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Manufacturers should consider the benefits and risks of contract packaging for stability studies.
The average cost of bringing a new drug to market is estimated at $1.3 billion (1), and the average timescale from initial discovery to market often spans 10 years or more. It is well documented that the investment and time involved in developing new drugs has resulted in big pharma organizations choosing to outsource some or all of their R&D operations to academia, contract research organizations (CROs), or contract development and manufacturing organizations (CDMOs). CROs and CDMOs are facing increasing competition, cost pressure, technological innovation, and consolidation activities (2), meaning that they, in turn, might outsource specific activities, such as stability studies and the associated requirements, to smaller specialists.
Many big pharma organizations instead choose to acquire or buy formulations from small-cap developers once they have been proven. A report in 2020 found that large and mega-cap companies were the most likely group to source new molecular entities (NMEs) through company acquisitions (3). For example, in October 2020, Gilead purchased US biotech Immunomedics and its potential cancer blockbuster Trodelvy (sacituzumab govitecan-hziy), and Sanofi added a potential multiple sclerosis drug to its pipeline when it bought Principia Biopharma in August 2020. These smaller players are likely to be dependent on outsourcing, with key partners already firmly in place when they are acquired.
As of February 1, 2021, there were 365,829 clinical studies registered globally, which is a monumental increase since 2000, when there were just 2119 (4). In that time, the focus has also shifted to rare disease and personalized medicine, with orphan drugs, biotechnology, and gene therapies attracting significant investment. Because of this, packaging requirements are becoming more complex, to accommodate sensitive formulations and APIs, as well as the small-scale nature of personalized medicines. The more sensitive or potent a drug is, the higher the barrier properties are, therefore, the more emphasis placed on the packaging.
With discovery work of these kinds of drugs being done more often by smaller players, the scale, size, and resources of these smaller players dictate their dependence on outsourcing of key activities, such as stability testing, to specialists. These activities often require small batches of packaging to be produced. Developers might invest in small-scale equipment to produce the packaging in-house, or they might outsource production; there are benefits and possible risks to both approaches that need to be weighed.
The shift towards personalized medicine sees therapies targeted to particular groups of patients (stratified) or individuals (personalized), such as the case of patient-specific autologous cell and gene therapies (5). These therapies will require a shift in manufacturing to agile, small-scale individualized production, in which the patient quickly receives individualized drugs, suited to their specific needs. This new reality is to be facilitated by Industry 4.0—which includes connectivity, advanced analytics, automation, and advanced-manufacturing technologies (6)—and is expected to better enable quality by design. In this new paradigm, outsourcing becomes even more important, with fast, efficient, small-batch packaging a key requirement.
Each new drug application requires a stability study, as regulation requires expiration dates to be indicated on all pharmaceutical products, and stability is a critical quality attribute.
In a stability study, the effects of variations in temperature, time, humidity, light intensity, and partial vapor pressure on the pharmaceutical product are investigated (7). Accelerated stability studies are common for process validation and material selection pre-commercialization. In accelerated studies, developers imitate a two-year shelf life in the space of around three months, usually at 45 ºC and 75% humidity.
Multiple accelerated stability studies might be required to test different packaging materials pre-production. Some stability studies may require one to 200 packs, while others may require up to 2000, depending on the amount of pull points in the stability study. Developers need flexibility and speed from their packaging department or supplier to accommodate increasingly complex and varied stability studies.
Stability studies are not only critical for regulatory approval, they prove key for the newer types of drugs when material selection can be challenging. When it comes to material selection, it is common that developers will over-specify their blister-pack material. They might know from past experience that aluminum gives close to the best barrier possible, so without always knowing exactly how sensitive their material is, might request it regardless of need.
Contract packaging suppliers can provide advice on material selection and, for example, recommend testing the originally requested high-spec packaging alongside alternatives, such as high barrier thermoform materials, which might be half the price and also faster to form, easier to fill, and smaller. Stability studies will then establish what barrier is actually required, for example, whether thermoform is suitable, or whether cold form is necessary. The small investment in running stability trials with different blister packaging materials could save a significant amount of time and money when the product is scaled up.
Stability studies are required for material selection or shelf-life validation, process validation, and through the lifecycle of the drug. While post-commercialization studies will use the final product and packaging, for the accelerated studies, it is important to have ready access to quick turnaround, small-batch packaging to achieve compliant, effective stability studies.
Whether drugs are developed by CDMOs or by small cap players, careful consideration would need to be made as to whether to outsource the packaging for stability studies. In both cases, a hesitation not to do this might be to protect intellectual property (especially with experimental, high-value drugs); the benefits of outsourcing, however, might outweigh that risk.
In the case of CDMOs, some key benefits of outsourcing packaging for stability studies might include:
For smaller developers, the benefits might include:
If the decision is made to outsource packaging for stability studies, there are some key questions to ask of a potential supplier. These questions might include:
In the case of stability studies, experts in packaging can deliver small batches quickly and cost-effectively for accelerated stability studies that are crucial to the future success of a new drug.
1. O. Wouters, M. McKee, and J. Luyten, JAMA 323 (9) 844–853 (2020).
2. PWC, “Current Trends and Strategic Options in the Pharma CDMO Market,” PWC.de (November 2019).
3. GlobalData, Contract Manufacturing of Novel In-Licenced Drugs, www.globaldata.com (February 2020).
4. Statista, “Total number of registered clinical studies worldwide since 2000,” statista.com (Feb. 2, 2021).
5. J. Branke, S. Farid, and N. Shah, Cell and Gene Therapy Insights, 2 (2) 263-270 (2016).
6. M. Agrawal, “Industry 4.0: Reimagining Manufacturing Operations After COVID-19,” mckinsey.com (July 2020).
7. K.V.Vilegave, Res. J. Pharma., Biological and Chem. Sci. 6 (1) 1557–1563 (2015).
Scott Kenny is Business Development Manager, Sepha Ltd.
Vol. 34, No. 8
When referring to this article, please cite it as S. Kenny, “Packaging for Stability Studies: to Outsource or Not?,” BioPharm International 34 (8) 46–48 (2021).