Formulation Development

Transcription

1 Quality by Design and Formulation Development WF Busch Senior Application Development Specialist Dow Chemical Company IPEC Americas, Quality by Design Committee 5 May 2010 Disclaimer The views and opinions expressed in the following presentation are those of the presenter and should not be attributed to The Dow Chemical Company or the IPEC Americas Association 1

2 Quality by Design FDA Perspective Pharmaceutical QbD is a systematic, scientific, risk-based, holistic and proactive approach to pharmaceutical development that begins with predefined objectives and [emphasizes] product and [process] understanding and process control. Moheb Nasr, FDA s quality initiatives: An update (10 November 2007) The Final Product (Focus on Solid Oral Dosage Forms) Finished Pharmaceutical Dose Functionality depends on two key items: Formulation The Active Pharmaceutical Ingredient (API) Various additional ingredients (Excipients) Manufacturing Process Various Unit Operations required to get the formulation into the finished dosage form 2

3 Excipients Can be Critical Components in the formulation Important for efficacy Help the API meet the desired therapeutic effect Can be rate controlling Important for processing Help formulation homogeneity Help processing in the various unit operations to insure finished product integrity Excipients Functionality transcends the excipient molecular l composition or particle form Pharmacopeia listing is a minimum requirement for the excipient Focus is on safety and purity Not a guarantee of functionality Limited physical characterization May in fact be limited chemical characterization 3

4 Excipients Functionality is application specific Is it a processing aid? (binder, lubricant) Is it an efficacy aid? (solubilizer, coating agent, modified release agent) USP utilizes General Chapters to help define Functionality Related Characteristics (FRCs) Ph EUR utilizes material-specific FRCs Excipients Are a source of variability Many produced from natural resources Variability exists between suppliers Raw material source Manufacturing process Variability exists with a given supplier Raw material source lot-to-lot variability Manufacturing variability Different grades for different applications 4

5 Excipients Typically less characterized than APIs Have not been considered a high priority even though they may encompass 80% of the finished dosage form Quality by Design requires understanding of raw material variability and their impact on finished product quality FDA 21 st century cgmp ICH Q8(R) A1 Traditional Formulation Development Traditionally excipient supplier s involvement in formulation development minimal to non-existent Typical formulator will pick a sample off the shelf or just order one and begin formulation development Typically few formulators have requested multiple samples to attempt to explore formulation robustness 5

6 Slide 10 A1 2nd bullet: Typically few users have requested multiple samples to explore formulation robustness Author, 3/8/2010

7 Traditional Formulation Development Supplier Unaware of application (may be unaware of sale) User Unaware of the excipient variability Unaware of the excipient suppliers process capabilities and limitations Ends with a fixed formulation Traditional QbD Thinking Process Focus QbD refers to the ability of the drug manufacturer to use their knowledge of the manufacturing process to smooth out variability brought into the process by the formulation 6

8 Traditional Thinking - Process Flexibility Raw Material (Fixed Formulation) Process (using PAT) Finished Product New Formulation Development requires a Collaboration in Formulation Development QbD excipient supplier s involvement in formulation development must be open and collaborative Supplier needs knowledge of the end use Is able to recommend products based on the end use application Can help determine Critical Attributes Can help supply useful samples in formulation development 7

9 New Formulation Development requires a Collaboration in Formulation Development QbD excipient supplier s involvement in formulation development must be open and collaborative User needs knowledge of the excipient Understand the variability and how it may affect performance Develop a Formulation Design Space to demonstrate understanding of the interactions of all formulation components Design Space Development Example 50% diclofenac sodium, 40% METHOCEL K15M PRM, mpa-s 9.5% lactose, 0.5% mag stearate Internal investigation by Dow Chemical of hypromellose substitution on dissolution 8

10 Design Space Development Example 40% salicylic acid, 30% METHOCEL K15M PRM mpa-s 29% lactose, 1% mag stearate Internal investigation by Dow Chemical of hypromellose substitution on dissolution New QbD Thinking Formulation and Process Focus QbD refers to the ability of the drug manufacturer to use their knowledge of the formulation components and manufacturing process to smooth out variability brought into the process by the formulation 9

11 New Thinking Formulation and Process Flexibility Raw Material (Initial) Finished Product Raw Material (Flexible Formulation) Process (using PAT) Excipient User s Desire Ideal DOE protocol for Design Space Development Allows of a study of Primary and Secondary Factors A Full Factorial approach (2 k design) with duplicate center points Samples with variables at desired levels Randomized order of trials 10

12 Excipient Supplier s Reality Many suppliers run a continuous process Many manufacture product that meets a normal or Gaussian distribution Unable to produce samples at the edge of the Design Space (DOE samples) for a given attribute without significant amount of offgrade For an excipient having multiple parameters, finding a batch that simultaneously meets all of the characteristics prescribed by the DOE is extremely difficult A4 Lot-to-Lot Variability* *2009 AAPS National Meeting Presentation by Bruno Hancock, Pfizer (Data courtesy of FMC BioPolymer) 11

13 Slide 22 A4 The footnote implies Bruno is at FMC, which he is not. Maybe something like: From presentation given by Bruno Hancock at 2009 AAPS National Meeting. Same thing on the next slide. Author, 3/8/2010

14 Lot-to-Lot Variability* *2009 AAPS National Meeting Presentation by Bruno Hancock, Pfizer (Data courtesy of FMC Biopolymer) Excipient Supplier s Reality To target the edge of specification limit will result in 50% of material produced being OOS Waiting for random chance to get desired sample may require a lot of time, depending upon limits of process control and acceptable range Multiple parameters compound this problem factorially 12

15 Three Parameter - 2 k Design Experiments w/ Duplicate Center Points Order A B C Lot-to-Lot Variability So how can one obtain samples p for Design Space development? 13

16 Case Study (Polyethylene Oxide)* Want to develop a Formulation Design Space for a hydrophilic hili matrix tablet t using PEO as a rate controlling excipient Want to study the dissolution profile over a range of a given grade of product Evaluate of the influence of molecular weight (as measured by viscosity) Utilize grades above and below target grade *Pharmaceutical Technology, December 2009, Jennifer L Hote-Gaston, Dow Chemical Case Study (Polyethylene Oxide)* Several viscosity grades available WSR 205 NF ( cps; 5% solution) WSR 1105 NF ( cps; 5% solution) WSR N-12K NF ( cps; 2% solution) In Formulation Development blend high and low viscosity grades to encompass the entire range of the mid-level grade ( cps) Samples of WSR 1105 NF were 9120, 9250, and cps Blending allows for evaluation of the entire viscosity specification range Blending assures the Design Space covers the entire range of the viscosity *Pharmaceutical Technology, December 2009, Jennifer L-Hote-Gaston, Dow Chemical 14

17 Case Study (Polyethylene Oxide)* Conclusions Blends of PEO produced viscosities across the range of the standard product Blends were consistent with Molecular Weight and Polydispersity of the mid-level grade, showing unimodal distribution Blends showed good f2 similarity in dissolution profile More variation noted in early dissolution profile *Pharmaceutical Technology, December 2009, Jennifer L-Hote-Gaston, Dow Chemical Extend to Commercial Application Commercial Production incorporating levels of low and high h viscosity it grades to complement the targeted viscosity grade will provide a more consistent product Ability to reduce formulation variability via incorporation of other grades a logical extension of formulation development work Builds in flexibility for continuous improvement throughout the product lifetime 15

18 Commercial Example Used Today (Film Coatings) Color film coatings often formulated with small amounts of secondary pigments Batch-to-Batch variability of primary pigment is compensated by adjusting proportions of secondary pigments to achieve a consistent color Final result is a consistent function (color) achieved with different quantitative formulations for each individual batch Functionality trumps Fixed Formulation Commercial Example Used Today (Capsule Manufacturing) Vegetable Capsule manufacture dependent on may attributes of hypromellose Viscosity Salt level Substitution Finished Capsule Quality improved by Finished Capsule Quality improved by blending of different lots of the same grade with different attributes to achieve more consistent functionality 16

19 US FDA s Office of Generic Drugs Workshop June 2009* Objective was to identify gaps in the understanding of QbD between FDA and industry ANDA sponsors generally agreed that a formulation design space would be valuable to the industry if appropriate regulatory flexibility is granted It was suggested that FDA consider the establishment of formulation design space as a post approval activity *Pharmaceutical Technology, October 2009, Lawrence Yu, FDA Conclusions Excipients are necessary in order to obtain efficacy of the API in the finished dosage form Excipients are a source of variability Blending of different grades of excipients may be a good means of obtaining samples needed to develop a robust Design Space 17

20 Conclusions Formulation flexibility enhances the ability to manufacture consistent, t reproducible dosage forms using process flexibility, and is a natural extension of the Design Space development activities Formulation flexibility provides assurance against both short term raw material variability and long term changes due to material supply changes or tightened finished dosage form requirements Acknowledgements The IPEC-Americas Quality by Design The IPEC Americas Quality by Design Committee members, and specifically the Committee Chairperson, Dr. Brian Carlin of FMC Corporation 18