1. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 1 Extemporaneous Preparation (EP) of Clinical Trial Materials for Phase 1 Clinical Studies DIA CMC Working Group Richard Hoffman, MS Eli Lilly & Co. Regulatory Affairs, CM&C DIA, March 19 th 2009

2. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 2 Agenda Topics for Discussion Introductory Definition Traditional Drug in Bottle (DiB) and EP DiB Approach EP Overview & Advantages / Disadvantages US Laws and Guidance EU & Other Countries RA CM&C Approach

3. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 3 Introductory Definition Extemporaneous (ek-stem-pə-rā-nē-əs) Preparation Composed or performed on the spur of the moment, but it can be prepared/rehearsed ahead of time Drug substance ClinicDrug Product Shipped toPrepares

4. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 4 Traditional DiB vs. Extemporaneously Prepared DiB Ship GMP DP to Clinic Individual Doses DS weighed into bottles in GMP facility Traditional DiB Individual Doses Ship GMP DS to Clinic Weigh out by pharmacist Clinical dilution Extemporaneously Prepared DiB ~1000 bottles Same qty. in each Clinical dilution bulk individual

5. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 5 Compounding & Extemporaneous Prep. Compounding – to put together (parts) so as to form a whole Extemporaneous – composed or performed on the spur of the moment, but it can be prepared/rehearsed ahead of time “Extemporaneous Preparation” - Pharmacist preparation of drug product after physician request on the spur of the moment Traditional compounding is typically used to prepare medications not commercially available, based on Physician – Patient – Pharmacist relationship at local pharmacy Quantity and scale of medication prepared in the anticipation of receiving a prescription is critical (compounding vs. manufacturing)

6. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 6 Utilizing the EP Approach for Clinical Trials Medical ‘approval’ and agreement for approach Appropriate scientific data (stability, dose recovery, etc.) Site appropriately qualified Formulation prepared at approved clinical site Drug product is prepared as needed and given to a patient: –Solutions –Suspensions –API in a capsule (AiC or DiC) –Over-encapsulation Made fresh with in use period Used for Ph 1 studies (Single Ascending Dose and if possible Multiple Ascending Dose)

7. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 7 Advantages / Disadvantages of EP Advantages Very short development time and resource Reduce API, no CT manufacture, no long term stability & reduced analytical method development Overall reduced expenses >$100K’s Flexible dosing to enable response to emerging clinical data Ideal for Ph I studies or exploratory IND (eIND) DIC Dev CT Dev DEV EP DIC Tablet EP DIC Tablet API to develop formulation FTE/Year burn EP Tablet Time-Line

8. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 8 Advantages / Disadvantages - EP Disadvantages – For in-patient studies only – Limited scope for complex formulations – No learning for the formulation development organization – Post Phase 1 – Change to oral solid – Some uncertainties regarding intercontinental regulatory requirements – Internal challenges to new approach

9. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 9 3 Areas of RA CMC Focus US EU Other Countries

10. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 10 Compounding vs. Manufacturing in US Where does GMP manufacturing stop and Practice of Pharmacy begin? Practice of Pharmacy ? GMP Manufacturing Quantity – batch size? Commercial scale equipment? How far in advance? Complexity of preparation? Within state law? Conditions of sale: immediate or future? FDA judgment call?

11. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 11 US Compounding Laws, Guidance, etc. USP Chapters: - Good compounding practices - Compounding – Non-sterile preparations - Compounding – Sterile preparation - Stability consideration in dispensing practices FDCA Section 503A “Pharmacy Compounding” FDA Compliance Policy Guides Manual, May 2002, “Sec. 460.200 Pharmacy Compounding”  A comprehensive list of factors to consider are provided (“not intended to be exhaustive”) Warning Letter http://www.fda.gov/cder/pharmcomp/default.htm State pharmacy laws FDA Change to 21CFR210 & Guidance Document: CGMP for Phase 1 Investigational Drugs

12. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 12 New FDA Regulations & Guidance Document for Phase 1 Compounds New paragraph added to 21CFR210 Law went into effect September 15, 2008 Newly approved CGMP Phase 1 Guidance Document (July 2008) published Applies specifically to Phase 1 Must be compliant with CGMP as stated in FD&C Act (Sec. 501): statutory requirement Most Phase 1 compounds no longer need to comply with 21CFR211 Applies to small molecule, biologics, placebos but not all phase 1 (human cell/tissue, device, PET, etc.)

13. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 13 New FDA Regulation Paragraph 210.2 added: Applicablitiy of cGMP practice regulations –“(c) An investigational drug for use in a phase 1 study, as described in § 312.21(a) of this chapter, is subject to the statutory requirements set forth in 21 U.S.C. 351(a)(2)(B). The production of such drug is exempt from compliance with the regulations in part 211 of this chapter.”

14. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 14 New FDA Regulation V. Recommended CGMP for Phase 1 Investigational Drugs –“Consistent with the FD&C Act (§ 501(a) (2) (B)), CGMP must be in effect for the manufacture of each batch of investigational drug used during phase 1 clinical trials. Manufacturers should establish manufacturing controls based on identified hazards for the manufacturing setting that follow good scientific and QC principles. –“These recommendations provide flexibility to the manufacturers in implementing CGMP controls appropriate to their specific situation and application.” Replaces 1991 guidance “Preparation of Investigational New Drug Products (Human and Animal)” as it applies to Phase 1 only; still applies to Phase 2 Material used for, or produced for Phase 2 & beyond, needs to comply with part 211 (i.e., Phase 1 material not manufactured under 211 cannot be used for Phase 2)

15. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 15 Various Sections with FDA Phase 1 Guidance Document “All personnel should have the education, experience, and training or any combination thereof to enable each individual to perform their assigned function. In particular, personnel should have the appropriate experience to prepare the phase 1 investigational drug and be familiar with QC principles and acceptable methods for complying with the statutory requirement of CGMP…” Personnel & QC Function “adequate work areas and equipment for the intended task” & “written procedures describing the handling, review, acceptance, and control of material (i.e., components, containers, closures) used in the manufacture of a phase 1 - Facility & Equipment; Control of Components, and Containers and Closures; Manufacturing and Records “As indicated in previous sections, manufacturers should keep complete records relating to the quality and operation of the manufacturing processes” Laboratory Testing; Packaging, Labeling, and Distribution; Recordkeeping We recommend that you manufacture only one phase 1 investigational drug at any given time, in an area or room separate from unrelated activities. However, you could use the same area or room for multiple purposes, including manufacture of other investigational products or laboratory research, provided that appropriate cleaning and procedural controls are in place to ensure that there is no carry-over of materials or products, or mix- ups.” Multi-product facilities Phase appropriate GMP

16. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 16 European Regulations CT Directive 2001/20/EC (Article 13) 1.“Member States shall take all appropriate measures to ensure that the manufacture or importation of investigational medicinal products is subject to the holding of authorisation.” 2. “Member States shall take all appropriate measures to ensure that the holder of the authorisation referred to in paragraph 1 has permanently and continuously at his disposal the services of at least one qualified person…” Directive 2005/28/EC (Article 9) 2. “Authorisation, as provided for in Article 13(1) of Directive 2001/20/EC, shall not be required for reconstitution prior to use or packaging, where those processes are carried out in hospitals, health centres or clinics, by pharmacists or other persons legally authorised in the Member States to carry out such processes and if the investigational medicinal products are intended to be used exclusively in those institutions.”

17. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 17 Other Country Regulations Canada CMC information provided as normal to Health Canada Request for protocol or preparation record with submission Singapore No CMC provided to Health Sciences Authority Minimal information provided in IB

18. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 18 Recommended CMC RA Requirements Strategy for proposed methodology, facility approval, country experience, etc. must be understood Generate adequate scientific data to support the EP activities (e.g., stability and % recovery) Solution stability must be conducted (at least 24hrs.) and included in submission; consider 1 month for DiC Batch (preparation) record should be approved prior to execution, ensuring appropriate documentation and compliance with submission documents Acceptable range of dose for weight (+/-3 to 5%) Control of drug product likely to be simple physical appearance examination by the pharmacist (e.g. free from undissolved material) Applicable Drug Product sections would be filled out accordingly Drug Substance sections would not change

19. R. Hoffman March 2009 Company Confidential Copyright © 2000 Eli Lilly and Company 19 Conclusions EP approach is flexible, economic, medically useful tool Practice performed by many companies for many years Favorable experience in some countries (US, EU, Singapore) Submission requirements similar but less extensive for DP section Delivering compounds safely to patients is top priority Questions / Comments?