By Pharmaceutical Commerce Staff

The FDA has approved a supplemental new drug application (sNDA) to expand the indication for bupivacaine liposome injectable suspension (Exparel; Pacira BioSciences, Inc.) for use in adult patients as an adductor canal block and a sciatic nerve block in the popliteal fossa. Exparel was initially approved in 2011 for single-dose infiltration into a surgical site, and has since been administered to more than 4 million patients in the post-marketing setting since the approval, according to Pacira.

“We are thrilled that today’s approval offers clinicians and patients another option for achieving long-lasting non-opioid pain control with Exparel and an increased ability to transition procedures to the ambulatory environment,” Dave Stack, chief executive officer and chairman of Pacira BioSciences, said in a press release. “In line with our corporate mission to provide a non-opioid to as many patients as possible, this new indication provides additional flexibility in the use of Exparel as a regional analgesic for more than 3 million lower extremity procedures annually, further increasing the utility of Exparel for major orthopedic procedures.”

Surgeons use an adductor canal block for anesthesia and analgesia to perform operations on the knee, medial lower leg, and ankle. A sciatic nerve block in the popliteal fossa is administered to provide anesthesia and analgesia for use in medical procedures on the foot, ankle, Achilles tendon, and other parts of the lower leg.

The regulatory action was supported by a pair of randomized, double-blind, active-controlled, multicenter Phase 3 studies analyzing the efficacy, safety, and pharmacokinetics of Exparel compared with bupivacaine HCl.

The first study analyzed Exparel for use as a single-dose adductor canal block and the other trial study analyzed it for use as a single-dose sciatic nerve block in the popliteal fossa.

In the trial evaluating Exparel as an adductor canal block, investigators compared its efficacy when admixed with bupivacaine HCl for postsurgical analgesia in patients receiving primary unilateral total knee arthroplasty compared with bupivacaine HCl. Investigators randomly assigned 166 patients 1:1 to receive either 10 mL of Exparel admixed with 10 mL 0.5% bupivacaine HCl or 10 mL 0.5% of bupivacaine HCl mixed with 10 mL normal saline. Patients were also administered 15 mL of 0.25% bupivacaine HCl infused between the popliteal artery and capsule of the knee block.

The primary endpoint of the trial was area under the curve of the Numerical Rating Scale pain intensity scores from 0 to 96 hours following surgery, with secondary endpoints that included total postsurgical opioid consumption from 0 to 96 hours. Researchers conducted the second trial assessing Exparel as a single-dose sciatic nerve block in the popliteal fossa in two parts, with the first part finished and evaluated prior to the initiation of enrollment in the second part.

Researchers randomly assigned 185 patients in the trial, with 66 patients in Part A who were undergoing a bunionectomy randomized 1:1:1 to receive a sciatic nerve block in the popliteal fossa with a single dose of Exparel either at 266 mg, 133 mg, or bupivacaine HCl 20 mL 0.25%.

Another 119 patients undergoing bunionectomy were randomly assigned 1:1 to receive a sciatic nerve block in the popliteal fossa with a single dose of Exparel 133 mg or bupivacaine HCl 20 mL 0.25%.

Patients across both parts received a Mayo field block with 20 mL 0.5% bupivacaine HCl following administration of Exparel in the operating room immediately before surgery. The study’s primary endpoint was the area under the curve in the Numerical Rating Scale pain intensity scores from 0 to 96 hours with Exparel compared to bupivacaine HCl following surgery. The trial’s secondary endpoints included total postsurgical opioid consumption from 0 to 96 hours with Exparel compared with bupivacaine HCl and percent opioid-free from 0-96 hours.

Exparel achieved the primary endpoints in both Phase 3 trials by showing a statistically significant drop in cumulative pain scores from 0 to 96 hours vs bupivacaine HCl. Further, Exparel reached the threshold of statistical significance in the secondary endpoint of decreased postsurgical opioid consumption. In addition, in the trial assessing its use as a sciatic nerve block in the popliteal fossa, the drug showed statistical significance in the percentage of opioid-free patients.

In terms of safety, Exparel demonstrated a safety profile consistent with bupivacaine HCl. In the press release, Pacira announced the submission of the full results from both studies for publication in a peer-reviewed journal.

“The addition of these new blocks, coupled with the previously approved interscalene brachial plexus nerve block and the ability to utilize Exparel as a fascial plane block provides clinicians with a wide array of applications to treat postsurgical pain with long-lasting, non-opioid analgesia via a single dose administration,” said Jeffrey Gadsden, MD, chief of Orthopaedic, Plastic, and Regional Anesthesiology and professor of Anesthesiology at Duke University School of Medicine, in the release. “Enhanced recovery protocols built around Exparel regional and fascial plane blocks continue to play a critical—and expanding—role in achieving increased clinician and patient preference to avoid opioids and achieve same-day discharge when appropriate.”

Pacira Announces FDA Approval of Expanded EXPAREL Label to Include Two Additional Nerve Block Indications. Pacira BioSciences, Inc. News release. Published November 11, 2023. Accessed November 13, 2023.

Articles

Exparel was initially approved in 2011 for single-dose infiltration into a surgical site.

Pacira BioSciences Announces FDA Approval of Expanded Indications for Exparel

There is true excitement in the rapid pace of advances in cellular and genetic therapies—Kite Pharma, for example, one of the leaders in developing this science, has gone from concept to Phase III trials in 27 months, and an FDA approval is possible this year for one of its products. Dozens of other companies are pursuing targets in immuno-oncology, autoimmune disorders and a variety of rare diseases. Still with the wind at their back are a variety of stem cell therapies that continue to advance.

While all of this is generating high enthusiasm in R&D circles, logistics service providers are scrambling to revise their processes to meet the new demands of these therapies. A “new paradigm” is evolving, in the words of Bruce McCormick, president of Savsu, a logistics equipment and services provider, replacing what he calls “cold chain 1.0,” the traditional practices associated with shipping refrigerated (2–8°C) products.

This new paradigm is driven by two radical changes:

The prevalence of cryogenic temperatures to ship and store living cells

The need to make cell collection (often from individual patients) part of the drug-approval process, which in turn taxes parts of the healthcare system—hospitals, blood collection networks, infusion centers—with GMP responsibilities that are new to them.

A third factor—not unique to subzero pharma logistics, but arguably more consequential—is that there is no turning back once a frozen cell or biospecimen has improperly thawed. A point of reference: in April, Arctic ice cores stored at the University of Alberta thawed due to a freezer malfunction, ruining some part of the specimens representing millions of dollars of work and constituting an invaluable record of climatic history. More to the point: in 2012, 150 autopsied brains of autism patients stored at a Harvard biorepository thawed and were ruined; the director called the collection “priceless.” Potentially, a process upset like these at any point in cells going to or from patients undergoing cellular therapy could be a last chance at life.

“A reliable cell therapy development strategy is imperative to ensuring [the industry’s] biopharmaceutical products, therapeutic materials and patient biological samples remain viable from the point of collection to the final clinical site delivery,” reads a statement from Fisher BioServices, one of a number of service organizations preparing for the new technology.

It’s not industry vendors alone who are paying attention to the growing challenges. In Europe, the European Medicines Agency is struggling to develop a tailored regulatory system for what it calls “advanced therapy medicinal products” (ATMPs). There is pushback from the PIC/S organization, a non-governmental body focused on GMP policies and practices; it sees problems in a potential “loss of harmonization” between the conventional GMP policies it follows, and new ATMP regulatory scheme.

A research-oriented EU project is CARAT—Chimeric Antigen Receptors (CARs) for Advanced Therapies, which kicked off in January 2016 with a goal of integrating “novel cell manufacturing tools and enabling technologies into a new, comprehensive platform that will facilitate the safe, automated and cost-efficient manufacture” of CAR-T cells. The project has €6 million in EU funding, will last until 2020, and is being project-managed by Miltenyi Biotec (Bergisch Gladbach, Germany).

 Fig. 3. Logistics-specific elements of the NCMC roadmap, and their developmental timelines. Credit: NCMC[/caption]

In the US, besides ongoing efforts at FDA Office of Cellular, Tissue and Gene Therapy within the Center for Biologics Evaluation and Research, a collaboration between the Georgia Institute of Technology and the Georgia Research Alliance, with support from the National Institute of Standards and Technology (NIST) has established a National Cell Manufacturing Consortium (NCMC). NCMC, in turn, has published “A Technology Roadmap to 2025,” to define manufacturing and supply chain needs. (Fig. 3) NCMC has a distinctly American slant: “The cell manufacturing community can facilitate the advancement and market penetration of next-generation cell-based medical products, and support the long-term growth and global competitiveness of the US cell manufacturing industry.”

In a like manner, the UK government, through its Innovate UK program, has supported the creation of a center of excellence, the Cell and Gene Therapy Catapult. Interestingly, it is headquartered inside a London, England hospital; there is also a manufacturing center currently under construction in Stevenage, just north of London. Its vision “is for the UK to be a global leader in the development, delivery and commercialization of cell and gene therapy.” In March, Fisher BioServices announced that it would locate units of its CryoHub setup there. CryoHub is a combination of storage and logistics handling systems, modularized so that it can be expanded from clinical through to commercial operations.

Meanwhile, the field is getting another momentum boost from a handful of IT vendors, such as the UK’s TrakCel and a GE-Mayo Clinic partnership, Vineti, both of whom are offering IT platforms not only to manage logistics processes, but also the internal manufacturing steps (customized to manufacturer requirements), and even the reimbursement and patient follow-up steps desirable for commercial viability of the technology.

Cryogenic (technically, under -180°C; we’ll use “subzero” to cover the entire range) processing is not new to pharma research labs and some healthcare processes: Biorepositories have been using liquid nitrogen (LN2, at -179°C) for decades, and there are various low-temperature refrigeration processes and equipment for subzero storage and shipping. Companies like Fisher BioServices, Chart Industries, Taylor-Wharton (now part of Worthington Industries) and Brooks Instrument, have been providing dewars (generally, a metal, double-walled container), freezers and related equipment for many years, used in biobanks, at in-vitro fertilization clinics and in research labs. (There is also a substantial industry around cryogenic air separation, liquefied natural gas, and cryogenic application in aerospace and electronics). Thermo Scientific, Panasonic and others sell mechanical refrigerator/freezers, which can reach temperatures as low as -86°C. When products or research materials need to be transported, a dewar containing liquid nitrogen or dry ice is customary.

Those dewars present two problems for routine, commercial-scale distribution of cellular therapy products: they can be big and bulky (the transportable units are generally more than 50 lbs.); and they are prone to tipping over, which can cause LN2 vapor to leak out more rapidly, cutting into the stable temperature range of the device. Savsu, which has been providing reusable containers for 2–8°C shipping for years, is addressing both of these concerns with the just-introduced “evo DV” line (Fig. 2), which has redesigned dewars equipped with what it calls a Smart Cap top (to make the device relatively immune to tipping complications), and in a range of sizes that are manageable. “If you think about a cellular therapy provided to a patient at a hospital, you need to consider where and how the drug is going to be warmed prior to administration,” notes Savsu’s McCormick. “If it’s at bedside, you’d need a forklift to deliver a conventional dewar and that’s not going to happen.”

Another logistics problem with conventional dewars is that it takes upwards of 24 hours to load them with LN2 and stabilize the container’s temperature. The DV device is said to cut this to less than an hour. The unit can be specified for -196, -80, and 2–8°C operating temperatures.

Another player that has targeted cellular therapies specifically is Cryoport, which has offered a tailored LN2 shipping container for a number of years. The company has expanded its offerings to include the SmartPak II condition-monitoring system. Smartpak starts with a communications-enabled (Wi-Fi or cellular) datalogger, which transmits data through the Cryoportal, a website where Cryoport or its clients can monitor a shipment. Cryoport works with a variety of carriers, but also has arrangements at multiple airports to replenish LN2 if necessary, with dedicated depots at Rotterdam, Singapore and Irvine, CA, its headquarters.

Mark Sawicki, chief commercial officer at the company, says that a number of clients are now requesting Cryoport to collocate a shipping center at their sites; the service would entail preparing containers for shipment, packaging the product and managing the logistics processes to ensure safe delivery. He also touts the company’s customized shipping containers: “In some cases, we take a commercial package and make as many as 50 modifications to it, providing better locking mechanisms, our datalogging and condition-monitoring technology, and other improvements,”

The company’s most recent announcement is CryoStork Next Flight Out, a branded service specifically for IVF centers (Cryoport says that as many as 400 IVF clinics make use of Cryoport services). CryoStork will handle sperm, eggs, embryos and reproductive health tissues, according to the company, with global delivery.

Another service, about to be announced, expands Cryoport’s offerings to the 2–8°C refrigerative world. Sawicki says that it is typical, in applications such as CAR-T therapy with autologous T-cells from individual patients, to collect the T-cells via apheresis, and to ship that blood component under 2–8°C conditions. The return trip of the treated cells is performed cryogenically. “Adding the 2–8°C service enables us to provide a closed-loop service to clients,” he says. Cryoport has partnered with Pelican BioThermal to make use of the latter’s Credo line of cold-chain containers, which feature vacuum insulated panels and specialized gels as a source of cold.

Pelican BioThermal has developed a range of phase-change materials (PCMs) that can be effective in ranges as low as -40C. There are products, such as vials with rubber stoppers, that need to be kept within a lower and upper limit, even in the subzero range; Pelican’s PCM expertise enables them to meet this need. The main goal is to sidestep the use of dry ice, which has limitations in air freight (since it’s regulated as a “dangerous good”). Bill Mayer, director of research there, also makes the point that better insulation (such as the vacuum panels that Pelican uses) can also make PCMs viable in subzero regimes relative to dry ice.

Sawicki and others in the field point out the extraordinary demands cellular and related therapies put on traditional pharma logistics practices. Autologous therapies (using the patient’s own cells) must, of course, be tracked precisely to and from the patient; on the other hand, allogeneic therapies (which includes a number of stem cell approaches) are a “one to many” process where one source of cells might treat multiple patients—but the same tracking details need to be preserved. Some proposed cancer treatments require both the patient’s T-cells and biopsied tumor tissue. A further complication is that the re-infusion of the cells in the patient is dependent, in part, on the health and well-being of the patient; while the extraction and initial processing might proceed rapidly, once the treated cells are cryogenically stored, the re-infusion can be scheduled at an appropriate time.

There is considerable variation in the sub-zero temperatures called for in clinical protocols: -40, -60, -79 (the transition point of dry ice) and -196° all show up in cellular therapy literature. Much of this appears to come simply from traditional lab practices to the preferred, modern modality—LN2 at -196°C, where nearly all cellular activity ceases. Most logistics processes depend on maintaining one set of standard conditions; the variety of temperatures involved here is one of the reasons that specialized life sciences logistics services are desirable.

“There’s considerable debate about suitable temperature ranges,” says Savsu’s McCormick. “A big part of this is the transition from clinical practices to commercial-level activity,” he says.

Cryogenic freezing and thawing are performed gradually to prevent shocks to the living cells; but whether slow or fast, cryogenics usually calls for use of a cryopreservative to minimize freeze-thaw damage. BioLife Solutions is one company that has taken a proprietary position on cryopreservation, with two products, CryoStor (for the -70 to -196°C regime) and HypoThermosol (for 2–8°C). The products contain (among other components, some of which are trade secrets) dimethyl sulfoxide (DMSO), which has been a common cryopreservation agent for many years. Many researchers have “home brew” preservatives with little in the way of rigorous analysis or consistency—problems that BioLife is seeking to address with its products.

“Cryopreservatives minimize damage from ice crystals forming during the freezing phase; when these cells are thawed, they have near immediate need for pH buffering, free radical scavenging and providing a source of energy for the cells,” explains Mike Rice, CEO of BioLife. BioLife’s products are regulated essentially as excipients, he says; and because they have been written into more than 100 clinical protocols they could eventually become part of formal drug applications. From that, BioLife expects to generate revenue as it supplies the preservatives as essential ingredients.

Rice says that cell viability, a critical measure of a therapy’s potential efficacy, varies all over the lot in clinical trials being conducted currently; a rough measure is that 20–50% of cells lose viability during freeze-thaw transitions. Using cryopreservatives like BioLife’s can cut that to below 20%.

BioLife and Savsu formed a joint venture in 2015, biologistex, to handle the courier-based or freight-forwarding operations of their clients. The service makes use of Savsu’s evo Cold Chain 2.0 platform for data collection, monitoring and quality control.

Arguably, the clearest indication of how different cellular therapies are shaping up, relative to conventional drug development, is that there wasn’t a ready-made IT platform to manage production and distribution processes. Researchers are accustomed to working with clinical trial management systems (CTMS) and laboratory information management systems (LIMS); plant managers have used manufacturing execution systems (MES) or extensions of enterprise resource planning (ERP) for years. But the scope of cellular therapy, involving steps at a healthcare facility (apheresis or other cell extraction), advanced genetic manipulation of cells (and cell proliferation), re-infusion, and all the logistical steps in between, don’t fit any of these IT platforms. Business managers looking at eventual commercialization have realized that the need for monitoring outcomes of individual patients—and how that could become an integral part of a value-based reimbursement for the therapy—should also be digitized.

TrakCel, which has been operating since 2012, has coined the term “Cellular Orchestration Platform” (COP) to characterize this broad foundation. “There are many stakeholders to bring together in a cellular therapy project; and some of those stakeholders follow lab-based protocols, others, good manufacturing practices (GMPs), and yet others in health-related procedures,” notes Martin Lamb, EVP at the Cardiff, Wales firm. “All of this has to come together in a tight scheduling framework.”

TrakCel’s product is cloud-based, and while it encompasses a variety of specific functions (such as data collection during logistics processes), it is also built with interfaces to enable data transfer from lab, manufacturing and other IT systems. For a client, the company maps out a customized flowchart of necessary processes, combined with the necessary interfaces. Some risk-based contingency planning is also enabled; for example, a patient might require preparatory treatments before a cell-extraction process is carried out; ensuring that these steps are carried out is accounted for in the system.

TrakCel looks like it’s about to get some head-to-head competition from a joint venture between General Electric Healthcare and the Mayo Clinic, Vineti (which changed its name from Vitruvian at the beginning of the year). Like TrakCel’s approach, Vineti also encompasses healthcare-facility steps, manufacturing and reimbursement (see Fig. 4). In some yet-to-be-determined fashion, Vineti will also tap into GE’s storehouse of manufacturing knowledge, as well as resources tied to other parts of GE Healthcare, and Mayo Clinic’s experience in biomarker development, cell therapy processes and outcomes.

Cellular and genetic therapies drive a ‘new paradigm’ for logistics

Pharma’s cold chain is going below zero

Unit-dose packaging—blister cards or strips, pouches, sticks, or certain types of vials and prefilled syringes—is taking on a new emphasis in an era where drug packages are going to be traced from place of manufacture to place of dispensing in the US, and in much of the rest of the world. Traditionally, most oral solids (pills, capsules) are packaged in bottles of 30- or 90-counts, especially for chronic care. But in Europe and elsewhere, unit-dose packaging takes priority. There are technological reasons to prefer unit-dose packaging in Europe; there are business reasons to prefer bottles in the US.

With passage of the Drug Supply Chain Security Act in 2013—and with the deadline for manufacturers having a unique serial code on each package (whether in bottle or unit-dose form) by November 2017, the scale tips somewhat more in the direction of unit-dose packaging, according to Walter Berghahn, executive director of the Healthcare Compliance Packaging Council (Bon Air, VA). “The problem with serialization in the US is that, for many bulk oral-solid deliveries, you lose the serialization information at the pharmacy, where the drug gets dispensed into generic yellow pill bottles. So, in the context of extending supply chain security all the way to the patient—which was supposed to be the goal of that law—drug identification can be lost.”

To a degree, this depends on how methodical local pharmacies are in storing data on their drug inventories—something that the US retail pharmacy business is required to do, but which is coming into force slowly—but Berghahn’s point is that supply chain security all the way into the patient’s home medicine cabinet has an extra hurdle to overcome. In a related context, he points out that the crisis over the distribution of opioid-based drugs, which are prone to excessive abuse and have become a subject of national concern, could partially be addressed by having those drugs dispensed in unit-dose form. “Serialized unit doses of these drugs would provide law enforcement more opportunities to trace their origin, and could address the issue of counterfeit versions of the pills currently showing up on the street,” he says.

HCPC’s historic emphasis (the organization is celebrating its 25th anniversary this year) has been on the benefits of unit-dose packaging to improve patient adherence and compliance with therapeutic regimens (hence the term “compliance packaging”), and here, too, there are developments that are tipping the scales more in unit-dose packaging’s favor. Insurers and their pharmacy benefit managers (PBMs) want better adherence in order to minimize the cost of healthcare; when patients take their medications as prescribed, there should be fewer hospital visits or reduced disease progression, especially with the high cost of specialized therapeutics today (to cite one obvious example: if a hepatitis C patient does not stick to the 12-week regiment for the latest treatments, the $50—$100-thousand cost of the regimen goes for naught).

Healthcare providers have always wanted patients to stick to their therapies; now they have incentives, under HHS guidelines, to record adherence rates and to reduce return visits to hospitals. Manufacturers, of course, have always encouraged better adherence at least as a policy stance; now some of them are investing in compliance packaging to improve overall adherence rates, and using that investment to justify better formulary placement with PBMs.

“Unit-dose packaging is well positioned to address a part of this concern by providing a package that dispenses one tablet at a time and in some cases shows an indication of when a medication should be consumed,” says Anna Frolova-Levi, VP & director of sales and marketing at Bilcare Research. “While the pharmaceutical industry has been experiencing many changes in the last decade, it is entering a period where more attention is paid to the final patient outcome.” Bilcare, with manufacturing and service units around the globe, provides films and foils for unit-dose packaging, as well as manufacturing of clinical trial materials including packaging.

“As a general rule, there’s a market trend toward specialized drugs of high value for rare diseases, oncology and the like,” notes Justin Schroeder, communications manager at PCI (Packaging Coordinators Inc., Philadelphia, PA). “This trend, combined with the select patient populations for these drugs, reinforces the demand for better and more effective packaging that improves adherence.” PCI, now with operations in both the US and Europe, provides contract packaging and contract manufacturing of oral solids; a relatively new clinical trial services unit is building capacity.

PCI has a chance to demonstrate these principles with its work on the Freeze (inhaled insulin) product—although the long-term outcome of that is in doubt. Afrezza was approved, for MannKind Corp. (Valencia, CA) in 2014, which then entered into a commercialization agreement with Sanofi-Aventis, but at the beginning of this year, based on poor sales, Sanofi backed out of the agreement. As of presstime, MannKind remains committed to keeping the product on the market, citing the enthusiasm of some patients for a non-injectable form of insulin for diabetes care.

The Afrezza kit comprises a pair of inhalers (each meant to be used for 15 days) and four boxes of blister-carded “pods” that contain the powdered, inhalable insulin. The blister cards not only enable patients to keep track of usage, but, because they contain different amounts of insulin, can be combined to give a variety of dosages depending on patients’ need. All of this is color-coded for ease of use.

“It’s a coordinated approach,” notes Schroeder. “PCI didn’t make the inhaler or pods, but we’ve been responsible for the overall packaging and kit assembly.” PCI has submitted this product as a contender for HCPC’s Annual Compliance Package of the Year, set to be announced just after presstime.

It has been a fairly conventional practice to use compliance packaging with therapy regimens that involve a strict schedule of administration for effectiveness (such as birth-control pills) and with regimens that involve a variation from day to day or week to week of dosage strengths (also a feature of birth control as well as other therapies). Those applications, as well as the starter or sample kits offered at launch by manufacturers, have been the bread-and-butter applications of unit-dose packaging in the US in recent years.

The enhanced attention being paid to adherence for chronic therapies is attracting manufacturers to “calendarized” packaging, which gives patients an easy-to-observe pattern of pill counts over the course of a month. Blister cards color-coded by week of the month or with simple day-by-day counts (pill 1, pill 2, etc.) can do the trick. WestRock (the merger of MeadWestvaco and RockTenn, finalized in mid-2015) announced its latest calendarization package in February, the PerfPak, which features a multi-day calendarization layout, along with child-resistant security features for each pill cavity (as opposed to alternative designs that provide security for the entire blister card within a “wallet” container).

One of the more hospitable situations for unit-dose packaging is in clinical trials, where, typically, limited production runs of a product being developed are used, and where careful control of environmental conditions are maintained. PCI’s Schroeder, whose company has invested substantially recently in clinical trial packaging, says that unit-dose packaging is more popular than in commercial packaging, in part because the patient experience of the drug is more controllable. “Drug developers go through amazing gyrations to mask the trial drug’s identity from the comparator drug,” citing the example that if pills in a bottle don’t have the same shaking sound, it can create a problem for the trial. Additional features to be matched are the color and smell of the pills, the paperboard used for cartons, and, in the case of vials, ensuring that the liquid appears the same under refrigerated and room-temperature conditions. “All this is even more important in crossover trials, when the same patient starts on, say, the comparator drug but then switches over to the trial drug. All sensory characteristics need to be the same.”

PCI, like a few other leading contract manufacturers, is positioning itself to be a one-stop shop, from drug development to commercial manufacturing. Still, he notes in a unit-dose context, the frustration of seeing “a drug in unit-dose packaging during trials, and then bulk packaging when it’s commercialized.”

Berghahn’s HCPC has another rabbit to pull out of its hat for drawing attention to unit-dose packaging: shelf stability of oral solids. It has long been known, although only loosely attended to by FDA, that pills in bottles in patients’ homes can degrade over time; for this reason, some pill bottles include a desiccant module to reduce humidity (as one several countermeasures available). Last year, HCPC published a study* evaluating the physical properties of three common drugs (simvastatin, lisinopril and metformin) when subjected to elevated relative humidity and/or elevated temperature. While cautioning that the results were not definitive on the long-term efficacy of the drugs, Berghahn said that “We feel additional research should be conducted to determine whether current packaging formats are effectively protecting the wide variety of drug products on the market, each with unique environmental sensitivities, as they relate to moisture and oxygen ingress and exposure during ‘in-use’ conditions.”

The study looked at three packaging materials: polypropylene (typically used in amber bottles at pharmacies); high-density polyethylene (typical for white pill bottles) and polyvinyl chloride film (typical for the basic blister packaging in long-term care settings). By contrast, packaging suppliers such as Bilcare, Klöckner Pentaplast, Honeywell and others have been offering high-barrier films that resist the intrusion of water vapor or oxygen; and foil film providers like Constantia Hueck offer aluminum film or aluminum-containing multilayer films not only for ease of opening the pill cavity but also to provide a water vapor barrier.

These barrier films aren’t new by any means; Honeywell has been offering what is arguably the best known film, Aclar (chemically, polychlorotrifluoroethylene, or PCTFE) for years to the pharma industry; what the HCPC study does is draw attention to an apparent gap in drug stability—what happens after it has been dispensed by the pharmacy, and sits in the patients’ homes for upwards of three months. Berghahn says that an updated version of the 2015 study is about to be published by the US Pharmacopeia organization, to draw further attention to the issue among pharmaceutical scientists.

Packaging developers are moving the debate yet one step deeper into packaging science with the development of computer programs to analyze and predict barrier films’ performance, and to provide meaningful design information even while drugs are in the clinical research stage. Bilcare has been offering the BilcareOptima service for several years now, providing what it says is the first instance of packaging design via FDA’s Quality by Design standards (QbD generally is intended to predict performance before manufacturing machinery and processes are specified in FDA approval documents).

“Tests that determine the optimum blister film barrier properties for packaging certain pharmaceutical products can take as little as 15 business days,” says Bilcare’s Frolova-Levi. “This sort of expedited drug stability testing helps packaging engineers and formulators at pharmaceutical companies overcome the time and resource crunch they face when attempting to achieve successful stability studies.” And it not only predicts needed packaging requirements ahead of time; it can also preclude expensive “over-packaging” or use of unnecessarily expensive materials, she adds.

Klöckner Pentaplast, meanwhile, opened what it calls the “kp i.center” in Charlottesville, VA, a year ago, to provide a pilot and testing facility for packaging clients to work with Klöckner experts on packaging prototypes. The research center makes use of software and expertise developed by the company, called the BlisterPro XCEL Suite of design services. And that system, in turn, incorporates technology acquired by the company a couple years ago from FreeThink Technologies, called ASAPrime shelf life modeling software and ASAP laboratory studies.

Glass vials with a crimped aluminum cap are the standard for delivering injectable drugs, or at least those that have not been lyophilized (freeze-dried, which then necessitates a reconstitution step before administration) or supplied as prefilled syringes. Frequently, they represent the most expensive drugs available, containing biologic substances that must be carefully handled.

Much attention has been paid in recent years to prefilled syringes, which typically can be used by patients themselves and therefore represent a savings to healthcare systems and, for some patients, a desirable degree of self-reliance. Visiongain, a UK market research firm, published a recent study estimating the 2020 market size for prefilled syringe packaging at just under $7 billion in 2020, and predicts “strong growth” through 2026.

Even so, conventional vial packaging has seen its fair share of continuing development. Rondo-Pak (Camden, NJ) announced a “Quick-to-Market” carton assembly service at this year’s Interphex meeting (New York, NY, April 26—28) to enable manufacturers to provide sample packages, short or extended production runs, or backup packaging services with a quick turnaround. “Our Quick-to-Market carton assembly services are a reassuring security blanket for customers who find themselves challenged to fulfill a sudden need or unforeseen opportunity,” said Victor Dixon, president of Rondo-Pak, in a statement.

Meanwhile, there was considerable buzz in the business press about a study issued from Memorial Sloan Kettering earlier this year, highlighting the potential waste of expensive biologics that are provided in a limited number of vial sizes, even when those biologics are carefully calibrated for dosage by patient weight and other considerations. The study, “Overspending driven by oversized single dose vials of cancer drugs,” published in the British Medical Journal* made the point that somewhat arbitrary choices by manufacturers in the vial sizes can cause wastage of those drugs, since by usual pharmacy standards leftover medicine cannot be saved indefinitely for later administration. By some rough calculations of drug use, patient profiles and Medicare reimbursement data, the authors concluded that some $1.8 billion of 20 key injectable cancer drugs will be wasted this year. “Regulators could require manufacturers to provide drugs in a reasonable set of size options to ensure the amount of wasted drug is low, say 3%,” suggest the authors, or to “leave manufacturers free to select their vial sizes but also require them to refund the cost of leftover drug.”

This study presupposes that there is minimal or no additional cost to supplying and then distributing certain drugs in multiple vial sizes, let alone the complexity of stocking them at hospitals and pharmacies; and it was also a little vague on the practices of specialty pharmacies, where patient-specific dosages of drugs are usually compounded. But, in an era where closer and closer attention is being paid to both drug costs and pharmacy practices, it highlights the importance of better packaging decisions by manufacturers.

Packaging designers continue the uphill battle for converting the US pharma industry to unit-dose, compliance-improving packaging