1. 1 Strategies and Technologies to Improve the Detection of Pharmaceutical Adulterants Michael Hunnicutt, Ph.D. Pfizer Global Quality Operations Analytical Sciences

2. 2 CFR Part 210 – Adulterated Drugs Section 501 (a) (2) (B) –A drug or device shall be deemed to be adulterated, –if it purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standards set forth in such compendium –if its strength differs from, or its purity or quality falls below, that which it purports or is represented to possess –if any substance has been (1) mixed or packed therewith so as to reduce its quality or strength or (2) substituted wholly or in part

3. 3 Economically Motivated Adulteration Working Definition –May 2009, FDA Public Meeting –Fraudulent, intentional substitution or addition of a substance in a product for the purpose of increasing the apparent value of the product or reducing the cost of its production, i.e. for economic gain.

4. 4 Occurrence and Consequences Increased prevalence with supply chain globalization Examples across many business sectors Associated with serious adverse events Disruption of product supply Financial impact associated with recall, destruction, and root cause investigation Reduced consumer confidence in industry and regulatory authorities

5. 5 Quality Control Testing Current paradigm –Methods and specifications developed based on an in-depth knowledge of what is expected in the raw material or product, and attributes critical to Safety and Quality –Methods not designed to detect unanticipated contaminants or intentional adulterants –How do you design a specific test for something you are not looking for ?

6. 6 Quality Control Testing Evolving paradigm –Identity, Strength, Quality, Purity, and ……. –Test(s) included for specific adulterants associated with ‘at-risk’ materials EG and DEG in sugar alcohols, propane diols and triols, polyols, and associated derivatives Pharmaceutical components at risk for melamine contamination –Ingredients or raw materials that rely on a test for nitrogen content for their identity or purity or strength, and that contain nitrogen in amounts greater than 2.5 percent –Sourced starting material can be derived from animal materials and tested for total nitrogen for protein content

7. 7 Analytical Strategies & Adulteration Are there analytical strategies that can prevent future cases of adulteration? –What can be done to…….. Predict and/or Prevent Deter and/or Detect –Case Studies of Known Adulterants

8. 8 Predicting and Preventing Understand potential risks related to sourcing and material management that could lead to adulteration or unintentional contamination –Demand, availability, and pricing of materials –Sourcing of starting materials and intermediates –Manufacturing, packaging, shipping of the final material Use of risk management tools to identify potential control points FMECA: Failure Mode Effect and Criticality Analysis HACCP: Hazard Analysis and Critical Control Points

9. 9 Predicting and Preventing Understand if there are materials with similar properties that could be substituted for an authentic material and go undetected by….. –the existing ID or impurity method –the existing potency method chemical vs. biological end-point assays Analytical technologies and methods alone cannot predict or prevent adulteration

10. 10 Deterring and Detecting Supplier’s Certificate of Analysis –Require testing for potential adulterants for materials identified as ‘at-risk’ –Consider periodic surveillance testing Screening incoming materials based on spectral matching versus reference materials with appropriate mathematical treatment –NIR, mid-IR, Raman (portable and non-portable) –Spectral library of known and suspected adulterants

11. 11 Deterring and Detecting Heightened awareness when verifying the identity, strength, and purity of incoming ‘at risk’ raw materials Integrated testing regimens increase probability of detecting (e.g. orthogonal methods) No testing approach or analytical methodology alone is foolproof (e.g. universal detector)

12. 12 Case Studies Retrospective Analysis of Adulteration –Glycerine –Heparin –Melamine

13. 13 Glycerine Original ‘Approved’ Assay and Identification Methods –Lacked specificity to detect and measure contaminates/adulterants Complex issue due to identification requirement –Requires specific ID testing when not performing full USP testing New Method(s) with improved specificity for adulterants –Approaches explored: TLC, HPLC, GC-FID, GC-FID (IS) –Current: GC-FID with internal standard to avoid false positives A number of related raw materials identified by FDA as ‘high priority’ for adulteration with DEG and EG –Sugar alcohols, propane diols/triols, polyols, & derivatives

14. 14 Heparin Similar compendial implications but for a complex polysaccharide isolated from a biological source Lack of specificity and sensitivity of original identification and assay method to detect unknown contaminants Age of monograph –Evolution of analytics / bioassay science and technology Original monograph included –Flame test for sodium (I.D.) –Sheep plasma clotting (Assay)

15. 15 Heparin Monograph evolved as the analytical techniques capable of detecting the adulterant were identified Transformed the concept of identity testing –Specificity to the point of detecting a specific impurity Application of orthogonal methods to increase the probability of detecting unknowns –Proton NMR, Anion Exchange Chromatography, and Potency Assay Specificity and selectivity of the assay –Sheep Plasma Clotting  Chromogenic anti-Factor IIa

16. 16 Melamine Animal Feed, Food, Infant Formula, and Pharmaceuticals Ingredients that rely on a test for nitrogen content Source starting material can be derived from animal materials Adulteration went undetected due to non-specific assay Current Analytical Technologies and Test Methods  Chromatography & Detection (LC-UV, DAD; GC-FID)  Chromatography & Mass Spec. Detection (GC-MS, LC-MS, LC-MS/MS)  Enzyme Immunoassays (ELISA, EIA)  Surface Enhanced Raman (SERS)  Near- and Mid-Infrared (NIR, FTIR-ATR, FTIR-DRIFT)

17. 17 Melamine Total Time to Detection 2 – 3 h: Conventional and High Power Chromatography/Detection 1.5 h: Enzyme Immunoassay 0.25 – 1 h: SERS, Near- and Mid-Infrared ‘Ideal’ Method Characteristics for Adulterant Testing –High Specificity and Accurate –Sensitivity (ppb to ppm) –Simple, Rugged, and High Throughput –Portability –Cost Effective and Reliable Instrumentation –Method Independent of Matrix

18. 18 Additional Approaches - Predict, Prevent, Deter, and Detect What else have we learned? Awareness and Intelligence Gathering Public Forums and Global Harmonization Speed – Detection, Mobilization, Coordination Excellent Science and Cutting Edge Technologies Industry – Regulatory Information Sharing ‘Integrated’ Surveillance Programs for ‘At-Risk’ Materials Prosecution and Penalties Continued Efforts to Improve Supply Chain Integrity

19. 19 Acknowledgements Pfizer: S. Grode, J. Leary, A. Motwani, J. Strickland, J. Strode, W. Workman 1.R. Sasisekharan, Z. Shiriver, From Crisis to Opportunity: A Perspective on the Heparin Crisis, Thromb Haemost 2009, 102: 854. 2.R. Abernethy, Heparin, Glycerine – Case Studies and Compendial Implications, USP-IPC 8 th Annual Scientific Meeting, Feb. 2009. 3.D. Bugay, Adulteration and Contamination: Technologies of the Future Overview of Instrumentation, USP Annual Scientific Meeting, Sept. 2009. 4.R. Lutter, Addressing Challenges of Economically-Motivated Adulteration, FDA Public Meeting, May 2009. 5.L. Mauer et.al., Melamine Detection in Infant Formula Powder Using Near and Mid Infrared Spectroscopy, J. Agric. Food Chem. 2009, 57, 3974. 6.C. Sheehan, New Tests for Identifying Harmful and Potentially Deadly Adulterants in Pharmaceutical Ingredients: The Role of USP in Setting Revised Standards, May 2010. 7.Guidance for Industry, Pharmaceutical Components at Risk for Melamine Contamination, CDER-FDA, Aug. 2009. 8.J. Spink, Food Fraud & The Chemistry of the Crime, FDA Public Meeting, May 2009. 9.J. Kauffman, C. Gryniewicz, et.al., Pharmaceutical Surveillance with Rapid Spectroscopic Screening Technologies, American Pharmaceutical Review, Jan. 2010.