Guidance for Industry Investigating Out-of-Specification (OOS)
Test Results for
Pharmaceutical Production
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Rearch (CDER)
October 2006
Pharmaceutical CGMPs暑期出游
Guidance for Industry Investigating Out-of-Specification (OOS)
Test Results for
Pharmaceutical Production
逃人法
Additional copies are available from:
Office of Training and Communication
Division of Drug Information HFD-240
Center for Drug Evaluation and Rearch
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
v/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
怎样炖牛肉又烂又好吃Center for Drug Evaluation and Rearch (CDER)
October 2006
Pharmaceutical CGMPs
TABLE OF CONTENTS
秋天奏鸣曲若歌诗I.INTRODUCTION (1)
II.BACKGROUND (2)
III.IDENTIFYING AND ASSESSING OOS TEST RESULTS —
PHASE I: LABORATORY INVESTIGATION (3)
A.Responsibility of the Analyst (4)
B.Responsibilities of the Laboratory Supervisor (4)
IV.INVESTIGATING OOS TEST RESULTS —
PHASE II: FULL-SCALE OOS INVESTIGATION (6)
A.Review of Production (6)
B.Additional Laboratory Testing (7)
C. Reporting Testing Results (9)
V.CONCLUDING THE INVESTIGATION (12)
A.Interpretation of Investigation Results (12)
戒指折纸B.Cautions (14)
室内设计师简历C.Field Alert Reports (14)
GUIDANCE FOR INDUSTRY1
Investigating Out-of-Specification (OOS) Test Results
for Pharmaceutical Production
This guidance reprents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can u an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
I. INTRODUCTION
This guidance for industry provides the Agency’s current thinking on how to evaluate out-of-specification (OOS) test results. For purpos of this document, the term OOS results includes all test results that fall outside the specifications or acceptance criteria established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications.2
This guidance applies to chemistry-bad laboratory testing of drugs regulated by CDER. It is directed toward traditional drug testing and relea methods. The laboratory tests are performed on active pharmaceutical ingredients, excipients and other components, in-process materials, and fin
ished drug products3 to the extent that current good manufacturing practice (CGMP) regulations (21 CFR parts 210 and 211) and the Federal Food, Drug, and Cosmetic Act (the Act) (ction 501(a)(2)(B)) apply. The principles in this guidance also apply to in-hou testing of drug product components that are purchad by a firm. This guidance can also be ud by contract firms performing production and/or laboratory testing responsibilities. Specifically, the guidance discuss how to investigate OOS test results, including the responsibilities of
1 This guidance has been prepared by the Office of Compliance/Division of Manufacturing and Product Quality in the Center for Drug Evaluation and Rearch (CDER).
2 In certain instances, in-process testing is done solely for purpos of triggering real time equipment or system adjustments to prevent process drift. This guidance does not address the situations.
3 Chemistry-bad laboratory testing of biotechnology products that are under the jurisdiction of CDER are within the scope of this guidance. However, this guidance is not intended to address biological assays (e.g., in vivo, immunoassays).
laboratory personnel, the laboratory pha of the investigation, additional testing that may be necess
黑啤ary, when to expand the investigation outside the laboratory, and the final evaluation of all test results.
The Agency, in accordance with its August 2002 “Pharmaceutical CGMPs for the 21st Century” initiative, encourages modern approaches to manufacturing, monitoring, and control to enhance process predictability and efficiency. Process Analytical Technology (PAT) takes a different approach to quality assurance by using process controls and in-process data as the relea specification instead of relying on single laboratory determinations to make batch acceptability decisions. This guidance is not intended to address PAT approaches, as routine in-process u of the methods might include other considerations. For information on timely in-process testing, e the CGMP guidance entitled PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.
FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The u of the word should in Agency guidances means that something is suggested or recommended, but not required.
II. BACKGROUND
Laboratory testing, which is required by the CGMP regulations (§§ 211.160 and 211.165), is necessary to confirm that components, containers and closures, in-process materials, and finished products conform to specifications, including stability specifications.
Testing also supports analytical and process validation efforts.4 General CGMP regulations covering laboratory operations can be found in part 211, subparts I (Laboratory Controls) and J (Records and Reports). The regulations provide for the establishment of scientifically sound and appropriate specifications, standards, and test procedures that are designed to ensure that components, containers and closures, in-process materials, and finished drug products conform to the established standards. Section 211.165(f) of the CGMP regulations specifies that finished drug products that fail to meet established standards, specifications, or other relevant quality control criteria will be rejected.
Both finished pharmaceuticals and active pharmaceutical ingredients (APIs) are to be manufactured in accordance with current good manufacturing practice under ction
4Specifications must be scientifically sound and appropriate (§ 211.160(b)), test procedures must be
validated as to their accuracy, nsitivity, specificity, and reproducibility (§ 211.165(e)), and the suitability of the test procedures under actual conditions of u must be documented (§ 211.194(a)(2)). For products that are the subjects of new drug applications (NDAs), abbreviated new drug applications (ANDAs), or investigational new drug applications (INDs), specifications are contained in the application or DMF. Specifications for nonapplication products may be found in official compendia or established by the manufacturer.
