Understanding CGMPs – What Attorneys Need to Know

The Nuts & Bolts of CGMPs:FDA Guidance for Industry

Paula R. KatzActing Branch Chief, Regulatory Policy and Collaboration

CDER/Compliance/Office of Manufacturing and Product Quality

July 10, 2013

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!

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

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

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

Some Practical Matters• All Human Drug GFIs on the web at

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/UCM314767.pdf

• Comments: – You can comment on any guidance at any time.– Especially for drafts, submit electronically at www.regulations.gov

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

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

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

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

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.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

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

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

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)…

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 athttp://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

You’ve Got Questions? We’ve Got Answers!

• CGMP Subject Matter Contact Listhttp://www.fda.gov/AboutFDA/CentersOffices/

OfficeofMedicalProductsandTobacco/CDER/ucm096102.htm

• Paula KatzPaula.Katz@fda.hhs.gov

301-796-6972