1.6. The changing focus in the attempts to demonstrate the value proposition of QbD fort he pharmaceutical industry

Because of the need to generate a positive value proposition for the pharmaceutical industry to obtain acceptance for the resources and costs associated with a roll out of QbD many presentations and publications have tried to achieve exactly this objective over the last 5-6 years.

At the beginning the authorities tried to promote QbD focusing on regulatory flexibility as an incentive (e.g. Nasar Moheb from CDER, FDA).

• Thus risk-based regulatory decisions (reviews and inspections), manufacturing process improvements, within the approved design space described in the dossier, without further regulatory review, reduction of post-approval submissions, real-time quality control, leading to a reduction of end-product release testing were cited as potential benefits.²²

However, as the experiences gained during filing of applications as part of the CMC Pilot Program demonstrated this flexibility was still rather limited. Furthermore, the lack of harmonisation between Europe and the USA and even within the FDA itself failed to live up to the expectations of the industry.

During 2008 and 2009, the FDA’s Office of Pharmaceutical Sciences received 99 initial applications that it considers “QbD related”, i.e. around 10 percent of the 980 total applications across new drugs, biologics and generics.²³ Even though this demonstrates an increasing trend to adopt QbD or at least some of its principles it also shows that widespread acceptance has not been achieved despite the 5 years that had passed since its introduction.

Since then, the focus for the returns from a QbD driven development approach shifted more towards economic benefits trying to emphasise on the advantages perceived in CMC activities, manufacturing of drug products, and for a product’s lifecycle.

In 2009 T. Fuhr from McKinsey published a strategy discussing the benefits of QbD as substantial cost savings for CMC activities (active ingredient manufacturing, formulation and analytical method development, regulatory review and approval, validation and preparation for commercial manufacture) during development, which “account for 15 to 30% of overall R&D expenditures.” Translating this to the published development costs of 1.2 billion $ per NDA this can be summed up to approximately 180 – 360 million $ alone for each new drug product on the market – not even considering the number of candidates that failed to make it to the market.²⁴

Fuhr also claims that optimised practises in this area “would reduce COGS by 10 to 20%, which could produce $15 billion to $25 billion of annual savings on the industry’s $145 billion to $166 billion COGS. In addition to value gained through operational efficiency, companies can find value in reducing compliance remediation costs and improving product development-enabled sales, such as novel dosage forms or line extensions.” Improved CMC activities as directed by QbD can in his opinion also “increase revenue by ensuring smooth scale-up and product launch, and make it easier for companies to create differentiated products.”²⁵

G. Migliaccio, SVP of Global Supply at Pfizer reported during a FDA meeting on QbD in July 2011 that “no single pharmaceutical company can show comprehensive data on its impact. Nevertheless, trends can be seen.” In his opinion “it will take a few more years to have a full business case for QbD, but that case will eventually emerge, showing the value of QbD.” And without giving any real figures he pointed in the direction of the essential question that so far awaits an answer to really push QbD forward, when stating “the carrot, however, is lower ROI. Although that figure depends on inventories and other specifics, we’ve seen examples where ROI is less than 12 months.²⁶

Even though this outlook definitely sounds encouraging, the lack of real figures behind the statement makes it still very difficult for most companies to evaluate the potential cost – benefit ratio of QbD for their own business.

In trying to generate measurable metrics the benefits of QbD were also tried to link to the total “Costs of Quality” calculated as “Cost of Conformance + Cost of Non-Conformance” to demonstrate the obtainable benefits.²⁷ However, this fails to realise that QbD goes far beyond compliance as represented by CGMP and QA systems. The objective for QbD can not be reduced to issues only dealing with the manufacturing and marketing of drug products but needs to address the very start of the value chain of a proprietary pharmaceutical company, its R&D function.

This is also very essential for generic drug companies, whose most important objective has been and will be winning the race against its competitors in maximising its market share and profits by being the first to file. “If the rate of QbD adoption is going to increase in the marketplace, the emphasis behind QbD must evolve to a business proposition.... To be successful QbD must facilitate a generic product development organization whose primary objective is to be first to file. Many R&D organizations within the generics industry are measured by the timing and number of ANDAs filed, not the quality of the ANDA”.²⁸ This statement by Bikash Chatterjee, President and CTO, Pharmatech Associates focuses on the very core of the limited adoption of QbD so far: most companies are still not seeing the benefits, but consider it to be another increase of the burdens by the regulatory bodies in favour of big pharmaceutical industries, that can afford increasing expenditures for quality without a tangible payback.

²² Nasr; Implementation of Q8 – FDA perspective; 2006
²³ Koiakiniti E.; Regulatory Assessment of Applications Containing QbD; 2011
²⁴ Fuhr; Why quality-by-design should be on the executive team’s agenda; p 195-203
²⁵ Fuhr; Why quality-by-design should be on the executive team’s agenda; p 195-203
²⁶ Migliaccio; The Impact of Quality by Design; 2011
²⁷ Guido-Redden; The Holy Grail of The Modern Quality System; 2011
²⁸ Chatterjee ; Making Cents: QbD Must Shift Its Focus;.2011