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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DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.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
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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

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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
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Guidance for Industry1 1

2

3 Powder Blends and Finished Dosage Units — Stratified In-Process

4 Dosage Unit Sampling and Assessment

5

6

7 This draft guidance, when finalized, will represent 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 use 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. 

13 .

14

15

16 I. INTRODUCTION 

17

18 This guidance is intended to assist manufacturers of human drug products in meeting the

19 requirements of 21 CFR 211.110 for demonstrating the adequacy of mixing to ensure uniformity

20 of in-process powder blends and finished dosage units. This guidance describes the procedures

21 for assessing powder mix adequacy, correlating in-process dosage unit test results with powder

22 mix test results, and establishing the initial criteria for control procedures used in routine

23 manufacturing.

24

25 FDA's guidance documents, including this guidance, do not establish legally enforceable

26 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

28 cited. The use of the word should in Agency guidances means that something is suggested or

29 recommended, but not required. 

30

31

32 II. BACKGROUND

33

34 This guidance is the result of an Agency effort to achieve a science-based policy and regulatory

35 enforcement. Experts from industry, academia, and the FDA developed the principles

36 underlying this guidance after extensive public discussion. A brief history of the evolution of

37 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 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.
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38

39 In response to industry concerns regarding regulations for demonstrating the adequacy of in40 process powder mixing, the FDA published a draft guidance for industry on blend uniformity

analysis in August 1999.2 41 Comments submitted to the docket resulted in the formation of the

Blend Uniformity Working Group (BUWG) by the Product Quality Research Institute (PQRI).3 42

43 The PQRI BUWG conducted a public meeting, PQRI Workshop on Blend Uniformity, on

44 September 7 and 8, 2000. 

45

46 Using the consensus reached by participants in this workshop, the BUWG developed a draft

47 recommendation, The Use of Stratified Sampling of Blend and Dosage Units to Demonstrate

48 Adequacy of Mix for Powder Blends. The draft recommendation received examination and peer

49 review in multiple scientific and public venues. In addition, the Advisory Committee for

50 Pharmaceutical Science (ACPS) reviewed the draft recommendation and received public

comment during scheduled meetings of the committee.4 51 The draft recommendation was revised

52 to incorporate the results of peer review and public comment and was presented to CDER's

53 Center Director in final form on December 30, 2002. The recommendation was subsequently

published in the PDA Journal of Pharmaceutical Science and Technology.

5 54 This draft guidance

55 reflects CDER's effort to incorporate the draft recommendation into regulatory policy.

56

57

58 III. SCOPE

59

60 Stratified sampling is the process of sampling dosage units at predefined intervals and collecting

61 representative samples from specifically targeted locations in the compression/filling operation

62 that have the greatest potential to yield extreme highs and lows in test results. These test results

63 are used to monitor the manufacturing process output that is most responsible for causing

64 finished product variability. The test results can be used to develop a single control procedure to

65 ensure adequate powder mix and uniform content in finished products. 

66

67 The methods described in this guidance are not intended to be the only methods for meeting

68 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

70 product, can be used to comply with current good manufacturing practice requirements

 

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.
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71 (CGMPs). Use of at-, in-, or on-line measurement systems can also be appropriate and are

described in other guidance documents.6 72

73

74 This guidance provides recommendations on how to:

75

76 • Conduct powder blend sampling and analyses.

• Establish initial criteria for stratified sampling of in-process dosage units7 77 and evaluation

78 of test results.

79 • Analyze the stratified samples and evaluate data.

80 • Correlate the stratified sample data with the powder blend data.

81 • Assess powder mix uniformity.

82 • Correlate the stratified sample data with the finished dosage unit data and assess

83 uniformity of content. 

84 • Test exhibit and validation batches for adequacy of powder mix.

85 • Test and evaluate routine manufacturing batches.

86 • Report the use of stratified sampling in the application.

87

88 The methods described in this guidance can be used to monitor active ingredient homogeneity of

89 powder blends and to ensure uniform content of the finished product for solid oral drug products.

90 These methods are only one way to satisfy the CGMP and application review requirements for

91 in-process testing to demonstrate adequacy of powder mix and uniform content of the finished

92 product. The method assumes appropriate monitoring of all manufacturing steps as required by

93 the regulations or application commitments. This guidance does not discuss the assessment of

94 the potency and other attributes that can affect the finished dosage units, or the homogeneity of

95 inactive ingredients. Formulations with extremely low dose and/or high potency may call for

96 more rigorous sampling than that described in this guidance to assess the uniformity of powder

97 blends or the uniformity of content of the finished dosage units.

98

99 When using the methods described in this guidance, certain data or trends may be observed. We

100 recommend that manufacturers scientifically evaluate these types of research data to determine if

101 they affect the quality of a product and, if so, how. The FDA does not intend to inspect research

102 data collected on an existing product for the purpose of evaluating the suitability of proposed

103 methods. Any FDA decision to inspect research data would be based on exceptional situations

 

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. 
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similar to those outlined in Compliance Policy Guide Sec. 130.300.8 104 Those data used to support

105 validation or regulatory submissions will be subject to inspection in the usual manner.

106

107

108 IV. CORRELATION OF IN-PROCESS STRATIFIED SAMPLING WITH POWDER

109 MIX AND FINISHED PRODUCT 

110

111 If you plan to follow the procedures described in this guidance document, we recommend that

112 you first complete the process development procedures described in this section before using the

113 methods described in sections V, VI, VII. The subsections below describe how to assess the

114 adequacy of powder mix, uniformity of content of the in-process and finished dosage units

115 through correlation and assessment of data from development, validation and manufacturing

116 batches. These procedures can reveal deficiencies in the blending operation that may not have

117 been previously detected. We recommend that manufacturers correct deficiencies in the

118 blending operation before implementing the routine manufacturing control methods described in

119 this guidance.

120

121 A. Assessment of Powder Mix Uniformity

122

123 We recommend the assessment of powder mix uniformity using the following procedures:

124

125 • Conduct blend analysis on batches by extensively sampling the mix in the blender and/or

126 intermediate bulk containers (IBCs). 

127 • Identify appropriate blending time and speed ranges, dead spots in blenders, and locations

128 of segregation in IBCs. Determine sampling errors. 

129 • Define the effects of sample size (e.g., 1-10X dosage unit range) while developing a

130 technique capable of measuring the true uniformity of the blend. Sample quantities larger

131 than 3X can be used with adequate scientific justification. Appropriate blend sampling

132 techniques and procedures should be developed for each product with consideration to

133 various designs of blend powder sampling and the physical and chemical properties of

134 the blend components. 

135 • Design blend-sampling plans and evaluate them using appropriate statistical analyses.

136 • Quantitatively measure any variability that is present among the samples. Attribute the

137 sample variability to either lack of uniformity of the blend or sampling error. Significant

138 within-location variance in the blend data can be an indication of one factor or a

combination of factors such as inadequacy of blend mix, sampling error9 139 or

 

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.
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agglomeration.10, 11 140 Significant between-location variance in the blend data can indicate

141 that the blending operation is inadequate. 

142

143 B. Correlation of Powder Mix Uniformity with Stratified In-Process Dosage

144 Unit Data

145

146 We recommend the following steps for correlation:

147

148 • Conduct periodic sampling and testing of the in-process dosage units by sampling them at

149 defined intervals and locations throughout the compression or filling process. Use a

150 minimum of 20 appropriately spaced in-process dosage unit sampling points. There

151 should be at least 7 samples taken from each of these locations for a total minimum of at

152 least 140 samples. 

• Take 7 samples from each additional location to further assess each significant event,12 153

154 such as filling or emptying of hoppers and IBCs, start and end of the compression or

155 filling process and equipment shutdown. This may be accomplished by using process

156 development batches, validation batches, or by using routine manufacturing batches for

157 approved products. 

158 • Significant events may also include observations or changes from one batch to another

159 (e.g., batch scale-up and observations of undesirable trends in previous batch data).

160 • Prepare a summary of the data and analysis used to correlate the stratified sampling

161 locations with significant events in the blending process. We recommend you submit this

162 summary with the application as described in section VIII of this guidance.

163 • Compare the powder mix uniformity with the in-process dosage-unit data described

164 above. 

165 • Investigate any discrepancies observed between powder mix and dosage-unit data and

166 establish root causes. At least one trouble-shooting guide is available that may be helpful

with this task.13 167 Possible corrections may range from going back to formulation

168 development to improve powder characteristics to process optimization. Sampling

 

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.
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169 problems may also be negated by use of alternate state-of-the-art methods of in situ real170 time sampling and analysis. 

171

172 C. Correlation of Stratified In-Process Samples with the Finished Product 

173

174 We recommend the following steps:

175

176 • Conduct testing for uniform content of the finished product using an appropriate

177 procedure or as specified in the Abbreviated New Drug Application (ANDA) or the New

178 Drug Application (NDA) for approved products.

179 • Compare the results of stratified in-process dosage unit analysis with uniform content of

180 the finished dosage units from the previous step. This analysis should be done without

weight correction.14 181

182 • Prepare a summary of the data and analysis used to conclude that the stratified in-process

183 sampling provides assurance of uniform content of the finished product. We recommend

184 you submit this summary with the application as described in section VIII of this

185 guidance. 

186

187

188 V. EXHIBIT/VALIDATATION BATCH POWDER MIX HOMOGENEITY 

189

190 This section describes sampling and testing the powder mix of exhibit and process validation

191 batches used to support implementing the stratified sampling method described in this guidance. 

192

193

194 We recommend that during the manufacture of exhibit and process validation batches, you assess

195 the uniformity of the powder blend, the in-process dosage units, and the finished product

196 independently. We recommend you use the following steps to identify sampling locations and

acceptance criteria prior to the manufacture of the exhibit and/or validation batches.15 197 

198

199 1. Carefully identify at least 10 sampling locations in the blender to represent potential areas

200 of poor blending. For example, in tumbling blenders (such as V-blenders, double cones,

201 or drum mixers), samples should be selected from at least two depths along the axis of

202 the blender. For convective blenders (such as a ribbon blender), a special effort should

203 be made to implement uniform volumetric sampling to include the corners and discharge

204 area (at least 20 locations are recommended to adequately validate convective blenders). 

205

206 2. Collect at least 3 replicate samples from each location. Samples should meet the

207 following criteria: 

 

14 Weight correction is a mathematical correction to eliminate the effect of potentially variable tablet weight on

measurement of mix adequacy—see Glossary, Section IX.

15 This is described in Section IV of this guidance. 
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208

209 • Assay one sample per location (number of samples (n) ≥ 10)

210 (n = 20 for ribbon blender).

211

212 • RSD (relative standard deviation) of all individual results ≤ 5.0 percent.

213

214 • All individual results are within 10.0 percent (absolute) of the mean of the results. 

215

216 If samples do not meet these criteria, we recommend that you investigate the failure according to

217 the flow chart in Attachment 1. We also recommend that you not proceed any further with

218 implementation of the methods described in this guidance until the criteria are met.

219

220 Sampling errors may occur in some powder blends, sampling devices, and techniques that make

221 it impractical to evaluate adequacy of mix using only the blend data. In such cases, we

222 recommend that you use in-process dosage unit data in conjunction with blend sample data to

223 evaluate blend uniformity.

224

225 Some powder blends may present unacceptable safety risk when directly sampled. The safety

226 risk, once described, may justify an alternate procedure. In such cases, process knowledge and

227 data from indirect sampling combined with additional in-process dosage unit data may be

228 adequate to demonstrate the adequacy of the powder mix. Data analysis used to justify using

229 these alternate procedures should be described in a summary report that is maintained at the

230 manufacturing facility.

231

232 As an alternative, you can substitute the procedures described in the PDA Technical Report No.

233 25, (see reference in footnote 8) to ensure that the blend is uniform and that the method meets or

234 exceeds the criteria described above.

235

236

237 VI. VERIFICATION OF MANUFACTURING CRITERIA

238

239 You should complete the assessment of powder mix uniformity and correlation of stratified in240 process dosage unit sampling development procedures before establishing the criteria and

241 controls for routine manufacturing. We also recommend that you assess the normality and

242 determine RSD from the results of stratified in-process dosage unit sampling and testing that

243 were developed. The RSD value should be used to classify the testing results as either readily

244 pass (RSD ≤ 4.0%), marginally pass (RSD ≤ 6.0%) or inappropriate for demonstration of batch

245 homogeneity (RSD > 6.0%). The procedures are discussed in the following sections: 

246

247 A. In-Process Dosage Unit Sampling and Analysis 

248

249 We recommend the following steps: 

250

251 • Carefully identify locations throughout the compression or filling operation to sample in252 process dosage units. The sampling locations should also include significant process
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253 events such as hopper changeover, filling or machine shutdown and the beginning and

end of the compression or filling operation.16 254 There should be at least 20 locations with 7

255 samples each for a minimum total of 140 samples. These include periodic sampling

256 locations and significant event locations. 

257 • Sample at least 7 in-process dosage units from each sampling location. 

258 • Assay at least 3 of the 7 and weight correct each result. (The number of samples should

259 be specified and justified for a given product and process.) 

260 • Conduct an analysis of the dosage unit stratified sampling data to demonstrate that the

261 batch has a normal distribution of active ingredient. Indications of trends, bimodal

262 distributions, or other forms of a distribution other than normal should be investigated. If

263 these occurrences significantly affect your ability to ensure batch homogeneity, they

264 should be corrected. 

265 • Prepare a summary of this analysis. Potential investigation results along with a

266 description of batch normality should be included in the summary. Submit this summary

267 with the application as described in section VIII of this guidance.

268

269 In addition to this analysis of batch normality, we recommend that you classify the test results as

270 readily pass or marginally pass according to the following procedure:

271

272 B. Criteria to Meet the Readily Pass Classification

273

274 For each separate batch, compare the test results to the following criteria: 

275

276 • For all individual results (for each batch n ≥ 60) the RSD ≤ 4.0 percent. 

277

278 • Each location mean is within 90.0 percent to110.0 percent of target strength.

279

280 • All individual results are within the range of 75.0 percent to 125.0 percent of target

281 strength.

282

283 If your test results meet these criteria, they are classified as readily pass and you can start routine

284 batch testing using the Standard Verification Method (SVM) described in section VII. If your

285 test results fail to meet these criteria, we recommend that you compare the results with the

286 marginally pass criteria described below. 

287

288 C. Criteria to Meet the Marginally Pass Classification 

289

290 If your dosage unit test results fail to meet the criteria for the readily pass classification, you

291 should assay the remaining dosage units (all 7 units per location) and compare the test results to

292 the following criteria:

 

16 The beginning and end samples are taken from dosage units that would normally be included in the batch.
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293

294 • For all individual results (for one batch n ≥ 140) the RSD ≤ 6.0 percent.

295

296 • Each location mean is within 90.0 percent to 110.0 percent of target strength.

297

298 • All individual results are within the range of 75.0 percent to 125.0 percent of target

299 strength.

300

301 If your test results meet these criteria, results can be classified as marginally pass. If your

302 samples do not meet these criteria, we recommend that you investigate the failure, find justified

303 and assignable cause(s), correct the deficiencies, and repeat the powder mix homogeneity

304 assessment, in-process dosage unit sampling correlation, and initial criteria establishment

305 procedures. The disposition of batches that have failed the marginally pass criteria is outside the

306 scope of this guidance. 

307

308 D. Sample Locations for Routine Manufacturing

309

310 We recommend that you prepare a summary of the data analysis from the powder mix

311 assessment and stratified sample testing. From the data analysis, you should establish the

312 stratified sample locations for routine manufacturing, taking into account significant process

313 events and their effect on in-process dosage unit and finished dosage unit quality attributes. You

314 should identify at least 10 sampling locations during capsule filling or tablet compression to

315 represent the entire routine manufacturing batch. 

316

317

318 VII. ROUTINE MANUFACTURING BATCH TESTING METHODS

319

320 We recommend that you evaluate the routine manufacturing batches against the following

321 criteria after completing the procedures described above to assess the adequacy of the powder

322 mix and uniform content in finished dosage form. 

323

324 These routine manufacturing batch-testing methods include the Standard Criteria Method (SCM)

325 and the Marginal Criteria Method (MCM). The SCM consists of two stages, each with the same

326 accept/reject criteria. The second of the two stages recommends using a larger sample size to

327 meet these criteria. The MCM uses accept/reject criteria that are different from the SCM.

328

329 If the batch data fail to conform to the SCM criteria, we recommend continued sampling and

330 testing to intensified criteria (MCM). Both verification methods and the procedures for

331 switching from one to the other are detailed below and in the flow chart in Attachment 2. 

332

333 A. Standard Criteria Method (SCM) 

334

335 We recommend using the SCM verification method when either of the following conditions is

336 met:

337 • Results of establishing initial criteria are classified as readily pass.
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338

339 • Results of testing to the MCM pass the criteria for switching to the SCM (see section C

340 below). 

341

342 The SCM should meet the same criteria using a different number of sample test results as

343 described below:

344

345 1. Stage 1 Test 

346

347 To perform the stage 1 test, we recommend that you (1) collect at least 3 dosage units from each

348 sampling location, (2) assay 1 dosage unit from each location, (3) weight correct the results, and

349 (4) compare the results with the following criteria:

350

351 • RSD of all individual results (n ≥ 10) ≤ 5.0 percent.

352

353 • Mean of all results is 90.0 percent to 110.0 percent of target assay. 

354

355 If the results pass these criteria and the adequacy of mix and uniformity of dosage unit content

356 for the batch are adequate, you can use the SCM for the next batch. If test results fail stage 1

357 criteria, you should conduct extended testing to stage 2 acceptance criteria.

358

359 2. Stage 2 Test

360

361 To perform the stage 2 test, we recommend that you assay the remaining two dosage units (from

362 stage 1) for each sampling location and compute the mean and RSD of data combined from both

363 stage 1 and stage 2. Compare the results with the following criteria: 

364

365 • For all individual results (n ≥ 30) the RSD ≤ 5.0 percent.

366

367 • Mean of all results is 90.0 percent to 110.0 percent of target assay.

368

369 If your results pass these criteria, the adequacy of mix and uniformity of content for the batch are

370 adequate and you can use stage 1 of SCM for the next batch. If test results fail the criteria, use

371 the MCM described in the next section. 

372

373 B. Marginal Criteria Method (MCM)

374

375 After powder mix assessment, in-process dosage unit stratified sampling correlation and initial

376 criteria establishment, we recommend that you use the MCM when either of the following

377 conditions is met:

378

379 • Results of initial criteria establishment qualified as marginally pass.

380

381 • Results of initial criteria establishment qualified as readily pass or a batch was tested

382 according to SCM and the test results failed both stage 1 and stage 2 criteria.
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383

384 Then, we recommend you use the weight-corrected results from the stage 2 SCM analysis and

385 compare this with the MVM criteria: 

386

387 • For all individual results (n ≥ 30) the RSD ≤ 6.0 percent.

388

389 • Mean of all results is 90.0 percent to 110.0 percent of target assay.

390

391 We recommend that all results from analysis of any remaining location samples be computed

392 with the stage 2 SCM data. No test results should be removed from the analysis. If the test

393 results pass these criteria, the adequacy of mix and uniformity of content for the batch are

394 adequate. We recommend that you continue to test routine manufacturing batches with MCM

395 criteria. If the test results fail the criteria, you should no longer use the verification testing

396 methods to ensure adequacy of mixing or uniformity of content until you investigate the failure

397 (per 21 CFR 211.192) to establish justified assignable cause(s), take necessary corrective actions

398 and repeat the powder mix assessment, stratified sample correlation, and initial criteria

399 establishment procedures. 

400

401 C. Switching to Standard Test Method from Marginal Test Method

402

403 It is appropriate to switch to the SCM when the following criterion is met:

404

405 • Five consecutive batches pass the MCM criteria and result in RSD ≤ 5.0 percent 

406

407

408 VIII. REPORTING THE USE OF STRATIFIED SAMPLING

409

410 A. Applications Not Yet Approved

411

412 This section refers to the scientific data analysis and other information that should be submitted

413 to an NDA or ANDA. Information submitted in the application should include summary reports

414 and scientific analyses or statements about the method being used. The raw data collected to

415 support using this method should be maintained at the manufacturing site.

416 We recommend that you provide the following information in the Manufacturing Process and

Process Controls section of the application (CTD17 417 3.2.P.3.3).

418

419 • Statement that the methods in this guidance are being used to demonstrate the adequacy

420 of powder mix or a description of alternative methods that demonstrate the adequacy of

421 the powder mix

422 • Summary of data analysis from the powder mix assessment and from stratified sample

423 testing 

 

17 M4Q: The CTD – Quality, one in a series of guidances that provide recommendations for applicants preparing the

Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) for submission to the

FDA.
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424 • Summary of the in-process dosage unit stratified sampling data analysis demonstrating a

425 normal distribution of active ingredient in the batch

426 • Summary of the powder mix sampling data analysis demonstrating that it met the

427 minimum criteria for validation and establishing initial criteria 

428

429 We recommend that you provide the following information in the Drug Product Specification

430 section of the application (CTD 3.2.P.4.1):

431

432 • Statement in the product specification stating that the methods in this guidance are being

433 used to demonstrate finished product uniformity of content or a description of alternative

434 methods used to demonstrate finished product uniformity of content

435

436 We also recommend that you provide the following information in the Pharmaceutical

437 Development Information section of the application (CTD 3.2.P.2.2):

438 

439 • Summary of data analysis for correlation of in-process dosage unit stratified sampling

440 with finished product uniformity of content

441

442 • Summary of data analysis for correlation of powder mix uniformity with in-process

443 dosage unit stratified sampling

444

445 B. Postapproval Change

446

447 If you plan on changing the existing controls for adequacy of mix and uniformity of content to

448 the methods described in this guidance, the change should be considered a minor change as

described in the postapproval changes guidance.18 449 We recommend you provide a notice of the

450 change in the next annual report along with the information indicated in section A, above. The

451 raw data collected to support changes can be maintained at the manufacturing site.

 

18 FDA's guidance for industry on Changes to an Approved NDA or ANDA.
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452

453 GLOSSARY

454

455 Absolute as used to define the acceptable range (+/- 10%) in which individual blend sample

456 values must fall and which is independent of the value of the mean. For example, if the mean of

457 all blend samples is 95.0%, the absolute range is 85.0% to105.0%, (not 95.0% +/- 9.5%).

458

459 Exhibit Batches refer to any batch submitted in support of an NDA or ANDA. This includes

460 bioequivalence, test, and commercial production batches of a drug product.

461

462 In-process dosage unit is a capsule or tablet as it is formed in the manufacturing process before

463 it is coated or packaged. 

464

465 RSD is relative standard deviation; RSD = [(standard deviation)/(mean)] x 100%.

466

467 Significant event is any operation during solid dosage production process that can affect the

468 integrity of the in-process materials and, hence, their quality attributes. Transferring powder

469 from a blender to a bin or from the bin to a hopper are two examples of significant events in the

470 blending and compression process.

471

472 Stratified sampling is the process of collecting a representative sample by selecting units

473 deliberately from various identified locations within a lot or batch, or from various phases or

474 periods of a process to obtain a sample dosage unit that specifically targets locations throughout

475 the compression/filling operation that have a higher risk of producing failing results in the

476 finished product uniformity of content.

477

478 Target assay is the intended strength or intended amount of active ingredient in the dosage unit.

479

480 Validation batch is a batch manufactured and tested to verify the proposed routine

481 manufacturing process controls are adequate.

482

483 Weight correct is a mathematical correction to eliminate the effect of potentially variable tablet

484 weight on measurement of mix adequacy. For example, a tablet with a strength of 19.4 mg and

485 weight of 98 mg = 19.4 ÷ 98 = 0.198 mg/mg. Label claim is 20 mg per each 100 mg tablet, so

486 the weight corrected result is 0.198 ÷ 0.20 * 100 = 99% of target blend assay.
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487 ATTACHMENT 1: VERIFICATION OF MANUFACTURING CRITERIA

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522 1 523 Examples of “mean +/- 10% (absolute)” are: If the mean strength = 95%, then the interval is 95% +/- 10%; thus, all individuals must fall within

524 85.0% to 105.0%. If the mean strength = 103.0%, then the interval is 103.0% +/- 10.0%; thus all individuals must fall within 93.0% to 113.0%.

525

526 2 When comparing individual dosage units to 75.0% - 125.0% of target strength, use the as is results (not corrected for weight).

Dosage Units

During Filling or compression take 7 dosage

unit samples from each of at least 20 locations

From blend, sample at least 10 locations, with at

least 3 replicates from each location

Blend Sample Criteria:

RSD<5.0% and all individuals are within

+/- 10% of mean (absolute)1

Assay 1 per location

Meet criteria?

Assay at least 3 dosage units per each

location, weight correct each result

Dosage Unit Readily Pass Criteria:

RSD of all individuals <4.0%, Each location mean is within

90.0% - 110.0% of target potency, and all individuals are within

75.0% and 125.0% of target potency2

Meet criteria?

Adequate Powder Mix Assay remaining dosage units from each location (7

per location altogether), weight correct each result

Dosage Unit Marginally Pass Criteria:

RSD of all individuals <6.0%, Each location mean is within 90.0% -

110.0% of target potency, and all individuals are within 75.0% and

125.0% of target potency

2

Meet criteria?

Assay 2nd and 3rd blend

samples from each location

Investigate original criteria

“failure”

Investigation points

to blend sampling

error or some other

attributable cause

Is mixing

problem

identified?

Assay at least 7 dosage units per

each location, weight correct

each result

Blend is not

uniform

Go back to

development

Blend is not uniform

or post blending

practices are causing

segregation

No Yes

No Yes

No

No

Yes

Yes
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527 ATTACHMENT 2: ROUTINE MANUFACTURING BATCH TESTING

528

529 Before using this chart to demonstrate adequacy of mix and content uniformity during routine

530 manufacture conduct assess the powder mix, stratified sample correlation and establishes initial criteria.

531 Identify at least 10 sampling locations during filling or compression to represent the entire batch. Remove

532 3 or more dosage units at each sampling location.

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534

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536

Assay 4 remaining

dosage units per

location and weight

correct the results.

Meet criteria for using

SCM routine criteria?

Stage 1: Assay 1 dosage unit

per location and weight

correct the results

Standard Testing Stage 1 Acceptance Criteria:

Mean is within 90.0% to 110.0% of target and

RSD < 5.0%

Meet criteria?

Adequacy of mix is

demonstrated

Stage 2: Assay 2 more

remaining dosage units

 per location and

weight correct the results

Compute mean and

RSD of all samples

combined from both

stage 1 and stage 2

Stage 2 Acceptance

Criteria: Mean is within

90.0% to 110.0% of target

and

RSD < 5.0%

Meet criteria?

Marginal Criteria Method (MCM)

Acceptance Criteria:

Mean is within 90.0% to 110.0%

of target and

RSD < 6.0%

Meet criteria?

Adequacy of mix is

demonstrated

Adequacy of mix is

NOT demonstrated

Continuing Routine Use of

Standard Criteria Method (SCM):

Last batch met STM acceptance criteria

or

Last 5 batches were tested using Marginal Criteria Method

(MTM) and met acceptance criteria with RSD < 5.0%

yes no

yes

yes no

no

Standard Critera Marginal Criteria

yes no

Use stage 1 and stage 2

results. You may add

results from analysis of

remaining location

samples.

 Beginning Routine Testing to

Standard Criteria Method (SCM):

No routine testing was done since completion

of method development

and

result of method development was readily pass

If MCM is used because of SCM failure,

then MCM testing continues for all future

batches until 5 consecutive batches meet

the criteria of RSD < 5.0%.