1. Integration of Excipients into the Design of Experiments for Pharmaceutical Product and Design Space Development Chris Moreton, Ph.D. FinnBrit Consulting IPEC-Americas FDA Seminar, October 21, 2013 1

2. Presentation Outline Background and Introduction Incorporating excipients into the DoE – Single grade excipients – Multiple grade excipients Examples Conclusions 2

3. Objective To establish a Design of Experiments, Design Space and Control Strategy that will provide for the manufacture of a robust pharmaceutical product. 3

4. What is a Robust Formulation? A formulation that is able to accommodate the typical variability seen in: – API – Excipients – Processes Without compromising the manufacture, stability, performance or any other attribute of the product critical to the patient’s care or well being. 4

5. Product variability Bulk Active Drug Variability Excipients Variability Process Variability Product Variability 5

6. Design of Experiments Excipients are an important part of any formulation. Excipient variability will therefore be an important part of the Design of Experiments (together with the API and the process) 6

7. Excipients: a recap Made in large quantities often in dedicated plants/equipment trains. They may be of natural, synthetic or semi-synthetic origin. Excipient manufacturing plants are designed to manufacture the excipient at the center of the range for a given specified parameter (i.e. that is controlled). They are NOT designed to produce material at the extremes of specification. Some excipients are available in more than one grade; others may only be available in a single grade. 7

8. So how can we incorporate Excipient variability into the DoE? QbD offers easier methods than trying to persuade suppliers to prepare material at the upper and lower limits of specification. The methods available will depend on the nature of the excipient and the type of application (formulation). 8

9. Determine which excipient parameters are likely to impact product performance Use of prior knowledge and expertise to assess each excipient and which properties may impact product performance: – in product manufacture, – product stability, – and product performance during and after administration to the patient. Analogous to a risk assessment (but with the emphasis on product manufacturing, stability and in vivo performance) But, we need to take the formulation into consideration: – If we are making a powder-filled capsule, do we need to worry about the excipient’s compaction profile? – If we are making a liquid product do we need to worry about tapped density? 9

10. Options for single grade excipients There is a basic assumption that we can measure the excipient parameters that are likely to influence product performance. – Is this always a valid assumption? – Sometimes not (Unknown Unknowns)! We need ways to simulate the extremes of specification for those parameters assessed as having potential to impact excipient performance in the application (formulation). 10

11. Options for single grade excipients There are three options relying on physical methods: – Fractionation For example, in the case of particle size, we can take sieve cuts to create extremes of particle size. – Level of incorporation For example, in the case of viscosity, we can add less or more of the excipient to simulate preparation of lots at or outside the limits of specification for the particular parameter and excipient. – Conditioning For example, equilibrating the excipient at higher humidity to increase the moisture content. Changes in, for example, the degree of chemical substitution, are beyond these simple physical changes: – Talk to the excipient manufacturer/supplier. 11

12. Options for excipients having more than one grade There are some implicit assumptions in the use of this approach: – The differentiation between grades is linked to excipient performance in the particular application Otherwise, why be concerned with it? – The parameter of interest can be measured With sufficient precision Using a method that is relevant to the application – The within grade variability is much less than the variability between grades If it isn’t, then why have a different grade? 12

13. Options for excipients having more than one grade The options available for a single grade can be used. There are further options which may be more useful: – Evaluate the grades either side of the target grade (bracketing) If there is no effect of grade on the performance of the finished product, then the parameter(s) is (are) not related to product performance, and do not need to be included in the DoE. – If there is an effect of the grade on finished product performance, then blends of grades may be used to simulate excipient at the extremes of specification. – If there is an effect of materials simulating the extremes of specification, then is the formulation viable? Excipient batch (lot) selection is a disaster waiting to happen! – For materials at the extremes of the grade range, bracketing is not possible. Proceed as for single grade excipients at the extreme of specification away from the closest grade. 13

14. Examples Microcrystalline cellulose Carmellose sodium 14

15. Main Grades of Microcrystalline Cellulose Grade Size Characteristics PH 101ca. 50 µm PH 102ca. 90 µm PH 103ca. 50 µmMoisture content < 3% PH 105< 20 µm PH 112ca. 90 µmMoisture content < 1.5% PH 113ca. 50 µmMoisture content < 1.5% PH 200ca. 180 µm PH 200 LMca. 180 μmMoisture content < 3% PH 301ca. 50 µmHigher density PH 302ca. 80 µmHigher density Ceolus KG 802ca. 50 µmLower density Ceolus UF 711ca. 50 μmLower density, better flow Ceolus KG 1000ca. 50 μmVery low density 15

16. Grades of Carmellose Sodium Many grades available Grade differentiation is based on: – Substitution range – Intended use: Food, pharmaceutical, cosmetic or industrial use – Viscosity High, medium or low Viscosity range – Particle size 16

17. Conclusions Incorporation of excipient variability into the Design of Experiments does not have to be complicated. Manufacture of excipients at the extremes of specification is not necessary. QbD offers better options for both single grade excipients and excipients available in multiple grades. 17