The aim of this paper is to describe a methodology for developing a per product qualitative and semi-quantitative business
case for application of quality-by-design (QbD) for a biopharmaceutical product. Previous authors have not frequently approached
the business case topic on a per product basis. Instead, they have examined benefits across a portfolio for a company or aggregated
across the pharmaceutical industry as a whole (1). In contrast, this effort focuses on a per product basis of business benefit
The primary purpose of a quality-by-design (QbD) business case is to demonstrate and elucidate the expected value that QbD
is to deliver (2). Lack of belief in QbD's business case has been cited as a key challenge within pharmaceutical companies
preventing successful QbD implementation (3, 4). Regardless, many companies already have adopted QbD concepts as their standard
business practice for process and analytical development execution (5). Recently, momentum has increased based on QbD's recognized
role as a new approach to improve product manufacturing and quality (6).
In 2010, FDA approved only six new biologics, giving few opportunities for QbD submissions (7). Overall, there have been few
biopharmaceutical QbD submissions to date despite seven elapsed years from the first draft of the International Conference
on Harmonization (ICH) Q8 guidance in November 2004 and longer since the first mention of risk-based quality approaches by
FDA's Janet Woodcock in October 2002 (8, 9). Although submissions containing enhanced development data and parameter interaction
studies have increased, there have been few, if any, design-space claims (10). Several biopharmaceutical QbD efforts have
focused on retrospective QbD for licensed processes, leveraging larger amounts of manufacturing data, experience, and knowledge
compared with processes for pipeline products (5).
Often, business cases are based on return-on-investment (ROIs) with minimal ROIs of less than a few years considered most
attractive. During the early stages of QbD introduction, the business case was based on qualitative potential benefits in
a few key areas: minimized manufacturing-scale development studies, fewer quality issues, greater flexibility to optimize
postlicensure, improved patient-focus for the product, more clinically meaningful product specifications, and reduced effort
in regulatory interactions. The business case needs to be updated based on the current level of biopharmaceutical QbD implementation
maturity, considering that some of the potential benefits achievable for current pipeline products now may be substantially
QUANTIFIABLE COST AND TIME BENEFITS
Costs of goods
Selling costs for a product are lowered by lowering production costs, albeit not proportionally. In turn, production costs
are fixed by Phase III clinical production processes. These processes are often developed to meet tight clinical trial timelines
that do not permit substantial optimization for efficient licensed manufacturing, nor the ability to incorporate new process
or analytical technologies (1). Simulated production costs, including indirect/fixed costs, for a typical aglycosylated protein
ranged from $100–800/g depending on production host and selected yield assumptions (11). Lower production costs arise from
reduced wastes (i.e., fewer rejected batches, deviations, or reprocessing), higher yields, and better utilization of assets
(ie, greater overall equipment effectiveness) (12, 13). Specifically, the true aggregated cost of poor quality (COPQ) can
often be greater than the more readily quantifiable cost of waste (14).
Development timelines directly affect the product's net present value (NPV). In one model, a 6-month delay to launch (type
of product not given) translated to a $100-million loss in NPV (15, 16). In contrast, an 18 month acceleration increased NPV
by $180 million by the model (15, 16). The average internal rate of return (RIR) for R&D for a biologic is 13% and NPV is
$1.26 billion (15, 16).One author estimates a cost of $1 million in expenses for each day of product development and > $0.5
million in losses for each day delay in product commercialization (17).
Later parts of clinical phase timelines to final filing are primarily affected by assembly of clinical data, but timelines
in early clinical phases can be highly affected by chemistry, manufacturing, and controls (CMC) activities. Even the availability
of nonclinical bulk material can be rate-limiting because often the goal is to start pharmacology and toxicity studies as
soon as possible (18). In addition, the entire timeline benefit associated with reducing CMC risks likely is under-estimated
because some lurking CMC issues never are uncovered when clinical issues halt product candidate development.
Quantifying cost and timeline benefits
Table I shows a sample matrix of QbD-related benefits and proposed steps for how to evaluate them. Ultimately all benefits
can be related to a cost, either directly or indirectly, because timeline extensions are converted into opportunity costs.
Direct costs can further be broken down into cost reductions or cost avoidance, based on the ability to either allocate fewer
resources initially to complete a deliverable or request fewer resources to revise or redo a deliverable. Overall, the cost
avoidance category serves as the most frequently estimated QbD benefit, primarily because it focuses on minimizing additional
unexpected resources not already allocated.
Table I: Sample matrix for quantifying biopharmaceutical QbD benefits.