Guidance for Industry

Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients

DRAFT GUIDANCE

This guidance document was distributed for comment purposes only.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Center for Veterinary Medicine (CVM)
March 1998

TABLE OF CONTENTS

I. INTRODUCTION

II. ORGANIZATION AND PERSONNEL

A. Responsibilities of the Quality Control Unit
B. Personnel Qualifications
C. Personnel Responsibilities
D. Consultants

III. BUILDINGS AND FACILITIES

A. Design and Construction Features
B. Lighting
C. Ventilation, Air Filtration, Air Heating and Cooling
D. Steam, Gases, and Other Utilities
E. Plumbing, Washing, and Toilet Facilities
F. Sewage and Refuse
G. Sanitation
H. Maintenance

IV. PROCESS EQUIPMENT

A. Equipment Design, Size, and Location
B. Equipment Construction and Installation
C. Equipment Cleaning and Maintenance Procedures
D. Equipment Cleaning Methods
E. Validation of Equipment Cleaning Methods
F. Clean in Place Methods
G. Automatic, Mechanical, Electronic, and Computer Equipment

V. CONTROL OF RAW MATERIALS

A. General Controls
B. Receipt, Sampling, Testing, and Approval of Raw Materials
C. Use and Reevaluation of Approved Raw Materials
D. Rejected Raw Materials
E. Control of Recovered Solvents, Mother Liquors, and Second Crops
F. Process Water Quality

VI. PRODUCTION AND PROCESS CONTROLS

A. Written Procedures and Deviations
B. Raw Material Weighing and Measuring
C. Calculation of Yield
D. Equipment Identification
E. In-Process Controls, Sampling/Testing of APIs and Intermediates
F. Time Limits on Production of APIs and Intermediates
G. Control of API Contamination
H. Blending of APIs and Intermediates

VII. PACKAGING AND LABELING CONTROLS

A. Materials Examination and Usage Criteria
B. API Label Issuance
C. Packaging and Labeling Operations
D. API Packaging Materials
E. Expiration or Retest Dating

VIII. HOLDING AND DISTRIBUTION OF APIs AND INTERMEDIATES

A. Warehousing Procedures
B. Distribution Procedures

IX. LABORATORY CONTROLS

A. General Controls 1
B. Testing and Release for Distribution
C. Stability Testing
D. Reserve Samples
E. Laboratory Animals

X. RECORDS AND REPORTS

A. General Controls
B. Equipment Cleaning and Use Record
C. Raw Material, API Packaging Materials, and Labeling Records
D. Master Production and Control Records
E. Batch Production and Control Records
F. Production Record Review
G. Laboratory Records
H. Distribution Records
I. Complaint Files
J. Returned APIs and Intermediates
K. API and Intermediate Salvaging

XI. VALIDATION

A. Process Validation Strategy
B. The Validation Protocol
C. Prospective Validation
D. Concurrent Validation
E. Retrospective Validation

XII. CHANGE CONTROL/REVALIDATION

A. Change-Control System
B. Change-Control Classification

XIII. REPROCESSING/REWORKING OF APIs AND INTERMEDIATES

A. Reprocessing by Repeating a Chemical Reaction
B. Reprocessing by Physical Manipulations
C. Reworking of APIs and Intermediates

XIV. CONTROL OF CHEMICAL, BIOLOGICAL, AND PHYSICAL CONTAMINANTS

XV. APIs FOR CLINICAL TRIALS

A. Quality Assurance Measures
B. Quality Control Unit
C. Equipment and Facilities
D. Control of Raw Materials 1
E. Production and Process Controls
F. Process Validation
G. Change Documentation
H. Laboratory Controls
I. Documentation

BIBLIOGRAPHY

GLOSSARY

__________________________________________________

For questions on the content of this draft document contact (CDER) Edwin Rivera, 301-594-0095; or (CBER) John A. Eltermann, 301-827-3031; or (CVM) Jose R. Laureano, 301-594-1785.