SafeBridge Consultants, Inc.

1. Risk-MaPP Quality & IH Implications Robert Sussman, Ph.D., DABT Managing Principal, Eastern Operations John P. Farris, CIH President & CEO Pharmaceutical IH Forum – May 18, 2011 Some slides courtesy of ISPE and PharmaConsult US SafeBridge Consultants, Inc.

2. Product Quality Applications

3. Causes of Cross-Contamination • Mix-up • Wrong ingredient in wrong equipment/batch • Retention • Inadequate cleaning • Mechanical transfer • Moving residue from one place/device to another • Airborne transfer • Airborne powders can contact product or product contact surfaces

4. Current Guidance – ICH Q7A (FDA 2001) • “The use of dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained.” • Similar language in Canadian, European, and Brazilian regulations. • certain antibiologics, certain hormones, certain highly active drugs

5. Highly Hazardous Compounds • Adapted from the NIOSH Hazardous Drug Alert • Genotoxic compounds that are known or likely to be carcinogenic to humans • Compounds that can produce reproductive and/or developmental effects at low dosages • Compounds that can produce serious target organ toxicity or other significant adverse effects at low dosages • “for which validated cleaningor inactivation procedures cannot be established (e.g., the acceptable level of residue is below the limit of detection by the best available analytical methods).”

6. Approaches to Establishing Cleaning Limits • 1/1000 of the low clinical dose – May be over-protective or under-protective, depending on the data set • LD50/50,000 – May be over-protective or under-protective, depending on the data set • 10 ppm– Arbitrary GMP-based value permits carryover based on potency of subsequent product • 100 µg/swab – Upper limit to ensure visual cleanliness (VRL – Visual Residue Limit) • No standard, prescribed approach • Above methods are NOT science- or risk-based

7. History • June 2005 ISPE Meeting • FDA thinking of requiring “potent” or “hazardous” compounds to be segregated similar to penicillins • Big Pharma representatives discussed alternatives • Several speakers invited to present approach at FDA • January 2006 – presentation to FDA • How to set ADEs • Exposure assessments • Flexible approaches to containment • Cleaning validation • FDA very supportive of ISPE’s Guideline approach & wanted to be involved in development

8. Risk-Based Manufacturing of Pharmaceutical Products HAZARD QUALITY CONTROL RISK

9. What is Risk-MaPP? • Risk-MaPP provides a scientific, risk-based approach based on ICH Q9 for setting health-based cross-contamination and cleaning validation limits • These limits drive the risk controls that are implemented on a case-by-case basis to maintain product quality • Engineering controls may reduce airborne dust and obviate the need for segregation • Dedication / segregation always remain an option, but should not be seen as precedent-setting

10. ICH Q9 - Quality Risk Management Risk Identification Systematic use of information to identify hazards. Risk Analysis Estimation of risk associated with identified hazards. Risk Review Risk Evaluation Comparison of analyzed risk against given risk criteria. Risk Control Decision making to reduce and/or accept risks.

11. Concepts of a Risk-Based Approach • Hazard is an inherent property of a drug • Zero risk not scientifically achievable or necessary • Risk = (Hazard X Exposure) • Hazard is fixed • Exposure can be controlled • High Hazard does not necessarily mean high Risk • Use a consistent, robust, science-based approach • Make decisions case-by-case, not by class • Control risk by methods other than segregation

12. Establishing Health-Based Limits:Acceptable Daily Exposure (ADE) • Define a daily dose of a substance, below which no adverse effects are anticipated, even if exposure occurs over a lifetime: • Identify the critical endpoint (most sensitive clinically significant health effect) • Define the No-observed-adverse-effect level (NOAEL) or Lowest-OAEL (LOAEL) • Consider sources of uncertainty and choose appropriate “safety factor(s)” • Calculate an ADE for that route of exposure

13. Calculating an ADE ADE (mg/day) = NOAEL (mg/kg/day) x BW (kg) UFC x MF where: NOAEL = No-observed-adverse-effect level BW = Body weight UFC = Composite uncertainty factor(s) MF = Modifying factor

14. Threshold of Toxicological Concern (TTC) • Compounds likely to be carcinogenic ADE = 1 µg/day • Compounds likely to be potentor highly-toxic ADE = 10 µg/day • Compounds NOTlikely to be potent, highly toxic, or genotoxic ADE = 100 µg/day Provides guidance for unstudied compounds that fall into one of three categories: Dolan DG, Naumann BD, Sargent EV, Maier A, Dourson M Application of the threshold of toxicological concern concept to pharmaceutical manufacturing operations. Regul. Tox. Pharm. 43:1-9 (2005)

15. Application of ADE • Calculate maximum allowable carry-over (MACO) from one product to another (Parenteral Drug Association cleaning guidance, 1992) • Calculate cleaning limit for product contact surfaces based on surface area, batch size, and dose of the next drug

16. Compound A • Opioid Analgesic • LD50 = 10,000 mg/kg • Lowest Clinical Dose (LCD) = 10 mg/day • UFC = 30 • MF = 3 • ADE = (10 mg/day)/(30 x 3) = 100 µg/day

17. Compound B • Genotoxic antineoplastic agent • LD50 = 3,400 mg/kg • LCD = 70 mg/day • ADE = 1 µg/day • TTC

18. Comparison to Other Limits

19. ADE Caveats • An ADE is for patient use and may need to include sensitive subgroups (elderly, children) that are not considered in developing an OEL • An ADE is NOT equal to the OEL x 10 m3 • May use same data set, but different safety factors and bioavailability data may be applied • Consider sensitive sub-populations • Consider bioavailability by the route of administration

20. FDA’s Response to Risk-MaPP • “… the firm’s rationale for the residue limits established should be logical … and be practical, achievable, and verifiable…” • “Check the manner in which limits are established… The objective of the inspection is to ensure that the basis for any limit is scientifically justifiable.” • “Encourage implementation of risk-based approaches that focus both industry and Agency attention on critical areas…” • “Ensure that regulatory review, compliance, and inspection policies are based on state-of-the-art pharmaceutical science.”

21. Industrial Hygiene Applications

22. Industrial Hygiene Applications • Traditionally IH tools have not been accepted for quality determination purposes • Risk-MaPP incorporates basic safety elements of risk assessment and risk management used for decades • Air monitoring studies now requested by regulatory inspectors in EU and FDA • Sterile fill/finish company • Generics company • Specialty Device CMO • API CMO

23. Air Sampling Factors • Some drug agency regulators: • Interested in personal sampling and demonstration of health protective environment; and • Interested in quality and prevention of releases out of primary process rooms • Other drug agency regulators: • Interested only in detection of materials in adjacent areas

24. Industrial Hygiene Air Monitoring • IH monitoring data intended to be compared to health-based limits • Limits of detection of sampling & analytical methods should be based on health limits (OELs, PELs, TLVs etc.) • Methods must be validated for air monitoring • Samples stable in air streams • Volume limitations determined • Device types and samples extraction procedures established • Sampling plan should be established prior to survey • Include personal and area samples to answer particular questions

25. Issues with Air Monitoring and Quality • Air samples may be indicative of a potential to impact product quality • Not proof • Interpretation of data without limits established in advance • Method sensitivity may not be appropriate • Quantitative results must be compared to something • Detection does not equal risk • Inherent limitations of monitoring • +/- 25% accuracy • Number of samples required to determine confidence

26. Surrogate Monitoring Results:Clinical Scale Operations (µg/m3)

27. API Monitoring Results (µg/m3) Testing and release process inside ventilated enclosure

28. Summary • Quality audits should review cleaning validation programs • Cleaning limits should be health-protective, i.e.: • Based on the ADE developed by toxicologists • Using well-established methodology • From data in regulatory filings or the open literature • Air monitoring is a useful indicator of potential for release of material • Designed for occupational health determinations • May be used as one aspect of product quality and assist with case for multiproduct facilities • Interpretation of that data is dependant on a number of factors • Be careful what you ask for!