	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. 

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

Modeling Streamlines Package Stability Testing

	As the biopharmaceutical industry races ahead with development of vaccines and therapeutics to address the COVID-19 pandemic, experts have acknowledged that building up adequate capacity for fill/finish and ensuring the supply of materials for primary packaging containers are crucial requirements. In an unprecedented compression of manufacturing timelines and with significant investment from government and non-profit sources, commercial fill/finish manufacturing capacity is being built at-risk, while drug development and clinical trials are ongoing. 

	“A vaccine will only be effective if we can make and distribute adequate supply,” John Shiver, senior vice-president of Vaccines Global R&D at Sanofi pointed out in a March 23, 2020 post (1). He expressed confidence that industry is up to the task, saying, “If we can develop a safe and effective vaccine, the global pharmaceutical industry has the capacity to make and deliver it. [Sanofi] has the established capacity and infrastructure to make up to 600 million doses in two existing facilities based in New York and Pennsylvania, without compromising the supply of vaccines for other illnesses, including influenza. Other companies have similar capacity.” Furthermore, he noted, “Fighting an emerging pandemic is an enormous undertaking requiring the entire pharmaceutical ‘ecosystem’ to come together at pace and at a scale that are both extraordinary.”

	Contract development and manufacturing organizations (CDMOs) are crucial components of this ecosystem for handling the expected surge of capacity needed for vaccines against COVID-19, and several have announced manufacturing agreements and capacity expansions.

	Catalent, for example, has announced manufacturing agreements with COVID-19 vaccine candidate developers including Johnson & Johnson’s Janssen (2), Moderna (3), and AstraZeneca (4) to provide fill/finish capabilities. Catalent says it is working with more than 40 customers on COVID-related antivirals, vaccines, diagnostics, and treatments for symptoms and effects of COVID-19 (5). At the Catalent Biologics business unit’s facility in Bloomington, IN, the company reported that the scale-up in production would include the use of two new high-speed machines, including an Optima vial filling line and a Dividella NeoTOP 1604 top-load cartoner (2). The company is rapidly scaling segregated manufacturing capacity at the Bloomington facility to support dedicated production of Johnson & Johnson’s investigational vaccine candidate and plans to hire approximately 300 additional employees “to meet operational readiness and 24x7 manufacturing schedules by January 2021” (2).

	The Bloomington facility is also being prepared to provide vial filling and packaging capacity for Moderna’s mRNA-based COVID-19 vaccine candidate (mRNA-1273). Barrier isolator technology will be used for filling. The capacity and the staff for commercial-scale production expect to produce an initial 100 million doses of the vaccine candidate for the US market starting in the third quarter of 2020, and the companies are discussing fill/finish capacity for continued production of hundreds of millions of additional doses (3).

	Catalent Biologics facility in Anagni, Italy is being prepared for commercial-scale vial filling and packaging for AstraZeneca and the University of Oxford’s adenovirus vector based COVID-19 vaccine candidate, AZD1222. The facility will be able to supply hundreds of millions of doses of the vaccine candidate from August 2020, and potentially through to March 2022 should the product be approved by regulatory agencies, Catalent reported (4). 

	One of the funding sources for COVID-19 countermeasures is the US government, which is building a network of manufacturing partnerships through programs including Operation Warp Speed, which is a partnership among components of the Department of Defense (DoD) and the Department of Health and Human Services (HHS), including the Centers for Disease Control and Prevention (CDC), FDA, the National Institutes of Health (NIH), and the Biomedical Advanced Research and Development Authority (BARDA) (6). In addition to contracts with Johnson & Johnson, AstraZeneca, and Moderna, in June 2020 HHS contracted with Emergent BioSolutions for manufacturing capacity, including an investment of approximately $85.5 million for the rapid expansion of the company’s viral and non-viral CDMO fill/finish capacity for vaccine and therapeutic manufacturing (7).

	Operation Warp Speed is also investing in US domestic capacity for glass vials, with $204 million going to Corning to expand capacity for its Valor Glass vials, and for two more unconventional container types-$143 million to SiO2 Materials Science to increase capacity to produce the company’s glass-coated plastic containers and a $138 million contract with ApiJect to produce prefilled syringes using the blow-fill-seal process for plastic containers (6). 

	These announcements illustrate a piece of the global puzzle and the drive to increase capacity for the anticipated billions of doses of vaccine that will be produced, once approved.

	1.  Sanofi, “Sanofi Mobilizes to Develop a Vaccine against COVID-19,” 

	2.  Catalent, “Catalent Signs Agreement with Johnson & Johnson to be US Manufacturing Partner for Lead COVID-19 Vaccine Candidate,” Press Release, April 29, 2020.

	3.  Catalent, “Moderna and Catalent Announce Collaboration for Fill-Finish Manufacturing of Moderna’s COVID-19 Vaccine Candidate,” Press Release, June 25, 2020. 

	4.  Catalent, “Catalent Signs Agreement with AstraZeneca to Manufacture COVID-19 Vaccine Candidate,” Press Release, June 15, 2020.

	5.  Catalent, “Catalent COVID-19 Response,” 

	6.  HHS, “Fact Sheet: Explaining Operation Warp Speed,” 

	7.  HHS, “HHS Adds $628 Million to Contract with Emergent BioSolutions to Secure CDMO Manufacturing Capacity for Operation Warp Speed,” Press Release, June 1, 2020.

Filling and packaging of primary containers is a crucial piece of COVID-19 vaccine and therapeutic production.

Equipment and Processing Report-07-15-2020

Modeling Streamlines Package Stability Testing

Industry Builds Fill/Finish Capacity for Pandemic Response