Hallie Forcinio is packing editor for Pharmaceutical Technology and Pharmaceutical Technology Europe, editorhal@sbcglobal.net.

Hallie Forcinio

Sustainability concerns rank high with biopharma companies. According to the 2020 Biopharma Cold Chain Logistics Sustainability Survey by Pelican BioThermal (now known globally as Peli BioThermal), the biopharma industry is increasing its pace to prioritize sustainability in business and operational strategies. Nearly half of all respondents say that they always factor sustainability into cold-chain purchasing decisions, and 53% indicate that it’s very important to choose cold-chain packaging options that advance their organization’s sustainability profile. According to the survey, attributes that address sustainability needs include recyclability, weight reduction, and energy-efficient designs (1).

Many pharmaceutical products must be maintained at room, refrigerated, frozen, or deep-freeze temperatures. Preventing temperature excursions during distribution depends on maintaining the product within the required temperature range for the time it is in transit. Temperature-controlled packaging (TCP), or thermal shippers, typically consist of a coolant, insulating material, and outer shell. Designs can be one-way or reusable. Both formats are growing rapidly.

Kelly Cinelli, director of Marketing at Packaging Technology Group, reports, “We are finding the demand for single-use, curbside-recyclable shippers for direct-to-patient medication is at an all-time high.” However, she adds, “Reusable shippers also are in high demand due to the COVID-19 pandemic and supply-chain constraints.” 

A study of the pharmaceutical industry by Precedence Research estimates reusable packaging constitutes 74% of the market, and demand for it is growing faster than for single-use units (2). This demand for reusables is “due to the additional protections pharmaceutical products need including more robust packaging [and] stronger temperature control as well as the need for verification of temperature using a data logger or other temperature recording device,” says Mark Sawicki, president and CEO of Cryoport Systems.

Several suppliers cite sustainability as the major reason reusables are gaining market share. Ranjeet Banerjee, CEO of Cold Chain Technologies, reports, “A lot of customers have a very clear goal around reducing their environmental footprint. Reusables go a long way toward meeting that goal.”

“One easy way to reduce carbon footprint is to reduce materials,” explains Emilio Frattaruolo, vice-president of Innovation–Passive Systems at CSafe Global. Because reusables make multiple trips, less packaging waste is generated.

Reusable TCP also can offer cost and performance benefits. Although initially more expensive than a single-use unit, “the cost per use is equal or less,” says Frattaruolo. In addition, leasing programs can eliminate the capital investment required to buy shippers. Leasing also makes it easier to accommodate market growth or seasonal variations. “Our market research indicates that reusable TCP is significantly increasing its use of rental models,” reports Sean Austerberry, group research and product development director for Softbox Systems. He notes, “10% of spending was rental in 2020, and we estimate 25% of spending will be rental in 2024.”

Despite strong interest in reusables, there is ample demand for single-use TCP. “Single-use shippers are often a cost-effective solution in situations where a return/reuse program is either impractical or impossible,” explains Banerjee.

The decision between reusable and single-use depends on the application. Questions to consider include:

How many shipments go to that destination? How often?

How long will the shipment be in transit?

What temperature conditions will be experienced?

What preconditioning of refrigeration is required?

How is the shipment monitored and tracked?

What inventory management software is available?

For reusables, what percentage will be returned?

Is the end customer prepared to play its role in the return process?

Is there sufficient space and manpower available to prepare shippers for reuse?

What is involved in preparing the shipper for reuse (i.e., cleaning, inspection, and repair)?

For single-use, are end customers agreeable to disposing of the shippers?

How easy is the disposal process and how long will it be available?

Will the shipper chosen meet current and short- to medium-term needs?

Frattaruolo recommends mapping out the supply chain as the first step in deciding between reusable and single-use shippers. It is likely to be easier to recover shippers from distribution centers or intra-company operations. “Some remote areas don’t have the infrastructure to get reusables back … or won’t be receiving shipments [frequently] enough to justify a reusable,” explains Alex Arabea, marketing manager at Lifoam Industries, a business segment and subsidiary of LifeMade Products. Single-use also makes sense for many direct-to-consumer scenarios.

During the decision-making process, “It is important to understand that a reuse approach affords pharma manufacturers the ability to utilize higher-performance, more durable packaging material than is typically used in single-use shippers,” explains AeroSafe Global CEO Jay McHarg. He adds, “And since total cost is amortized over many turns, the investment in reuse can be quite comparable to single-use alternatives. Other cost factors to consider include possible fees, from shipper recovery to refurbishment. Conversely, there are cost items that reuse eliminates or reduces, such as stickers (printing and application), warehouse space, and sometimes even usage of freezers since, in the case of AeroSafe Global, we can supply preconditioned thermal material.”

If the decision is made to adopt reusables, time will be needed to plan and implement the recovery and refurbishment process. “A reuse model only works if the shippers are retrieved,” says McHarg. Another important consideration is that the buyer of the packaging usually is not the final recipient. “As such,” he advises, “retrieval programs must be tailored to the needs of the end user—clinician or patient—in both ease and simplicity.”

In situations where retrieval is not practical logistically or economically, a hybrid solution might be the answer. Dr. Joachim Kuhn, CEO and founder of va-Q-tec, explains: “va-Q-tec’s disposable solutions are manufactured for non-return, but due to their stability, they can be qualified for reuse. For example, our lightweight box, the va-Q-one, can be used several times for temperature-controlled transports when shipped to Africa. It only has to be requalified on-site.” 

Other important considerations in the review of reusable vs. single-use shippers include timing, product value, and stability range. Thus, a single-use design can provide adequate protection for a commodity product with a wide stability range and short hold time, but a higher performance reusable TCP is likely to perform better for an expensive, sensitive product with several days to travel. 

Consider the following pros and cons for reusable shippers in pharmaceutical packaging applications.

Equal or lower cost per trip if return rate is good

Can help meet corporate sustainability goals

Often consist of higher-performing materials

Tend to be more durable and resistant to damage

Costs increase if shippers or components are not returned

More work on the front end is needed to justify and identify the impact on internal and end-user processes

Must establish a practical process for return and preparation for reuse

End customer must be willing to participate in the returns process

Can be difficult to recover from direct-to-consumer applications

Requires inventory management system to prevent traceability and tracking issues

Custom configurations take longer to develop

Standardized sizes may not suit some payloads

Doesn’t generate costs/carbon emissions associated with return and refurbishment

Potential for on-site requalification at destination

Components can be environmentally friendly

Quick scale-up because no molding or tooling is required

Frequent decision making to determine correct packout for day/origin/destination/weather

Users must consider the specifics of their application when deciding whether the best option for TCP is a single-use or reusable model.

1. Pelican BioThermal, “Pelican BioThermal Survey Reveals Biopharma Companies’ Focus on Sustainability in Cold Chain Partnerships,” Press Release, July 28, 2020

2. Precedence Research, “Pharmaceutical Temperature Controlled Packaging Solutions Market Size, Share & Trends Analysis Report by Type (Reusable Solutions and Single Use Solutions), Application (Temperature-Sensitive Pharmaceuticals, Vaccines, Others) By Region, and Segment Forecasts, 2020–2027,” Market Report, www.precedenceresearch.com/pharmaceutical-temperature-controlled-packaging-solutions-market, accessed June 30, 2021.

Articles

Manufacturers seek more sustainable options for temperature-controlled packaging. 

Cold-Chain Shippers: One-Trip vs. Multiple Trips

Prefilled syringes continue to evolve to enhance operation, support increased automation of the fill/finish line, and boost productivity and output. Syringe innovations also increase patient and caregiver safety and efficiency and reduce waste of product and packaging materials. “Since it is already packaged ready for the injection, the prefilled syringe saves time and avoids unneeded handling prior to the actual application, minimizing the risk of the injection errors, dilution errors, or non-sterility issues [that are a risk in] multi-dose containers,” explains Wenzel Novak, global senior director of business development at Gerresheimer Medical Systems.

Novak estimates that prefilled syringes currently account for 10–15% of the parenteral market and anticipates rising demand. A market study by Emergen Research predicts sales of prefilled syringes will expand at a compound annual growth rate of 8.9% between 2019 and 2027 to nearly double in value to $9.11 billion in 2027 (1). Driving forces include vaccine production as well as the adoption of self-administered biologics for chronic conditions such as diabetes and auto-immune diseases (1).

“If you look at the top 40 injectable products, all are being used with prefilled syringes,” reports Dr. Nicolas Brandes, director of product management, Polymer Prefilled Syringes and Vial Containment at West Pharmaceutical Services.

Prefilled syringes can be made of glass or plastic such as cyclic olefin polymer/cyclic olefin copolymer (COP/COC) or polypropylene (PP). Glass dominates in most markets. Novak predicts, however, that the share of co-injection-molded COP/COC prefilled syringes will grow from 2% to more than 5% during the next decade.

“We have seen more approvals for products in plastics especially during the past five years,” reports Brandes. He notes plastic syringes often are chosen for specific applications such as contrast imaging agents, hyaluronic acid, and Botox as well as for products that are sensitive to silicone oil. Plastic syringes also function well in auto-injectors.

According to Novak, about 60% of prefilled syringes are staked-in needle syringes, but there are considerable regional variations. The most common prefilled syringes are 1-mL long and 1-mL short. The most prevalent applications include anti-coagulant (glass 1-mL long), vaccines (glass 1-mL short), and isotonic solutions where PP is the material of choice. “With the existing COVID-19 challenge, a significant increase in vaccines is expected worldwide,” says Novak. This growth will stem from COVID-19 vaccines as well as heightened interest in established vaccines (e.g., flu).

Prefillable syringes are delivered as bulk goods or ready-to-fill (RTF). Gerresheimer’s bulk syringes are provided as unsterilized glass bodies in flat (Rondo) trays or customized packaging designs (e.g., bags). Its Gx RTF syringes are presented as washed, sterilized RTF components to pharmaceutical and contract manufacturing operations and are available in glass or plastic. Fill volumes range from 0.5 to 5.0 mL, with the most common volumes falling between 0.5 mL and 3.0 mL.

Innovations from suppliers accentuate the ease-of-use attributes of prefilled syringes and focus on adding sizes (particularly for larger volumes), reducing waste, and patient and caregiver comfort and safety.

Gerresheimer has expanded its range of prefillable polymer syringes for sensitive biologics, biosimilars, and biobetters to include a Gx RTF ClearJect COP needle syringe, 1.0-mL luer lock.

At West Pharmaceutical Services, line extensions include insert needle syringes (the plastic version of a staked needle glass syringe) and more needle sizes and product volume options. “In the past three to five years, we have seen more approvals in the larger 2.5-mL format,” reports Brandes. The larger volume reduces the number of syringes needed per dose and improves efficiency and comfort. There’s a trend toward finer needles too. “Smaller, thinner needles mean less pain,” he explains.

User-friendliness is the goal behind a collaboration between Gerresheimer and Stevanto Group whereby Stevanato supplies its ITC twist-off closure system for Gerresheimer’s Gx RTF luer lock syringes. The integrated seal cap consists of an elastomeric component, which is available in different formulations, and a rigid, translucent polymer cap. Advantages include greater stability and shelf-life protection versus traditional luer cone systems (2).

Prefilled syringes offer sustainability benefits by eliminating multi-dose vials and related production and handling as well as product waste associated with leftover product. Still, says Brandes, “there’s a lot of room for improvement. Current systems create a lot of waste.” But efforts are being made to reduce scrap rates and to recycle tubs that hold nested containers during the fill/finish process. 

To meet the priority of product safety, suppliers seek designs to prevent needlestick injuries and to protect product quality by minimizing particulates and eliminating product interaction with tungsten or silicone residues. For tungsten-sensitive products, Gerresheimer Biological Solutions offers a metal-free manufactured syringe. With this patented technology, the pin used for conical shaping is made of a ceramic rather than tungsten or another metal.

Silicone oil is commonly used to facilitate syringe performance but can cause aggregation and particulate problems for sensitive biologics. “There’s a push by ophthalmologists and regulatory bodies to move away from siliconized formats,” reports Brandes. “Some patients have reactions to silicone, and over time with repeated injections, the material can accumulate [in the eye],” he explains.

One silicone-free option combines ImproJect plungers from W.L. Gore & Associates with syriQ BioPure silicone-free syringes from SCHOTT. The system opens the door for many sensitive products to move into the prefilled syringe format. Until the advent of a silicone-free design, “Pharmaceutical manufacturers seeking to avoid silicone-induced aggregation and sub-visible particles have had to choose vials even when they wanted to offer other delivery options,” said Christiane Gumera, product specialist at W.L. Gore & Associates. Careful attention to syringe geometry and dimensions of the syriQ BioPure syringes helps ensure a consistent gliding force and injection duration over the shelf-life of the product and maintains container/closure integrity without the use of silicone. Ultra-low tungsten residuals and minimal cannula adhesive residuals further reduce the extractible profile and the risk of container/drug interactions (3). 

To prevent potentially hazardous accidental needlesticks and comply with regulations in various parts of the globe, some syringes like Gerresheimer’s InnoSafe product incorporate a pre-applied, passive safety device. With the pre-applied device, there’s no need for post-filling assembly equipment or for healthcare professionals to install a guard before an injection is given. Advantages include improved compatibility with auto-injectors and a completely hidden needle that gives patients with needle-phobia a better experience. The design also prevents accidental reuse and runs on existing fill/finish lines without any additional equipment or process steps.

Finally, COVID-19 has spurred the development of prefilled syringes, particularly with regard to low-temperature storage. Brandes predicts, “Right now all COVID-19 vaccines are in vials, but in the next two to four years we will see a novel type of syringe that handles -80 ºC.”

Innovations on the fill/finish line focus on automation and flexibility for higher output, greater efficiency, and faster return on investment. As batch sizes shrink, demand for flexibility rises. Brandes explains, “Flexibility makes it possible to fill a batch of 10,000 units in vials and then switch to a different packaging format and drug on the same line. There’s no need to invest in separate lines for vials, cartridges, and syringes.” 

Driving forces behind automation include consistency, regulatory needs, and labor requirements. “Automation greatly increases consistency and decreases the possibility for human error, and also can provide opportunities for enhanced inspection capabilities—including those that consider visual attributes, weight, and fill volume,” says Deborah Smook, vice-president of Marketing & Business Development at TurboFil Packaging Machines. She notes, “FDA preferences are another consideration. FDA prefers less—ideally no—touching of syringe components for aseptic filling/processing. Finally, automation decreases labor requirements, diminishes the difficulties of working in a cleanroom with full personal protective equipment, and reduces the likelihood of repetitive motion injuries.”

A $50-million expansion at Baxter Biopharma Solutions in Bloomington, Ind., will boost efficiency and enhance product quality with the installation of a high-speed automated syringe fill line capable of handling up to 600 units/min and other improvements (4). A fully automated debagging system for RTF syringes has been installed on the newest fill line, and an automated inspection machine has replaced an older system. “[Secondary] packaging lines also feature new packaging options that are plastic-free, as well as tamper-evident,” reports Wendy Saffell-Clemmer, lead scientist and senior director, Baxter. In addition, she says, “Both one-dimensional and two-dimensional online barcode printing is available. Lastly, information technology systems supporting serialization can communicate with the customer’s system to ensure that the serial numbers applied are unique and traceable across the network of product manufacturing sites the customer may be using.” 

The new systems were carefully evaluated with particular attention to prior experience with the instrument manufacturer, anticipated customer requirements, and the available footprint for installation. “New automation technologies were selected to enhance efficiency as well as product quality,” says Saffell-Clemmer. “For example,” she reports, “the newly installed inspection machine has the latest vision systems, which can reduce the false detection rate as well as offer a solution to detect particles in heavy suspension products such as vaccines.”

Civica Rx is building a greenfield, 120,000-ft2 aseptic fill/finish operation in Petersburg, Va., as part of a manufacturing partnership with Phlow Corporation, AMPAC Fine Chemicals, and Virginia Commonwealth University’s Medicines for All Institute. The plant in Petersburg will start up with one syringe- and one vial-filling line with space available for another vial or syringe line. The syringe line is rated at up to 50 million units/yr. Isolator-equipped automated fillers with automatic vision inspection are designed to minimize manual intervention and maximize quality, compliance, and assurance levels. Automation “allows the product to be washed and filled at tight tolerances with no human touch,” reports Stan Benson, vice-president and general manager, Civica Petersburg.

In-process control and weighing of each syringe before and after filling ensure precise fill volumes. Automatic micro-adjustments maintain fill accuracy throughout the batch. Vacuum-assist stoppering minimizes oxygen levels within the headspace (i.e., the distance between the product and the plunger). The low oxygen levels and small headspace enhance product stability and protect product potency.

All product contact surfaces—from the compounding vessel to the filling needles—are single-use and arrive gamma-sterilized and ready to use. “Single-use systems eliminate the need for clean-in-place and sterilization processes that consume testing and energy [resources],” explains Benson. Each syringe will undergo automated visual inspection to confirm container and closure integrity and fill volume and check for container flaws and particulates. High-voltage leak testing will help check for glass deterioration.

On the equipment side, TurboFil Packaging Machines offers several syringe filling options including rotary indexing monoblocks, walking beam fillers, and robot-assisted parts assembly. “Syringe formats are more varied than vials and require a more flexible approach to overcome the challenging filling issues surrounding product viscosity, air evacuation, leakage, and of course, accuracy,” explains Smook.

Employing a versatile yet precise setup that accurately fills syringes via a ceramic piston, peristaltic pump, or direct draw from a reservoir bag, TurboFil’s SimpliFil syringe filling and assembly system handles small to medium batches. Its walking beam indexing configuration provides intuitive operation and simplified, recipe-based changeover. For heightened precision, TipFil technology allows syringes of all types to be filled through the tip—a step-saving innovation that eliminates the need to insert plungers post-filling.

Offering full control of filling parameters in single or dual operation, the benchtop TipFil syringe filler accurately and consistently fills up to 12 units/min. A servo-driven piston mechanism draws the needle back via the plunger, with the distance the plunger is moved dictating the amount of drug filled. Among other benefits, this method eliminates the need to clean an extraneous metering device. A key attribute of the system is its versatility. The unit can perform through-the-tip filling for liquids or viscous products for typical infeed scenarios including hoppers and reservoirs. An optional attachment makes it possible to fill bottles or vials. Suckback control heightens fill accuracy, and all product contact parts are fully disposable. 

1. Emergen Research, “Prefilled Syringes Market Share Growing Rapidly with Recent Trends and Outlook 2020–2027,” Press Release, April 5, 2021.

2. Stevanato Group, “Stevanato Group Sings an Agreement with Gerresheimer to Provide Its Integrated Twist-off Closure System Solution, ITC, for Gx RTF Syringes,” Press Release, Oct. 6, 2020,

Glass Syringe System Reduces Injection Force without Silicone

4. Baxter International Inc., “Baxter BioPharma Solutions Announces $50 Million Investment to Expand Sterile Fill/Finish Manufacturing Site in Bloomington, Ind.,” Press Release, Nov. 24, 2020.

When referring to this article, please cite it as H. Forcinio, “Innovations Meet Growing Demand for Prefilled Syringes,” 

Container and equipment innovations expand applications.

Innovations Meet Growing Demand for Prefilled Syringes 

On the Internet, dual-level authentication delivers more secure transactions. A similar multi-level strategy is needed to ensure the pharmaceutical product being dispensed to the consumer is the same one that left the factory.

The enhanced protection is needed because the COVID-19 pandemic and other forces are spurring growth in counterfeiting and gray market diversion. “Changing tariffs and Brexit also encourage counterfeiters,” reports Mark Manning, chief executive officer at iTRACE Technologies, a supplier of product authentication technology and partner with Global Automation and Identification Group, a specialist in anti-counterfeiting programs.

“Securing the supply chain must be part of the manufacturing process,” says Manning. Meeting the requirements of the Drug Supply Chain Security Act (DSCSA) in the United States and the European Union’s Falsified Medicines Directive (FMD) won’t completely solve the problem of counterfeiting. Loopholes in the laws mean “the supply chain isn’t as secure as we want it to be. Additional security steps will be needed,” explains Manning.

He advises starting at the beginning of the supply chain to secure the factory and production. He says, “Security needs to start before the product is made. Brand owners need to be able to validate the factory is secure. Starting with the ingredients enables a secure product all down the line to the patient.” Authentication from the beginning of the supply chain serves as the foundation of trust and depends on data. Then security must be maintained at each level of the supply chain, and each level has to work together.

Manning suggests that blockchain-based systems provide a solution. “Blockchain provides irrefutable proof of the existence of the product and tracks and traces it at every step so you know the product at the bedside is the same one that left the factory,” he explains. “That level of visibility is not something that can be done with a barcode or Datamatrix code. Barcodes and Datamatrix codes are open-source technologies and easily replicated and read by anyone. If I’m a counterfeiter, I can create my own barcode, based on the structure stipulated by the FMD or DSCSA.”

Unfortunately, says Michael Cizek, managing director and founder of Global Automation and Identification Group, “If the carrier for data can’t be trusted, then the data can’t be trusted.”

A multi-level strategy is needed. The iTRACE 2DMI technology is a hybrid technology relying on closed-source, proprietary software and an open hardware platform so the code is readable by virtually any reader, including smartphones. An iTRACE 2DMI code can be printed or laser etched by virtually any system, including desktop printers. Options include reproduction in very small (near-nano) spaces and with ultraviolet ink if covert coding is desired. When read, if the data generated by the iTRACE code matches the serialization, barcode, or Datamatrix code on the package, the product is authentic.

Another recent development in authentication technology, Covectra’s next-generation StellaGuard smart label and mobile authentication system, works in conjunction with its AuthentiTrack track-and-trace system. A free app allows consumers, field inspectors, and customs officials to scan a product barcode with their smartphone and verify authenticity in seconds (1).

The StellaGuard smart label combines a serialized QR barcode with a three-dimensional image of holographic “stars” embedded in a random, non-repeatable pattern at various levels and positioned inside a patented film. On the packaging line, cameras capture the star pattern on each product label and store it in the AuthentiTrack Cloud. When it’s time to authenticate the product, a smartphone scan of the label is compared to the scan captured on the packaging line (1).

1. Covectra, “Covectra Introduces Next Generation StellaGuard Smart Label and Mobile Authentication Solution to Combat Counterfeiting of Products,” Press Release, Feb. 22, 2021.

Drug product security requires anti-counterfeiting techniques such as authentication throughout the supply chain.

Package Authentication Depends on Multi-Level Tactics

	Stability tests determine if specific packaging choices will protect a pharmaceutical drug product for its required shelf-life-typically two to three years. Traditional time-based studies can take years and often involve testing many package variations. Data-based modeling, however, can streamline the package selection process, determining such factors as the lowest-cost options for package material, number of doses, and amount of desiccant. Modeling identifies the optimum configuration for the required shelf-life, assuring a high probability of passing the stability test, thereby eliminating the need to put more than one or two packaging options through the traditional test process. The modeling also prevents over-packaging and offers the potential for cutting costs since higher barrier materials tend to carry higher price tags.  

	Such modeling can be used for any product-solid doses, gels, ointments, small molecules, peptides, and biologics, according to Ken Waterman, president of FreeThink Technologies, a specialist in stability studies and supplier of the ASAP

 accelerated stability assessment program software. Results generated by the software have been proven to correlate well with traditional stability tests and have been accepted by FDA as proof that a post-approval packaging change will meet shelf-life requirements (1). Blister packaging provider Aptar CSP Technologies uses the program to help determine shelf-life as part of its 

 Development Services (2). Klöckner Pentaplast’s BlisterPro XCEL package design and prototyping services also rely on ASAP

	In a webinar on June 9, 2020, “Selecting Primary Packaging for Stability for Solid Dosage Forms,” Waterman explained that the accelerated stability assessment program takes less than one month to complete. It exposes the product to temperature, relative humidity (RH), and oxygen to the failure point; models stability performance via an isoconversion method; determines packaging impact based on the calculated environment inside the package; and calculates the probability of passing the stability test. Ideally, he said, “you want a >95% confidence level in the shelf-life [projection].” The software also can account for conditions the package will experience in different climate zones, for example, when shipping to the tropics. Other parameters can be calculated, such as whether a desiccant is necessary and what size it should be (1). 

	The physical testing involves ovens to control temperature and saturated salts to control RH. With exposure to different temperatures and RH levels, a drug product is examined for changes that indicate its stability has been affected, such as degradant formation, assay (potency) loss, dissolution changes, crystal growth, and appearance change (1). 

	Humidity can cause a sudden failure, including a phase transition, such as deliquescence or hydrate formation. In deliquescence, as soon as a product exceeds its critical RH, it begins taking water from the air to make a solution. “This is a sharp transition that depends on temperature,” said Waterman. But RH is more likely to work in a continuous fashion to shorten shelf-life. “This is because humidity impacts the mobility of the molecules and increases reactivity,” he explained (1). 

	Humidity sensitivity is, thus, a critical factor in determining shelf-life and optimizing the package structure. A calculation based on a modified Arrhenius Equation determines how humidity sensitivity affects shelf-life. In one example, a product with a high humidity sensitivity had a projected shelf-life of 3.0 years at 60% RH but only 9.3 months at 75% RH. Such a product would require packaging with high barrier properties (1). 

	With the humidity sensitivity and product degradation rate known, the RH inside the package must be determined with the knowledge that this level changes over time. Waterman said, “Headspace is not important,” but surface-to-volume ratio and moisture sorption by the dosages are. This means that larger bottles will provide a longer shelf-life with the same percentage fill. Several other factors impact the package RH level over time including water vapor transmission at temperature; the RH outside and inside the pack; moisture sorption vs. RH of the dosage, mass, and initial water content of dosages; and moisture sorption vs. the RH of any desiccants. Desiccants can absorb a lot of water vapor. In fact, under certain circumstances, a high-density polyethylene bottle with a desiccant can outperform a foil/foil blister (1). 

	Drug degradation is influenced by oxygen as well as RH. As with RH, oxygen’s impact is time-sensitive and temperature-dependent. Oxidation of the product consumes oxygen. As the oxygen in the package decreases, its transmission rate increases until oxygen consumption slows and a steady-state is reached. An equation similar to the one used for the RH calculation predicts oxygen consumption, sensitivity, and permeability as a function of initial conditions and sensitivity to moisture and temperature (1). 

	With the capability of modeling the impact of moisture, oxygen, and temperature on the product, optimum packaging options can be identified, with a high level of confidence that product quality will be protected for the required shelf-life (1). 

	1. K. Waterman, “Selecting Primary Packaging for Stability for Solid Dosage Forms,” Webinar (June 9, 2020).

	2. Aptar CSP Technologies, “Thank You For Joining the Rethinking Oral Solid Dose Packaging Live Webinar Last Week,” Email (April 2, 2019).  

	3. Klöckner Pentaplast Group, “Pentapharm BlisterPro XCEL Services,” www.kpfilms.com, accessed July 1, 2020. 

Data and software identify optimum pharmaceutical packaging choices for the required shelf-life.  