Guidance for Industry 混合时含量均匀度取样

G:\5831dft.doc 10/27/03 Guidance for Industry Powder Blends and Finished Dosage Units — Stratified In-Process Dosage Unit Sampling and Assessment DRAFT GUIDANCE This guidance document is being distributed for comment purposes only.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be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.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 Research (CDER) October 2003 Pharmaceutical CGMPs G:\5831dft.doc 10/27/03 Guidance for Industry Powder Blends and Finished Dosage Units — Stratified In-Process Dosage Unit Sampling and Assessment Additional copies are available from: Office of Training and Communication Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (Tel) 301-827-4573 http://www.fda.gov/cder/guidance/index.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Science (OPS) Office of Compliance (OC) October 2003 Pharmaceutical CGMPs Contains Nonbinding Recommendations Draft — Not for Implementation G:\5831dft.doc 10/27/03 TABLE OF CONTENTS I. INTRODUCTION................................................................................................................. 1 II. BACKGROUND ................................................................................................................... 1 III. SCOPE ................................................................................................................................... 2 IV. CORRELATION OF IN-PROCESS STRATIFIED SAMPLING WITH POWDER MIX AND FINISHED PRODUCT.............................................................................................. 4 A. Assessment 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 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 Contains Nonbinding Recommendations Draft — Not for Implementation G:\5831dft.doc 10/27/03 1 Guidance for Industry11 2 Powder Blends and Finished Dosage Units — Stratified In-Process3 Dosage Unit Sampling and Assessment4 5 6 This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current7 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to8 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of9 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA10 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call11 the appropriate number listed on the title page of this guidance. 12 .13 14 15 I. INTRODUCTION 16 17 This guidance is intended to assist manufacturers of human drug products in meeting the18 requirements of 21 CFR 211.110 for demonstrating the adequacy of mixing to ensure uniformity19 of in-process powder blends and finished dosage units. This guidance describes the procedures20 for assessing powder mix adequacy, correlating in-process dosage unit test results with powder21 mix test results, and establishing the initial criteria for control procedures used in routine22 manufacturing.23 24 FDA's guidance documents, including this guidance, do not establish legally enforceable25 responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should26 be viewed only as recommendations, unless specific regulatory or statutory requirements are27 cited. The use of the word should in Agency guidances means that something is suggested or28 recommended, but not required. 29 30 31 II. BACKGROUND32 33 This guidance is the result of an Agency effort to achieve a science-based policy and regulatory34 enforcement. Experts from industry, academia, and the FDA developed the principles35 underlying this guidance after extensive public discussion. A brief history of the evolution of36 this guidance is provided in the following paragraphs.37 1 This guidance has been prepared by the Office of Pharmaceutical Science and the Office of Compliance in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration in cooperation with the Product Quality Research Institute (PQRI) (see footnote 3). This guidance document represents the Agency's current thinking on assessment of the uniformity of powder blends and finished dosage units in the absence of new technology development or implementation. Contains Nonbinding Recommendations Draft — Not for Implementation G:\5831dft.doc 10/27/03 2 38 In response to industry concerns regarding regulations for demonstrating the adequacy of in-39 process powder mixing, the FDA published a draft guidance for industry on blend uniformity40 analysis in August 1999.2 Comments submitted to the docket resulted in the formation of the41 Blend Uniformity Working Group (BUWG) by the Product Quality Research Institute (PQRI).342 The PQRI BUWG conducted a public meeting, PQRI Workshop on Blend Uniformity, on43 September 7 and 8, 2000. 44 45 Using the consensus reached by participants in this workshop, the BUWG developed a draft46 recommendation, The Use of Stratified Sampling of Blend and Dosage Units to Demonstrate47 Adequacy of Mix for Powder Blends. The draft recommendation received examination and peer48 review in multiple scientific and public venues. In addition, the Advisory Committee for49 Pharmaceutical Science (ACPS) reviewed the draft recommendation and received public50 comment during scheduled meetings of the committee.4 The draft recommendation was revised51 to incorporate the results of peer review and public comment and was presented to CDER's52 Center Director in final form on December 30, 2002. The recommendation was subsequently53 published in the PDA Journal of Pharmaceutical Science and Technology.5 This draft guidance54 reflects CDER's effort to incorporate the draft recommendation into regulatory policy.55 56 57 III. SCOPE58 59 Stratified sampling is the process of sampling dosage units at predefined intervals and collecting60 representative samples from specifically targeted locations in the compression/filling operation61 that have the greatest potential to yield extreme highs and lows in test results. These test results62 are used to monitor the manufacturing process output that is most responsible for causing63 finished product variability. The test results can be used to develop a single control procedure to64 ensure adequate powder mix and uniform content in finished products. 65 66 The methods described in this guidance are not intended to be the only methods for meeting67 Agency requirements to demonstrate the adequacy of powder mix. Traditional powder blend68 sampling and testing, in conjunction with testing for uniformity of content in the finished69 product, can be used to comply with current good manufacturing practice requirements70 2 The FDA withdrew the guidance for industry ANDAs: Blend Uniformity Analysis on May 17, 2002. 3 PQRI is a collaborative body involving FDA's Center for Drug Evaluation and Research (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 research. Additional information about PQRI is available at www.pqri.org. 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 Use 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. Contains Nonbinding Recommendations Draft — Not for Implementation G:\5831dft.doc 10/27/03 3 (CGMPs). Use of at-, in-, or on-line measurement systems can also be appropriate and are71 described in other guidance documents.6 72 73 This guidance provides recommendations on how to:74 75 • Conduct powder blend sampling and analyses.76 • Establish initial criteria for stratified sampling of in-process dosage units7 and evaluation77 of test results.78 • Analyze the stratified samples and evaluate data.79 • Correlate the stratified sample data with the powder blend data.80 • Assess powder mix uniformity.81 • Correlate the stratified sample data with the finished dosage unit data and assess82 uniformity of content. 83 • Test exhibit and validation batches for adequacy of powder mix.84 • Test and evaluate routine manufacturing batches.85 • Report the use of stratified sampling in the application.86 87 The methods described in this guidance can be used to monitor active ingredient homogeneity of88 powder blends and to ensure uniform content of the finished product for solid oral drug products.89 These methods are only one way to satisfy the CGMP and application review requirements for90 in-process testing to demonstrate adequacy of powder mix and uniform content of the finished91 product. The method assumes appropriate monitoring of all manufacturing steps as required by92 the regulations or application commitments. This guidance does not discuss the assessment of93 the potency and other attributes that can affect the finished dosage units, or the homogeneity of94 inactive ingredients. Formulations with extremely low dose and/or high potency may call for95 more rigorous sampling than that described in this guidance to assess the uniformity of powder96 blends or the uniformity of content of the finished dosage units.97 98 When using the methods described in this guidance, certain data or trends may be observed. We99 recommend that manufacturers scientifically evaluate these types of research data to determine if100 they affect the quality of a product and, if so, how. The FDA does not intend to inspect research101 data collected on an existing product for the purpose of evaluating the suitability of proposed102 methods. Any FDA decision to inspect research data would be based on exceptional situations103 6 In August 2003, the Agency issued the draft guidance for industry PAT – A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance. Once finalized, it will represent the Agency's perspective on this issue. 7 The in-process dosage unit is a capsule or tablet as it is formed in the manufacturing process before it is coated or packaged. Contains Nonbinding Recommendations Draft — Not for Implementation G:\5831dft.doc 10/27/03 4 similar to those outlined in Compliance Policy Guide Sec. 130.300.8 Those data used to support104 validation or regulatory submissions will be subject to inspection in the usual manner.105 106 107 IV. CORRELATION OF IN-PROCESS STRATIFIED SAMPLING WITH POWDER108 MIX AND FINISHED PRODUCT 109 110 If you plan to follow the procedures described in this guidance document, we recommend that111 you first complete the process development procedures described in this section before using the112 methods described in sections V, VI, VII. The subsections below describe how to assess the113 adequacy of powder mix, uniformity of content of the in-process and finished dosage units114 through correlation and assessment of data from development, validation and manufacturing115 batches. These procedures can reveal deficiencies in the blending operation that may not have116 been previously detected. We recommend that manufacturers correct deficiencies in the117 blending operation before implementing the routine manufacturing control methods described in118 this guidance.119 120 A. Assessment of Powder Mix Uniformity121 122 We recommend the assessment of powder mix uniformity using the following procedures:123 124 • Conduct blend analysis on batches by extensively sampling the mix in the blender and/or125 intermediate bulk containers (IBCs). 126 • Identify appropriate blending time and speed ranges, dead spots in blenders, and locations127 of segregation in IBCs. Determine sampling errors. 128 • Define the effects of sample size (e.g., 1-10X dosage unit range) while developing a129 technique capable of measuring the true uniformity of the blend. Sample quantities larger130 than 3X can be used with adequate scientific justification. Appropriate blend sampling131 techniques and procedures should be developed for each product with consideration to132 various designs of blend powder sampling and the physical and chemical properties of133 the blend components. 134 • Design blend-sampling plans and evaluate them using appropriate statistical analyses.135 • Quantitatively measure any variability that is present among the samples. Attribute the136 sample variability to either lack of uniformity of the blend or sampling error. Significant137 within-location variance in the blend data can be an indication of one factor or a138 combination of factors such as inadequacy of blend mix, sampling error9 or139 8 FDA/ORA Compliance Policy Guide, Sec. 130.300, FDA Access to Results of Quality Assurance Program Audits and Inspections (CPG7151.02) 9 If blend sampling error is detected, more sophisticated, statistical analyses should be applied to assess the situation, such as the use of methods described in J Berman, DE Elinski, CR Gonzales, JD Hofer, PJ Jimenez, JA Planchard, RJ Tlachac, PF Vogel, “Blend Uniformity Analysis: Validation and In-Process Testing.” Technical Report No. 25, PDA J Pharm. Sci. Technol. 51(Suppl 3i-iii), S1-99, 1997. Contains Nonbinding Recommendations Draft — Not for Implementation G:\5831dft.doc 10/27/03 5 agglomeration.10, 11 Significant between-location variance in the blend data can indicate140 that the blending operation is inadequate. 141 142 B. Correlation of Powder Mix Uniformity with Stratified In-Process Dosage143 Unit Data144 145 We recommend the following steps for correlation:146 147 • Conduct periodic sampling and testing of the in-process dosage units by sampling them at148 defined intervals and locations throughout the compression or filling process. Use a149 minimum of 20 appropriately spaced in-process dosage unit sampling points. There150 should be at least 7 samples taken from each of these locations for a total minimum of at151 least 140 samples. 152 • Take 7 samples from each additional location to further assess each significant event,12153 such as filling or emptying of hoppers and IBCs, start and end of the compression or154 filling process and equipment shutdown. This may be accomplished by using process155 development batches, validation batches, or by using routine manufacturing batches for156 approved products. 157 • Significant events may also include observations or changes from one batch to another158 (e.g., batch scale-up and observations of undesirable trends in previous batch data).159 • Prepare a summary of the data and analysis used to correlate the stratified sampling160 locations with significant events in the blending process. We recommend you submit this161 summary with the application as described in section VIII of this guidance.162 • Compare the powder mix uniformity with the in-process dosage-unit data described163 above. 164 • Investigate any discrepancies observed between powder mix and dosage-unit data and165 establish root causes. At least one trouble-shooting guide is available that may be helpful166 with this task.13 Possible corrections may range from going back to formulation167 development to improve powder characteristics to process optimization. Sampling168 10 OS Sudah, PE Arratia, D. Coffin-Beach, FJ Muzzio, "Mixing of Cohesive Pharmaceutical Formulations in Tote (Bin)-Blenders,” Drug Dev. Ind. Pharm, 28(8): 905-918, 2002. 11 V Swaminathan, DO Kildsig, “Polydisperse powder mixtures: effect of particle size and shape on mixture stability,” Drug Dev. Ind. Pharm., 28(1):41-48, 2002. 12 A significant event is any operation during the solid dosage production process that can affect the integrity of the in-process materials – see section IX Glossary. 13 JK Prescott, TJ Garcia, "A Solid Dosage and Blend Content Uniformity Troubleshooting Diagram," Pharm. Technol., 25 (3):68-88, 2001. Contains Nonbinding Recommendations Draft — Not for Implementation G:\5831dft.doc 10/27/03 6 problems may also be negated by use of alternate state-of-the-art methods of in situ real-169 time sampling and analysis. 170 171 C. Correlation of Stratified In-Process Samples with the Finished Product