Blend Uniformity Sampling and Analysis

Standard Operating Procedure (SOP) and Guideline for Sampling, Analysis of Blend Uniformity (BU) samples, and Stratified In-process dosage unit Sampling.

Blend Uniformity (BU) – Sampling & Analysis

1.0   Purpose :

    • To define the procedure for the Blend uniformity analysis and Stratified In-process dosage unit Sampling.

2.0   Scope :

    • This guideline is applicable for Blend uniformity analysis of Solid unit dosage form manufacturing and Stratified In-process dosage unit Sampling.
    • In the case of event batches, extensive sampling shall be done.

3.0   Reference :

    • References :

    • Guidance for industry, Powder blends, and Finished dosage Units-Stratified in-process dosage unit sampling and assessment, Revised Attachments, USFDA, CDER, November 2003.
    • SOP for – Event reporting and investigation.

4.0   Definition of terms & abbreviations – Blend Uniformity (BU):

    • Stratified sampling:

    • It is the process of sampling dosage units at predefined intervals and collecting representative samples from specifically targeted locations in the compression/filling operation that have the greatest potential to yield extreme highs and lows in test results.
    • In-Process Dosage Unit :

    • The in-process dosage unit is a capsule or tablet as it is formed in the manufacturing process before it is coated or packaged.
    • Weight correct results:

    • This is a mathematical correction to eliminate the effect of potentially variable tablet weight on the measurement of mixed adequacy.
    • Example: Individual tablets assay of three tablets from one sampling location is 98.0%,100.0%, and 102.0% with a tablet weight of 98 mg, 100 mg, and 102 mg with a target weight of 100 mg.
    • Then results  shall be weight corrected as 98% x 100 mg / 98 mg = 100%, 100% x 100 mg / 100 mg and 102% x 100 mg / 102 mg = 100%.
    • Thus the mean of these three weights corrected assay results will be 100%.
    • Note: Throughout this guideline when comparing individual dosage units to 75.0% to 125.0% of target potency, use them as-is results ( not corrected for weight).

5.0   Procedure – Sampling and Analysis of Blend Uniformity Samples :

    • Blend Uniformity analysis :

    • Blend uniformity analysis shall be done for active ingredients only and not for other functional excipients e.g. Antioxidants.
    • The sample size of the blend material shall be not more than three times the weight of an individual dose.
    • If the problem is experienced in collecting small samples equivalent to 1 to 3 dosage units and demonstrates that small samples give out of specification values for Blend uniformity analysis (BUA) due to sampling bias, larger samples (usually not more than 10 dosage units) can be collected.
    • Justification for larger samples should be specific to the drug product under question.
    • Note: Justification based on literature references is not adequate.
    • Samples for Blend Uniformity Analysis shall be collected from the blender.
    • If a common blend is used for the manufacture of multiple strengths of the drug product,
    • The weight of the sample used should be equivalent to the weight of the lowest strength of the drug product.
    • 10 sampling locations shall be identified in the blender to represent potential areas of poor blending.
    • For Example :

      • In tumbling blenders (such as V-blenders, double cones, or drum mixers), samples should be selected from at least two depths along the axis of the blender.
      • For convective blenders (such as a ribbon blender), a volumetric sampling to include the corners and discharge area shall be done (at least 20 locations are recommended to adequately validate convective blenders)
    • At least three replicate samples shall be collected from each location.
    • If after three process validation batches it is established that blend uniformity does not pose the problem then in commercial manufacturing duplicate samples shall be collected from each location.
    • Samples shall meet the following criteria.

    • Mean : Between 90.0% and 110.0% of label claim (absolute)
    • RSD less than or equal to 5.0%
    • Note: This acceptance criterion may differ based on scientific rationale or based on queries from regulatory authorities for certain drug products.
    • If the first set of samples don’t meet acceptance criteria, the 2nd and 3rd set of blend uniformity samples from each location shall be analyzed and an investigation of failure shall be conducted.
    • If a mixing problem identified then the blend is not uniform shall be concluded and again investigation shall be done.
    • Even if exhibit and process validation batches meet Blend uniformity acceptance criteria, blend uniformity shall be performed in commercial batches.
    • After approval from regulatory agencies, blend uniformity testing in commercial batches can be deleted.
  • Stratified in-process dosage unit sampling validation stage- EXHIBIT BATCH

    • In exhibit batch Blend uniformity sampling and during compression/filling stratified in-process dosage unit sampling shall be performed.
    • Stratified in-process dosage unit sampling shall be done as explained below.

    • During compression 7 dosage units each from 20 locations shall be collected during the entire compression run.
    • These random sampling points shall cover the significant steps of the process
    • For Example :

      • Beginning of the run,
      • Filled hopper (Full hopper),
      • Half filled hopper,
      • Empty hoper (at the sensor level),
      • Change of blend containers,
      • Stoppage of the machine,
      • Re-start of the machine,
      • Machine adjustments,
      • Middle of run and
      • End of compression or filling operation.
    • Note: In the case of double rotary compression machine samples shall be collected alternatively.
    • In exhibit batch, if blend uniformity does not meet acceptance criteria as defined in the above section but mixing problem not identified then analysis of stratified in-process dosage unit sampling shall be performed.
    • In exhibit batch, sampling protocol acceptance criteria for both Blend uniformity and Stratified in-process dosage unit sampling shall be defined.
    • If mixing problem identified then the blend is not uniform shall be concluded and redevelopment of formulation shall be done.
    • Analysis and evaluation of the results of stratified in-process dosage unit samples shall be done as given below.

      • Assay at least 3 of the 7 dosage units from each location.
      • RSD of all individual results shall be ≤ 6.0%. ( for each batch n=60) Each location means shall be with in 90.0-110.0% of target potency.
      • All individual results shall be within the range of 75.0% to 125.0% of target potency.
    • If the results meet these acceptance criteria then are classified as readily pass.
    • Note: The above limit is a general limit based on guidance but it needs to be tightened based on the drug product potency requirement
    • For Example :

      • Warfarin Sodium tablets 2 mg and 2.5 mg strength. (RSD of all individual results shall be ≤ 3.0%. Each location means shall be within 95.0-105.0% of target potency.
      • All individual results shall be within the range of 92.5% to 107.5% of  target potency) as a higher limit of lower strength and lower limit of higher strength when converted to “mg” can deliver a nearby dose to the patient.
      • If results fail to meet the acceptance criteria, Assay remaining (4 of the 7 dosage units from each location) dosage units from each location.
      • RSD of all individual results shall be  ≤ 6.0%. ( for each batch n=140) Each location mean shall be within 90.0-110.0% of target potency.
      • All individual results shall be within the range of 75.0% to 125.0% of target potency.
    • If the results meet these acceptance criteria then are classified as marginally pass.
    • If the above acceptance criteria are met then the blend is uniform shall be concluded (inappropriate) otherwise redevelopment of formulation shall be initiated.
    • In the dossier, it shall be explained that Blend uniformity shall not be performed in Process Validation and Commercial batches.
    • In certain drug products risk of the Blend-Uniformity failure are more e.g. Potent drugs and dry powder mixing formulations (In dry mixing formulations there is no physical modification of raw materials hence the risk of Blend Uniformity failure is more)
    • In such cases, if during development at R&D if due to scientific reason it is known that the risk of Blend uniformity failure is more than during the validation stage and in routine batch testing Blend uniformity sampling shall not be done and only Stratified in-process dosage unit sampling shall be done.
  • Stratified in-process dosage unit sampling validation stage-Validation stage – PROCESS VALIDATION BATCH

    • In process validation batches Blend uniformity sampling and during compression/filling stratified in-process dosage unit sampling shall be performed.
    • Stratified in-process dosage unit sampling shall be done as explained above.
    • In process validation batches blend uniformity samples and stratified in-process dosage unit samples both shall be analyzed.

    • In process validation protocol acceptance criteria for both Blend uniformity and Stratified in-process dosage unit sampling shall be defined.
    • If the first set of Blend samples do not meet acceptance criteria then the 2nd and 3rd set shall be analyzed.
    • Upon investigation, if a mixing problem identified then the blend is not uniform shall be concluded and redevelopment shall be initiated.
    • If Blend uniformity meets acceptance criteria. then Analysis and evaluation of results of stratified in-process dosage unit samples shall be done.
    • If Blend uniformity does not meet acceptance criteria but mixing problem not identified then Assay at least 7 dosage units per each location.
  • Stratified in-process dosage unit sampling validation stage – ROUTINE BATCH TESTING (COMMERCIAL BATCH TESTING)

    • In process validation batches if Blend uniformity failure observed but stratified in-process dosage unit sampling meets acceptance criteria then during routine batches only stratified in-process dosage unit samples shall be collected and analyzed.
    • The above approach shall be concluded in the process validation report.
    • This approach shall be informed to regulatory agencies.
  • CASE 1: In process validation Stratified in-process dosage unit sampling is established.

    • In routine batch manufacturing Blend uniformity samples and during compression/filling stratified in-process dosage unit samples shall be collected.
    • In process validation batches if Blend uniformity and stratified in-process dosage unit sampling meet acceptance criteria then during routine batches upon Blend uniformity failure only stratified in-process dosage unit sampling analysis shall be performed.
    • Analysis and evaluation of the results of stratified in-process dosage unit samples shall be done as given below.
      • During compression/filling 3 dosage units each shall be sampled from at least 10 locations.
      • If during the validation stage results meet readily pass criteria then during routine batch testing standard criteria method shall be followed.
      • If the results do not meet the standard criteria method then the marginal criteria method shall be followed.
    • Standard criteria method

      • Stage 1 test: Assay 1 dosage unit from each location.
      • RSD of all individual results shall be  (n ≥ 10 ) ≤ 5.0%.
      • The mean of all results is 90.0% to 110.0% of the target assay.
      • If the results do not meet the stage 1 test then proceed to the stage 2 test.
      • Stage 2 test: Assay all remaining units. ( 2 dosage unit from each location)
      • RSD of all individual results shall be  (n ≥ 30 ) ≤ 5.0%.
      • The mean of all results is 90.0% to 110.0% of the target assay.
    • Marginal criteria method

      • RSD of all individual results shall be  (n ≥ 30 ) ≤ 6.0%.
      • The mean of all results is 90.0% to 110.0% of the target assay.
    • Switching to Standard test method from Marginal Test Method
      • Five consecutive batches pass the marginal criteria method criteria and result in RSD ≤ 5.0 %.
      • If the content of active ingredient is less than 50 mg in dosage form then throughout the life cycle of drug product assay all the 30 dosage units and follow marginal criteria method acceptance criteria.
      • Even if five consecutive batches pass the marginal criteria method acceptance criteria then also assay all the 30 dosage units and follow marginal criteria method acceptance criteria.
  • CASE 2: In process validation Stratified in-process dosage unit sampling is not established.

    • In routine batch manufacturing Blend uniformity samples and during compression/filling stratified in-process dosage unit samples shall be collected,
    • Stratified in-process dosage unit sampling validation stage-PROCESS VALIDATION BATCH.
    • The scale-up requirement for oral dosage forms manufactured by Dry Powder Mixing.
    • In the case of oral dosage forms manufactured by dry powder mixing, the active pharmaceutical ingredients and major excipients used in trial/scale-up batches shall have physical parameters (particle size, bulk density) as per the required specification.
    • During trial batches, Blend Uniformity shall be done.
    • If blend uniformity fails then a stratified sampling of finished product shall be done and Uniformity of dosage unit test shall be performed.
    • Stratified In-process dosage unit sampling shall be done.
  • Extensive sampling in case of event batches.

    • If Event detected before compression/filling
    • Stratified in-process dosage unit sampling shall be done.
    • If a mixing problem not identified assay at least 7 dosage units per each location.
    • If Event detected after compression/filling
    • In the case of drug products if Blend uniformity does not meet acceptance criteria then in that case from initial, middle, and end of each drum ten dosage units each shall be withdrawn.
    • Note: Extensive sampling shall be done from core tablets and if the coating is completed then extensive sampling shall be done from coated tablets.
    • If extensive sampling is done from core tablets then extensive sampling from coated tablets is not required.
    • For √n + 1 drums content uniformity by Assay shall be done and for the remaining containers, content uniformity by weight variation shall be done.
    • Thus from each location, 30 dosage units shall be sampled.
    • Initially, 10 dosage units shall be analyzed and content uniformity acceptance criteria shall be applied.
    • If content uniformity acceptance criteria are not met then the remaining 20 dosage units shall be analyzed and content uniformity criteria shall be applied.

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Janki Singh is experienced in Pharmaceuticals, author and founder of Pharma Beginners, an ultimate pharmaceutical blogging platform. Email: [email protected]

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