Powder Blends and Finished Dosage Units — Stratified In-Process Dosage Unit Sampling and Asssment
DRAFT GUIDANCE
This guidance document is being distributed for comment purpos only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document contact Jon E. Clark, 301-594-5613 or Mike Gavini, 301-827-9053.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Rearch (CDER)
October 2003
Pharmaceutical CGMPs
Powder Blends and Finished Dosage Units — Stratified In-Process Dosage Unit Sampling and Asssment
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
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(Tel) 301-827-4573
v/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Rearch (CDER)
Office of Pharmaceutical Science (OPS)
Office of Compliance (OC)
October 2003
Pharmaceutical CGMPs
Draft — Not for Implementation
TABLE OF CONTENTS
I.INTRODUCTION (1)
II.BACKGROUND (1)玫瑰花冠茶
III.SCOPE (2)
IV.CORRELATION OF IN-PROCESS STRATIFIED SAMPLING WITH POWDER MIX AND FINISHED PRODUCT (4)
A.Asssment of Powder Mix Uniformity (4)
B.Correlation of Powder Mix Uniformity with Stratified In-Process Dosage Unit Data (5)
C.Correlation of Stratified In-Process Samples with the Finished Product (6)
V.EXHIBIT/VALIDATATION BATCH POWDER MIX HOMOGENEITY (6)
VI.VERIFICATION OF MANUFACTURING CRITERIA (7)
A.In-Process Dosage Unit Sampling and Analysis (7)车内标志
B.Criteria to Meet the Readily Pass Classification (8)
C.Criteria to Meet the Marginally Pass Classification (8)
D.Sample Locations for Routine Manufacturing (9)
VII. ROUTINE MANUFACTURING BATCH TESTING METHODS (9)
A.Standard Criteria Method (SCM) (9)
1.Stage 1 Test (10)
2.Stage 2 Test (10)
B.Marginal Criteria Method (MCM) (10)
C.Switching to Standard Test Method from Marginal Test Method (11)
VIII.REPORTING THE USE OF STRATIFIED SAMPLING (11)
A.Applications Not Yet Approved (11)
B.Postapproval Change (12)
GLOSSARY (13)
ATTACHMENT 1: VERIFICATION OF MANUFACTURING CRITERIA (14)
ATTACHMENT 2: ROUTINE MANUFACTURING BATCH TESTING (15)
Guidance for Industry1
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Powder Blends and Finished Dosage Units — Stratified In-Process 3
Dosage Unit Sampling and Asssment
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This draft guidance, when finalized, will reprent the Food and Drug Administration's (FDA's) current 8
thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 9
bind FDA or the public. You can u an alternative approach if the approach satisfies the requirements of 10
the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 11
staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 12
the appropriate number listed on the title page of this guidance.
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I.INTRODUCTION
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This guidance is intended to assist manufacturers of human drug products in meeting the
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requirements of 21 CFR 211.110 for demonstrating the adequacy of mixing to ensure uniformity of in-process powder blends and finished dosage units. This guidance describes the procedures 20
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for asssing powder mix adequacy, correlating in-process dosage unit test results with powder 22
mix test results, and establishing the initial criteria for control procedures ud in routine
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manufacturing.
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FDA's guidance documents, including this guidance, do not establish legally enforceable
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responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 27
be viewed only as recommendations, unless specific regulatory or statutory requirements are
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cited. The u of the word should in Agency guidances means that something is suggested or 29
肉松蛋卷recommended, but not required.
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II.BACKGROUND
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This guidance is the result of an Agency effort to achieve a science-bad policy and regulatory enforcement. Experts from industry, academia, and the FDA developed the principles
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underlying this guidance after extensive public discussion. A brief history of the evolution of 37
爱心快餐this guidance is provided in the following paragraphs.
1 This guidance has been prepared by the Office of Pharmaceutical Science and the Office of Compliance in the
Center for Drug Evaluation and Rearch (CDER) at the Food and Drug Administration in cooperation with the Product Quality Rearch Institute (PQRI) (e footnote 3). This guidance document reprents the Agency's
current thinking on asssment of the uniformity of powder blends and finished dosage units in the abnce of new technology development or implementation.
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In respon to industry concerns regarding regulations for demonstrating the adequacy of in-
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process powder mixing, the FDA published a draft guidance for industry on blend uniformity 41
analysis in August 1999.2 Comments submitted to the docket resulted in the formation of the 42
Blend Uniformity Working Group (BUWG) by the Product Quality Rearch Institute (PQRI).3 43
The PQRI BUWG conducted a public meeting, PQRI Workshop on Blend Uniformity, on
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September 7 and 8, 2000.
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Using the connsus reached by participants in this workshop, the BUWG developed a draft
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recommendation, The U of Stratified Sampling of Blend and Dosage Units to Demonstrate
Adequacy of Mix for Powder Blends. The draft recommendation received examination and peer 48
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review in multiple scientific and public venues. In addition, the Advisory Committee for
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Pharmaceutical Science (ACPS) reviewed the draft recommendation and received public
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comment during scheduled meetings of the committee.4 The draft recommendation was revid 52
to incorporate the results of peer review and public comment and was prented to CDER's
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Center Director in final form on December 30, 2002. The recommendation was subquently 54
published in the PDA Journal of Pharmaceutical Science and Technology.5 This draft guidance 55
reflects CDER's effort to incorporate the draft recommendation into regulatory policy.
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III.SCOPE
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Stratified sampling is the process of sampling dosage units at predefined intervals and collecting reprentative samples from specifically targeted locations in the compression/filling operation 61
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that have the greatest potential to yield extreme highs and lows in test results. The test results 63
追女孩子的技巧are ud to monitor the manufacturing process output that is most responsible for causing
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finished product variability. The test results can be ud to develop a single control procedure to 65
ensure adequate powder mix and uniform content in finished products.
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The methods described in this guidance are not intended to be the only methods for meeting
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Agency requirements to demonstrate the adequacy of powder mix. Traditional powder blend 69
sampling and testing, in conjunction with testing for uniformity of content in the finished
product, can be ud to comply with current good manufacturing practice requirements
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2 The FDA withdrew the guidance for industry ANDAs: Blend Uniformity Analysis o n May 17, 2002.
3 PQRI is a collaborative body involving FDA's Center for Drug Evaluation and Rearch (CDER), industry, and
academia. Since its inception in January 1996, the mission of PQRI has been to generate scientific information in support of regulatory policies through rearch. Additional information about PQRI is available at www.pqri.
4 The PQRI BUWG recommendation appeared on the public ACPS agenda on November 28, 2001 (introduction),
May 8, 2002 (distribution and comment), and October 22, 2002 (final comment).
5 G Boehm, J Clark, J Dietrick, L Foust, T Garcia, M Gavini, L Gelber, J Geoffry, J Hoblitzell, P Jimenez, G
Mergen, F Muzzio, J Planchard, J Prescott, J Timmermens, and N Takiar, "The U of Stratefied Sampling of Blend and Dosage Units to Demonstrate Adequacy of Mix for Powder Blends, PDA J. Pharm. Sci Technol,. 57:59-74, 2003.
