How do you know the drug you are using is safe and effective?

Transcription

1 The Chemistry, Manufacturing, and Controls (CMC) Technical Section: The Big Picture of a Long-term Commitment AAVPT Workshop February 28, 2011 James K. Nitao, Ph.D. Biotherapeutics Team Division of Manufacturing Technologies U.S. FDA, Center for Veterinary Medicine How do you know the drug you are using is safe and effective? Because clinical studies demonstrated the drug is safe and effective? Hypothetical Timeline of a Drug s Life: 1999: Drug batches are made for clinical studies 2005: CVM approves the drug for marketing 2006: Drug product manufacturing moved from New Jersey to Missouri Clinical studies demonstrate that the drug is safe and effective First commercial batches are manufactured and sold to the public 1

2 2008: Product expiry extended from 12 to 24 months 2009: New stopper composed of different polymer 2010: Major renovations made to the aseptic fill facility Moved sterilization of vials and stoppers to another facility New HPLC method used to test drug prior to release Active ingredient manufacturing moved from US to China Summary: Eleven years ago, safety and effectiveness studies were performed using a drug made in a New Jersey facility, and formulated with an active ingredient made in the U.S. Today, the drug is made in a different facility using different equipment and procedures, with an active ingredient made by a different company (located overseas), and with containers made with different materials. How do you know - Impurity levels are still being adequately controlled? - The new HPLC method accurately measures the potency of the drug? - The new stopper adequately seals the vial after multiple needle punctures (if the drug is packaged in a multi-dose container)? - The current depyrogenation procedure still removes endotoxins from the new stopper polymer? - The drug and its container components are sterile? 2

3 How do you know the drug you are using is still safe and effective? Are clinical studies by themselves sufficient to assure the safety and effectiveness of a marketed drug? A well designed and controlled manufacturing process is needed to assure product quality and consistency from unit dose to unit dose from vial to vial from batch to batch Potency Which drug do you want to be using? Batches Batches 3

4 Why is there a CMC section? To assure that the drug sold to the public will have quality attributes similar to those of the drug demonstrated to be safe and effective To assure that the quality of the drug meets appropriate standards and is consistent To assure that the drug you are using is the drug described on the label CMC technical section How and where is the drug made? How are raw materials tested and monitored? What control procedures are in place to assure product consistency and quality? Are quality attributes adequately identified and characterized for the product? Are the test methods used to monitor product quality appropriate? How long does the product maintain its quality after it is made (shelf life)? Drug used in clinical studies Safe and effective CMC helps maintain the connection in quality between the drug used in clinical studies and the marketed drug Drug marketed to consumers Commercial product 4

5 Clinical Batches Safety and effectiveness studies Pilot Batches CMC information Engineering Batches Scale-up from pilot to commercial Process Validation Batches Implementation of commercial manufacturing processes Commercial Batches Product marketed to consumers Batches at each stage should be made using the same or similar processes and raw materials CMC is Specific to the Product How is the product sterilized? Is the sterilization process validated? Is the manufacturing environment monitored to control microbial contamination? How is sterility of the finished product monitored? Does the vial and stopper keep the product sterile? How is the vial and stopper depyrogenated? If the container is used for multiple doses, does the stopper keep the product sterile after punctured? Is a preservative needed in the formulation? Process Understanding is Vital to Quality and Consistency Testing of the finished drug product alone is insufficient for control of product quality The manufacturer should know which steps and variables in the manufacturing process need to be controlled and why Process understanding is the foundation of a controlled manufacturing process 5

6 Quality Attribute A manufacturing process under control exhibits consistency of product quality Batches Batches Current Good Manufacturing Practices Chemistry, Manufacturing, and Controls CMC review and cgmp compliance may overlap but are not the same Center for Veterinary Medicine Office of Regulatory Affairs Lead office for FDA domestic and foreign field activities including cgmp inspections Division of Manufacturing Technologies (CMC Reviewers) Division of Compliance (Compliance Officers) 6

7 CMC cgmp CVM Division of Manufacturing Technologies reviews the CMC technical section which is not an evaluation of current Good Manufacturing Practices (cgmps) and will request inspections if needed cgmp compliance is assessed by inspections by investigators in the FDA Office of Regulatory Affairs but FDA Centers are involved under certain circumstances District Offices (within the Office of Regulatory Affairs), CVM Division of Manufacturing Technologies, and/or Division of Compliance determine regulatory actions regarding inspections Manufacturing Facilities Every facility should be identified and approved in the CMC section, and every facility must comply with current Good Manufacturing Practices (cgmps) including: Manufacturers of API Manufacturers of finished drug product Contract sterilization facilities Packagers Testing Laboratories Over time, change is inevitable Raw material suppliers Manufacturing sites Manufacturing processes Manufacturing equipment Packaging Specifications Testing procedures But product quality should be constant (or improve) 7

8 Drug used in clinical studies Safe and effective CMC Review of Post-Approval Changes: Will the quality of the marketed product still be similar to that of the drug shown to be safe & effective? Drug marketed to consumers Commercial product The drug sponsor must report CMC changes to CVM for as long as it owns and markets the product Review of Drug Before Approval Drug Approval Post-approval CVM reviews CMC changes and stability data from on-going studies Role of CMC review and generic drugs 8

9 Pioneer (Innovator) Drug The manufacturer of the Generic Drug does not know how the pioneer drug is made or exactly what the components and composition are in the pioneer drug (other than the active ingredient) Generic Drug Pioneer (Innovator) Drug CMC review helps maintain the connection in quality between the pioneer drug and the generic drug Generic Drug CMC review helps assure that Quality is designed into the manufacturing process (and does not rely on testing alone) Quality is maintained as long as the product is marketed 9

10 For More Information: James K. Nitao, Ph.D. Biotherapeutics Team Division of Manufacturing Technologies Office of New Animal Drug Evaluation FDA, Center for Veterinary Medicine 7500 Standish Place Rockville, Maryland (240)