Scale-up and control strategy
Currently, the mechanistic understanding of pharmaceutical unit operations is limited. Scale-up is largely based on general
rule-of-thumb and trial-and-error approaches. During scale-up, process parameters may vary while material attributes will
not. Workshop participants agreed that QbD offers many more advantages for complex products than for simple ones. It was noted
that scale-up can be done without QbD, but with much higher risk.
ICH Q8(R1) defines control strategy as:
A planned set of controls, derived from current product and process understanding that ensures process performance and product
quality. The controls can include parameters and attributes related to drug substance and drug-product materials and components,
facility and equipment operating conditions, in-process controls, finished-product specifications, and the associated methods
and frequency of monitoring and control (1).
Specifically, the control strategy may include:
- Control of input material attributes, in terms of CMAs
- Product specifications
- Controls for unit operations (CPPs and process endpoints)
- In-process or real-time release testing
- A monitoring program (intermittent testing) for verifying multivariate prediction models (1).
Workshop participants agreed with the definition of control strategy. There was some confusion, however, about how the control
strategy is different from a specification and whether the control strategy should reflect target ranges or the acceptable
ranges. This issue merits further discussion.
The two-day FDA-OGD and GPhA workshop led to a common understanding of several specific topics related to QbD for generic
drugs. These issues include CQAs; drug substance and excipient properties, as well as their compatibility studies; formulation
design and development; manufacturing process design and development; CPPs and CMAs; risk assessment; and scale-up process
and control strategy. It is believed that ANDAs should include these elements. The following topics require further discussion:
- The QTPP
- Use of prior knowledge in formulation and process design and development
- Regulatory evaluation of generic-drug sponsors' risk assessment and mitigation plans as well as control strategy.
Another workshop is being held in Fall 2009 to continue QbD discussions between FDA and the generic-drug industry.
Lawrence X. Yu* is deputy director for science in the Office of Generic Drugs (OGD) at the US Food and Drug Administration, 7519 Standish
Place, Rockville, MD 20855, Lawrence.Yu@fda.hhs.gov
. Robert Lionberger is a chemist at OGD. Michael C. Olson is a chemist at the Office of Pharmaceutical Science (OPS) at FDA. Gordon Johnston is vice-president of regulatory sciences at the Generic Pharmaceutical Assocation. Gary Buehler is director of OGD. Helen Winkle is director of OPS. Additional contributors include Sam Bain, Mike Darj, Latiff Hussain, Anil Pendse, Vaikunth S. Prabhu,
Andre Raw, Aijin Shen, Zhigang Sun, Sivakumar Vaithiyalingam, Frank O. Holcombe Jr, Rashmikant M. Patel, Florence S. Fang,
Vilayat A. Sayeed, Paul Schwartz, Richard C. Adams, Devinder Gill, and Ubrani V. Venkataram, all at FDA.
*To whom all correspondence should be addressed.