1. Applications of Analytical Chemistry in Pharmaceuticals Corey M. Chong 10Mar10

2. Topics of Discussion -What to test: the drug product -Why to test: the Code of Federal Regulations (CFRs) -How to test: compendial and non-compendial methods presented in regulatory documents (IND/NDA)

3. About the Speaker -Started as environmental analytical chemist. -Transitioned to pharmaceuticals as a Quality Control analyst. -Worked for “Big Pharma” in Analytical R&D. -Now specializes in Regulatory CMC (Chemistry, Manufacturing, and Control).

4. The Big Picture (Drug Product for Sale to the Public) -Product Label (the box/carton and the individual container label) - List of ingredients including strength of the API - Expiration date - Recommended storage condition -Package Insert - Chemical formula and description of the API - Drug product composition (description of formulation) - Directions for use

5. Container Example Expiration date printed on container label

6. Label Information Example Usual Dosage: Read accompanying prescribing literature NDC 59011-100-10 OxyContin® (oxycodone hydrochloride controlled-release) tablets 100 Tablets Rx Only Swallow tablets whole. Do not crush or chew. Dispense in a tight, light-resistant container. Store at 25°C (77°F); excursions permitted between 15°–30°C (59°–86°F). 10 mg Purdue Pharma L.P. Stamford, CT 06901-3431 Lot 0137BA 0314540B

7. Package Insert Example See OxyContin® Package Insert PDF -Page 2: API description and drug product formulation -Page 25: packaging and drug product description -Page 27: storage conditions -Page 1 and 28: directions for use

8. 21 CFR Part 211 cGMPs for Finished Pharmaceuticals -Subpart B Organization and Personnel - Sec 211.22 Responsibilities of quality control unit. “Adequate lab facilities for testing and approval…”

9. 21 CFR Part 211 cont’d -Subpart E Control of Components and Drug Product Containers and Closures - Sec 211.84 Testing and approval or rejection of components and drug product containers and closures. (d)(1) “At least one test shall be conducted to verify identity…” (d)(2) “Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality.”

10. 21 CFR Part 211 cont’d -Subpart F Production and Process Controls - Sec 211.110 Sampling and testing of in-process materials and drug product. (c) “In-process materials shall be tested for identity, strength, quality, and purity…”

11. 21 CFR Part 211 cont’d -Subpart G Packaging and Labeling Control - Sec 211.137 Expiration dating. (a) “To assure that a drug product meets applicable standards for identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability testing described in Sec 211.166.”

12. 21 CFR Part 211 (cont’) -Subpart I Laboratory Controls - Sec 211.165 Testing and release for distribution. (a) “For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specification for the drug product, including identity and strength of each active ingredient prior to use.” - Sec 211.166 Stability testing (a) “There shall be a written testing program…”

13. Regulatory Information (IND/NDA using eCTD format) -Module 3 Quality - 3.2.S Drug Substance (Active Pharmaceutical Ingredient) - 3.2.P Drug Product

14. 3.2.S Drug Substance -3.2.S.1 General Information -3.2.S.2 Manufacture -3.2.S.3 Characterization -3.2.S.4 Control of Drug Substance -3.2.S.5 Reference Standards or Materials -3.2.S.6 Container Closure -3.2.S.7 Stability

15. 3.2.S.1 General Information -S.1.2 Structure - As determined in S.3.1 -S.1.3 General properties - Appearance - Solubility, aqueous and non-aqueous - Melting range - Polymorphism

16. 3.2.S.2 Manufacture -S.2.2 Description of Manufacturing Process and Process Controls - Flow diagram indicating when in-process testing occurs -S.2.4 Controls of Critical Steps and Intermediates - Moisture (USP ) - Residual solvents (USP ) - Heavy metals (USP ) - Content Uniformity (USP )

17. 3.2.S.3 Characterization -S.3.1 Elucidation of Structure - UV-Vis Spectroscopy (USP ) - XRD (X-ray Diffraction) (USP ) - MS (Mass Spectroscopy) - IR Spectroscopy (Infrared) (USP or ) - NMR (Nuclear Magnetic Resonance) (USP ) - DSC (Differential Scanning Calorimetry) - TGA (Thermogravimetric Analyses) - Melting Range (USP ) - Elemental analysis

18. 3.2.S.4 Control of Drug Substance -S.4.1 Specification - Purity (HPLC) - Impurities (HPLC), limits should conform to ICH Q3 - Residual solvents (GC, USP ) - Moisture (USP ) - Appearance (Visual) - Heavy Metals (USP ) - X-ray Diffraction (USP ) - Particle Size (USP ) - Bacterial Endotoxin (USP ) - Microbial Limits (USP )

19. 3.2.S.4 Control of Drug Substance (cont’) -S.4.2 Analytical Procedures - Actual method details e.g., chromatography column conditions, gradients, and mobile phases; instrument settings and detector wavelengths. -S.4.3 Validation of Analytical Procedures - Accuracy, Precision, Specificity, Linearity, Range, Ruggedness, LOD, LOQ. - See ICH Q2

20. 3.2.S.7 Stability -S.7.1 Stability Summary and Conclusions - Typically the same methods listed on the specification with all the stress conditions that support the recommended storage condition. Stress conditions designed following ICH Q1. -S.7.2 Post-Approval Stability Protocol and Stability Commitment - Typically the same methods listed on the specification with all the stress conditions that support the recommended storage condition. -S.7.3 Stability Data

21. 3.2.P Drug Product -3.2.P.1 Description and Composition of the Drug Product -3.2.P.2 Pharmaceutical Development -3.2.P.3 Manufacture -3.2.P.4 Control of Excipients -3.2.P.5 Control of Drug Product -3.2.P.6 Reference Standards or Materials -3.2.P.7 Container Closure -3.2.P.8 Stability

22. 3.2.P.1 Description and Composition of the Drug Product -Description of drug product including formulation and packaging options. A manufacturing formula for each formulation is presented per unit e.g., the amount of excipient and API per pill or vial.

23. 3.2.P.3 Manufacture: Example for Tablets -P.3.3 Description of Manufacturing Process and Process Controls - e.g., tablets via dry or wet granulation -P.3.4 Controls of Critical Steps and Intermediates - Loss on Drying (USP ) - Weight Variability - Bulk/Tap Density (dry, USP ) - Hardness (compression force) - Blend uniformity - Particle Size (USP )

24. 3.2.P.3 Manufacture: Example for Solution for Injection -P.3.3 Description of Manufacturing Process and Process Controls - e.g., asceptic fill -P.3.4 Controls of Critical Steps and Intermediates - pH (USP ) - Osmolality (USP ) - Bioburden (USP ) - Assay - Endotoxin (USP )

25. 3.2.P.4 Control of Excipients -Same format as Control of Drug Product but specific for individual excipients used in the formulation.

26. 3.2.P.5 Control of Drug Product: Example for Tablets -P.5.1 Specification(s) - Label Claim (HPLC) - Dissolution (HPLC, USP ) - Friability (USP ) - Moisture (Karl Fischer, USP ) - Bisect (HPLC) - Appearance (Visual, Munsell color) - Degradents (HPLC) - Disintegration (USP ) - Hardness (USP ) - Content Uniformity (USP ) - Residual solvents (USP )

27. 3.2.P.5 Control of Drug Product: Example for Solution for Injection -P.5.1 Specification(s) - Assay (HPLC) - Appearance (Visual) - Degradents (HPLC) - Determination of Volume of Inj in Containers (USP ) - Particulate Matter (USP ) - pH (USP ) - Osmolality (USP ) - Endotoxin (USP ) - Sterility (USP )

28. 3.2.P.5 Control of Drug Product (cont’) -P.5.2 Analytical Procedures - Actual method details e.g., chromatography column conditions, gradients, and mobile phases; instrument settings and detector wavelengths. -P.5.3 Validation of Analytical Procedures - Accuracy, Precision, Specificity, Linearity, Range, Ruggedness, LOD, LOQ. - See ICH Q2 -P.5.5 Characterization of Impurities - See ICH Q3

29. 3.2.P.8 Stability -P.8.1 Stability Summary and Conclusions - Typically the same methods listed on the specification with all the stress conditions that support the recommended storage condition. Stress conditions designed following ICH Q1. -P.8.2 Post-Approval Stability Protocol and Stability Commitment - Typically the same methods listed on the specification with all the stress conditions that support the recommended storage condition. -P.8.3 Stability Data

30. References -21CFR Part 211 -United States Pharmacopeia (USP) -International Conference on Harmonisation (ICH) Quality Guidelines - Q1 Stability - Q2 Analytical Validation - Q3 Impurities -FDA Guidance Documents - Changes to an Approved NDA or ANDA - INDs for Phase 2 and Phase 3 Studies CMC Infomation

31. Closing “It is not enough to do your best; you must know what to do, and THEN do your best.” W. Edwards Deming