Contains Nonbinding Recommendations

Draft — Not for Implementation

Guidance for Industry

Powder Blends and Finished Dosage

Units — Stratified In-Process Dosage

Unit Sampling and Assessment

Revised Attachments

These attachments are intended to replace the attachments contained in the draft guidance.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

November 2003
Contains Nonbinding Recommendations

Draft — Not for Implementation

REVISED ATTACHMENT 1: VERIFICATION OF MANUFACTURING CRITERIA

1

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

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%.

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

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 potency2

Meet criteria?

Adequate Powder Mix Assay remaining dosage units from each location,

weight correct each result

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

Yes

Yes

No
Contains Nonbinding Recommendations

Draft — Not for Implementation

REVISED ATTACHMENT 2: ROUTINE MANUFACTURING BATCH TESTING

You may add

results from

analysis of

remaining samples.

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 Testing Using

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 Criteria Marginal Criteria

yes no

 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%.

Continuing Routine Testing Using

Marginal Criteria Method (MCM):

Last batch met STM acceptance criteria

or

Last batch met MTM acceptance criteria

 Beginning Routine Testing to

Marginal Criteria Method (MCM):

No routine testing was done since completion

of method development

and

result of method development was marginally pass

Assay > 3 dosage

units per location

and weight correct

the results.