1. Understanding CGMPs – What Attorneys Need to Know The Nuts & Bolts of CGMPs: FDA Guidance for Industry Paula R. Katz Acting Branch Chief, Regulatory Policy and Collaboration CDER/Compliance/Office of Manufacturing and Product Quality July 10, 2013

2. Objectives Brief background –Where do guidance documents fit into the regulatory scheme? –What are the types of guidance documents? CGMP Guidances –Practical matters –Recent GFIs –ICH “Q” documents Help!

3. Admin Law 101 Congress says what is mandatory in the FDCA (or PHSA, etc.) Secretary (FDA) promulgates regulations that indicate details about what is required by the Act (21 CFR 210 & 211, 600s, etc.) Guidance documents describe FDA’s current thinking on a particular topic –Not binding on FDA or any party

4. Types of Guidances GGPs (21 CFR 10.115) establish 2 types Level 1: –First interpretations of statutory or regulatory requirements –Changes in interpretation or policy (not minor in nature) –Complex scientific and highly controversial issues –May solicit public input before issuance, but comments can be submitted at any time Level 2: –Existing practices or minor changes in interpretation or policy –Level 2 guidances post directly to the internet

5. Documents that are not “Guidance for Industry” (but we know you look at them ) Compliance Policy Guides (CPGs) –advise field inspection and compliance staff on standards and procedures for determining industry compliance http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/default.htm Compliance Program Guidance Manuals (CPGMs) –instructions to FDA staff for obtaining information to help fulfill agency plans in the specified program areas http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/default.htm

6. Some Practical Matters All Human Drug GFIs on the web at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm –For CGMP GFIs, click “Current Good Manufacturing Practices (CGMPs)/Compliance” –Don’t forget about International Conference on Harmonisation (ICH)-- especially the “Q”s (more later) Guidance Agenda: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC M314767.pdf http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC M314767.pdf Comments: –You can comment on any guidance at any time. –Especially for drafts, submit electronically at www.regulations.gov www.regulations.gov

7. Recent CGMP Guidances* Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality ( 06/25/13) Contract Manufacturing Arrangements for Drugs: Quality Agreements (Draft 05/24/13) Non-Penicillin Beta-Lactam Drugs: A CGMP Framework ( 04/17/13) *Excludes PET drug guidance documents and ICH documents

8. Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality Final Guidance published June 25, 2013 Purpose: help manufacturers prevent the use of crude heparin that might contain over-sulfated chondroitin sulfate (OSCS) or non-porcine ruminant material contaminants

9. Contract Manufacturing Arrangements for Drugs: Quality Agreements Draft Guidance published May 24, 2013 Comment period closes July 29, 2013 Purpose: describe how Quality Agreements can be used to define, establish, and document the responsibilities of each party contract manufacturing of drugs

10. Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross- Contamination Final Guidance published April 13, 2013 Second of three planned guidance documents on cross-contamination Purpose: –explains health risk from cross-reactivity in defined classes of sensitizing beta-lactams –promotes use of dedicated facilities/equipment

11. Other GFIs Pyrogen and Endotoxins Testing: Questions and Answers (06/28/12) Questions and Answers on Current Good Manufacturing Practices (CGMP) for Drugs –L2 Guidances; most recently updated12/21/11 –http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm124740.htmhttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm124740.htm Dosage Delivery Devices for Orally Ingested OTC Liquid Drug Products (5/4/2011) Process Validation: General Principles and Practice (01/24/11) Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 (01/26/10) Pharmaceutical Components at Risk for Melamine Contamination (08/06/09) Current Good Manufacturing Practice for Phase 1 Investigational Drugs (07/14/08) *Excludes PET drug guidance documents and ICH documents

12. Other GFIs Testing of Glycerin for Diethylene Glycol (05/01/07) Investigating Out-of-Specification Test Results for Pharmaceutical Production (10/11/06) Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations (09/27/06) PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (09/29/04) Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice (09/29/04) *Excludes PET drug guidance documents and ICH documents

13. ICH Q7 and APIs All drugs are subject to CGMP under FDCA 501(a)(2)(B); no distinction between APIs, excipients, or finished pharmaceuticals 21 CFR 210 & 211 apply to finished pharmaceuticals; FDA has not promulgated CGMP regulations specifically for APIs FDA has long recognized that CGMP requirements in Parts 210 and 211 are valid and applicable in concept to API manufacturing Principles include, but not limited to: –building quality into drug by using suitable equipment and employing appropriately qualified and trained personnel, –establishing adequate written procedures and controls designed to assure manufacturing processes and controls are valid, –establishing system of in-process material and final tests –ensuring stability for intended period of use

14. ICH Q7 and APIs In 2001, FDA adopted an internationally harmonized guidance to industry on API CGMPs in conjunction with regulatory partners in the International Conference on Harmonization of Technical Requirements for Re gistration of Pharmaceuticals for Human Use (ICH)…

15. That’s a long way to say, “ICH Q7” ICH Q7 represents FDA’s current thinking on CGMPs for APIs Remember—no CGMP regulations for API, so… API and related manufacturing and testing facilities that follow ICH Q7 generally considered to comply with statutory CGMP –alternate approaches may be used –requirements of 501(a)(2)(B) can be met if approach ensures that API meets its purported or represented purity, identity, and quality characteristics ICH Q7 and other ICH guidances on the web at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005.htm Especially: Q9 Quality Risk Management & Q10 Quality Systems –See also: Q8 (development of product) and Q11 (development of APIs) –You might hear “drug substance” instead of “API” when dealing with FDA reviewers

16. You’ve Got Questions? We’ve Got Answers! CGMP Subject Matter Contact List http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedic alProductsandTobacco/CDER/ucm096102.htm Paula Katz Paula.Katz@fda.hhs.gov 301-796-6972