At the farther ends of the digitization, developers are looking at applying blockchain technology to the cold chain.

Perhaps the broadest-based change going on in the pharma cold chain is the adoption of the CEIV Pharma certification, which now has nearly 300 organizations globally involved in renewing or receiving this designation. The Center of Excellence for Independent Validators – Pharma is an effort undertaken by the International Air Transport Assn. (IATA) to standardize (to the degree possible) global practices for any shipment or trade lane that involves air freight. But it goes well beyond air carriers: airport ground handling providers; warehouses that store pharma products for delivery to an airport; trucking companies that make such transfers into and out of airports; and freight forwarders and 3PLs that manage pharma shipments are all within scope. Arguably, the only parts of global logistics that don’t fit are seaports, and ground carriers that never deliver to an airport.

“A chain is only as strong as its weakest link,” notes Andrea Gruber, head of special cargo at IATA, under which the CEIV Pharma program operates. Besides getting many other logistics players involved beyond air carriers (who are the only formal members of IATA), the effort’s focus is to “harmonize practices and requirements to a uniform level globally, thus providing assurance to the pharma industry.”

IATA started the CEIV Pharma program in 2014 in part for clearly competitive reasons: it didn’t want to lose market share relative to ground and ocean transportation. IATA has some standards that, in effect, have force of law (such as regulations for cargo container construction), but CEIV Pharma is voluntary. Certification can be provided for an individual business (and by location); for a “community” (an international airport and its associated service providers) or a “coalition” (a regional grouping of airports, facilities and providers).

CEIV certification involves a two-step audit by IATA-approved (but independent) validators, who bring a 300-item list of criteria; the full program can take as long as six months and usually involves training personnel in addition to reviewing facilities and procedures. There are 10 validators currently; one company that touts the approved auditors within its staff is 4advice, based in Mechelen, the Netherlands.

Although the goal is global harmonization, IATA’s Gruber concedes that there will be national variations in practices; Saudi Arabia, for example, requires all refrigerated pharma deliveries to be temperature-monitored, something that is recommended but not required elsewhere. The main standards involved are the EU Good Distribution Practices (GDP) document, in place since 2013, and World Health Organization requirements; national standards are followed where applicable.

The list of organizations with CEIV Pharma validation is long. Some highlights: Kuehne + Nagel validated its entire air-freight network (86 locations) in 2017; DHL has validated nearly all of its North American operations; and the airports of Brussels, Miami, Singapore, Sharjah (Saudi Arabia) have community validation. Delta Air Cargo was the first US passenger-based airline to be validated, in 2017. But the program is not by any means universal; World Courier, a leading clinical trial logistics provider, opted for GDP certification (by a consulting firm called DQS) for its global network of offices early this year.

Meanwhile, standards-setting is not a done deal by any means. The US Pharmacopeia, which has a variety of standards relevant to cold chain logistics, issued a draft version of USP <1079> this summer, and is soliciting comments with a goal of finalizing the standard in early 2019. USP <1079> is being nearly totally rewritten; the new standard is focused primarily on setting up quality management systems to oversee logistics processes; it also refers to other USP standards for stability testing and packaging.

Standards will continue to evolve, just as industry practices have. “The industry has studied temperature and humidity and how it affects medicines for many years,” notes Rafik Bishara, a leading voice in pharma cold chain practices and member of USP expert committees (see p. 14). “Now, with new therapies such as personalized, genetically engineered pharmaceuticals appearing, additional factors such as shock, drop, shake, vibration and pressure should be investigated.”

Traditionally, bulk air shipments have been in pallet-sized unit-load devices (ULDs) pioneered by Envirotainer, which introduced a powered version containing its own heating and cooling unit in the mid-2000s. CSafe, DoKaSch and a few others have similar units, and in most cases, they are leased or rented, for a set period of time or for individual trips. (Since the units rarely leave airplanes or airports, there’s little incentive for pharma companies to have their own stock of the units.)

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The world of parcel containers, whether for air or ground transportation, has been a different matter. There, the boxes are inexpensive (relative to the value of the pharma products they are protecting); and most of the materials (cardboard, foamed-plastic insulation, gel packs) are disposed after a single use.

Two factors are changing this traditional dynamic: one, client companies are calling on packaging suppliers to provide a more integrated service, starting with the design and specs of the container, preconditioning to deliver them at an appropriate temperature, and helping manage the logistics processes and data collection. Second, risk-based analysis of higher-value pharma products calls for employing higher-quality containers, such as using vacuum insulated panels instead of expanded polystyrene, or advanced phase-change materials (PCMs) in gel packs. Together, these factors make a reuse program based on renting or leasing the containers, rather than a single-use purchase, more feasible.

“We are promoting the concept of ‘cold chain as a service,’” says Jay McHarg, CEO of AeroSafe Global. “Clients should tell us what level of service they need, and we provide the appropriate container, manage its reverse logistics, and handle the client’s variations in container inventory.” Pharma companies should not, in his opinion, devote substantial warehouse space to storing and prepping containers; by working with AeroSafe’s network of locations and service partners, these issues can be taken off the table.

AeroSafe is best known for its vacuum panels based on a proprietary form of open-cell, carbon-based aerogels, but it now offers a more economical line of EPS containers as well.

“Our pay-per-use reuse program is the fastest-growing part of our business,” says Ron Haub, commercial director of Sonoco ThermoSafe, the leading pharma cold-chain packaging vendor. “In the past, this was viewed as something of a fad for ‘greenness’, but now the growth of high-value products that require reliable temperature control, plus the cost advantages that are available when a container can be reused multiple times are making it a reality.” Haub says that the success of the program for a client depends on a well-characterized trade lane including reverse-logistics capabilities (to improve the probability of getting the box back), and accurately understanding the environmental conditions of the lane. Vishal Khushalani, global business development and marketing manager at Sonoco ThermoSafe, notes that his company is unusual in that it offers both bulk containers (pallet shippers) and parcels, in five distinct insulation materials ranging from EPS to vacuum panels. These degrees of freedom enable the company to dial in the appropriate packaging materials and designs, while evaluating the economics of reuse. “Reuse isn’t going to work in all instances,” he says, “we want to be proactive to provide options to clients.”

“Reuse/rental systems are another example of pharma companies getting back to core competencies—which is not packaging operations, asset management or logistics,” notes Jamie Chasteen, sr. product manager at Cold Chain Technologies (CCT). “We do conditioning and setup of shipping systems, both parcel and pallet, from our facilities, show up at your door, your product is placed inside, and the container goes right out the door.” CCT has facilities in the US, Latin America, and SE Asia as well as a longstanding partnership with Topa Thermal Packaging in the Netherlands for a European footprint facilitating reuse.

Pelican Biothermal, another provider of a range of containers and materials, is investing heavily in its reuse program. “We started the year with around 20 locations that could accept our containers after use,” says Adam Tetz, director of worldwide marketing. “By the end of this year, we will have 100 around the world. Our clients ship globally, so we have to be a global provider.” Tetz says that a rental or leasing program reduces the worries of clients whose shipment volumes vary from month to month, besides reducing the complexity caused by preconditioning, container packout, and managing the logistics of the out- and return-trips.

While the reuse programs are most suited to high-performance packaging solutions, providers of conventional parcels (EPS insulation plus a gel pack) have not been standing still. EFP, marketers of the PharmaTuff brand of EPS containers, has done two things to address the market, according to Keith Arentz, EFP president: It is building out a network of other shaped-plastic foam manufacturers to provide national coverage; and it is actively promoting the recycling of EPS through membership in the EPS-Industry Alliance, a network of foam processors that accept used material for recycling. EPS recycling remains a challenge (among other things, EPS is 98% air—a tough material to transport economically), but EPS manufacturers note that the volume of EPS in all applications continues to rise, so the industry needs to continue developing a recycling pathway.

The reuse model, having been developed for bulk, air shipments employing ULDs, is now being used against those ULDs by vendors of passive shipping systems. This active vs. passive debate has been going on for years in the industry; on the one hand, active systems offer the best assurance of keeping a shipment within its temperature limits, but at higher cost; on the other, passive systems provide economical air-freight rates while, say their proponents, offering temperature control as reliably as the active systems.

“Active and passive systems will both have a place in the industry going forward,” says Sonoco ThermoSafe’s Haub. “The deciding factor will be how to take risk out of the equation—what is the best solution for a given trade lane.”

Envirotainer, known for its active systems announced earlier this year that it now has over 1,000 RKN (active units) in circulation around the world. (Envirotainer blurs the distinction between active and passive by claiming that its “t”-type units, which use dry ice rather than a powered refrigerator, are still an “active” system.) CSafe, a competitor, has just come out with a RAP-designated active unit (“RAP” is airline-code lingo for size and refrigerative capability), that can carry four US-size pallets or five Euro-size, to compete with the RAP-e2 unit Envirotainer has had on the market for several years.

Meanwhile, passive systems vendors have been upping their game for several years now, overcoming the relatively poor reputation they had when first offering pallet-size air-freight containers. Pelican Biothermal has just introduced its CoolPall Flex line (Fig. 2), featuring modularized components and variations on PCM configurations for both refrigerated (2-8°C) and CRT (15-25°C) shipping, and claiming in-spec performance under nominal operating conditions for up to 144 hours. Many other vendors have similar designs.

Sonoco ThermoSafe now straddles the active/passive debate, having acquired the PharmaPort technology two years ago, and is now re-introducing it to the market (Fig. 3). PharmaPort “uses a different active technology, involving eutectic plates, fans and compressors to maintain a constant +5°C temperature (“eutectic” material changes its physical orientation as it warms).

Another element playing into passive ís favor is that transportation providers, airports and air cargo companies have substantially expanded their temperature-controlled infrastructure around the world: shipments can now hopscotch from one reefer space to another; active containers can get a power recharge, and passive systems can stay within a designated temperature, and sometimes even have their PCM packs “recharged,” so to speak.

This PCM recharging takes a more sophisticated knowledge of thermodynamics, says CCT’s Chasteen. “Some vendors claim that by having their PCM system in refrigerated storage, it is ‘hibernating’ and stopping the qualification clock,” he says. “But what is really necessary to accomplish this is to have a PCM whose freezing point is higher than the refrigerator. The industry’s standard 5°C PCM will not truly hibernate, rather it will lose some amount of ‘cold energy’ which reduces the remaining time the shipper has left.” For this reason, CCT has developed a proprietary family of gelled PCMs, including 3, 5, and 7°C versions. The 7°C PCM provides 2-8°C protection, allows for single step conditioning in refrigerators, and recharges during extended refrigerated storage while in transit.

When the EU GDP standards were promulgated in 2013, there was considerable attention paid to the requirement that all pharmaceuticals—not just 2-8°C ones—be transported within the temperature specified on the product’s label. Result: controlled room-temperature products (essentially, the other 90%+ of pharmaceuticals that are not refrigerated) need temperature control, possibly including CRT packaging.

The first industry response to this has been to tighten up the data and procedures for determining the stability budget of a pharma product—how long it can be outside its label temperature and retain efficacy. Many products (especially oral solids) are relatively immune to temperature. But the situation creates ambiguity: some customs inspectors or health authorities are rigorous about the matter; others, less so.

The most direct way to address CRT temperature control is to adopt the same technology as refrigerated containers—insulated boxes with gel packs. The challenge here is that it can be more difficult to keep a product at room temperature (because of the mass of PCM material necessary) than a refrigerated product, whose PCM can pack more cooling into a given mass). Packaging vendors have also engineered two-component PCMs, to protect against both the upper end and the lower end of the temperature range (this can also turn into a winter packout for cold, and a summer packout for heat).

In many cases, determining the necessary protection is a combination of stability budget and the characteristics of the trade lane—it might be necessary only to protect against extreme heat (such as when product pallets are sitting on a runway tarmac); the rest of the time, more moderate temperatures can exist. This, in turn, is opening up the use of thermal blanketing—a wrap that encloses a pallet, and offers several hours of protection against temperature extremes. Q Products, a blanketing manufacturer, has marketed its products successfully in such applications, including wrapping pallets that go into ocean-borne reefer containers. The blanketing can protect product while the container is being loaded or unloaded; the reefer container provides protection during the transit. The forms of blanketing have multiplied, with some including fiberfill layers, bubble wrap, and aluminized films to turn away sunlight.

Cold Chain Technologies expects to make significant headway in this market with its KoolTemp GTS Enshield pallet blanket product, which incorporates its advanced PCM Gel. The gel, says Chasteen, is shape stableóthe PCM remains a flexible solid even at its thawed temperature, said to be the first of its kind. (If the PCM packet were cut open, he says, it would not leak fluid. Conventional PCM ìbricksî are often an open-cell plastic foam with PCM suffused within it and if breached PCM will leak.) The Enshield knits together multiple packets of the gel, thus providing the temperature-sustaining properties of PCMs in a blanket form. CCT has multiple versions intended for frozen, refrigerated, and CRT applications.

Cost savings is the big driver of blanketing. CCT claims a 50% savings when using its blankets, relative to a fully equipped shipping container, depending on the specifics of a shipping lane; other manufacturers note that the lighter weight, ease of application and reuse all combine to lower shipping costs, and thus making temperature control for CRT products, in particular, cost-effective.

Clinical trial logistics is its own sub-specialty where, because of how critical trial results are to a drug’s approval, essentially no cost is spared to ensure safe and effective delivery, to and from the trial site. Well-insulated containers, often transported via courier services, are common. The practices of PCI Pharmaceutical Services (which recently acquired Pharmaceutical Packaging Professionals, a Melbourne, Australia service provider, to expand its global reach) are an example: “PCI performs the tertiary packaging, but based on the needs of the study it is not necessarily done right after secondary packaging. Due to the fact that we hold material and ship on an as-needed basis to investigational sites, PCI chooses the optimal temperature-controlled shipping solution after considering the amount of material being shipped, the shipping lane, and environmental conditions during transit. Most often PCI will perform this packaging but in some special circumstances, PCI will use a third party specialty logistics carrier to bring a pre-charged active system for transit.”

 Cold Chain Sourcebook estimates the 2017 clinical trial logistics market at $3.4 billion overall (with much of it requiring temperature-controlled services regardless of the compound being investigated). Within that, however, there is a boomlet around cellular and genetic therapies (CGTs) that involve the latest gene-editing techniques. The fact that many of these therapies are tied to a patient’s own cells (the ultimate in “personalized medicine”) puts a heavier burden on the logistics component of the process: the right cells have to be delivered, within narrow timespans.

“The challenge is that fresh cells, from and back to the patient, are best; this puts constraints on how the trials are performed, or how commercial therapy is carried out,” says Simon Ellison, CGT service director at World Courier. “Cryopreservation is often necessary for the processed cells, but it’s a balancing act to preserve as much cell viability as possible.”

Ellison, who notes that his company has been involved with CGT since 2005 and currently handles half of the growing number of trials around the world, says that the researchers are so focused in their early stages on finding a therapeutic pathway, they lose sight of the logistics obstacles in their way. “Many of the CGTs are targeted initially for rare diseases, and of necessity, finding patients with those diseases is often a global undertaking.”

The CGT field is already affecting logistics technology. Earlier, says Ellison, drug developers didn’t realize that some conventional laboratory dewars (which are used for cryogenic storage) didn’t fit or couldn’t be used for air freight. World Courier has now partnered with two of the firms offering tailored solutions: Savsu (Fig. 1) and Cryoport. Evidence of how the CGT boomlet is benefiting logistics service providers can also be seen at BioLife Solutions, which manufactures cryopreservation fluids used in both clinical and commercial development: the company saw a doubling of revenue in Q2 2018 over the year before, and then garnered a $20-million capital investment from a private equity firm. (BioLife is part owner of Savsu.)

While all these materials and process innovations are occurring, the most dynamic part of cold chain logistics is data collection. Data has long been a part of the process, to ensure that standards are being met, but increasingly, data are being used to rationalize the entire logistics process. An example of this is seen with Sonoco ThermoSafe’s PharmaPort 360, which features FAA-approved communications that include geolocation along with internal and external environmental conditions, as well as status checks of the container’s components. “Aside from the temperature control technology, we have clients that are as interested in the data gathering capabilities of PharmaPort,” says Sonoco’s Khushalani. The GPS capability means that the shipment can be tracked in real time (at least, while a plane is on the ground, since in-flight communications are forbidden by air regs); when matched with the temperature data, a more complete picture of a transit is created. The equipment status capability is of value to DHL Global Forwarding, which is partnering with Sonoco ThermoSafe in providing the service. “Getting equipment status enables us to anticipate potential problems, rather than simply reacted to what has occurred,” says Dave Bang, global head of temperature management solutions at DHL.

“If you’re collecting internal condition data only, that is for compliance,” says AeroSafe’s McHarg. “With external data and location, now you’re not just checking on the status of a box; you’re evaluating your entire supply chain.”

Bringing all the data together is an example of the “internet of things” (IoT) approach, with multiple sensors providing information and intelligence. But, as IoT advocates are finding in other industries, getting all the data from multiple supply chain participants is not straightforward. One potential solution to this is adopting blockchain technology, wherein various parties would share information on purpose-built network. This is the subject of study at the Center for Supply Chain Studies, which has 20-odd organizations participating in a proof-of-concept. At least one cold-chain equipment vendor, SkyCell, says that it has already built a blockchain network to provide clients data access with its pallet-scale shipping containers.

Ultimately, manufacturers will have to decide how much control and oversight they want to exert on their logistics services and equipment providers, and how much they want to leave in the hands of their providers. Robert Coyle, recently appointed SVP for planning and strategy at Kuehne + Nagel, says that it is striving to be the trusted advisor to its pharma clients, handling not only shipments but also contracted logistics services (including being a 4PL, or manager of various 3PLs serving global pharma). “We want to be the critical glue bringing data to provide an integrated, end-to-end supply chain,” he says.

Pharma supply chain managers now have options for dealing with cryogenic to room-temperature ranges

The 2018 Pharma Cold Chain: more data leads to less risk

 Biopharma Cold Chain Sourcebook details a trend that has continued almost since the first edition in 2008: biologics are entering the market at substantially higher rate than small-molecule drugs; combined with the growth of vaccines (which typically are temperature-sensitive products as well), the overall sales volume of temperature-controlled pharma products is growing at twice the rate of the pharma industry as a whole.

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Organizations such as the Healthcare Distribution Alliance report that, for its full-line wholesaler members, 7.6% of their stockkeeping units require refrigeration (2017-8 HDA Factbook). By comparison, HDA also reports that, among specialty distributors, 49% of their warehouse volume is given over to refrigerated or frozen products (2017 Specialty Distribution, Facts, Figures, Trends).

Moreover, the gradually broader adoption of Good Distribution Practices (GDPs) means that more pharma products are being required to demonstrate compliance with the temperature range listed on their labels. Translation: controlled room-temperature products need better management of the environmental conditions under which they are shipped. If refrigerated products represents 7.6% of current pharma volume, then “non-refrigerated” products represent the other 92.4%. Industry sources report that manufacturers are being selective in adding temperature monitoring, insulation and environmental conditioning to their shipments—but the volume of these are increasing.

The Sourcebook, as in the previous editions, is premised primarily on two things: a methodical review of the labels of most common pharmaceutical and biotech products to calculate how much of the overall pharma supply chain is dedicated to cold chain practices; and an analysis of as much data as can be collected on the costs of pharmaceutical logistics in the US and globally. A third element is an evaluation of the pharmaceutical “pipeline”—the pace at which drugs under development will come on the market, and how the market will grow for those and for existing commercial products. The forecast timeframe is five years (2016-2022).

A cautionary note: Unlike, say, the movement of automobiles, consumer electronics or other products, the movement of pharmaceuticals is complex at the front end (where products are manufactured, then packaged and then shipped, at the back end (where they are dispensed at retail pharmacies, hospitals, clinics, direct-to-patient and other channels), and in the middle (where wholesalers handle the bulk of products, but many are handled by manufacturers working directly with third-party logistics providers—3PLs); there are also many intermediate transfers from, say, a 3PL to a wholesaler, or one wholesaler to another. Products are packaged in cases, the cases in pallets, and the pallets are broken down to cases or even individual packages at different points and at different times. Obtaining an absolutely objective view of all of this is next to impossible.

As of 2018, global sales of biotech drugs and biologic products exceed $300 billion in value, and the special logistics for maintaining the quality of such temperature-sensitive products as they are shipped from manufacturers to hospitals, clinics, pharmacies and patients around the world account for more than 17% of all biopharma logistics spending.

Our updated forecast for cold-chain logistics spending in 2018 is that it will be more than $15 billion worldwide, in an $82 billion overall pharma logistics market, of which $10.6 billion will be transportation and $4.4 billion will be specialized tertiary packaging and instrumentation such as insulated boxes, blankets, phase-change materials, shipping containers and various temperature sensors and recorders. By 2022, cold-chain biopharma logistics spending will expand to more than $18 billion. The bulk of this spending is on 2-8 °C products. The amount of frozen and cryogenic products is small by comparison.

There is a trend toward more spending on devices and system for controlled-room-temperature (CRT) shipping, but to date, most of this involves more careful monitoring of shipping conditions, and greater use of temperature-controlled transport vehicles, and not necessarily extensive use of insulation or other environmental controls. With the expansion of cord-blood stem cell products, and other cellular therapies, there is also a trend to more cryogenics, below -150°C conditions maintained typically with liquid nitrogen, and some products that must be monitored carefully at room temperature.

The overall $82 billion biopharma logistics market can be further broken down by what is spent for transportation, and what is spent for packaging and instrumentation. For 2018, the breakout for cold-chain and non-cold-chain transport and packaging is shown in the following figure.

Finally, there is an analysis of logistics by mode—air, truck and ocean shipping. Most intercontinental shipping of cold chain products is by air. “Parcel” is generally regarded to include packages smaller than pallets, and shipped internationally by air. Domestic parcel delivery is a combination of air and truck transport.

Extraordinary excitement is being generated around the introduction of cellular and genetic therapies (CGTs), many of which are created from the patient’s own cells. Novartis’ Kymriah (tisagenlecleucel) and Gilead’s Yescarta (axicabtagene ciloleucel) are the first such drugs approved by US FDA, in late 2017. Yescarta, a lymphoma treatment, is engineered from T-cells extracted from the patient’s own blood couriered to a plant in California. After about 17 days of processing, the Yescarta product is couriered in a frozen state to a treatment center where it is stored, then thawed and immediately infused in the patient.

CGTs are a radical departure from conventional manufacturing, in that the manufacturing process is for a single patient, and also that the process is a closed loop, starting and ending with the patient. There are efforts going on to develop “allogenic” therapies (which can use a single source of cells, but can be administered to multiple patients), but as yet this form of CGT is still at the laboratory stage.

Hundreds of trials are being conducted around the world involving CGT approaches; various parts of the pharma industry, medical centers and logistics service providers are gearing up for expanding this form of treatment. As yet, the volumes of product involved is minuscule, but the outlook is very bright.

The Sourcebook also evaluates logistics spending trends in the clinical trials market. There are both pallet and parcel shipments of clinical trial materials, but no good way to characterize their respective volumes. A factor that is somewhat outside the scope of the Sourcebook is return logistics that occurs during clinical trials—the delivery of, for example, blood or tissue samples from a trial. Our analysis is based primarily on the trend in trial startups, enrollments and locations, along with estimates based on how much of a trial’s budget is dedicated to logistics issues.

Clinical trial logistics involves shipment of products to be used in trials to study sites which may be dispersed around the globe, as well as shipment of medical samples to centralized analytical laboratories. This year we are updating our estimate for the market size to about $3.4 billion in 2018, with a small part of the increase due to counting in “early phase 1” trials (about 2% of the total which exceeds 7,000), but mostly due to continued growth in the number and enrollment of trials, as well as pharma R&D. Based on estimates of trial volume, and location, and industry R&D spending overall, our forecast now is for a continued expansion of clinical trials logistics at a rate of 2-3% per year, to about $3.7 billion by 2022.

 analysis of the biopharma cold chain is based on a large number of government, industry and private-company data and forecasts, both of volumes and costs. This analysis is supplemented with direct contact with many of the leading pharma companies as well as logistics providers in the market. The analysis is refined as more data become available from year to year (so, to a certain degree, it is not valid to measure the forecasts in an earlier edition of the Sourcebook with later editions.) On the other hand, our analysis, confirmed by eight years of publishing the Sourcebook, has been validated by numerous consumers of the publication and its data.

More biologic-based therapies translates into more cold chain activity. As yet, new cellular and genetic therapies are a minute part of the overall market.

Pharmaceutical Commerce - September 2018

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The 2018 Pharma Cold Chain: more data leads to less risk

Biopharma cold-chain market forecast