- What is the difference between blend uniformity and content uniformity ??
- What are the pass or fail criteria for both blend uniformity and content uniformity respectively ??
Blend uniformity is a function of both the formulation and mixing action. Once the formulation is optimized from a theoretical process standpoint, blend uniformity must be validated during piloting and scale-up. From a manufacturerâs perspective; poor uniformity generates unacceptable amounts of discarded products, resulting in significant loss of revenue. However, no method currently exists that detects uniformity during the blending process, and as a result the true optimum endpoint is realized rarely.
Various chemical and physical properties of drug substances are affected by their particle size distribution and shapes, also very fine materials are difficult to handle. When large difference in size exists between the active components and excipients, demixing effects can occur making thorough mixing difficult. This effect is greater when the diluents and active raw materials are of significantly different sizes. Not only size but shape too influences the flow and mixing efficiency of powders and granules. Fine materials are relatively more open to attack from atmospheric oxygen, heat, light, humidity and interacting excipients.
It is insufficient to show that adequate distribution of the drug is obtained in the final product; it must be demonstrated within the blend also.
The Acceptance criteria of Blend Uniformity Analysis is as follows,
⢠RSD (relative standard deviation) of all individual results ⤠5.0 percent.
⢠All individual results are within 10.0 percent (absolute) of the mean of the results (90% to 110% of added amount of active drug substance- API).
The term âuniformity of dosage unitâ is defined as the degree of uniformity in the amount of the drug substance among dosage units.
To ensure the consistency of dosage units, each unit in a batch should have a drug substance content within a narrow range around the label claim. Dosage units are defined as dosage forms containing a single dose or a part of a dose of drug substance in each unit.
The uniformity of dosage units can be demonstrated by either of two methods,
- Content Uniformity or
- Weight Variation
The test for Content Uniformity of preparations presented in dosage units is based on the assay of the individual content of drug substance(s) in a number of dosage units to determine whether the individual content is within the limits set. The Content Uniformity method may be applied in all cases.
The USP criteria for content uniformity is that individual tablet (dosage unit) must contain 85%-115% (assay) of active drug substance - API added in it.
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hi @sunilrbudhkar, appreciate very much your explanation, thanks a lot.
Could you direct me to the references or guidelines that quote the said acceptance criteria of 90-110% of amount of labeled API and RSD not more than 5% for Blend Uniformity Analysis?
Thanks in advance.
Hello Mr Sunil @sunilrbudhkar,
Hope to hear from you regarding the reference or standard I can refer to for the acceptance criteria in blend uniformity analysis (ie. 90-110% and RSD<5%).
Thank you in advance.
Please refer following article and the link,
Establishing Blend Uniformity Acceptance Criteria for Oral Solid-Dosage Forms
February 2, 2017
Pharmaceutical Technology, Pharmaceutical Technology-02-02-2017, Volume 41, Issue 2
This article introduces the concepts of pooled variance and the central limit theorem, which are intended for establishing acceptance criteria for blend uniformity data of granular powder blends when a significant degree of sampling bias is involved.
Page Number: 42-52
In 2013, FDA withdrew its draft guidance on blend uniformity (BU)-Guidance for Industry: Powder Blends and Finished Dosage UnitsâStratified In-Process Dosage Unit Sampling and Assessment (1), in which Sections V and VII no longer represented the agencyâs current thinking (2). Section V recommended taking at least three replicate samples from each of at least 10 locations within the blenders (tumbler mixers; or 20 locations in convective mixers). However, it only required that one sample from each location be tested to assess BU as part of first-stage testing, and the current FDA preference is to analyze all of the three replicates from each location (i.e., at least 30 blend samples at each of the three blending time points are tested) (2). It should be noted that the BU data for the three time points are intended to demonstrate the blending process robustness.
Here is a link:
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Dear Mr Sunil @sunilrbudhkar,
Thank you for the link. I tried reading the article and throughout, somehow canât find any mention of the said acceptance criteria as quoted below:
âThe Acceptance criteria of Blend Uniformity Analysis is as follows,
⢠RSD (relative standard deviation) of all individual results ⤠5.0 percent.
⢠All individual results are within 10.0 percent (absolute) of the mean of the results (90% to 110% of added amount of active drug substance- API).â
I sincerely wish to know the reference so that I can proceed using these as our acceptance criteria too.
Hope to hear from you soon.
Thank you.
Thanks for your feedback on Blend Uniformity acceptance criteria of Oral Solid Dosage forms.
Please find herewith reference of comminication by BUWG to FDA,
I am also providing below link to the report published by BUWG titled,
THE USE OF STRATIFIED SAMPLING OF BLEND AND DOSAGE UNITS TO DEMONSTRATE ADEQUACY OF MIX FOR POWDER BLENDS, Final PQRI Blend Uniformity Working Group Recommendation to FDA- 20 December 2002 .
Rationale for Blend Samples and Acceptance criteria as recommended by BUWG (as referred above report) to USFDA is repeoduced below,
Attachment 2
Rationale for Blend Samples and Acceptance Criteria
Sampling Locations
The minimum number of sampling locations suggested is based upon current scientific knowledge of blenders. The PQRI BUWG supports the use of 10 - 15 locations to validate a tumbling blender and at least 20 locations to validate a convective blender. Sampling less than 10 locations will not adequately identify lack of blend uniformity.
Please refer Tables # 1, 2, 3 & 4 for details of sampling and acceptance criteria of blend.
Acceptance Criteria
In the past the FDA has proposed that in the testing of blends, either as part of a validation exercise or in routine blend testing, the RSD of the samples should not exceed 5.0% when the assays are expressed as a percent of the target concentration. In the current proposal we have retained the use of this limit during the testing of powder blends. We find this standard consistent with the intent of providing sufficient assurance, given the relatively small sample size, that the blend is adequately mixed. In addition to the RSD criteria, it is proposed that all individuals fall within +/- 10% (absolute) of the mean for validation, to allow for thief bias. This is a reasonable requirement for blends given the adjustment of thief sample quantity to accommodate for thief error (see Section IV, Process
Development), and the use of dosage unit data to validate the blending process if the blend data continue to demonstrate thief error.
PLEASE READ DETAILED REPORT ON THE ABOVE MENTIONED LINK.
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Thanks a lot for this valuable information.
I want to ask how to handle powder blend sample in test preparation, Should I grind the sample and then weigh the test weight used in procedure or weigh the powder directly without grinding?
Thanks.
Generally, when establishing blend uniformity, the powder blend sample should be weighed as such without any further processing/grinding. You can swirl /shake the sample solution after adding solvent or you can sonicate for a few minutes to get the powder disintegrated and the drug is completely extracted into the solvent and then dilute further with the solvent/extraction medium to make up the volume according to the method of analysis.
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