QbD-based predictive modeling for pharma packaging

 Ahead of this year’s INTERPHEX show in New York, Pharma Manufacturing caught up with Adrian Possumato, president of Sanner of America, to discuss the company’s latest protective packaging technologies and desiccants for oral solid dose (OSD) pharmaceuticals and how the protective packaging industry and pharma market has changed over the past decade and more recently due to COVID-19.

Q: You’ve spent 30+ years in the health care industrials space working with pharma manufacturers and packagers. What’s changed over the past 10 years?

A: During the period of 2011-2016, the pharma industry experienced the largest wave of drug product patent expirations in history. This ‘patent cliff’ was largely associated with small molecule, OSD drug products and a great number of these continue to rely on desiccants in commercial packaging presentations to improve their chemical and/or physical stability as generic formulations.

Following the patent cliff, Big Pharma embraced therapeutics made from biologically active proteins, large molecule drug substances, and enzyme inhibitors. The majority of these products cannot be taken orally, and thus are administered parenterally. As aqueous-based solutions, parenteral drug products obviously don’t rely on desiccants for stability.

However, OSD drug products account for 35% of the 25 top-selling drug products by value and comprise ~38% of drug product candidates in phase 3 clinical trials — many of which that will require desiccant in their packaging presentations.

Q: Where is pharma today on the selection and use of desiccants for OSD product packaging?

A: Increased free moisture in small molecule, OSD drug formulations will always result in increased molecular mobility and the likelihood of an increased rate of chemical and/or physical degradation. Consequently, there’s often no avoiding desiccant use in the packaging presentations of many inherently unstable OSD drug product formulations.

To arrive at the desired drug product stability profile using a desiccant, one needs to consider the desiccant type and mass, its impact on adsorbing free moisture from the OSD drug product formulation, and its impact on the moisture ingress into the primary packaging selected. The desiccant will not only adsorb free moisture from the drug product — it will also increase the Moisture Vapor Transmission Rate (MVTR) through the container resin and moisture ingress through any open container-closure joints. So, the solution to manage moisture drives more moisture ingress into a permeable packaging presentation like an HDPE bottle.

Q: How does the industry make the necessary calculations for desiccant determination?

A: Determination of primary packaging requirements is typically performed via empirical study. Probe stability studies involving a range of potential packaging presentations run for 3-6 months at accelerated stability conditions of 40-degrees C/75% RH would eventually identify the solution that would be submitted for registration stability testing. However, probe stability studies are expensive and time-consuming.

As a precision injection molder, Sanner developed its IDP® Process as a defined, standardized, GMP-compliant stage-gate development process from design to industrialization wherein we carefully consider container closure seal integrity and related MVTR performance in novel protective packaging designs.

These designs are co-engineered using our Atmo Guard System® which evaluates the package and built-in desiccant to USP <671> moisture testing standards at 23-degrees C/75% RH.

Industry scientists subsequently developed predictive stability modeling programs at a full range of ICH stability conditions using a Quality by Design (QbD) approach that could determine moisture management outcomes. This was accomplished by taking empirical measurements on the drug product via moisture adsorption/desorption isotherms, the MVTR of the primary packaging, and isotherms on the desiccant. Working with formulation chemists, these moisture management outcomes could be used to elucidate stability outcomes for the drug product in the packaging presentation modeled, thereby saving 6-12 months in development time for the pharma manufacturer.

The QbD standard for predictive stability modeling is FreeThink Technologies’ ASAPprime® software which is based on the Accelerated Stability Assessment Program and enables scientists to quickly and accurately determine product shelf life.

As many of Sanner’s pharma customers already use the ASAPprime software, we work with FreeThink Technologies’ analytical labs to develop MVTR data for our protective packaging solutions that can be used by our customers in the software along with their drug product data to predict shelf life outcomes.

Our Atmo Guard System QbD-based value proposition now incorporates ASAPprime to better align with customer needs. This combination allows customers to accelerate decision making, registration stability testing, regulatory submissions and time to market.

Q: How has the COVID-19 pandemic affected all of this?

A: The pandemic created a significant increase in demand for many life sciences manufacturers. This increase in demand was also complicated by massive supply chain issues that remain unresolved today.

For example, there is currently a significant supply issue with foil-laminate heat induction seals (HIS) used in drug product bottle package presentations common to the North American market. A foil laminate HIS provides the best possible MVTR protection for the typical HDPE bottle with child-resistant HDPE screw closure. But if they can’t be reliably sourced, companies are being forced to look at alternative packaging presentations.

Sanner recently launched its TabTec® CR desiccated, child-resistant container-closure system that can include up to 4.0g of Silica Gel or Molecular Sieves integrated into its base. The design includes Sanner’s famous olive seal design for its closure and base joints that significantly reduces MVTR. This olive design, coupled with the desiccant in the base component, form an effective passive-active barrier system that allow for customers to change from the current bottle presentation with HIS to TabTec CR.

To demonstrate this, we had FreeThink develop MVTR profiles on TabTec CR at ICH real-time and accelerated stability conditions for use in the ASAPprime by customers who licensed the software. Customers who have not licensed the software can work directly with the FreeThink’s analytical labs to determine the drug product moisture sensitivity (for chemical and/or physical stability) and corresponding packaging requirements to achieve the target shelf life on a fee-for-service basis.

In either case, FreeThink can supply the necessary predictive stability data for both the customer’s current packaging presentation and TabTec CR to support a change control and related CBE-30 filing with the FDA. FreeThink’s ASAPprime software is so robust that it has even supported change controls involving a reduction in packaging protection via both CBE-30 and Annual Report submissions to the FDA.

Drop-in desiccants such as packets and canisters have been traditionally used in OSD drug product bottle packaging presentations while desiccant packets have found their way into the secondary, pouch packaging of OSD drug product blister pack presentations when the primary package cannot deliver the required stability profile and related shelf life.

For new drug product filings (NDA, ANDA), we recommend the use of ASAPprime for drop-in desiccant requirement determination. However, the COVID-19 pandemic stressed supply chains to the point where much of the life sciences industries implemented dual-sourcing programs to mitigate supply risk.

Consequently, Sanner has provided prospective pharma customers with equivalency data for its AdCap® desiccant canisters and AdPack® desiccant packets to facilitate change controls using the CBE-30 process. Sanner manages a FIFO-controlled inventory of AdCap and AdPack in its New Jersey-based distribution center. They both can be used interchangeably on leading dispensing machinery.

Sanner is using the tools initially developed for QbD to help the pharmaceutical industry navigate the pandemic supply chain issues and future drug product planning needs as COVID-19 moves toward its endemic stage.