DOE Strategies for Accelerating Formulation Development

116 Pages·2016·2.3 MB·English

DOE Strategies for
Accelerating Formulation Development
Ronald D. Snee, PhD
Snee Associates, LLC
JMP Explorers Event
Houston, Texas
May 25, 2016
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About the Speaker …..
He is also an Adjunct Professor in the
pharmaceutical programs at Temple and Rutgers
Universities. He worked at DuPont for 24 years prior
to starting his consulting career.
Ron received his BA from Washington and
Jefferson College and MS and PhD degrees from
Ron Snee, PhD is Founder of Snee Associates,
Rutgers University. He is an academician in the
LLC, a firm dedicated to the successful
International Academy for Quality and Fellow of the
implementation of process and organizational
American Society of Quality, American Statistical
improvement initiatives. He provides guidance to
Association, and American Association for the
pharmaceutical and biotech senior executives in
Advancement of Science. He has been awarded
their pursuit of improved business performance
ASQ’s Shewhart, Grant and Distinguished Service
using Quality by Design, Lean Six Sigma and
Medals, and ASA’s Deming Lecture and Dixon
other improvement approaches that produce
Consulting Awards. He is a frequent speaker and
bottom line results.
has published 5 books and more than 280 papers
He has authored several articles on how to in the fields of quality, performance improvement,
successfully implement QbD, coauthored 2 books management, and statistics. He recently received
on QbD tools and speaks regularly at the Institute of Validation Technology’s Speaker of
pharmaceutical and biotech conferences. the Year Award.
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Formulation Development Topics
 Today’s Realities
 Rapid formulation is a competitive advantage
 FDA is thinking in terms of Quality by Design
 Value of Quality by Design Approach in Formulation
 Strategy of Formulation Development
 Dealing with Formulation Constraints
 Screening Formulation Ingredients
 Creating Robust Formulations
 Design of Mixture-Process Variable Experiments
 Guiding Principles, Tips and Traps
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Mixtures, Blends and Formulations
 Many products are manufactured by mixing together two or more
ingredients or components
 One of Americas first products was a mixture
 Black Powder
 75% Saltpeter
 12.5% Charcoal
 12.5% Sulfur
 The quality of the powder was a function of the proportions of the
components in the mixture
--NOT the total amount of the mixture
 The objective is to find a desirable balance between product
properties and manufacturing costs
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Black Powder - Formulation Depended on Use
Use Saltpeter Charcoal Sulfur
“Manufacturers would often
General 75 12.5 12.5
experiment, changing their
Hunting 78 12 10
formulas after tests of a finished
Military 75 15 10
powder proved it was not giving
Blasting 62 18 20 the results desired”
Explosives in History, N.B. Wilkinson,
The Hagley Museum,
Wilmington, DE (1966) p23
Blasting
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Products Formed by Blending Components
Gasoline Metal Alloy
X1 = Cat Cracked X1 = Chromium
X2 = Alkylate X2 = Nickel
X3 = Reformate X3 = Cobalt
X4 = Butane Y = Tensile Strength
Y = Octane, Miles/Gal
Textile Fibers Concrete
X1 = Polyester (65%) X1 = Cement
X2 = Cotton (35%) X2 = Sand
Y = Comfort, Durability X3 = Water
Y = Compressive Strength
Performance is a Function of Components in the Blend
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More Mixtures, Blends and Formulations
 Aerosol Propellants  Glass
 Cake Mixes  Insecticides
 Ceramics  Paints
 Coffee  Pancake Syrup
 Density of DNA  Pharmaceuticals
 Detergent  Plastics
 Dyes  Printing Ink
 Engine Lubricant  Rubber
 Fertilizer (N, P, K)  Soil (sand, silt, clay)
 Flares  Synthetic Enamel
 Foams  Vegetable Oil
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Formulation Scientist’s Experience
Question: Have you ever worked on a pharmaceutical
formulation development project?
Answer: Yes, one involved 11 different components.
Question: We’re you successful?
Answer: Yes; We found a formulation that worked.
Question: What was the experience like?
Answer: Very painful – took a long time - lots stress,
anxiety and uncertainty.
 We were never sure that the formulation we found
was even close to the best formulation.
There Must Be a Better Way…. Fortunately There Is!
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Developing Formulations – Classic Approach
 Vary one component at a time
 Start with a “best guess” formulation
 Vary the components in the formulation one at a time
 Observe the changes in the performance of the
formulation that result
 Easy to understand and use, BUT
 Is inefficient and costly; typically more formulations are
created than needed
 Results are uncertain
 Critical information is often missed
 Formulation “Design Space” is difficult to characterize
because formulation response models are not developed
 Can be time consuming and frustrating
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Developing Formulations Using
Quality by Design Approach
Statistical Design of Experiments
 A series of formulations are created and tested in a
planned sequence
 Levels of the candidate components are varied in a
blending design and the performance of the formulations
is measured
 A model (polynomial) is fit to the data and critical
components and blending characteristics are identified
 Response surface contours are examined to determine
the region of the best values of the response
 Design Space, Operating Window, Sweet Spot
 Formulations are tested to verify the model predictions
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