1. Excipient Variability Sources, Importance and Potential Impact Chris Moreton, Ph.D Past Chair IPEC-Americas Partner – FinnBrit Consulting consulting@finnbrit.com 1

2. Presentation Outline Background Why excipient variability is important How excipient variability can arise Options for addressing excipient variability 2

3. The Objective To manufacture robust medicines that deliver the drug to the patient: – In the required amount (content and assay). – At the optimum rate necessary to achieve the desired therapeutic benefit (in vivo dissolution). – Consistently: Within lots (blend uniformity for all components). Between lots (validated manufacturing process). – For the shelf life of the product (stability). At the same time, the development process has to be efficient. 3

4. Components of a medicinal product 4

5. Why is excipient variability important? Excipients are important components of drug products. Excipient variability may impact drug product variability. – But excipients are not the only sources of drug product variability API and process parameters may also be sources of product variability. 5

6. Excipient Variability There is inherent variability in everything: – Excipients are no exception. Why is it important? – It can contribute to product variability. But it is not the only potential source of product variability! 6

7. Excipient Variability We can sometimes see the effect of excipient variability in failed batches, but We cannot always control excipient variability adequately Why? – How does excipient variability arise? 7

8. Sources of Excipient Variability Many excipients are natural products, or derived from natural products. – Source of feedstock (crop) Species/varietal Soil composition Use of fertilizer – Weather is changeable Conditions during the growing season Conditions during harvesting Conditions during transportation to the processing site Conditions during storage of the crude feedstock Conditions during processing Conditions during packaging, storage and distribution 8

9. Sources of Excipient Variability Even for synthetic materials: – There is a misconception that synthetic or semi- synthetic materials are less variable than natural products It depends on the chemical processing – Single phase or multiphase, etc. – Most synthetic materials are derived from crude oil or gas which varies with location of the well: Content of sulfur Content and range of heavy metals Distribution of the different organic components 9

10. Sources of Excipient Variability Manufacturing process – Scale of manufacture Excipients frequently manufactured using continuous processing. – Location of manufacturing site Different scale of manufacture at different sites. – Alternate processes used by different manufacturers. Anti-oxidant vs. inert gas blanket – Normal wear and tear of the equipment train Supply chain – Type of transportation – Duration – Storage conditions en route 10

11. Excipient Variability We have to accept that there will be variability. We need to come to terms with it. Options may include: – Designing more robust formulations to cope with variability QbD will help – Using processing end-points to compensate for materials variability. 11

12. 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. 12

13. Formulation variability – a Simplistic View Bulk Active Drug Variability Excipients Variability Process Variability Product Variability 13

14. Formulation variability – a Wrong View Bulk Active Drug Variability Excipients Variability Process Variability Product Variability 14

15. In reality! Bulk Active Drug Variability Excipients Variability Process Variability Product Variability 15

16. Interactions in Product Manufacture Interactions include: – Powder – Powder – Liquid – Powder – Equipment – Liquid – Equipment For each unit process – Powder – Operator – Liquid – Operator – Equipment – Operator – etc. For each component 16

17. Which type of variability applies to our application? Batch number/Time of output Raw material parameter    17

18. Raw Material Variability Raw material Parameter Raw material batches 18

19. Raw Material Variability: Acceptable Raw material Parameter Raw material batches 19

20. Raw Material Variability: Possibly acceptable Raw material Parameter Raw material batches 20

21. Raw Material Variability: Impossible limits Raw material Parameter Raw material batches 21

22. Conclusions Excipient variability is important. There is inherent variability in excipients arising from a variety of possible sources. Designing product formulations and setting excipient specifications that do not allow for the inherent variability of the excipient is a recipe for disaster. 22

23. Thank you! We will now answer Questions. 23