UNIFORMITY OF DOSAGE UNITS

1.      The term “uniformity of dosage unit” is defined as the degree of uniformity in the amount of the drug substance among dosage units.

2.      Uniformity of dosage unit ensures the consistency of dosage units, each unit in a batch should have a drug substance content within a narrow range around the label claim.

3.      The uniformity of dosage units specification is not intended to apply to suspensions, emulsions, or gels in unit-dose containers intended for external, cutaneous administration.

4.   The uniformity of dosage units can be demonstrated by either of two methods, Content Uniformity or Weigh Variation.

5.      The test for Weight Variation is applicable for the following dosage forms:

Ø  Solutions enclosed in unit-dose containers and into soft capsules.

Ø  Solids (including powders, granules, and sterile solids) that arepackaged in single-unit containers and contain no active or inactive added substances;

Ø  Solids (including sterile solids) that are packaged in single-unit containers, with or without active or inactive added substances that have been prepared from true solutions and freeze-dried in the final containers and are labeled to indicate this method of preparation;

Ø  Hard capsules, uncoated tablets, or film-coated tablets containing 25 mg or more of a drug substance comprising 25%or more by weight of the dosage unit or, in the case of hard capsules, the capsule contents, except that uniformity of other drug substances present in lesser proportions is demonstrated by meeting the requirements for Content Uniformity.

6.      The test for Content Uniformity is applicable for the following dosage forms:

Ø  Hard capsules, uncoated tablets, or film-coated tablets containing less than 25 mg of drug substance comprising less than 25%, by weight, of the dosage unit.

Ø  Suspension, emulsion or gels enclosed into soft capsules.

Ø  Others

7.      Select not fewer than 30 units, and proceed as follows for the dosage form designated.

8.      Assay 10 units individually using an appropriate analytical method and calculate the acceptance value as content uniformity for uniformity of dosage unit determination.

9.      Carry out an assay for the drug substance(s) on a representative sample of the batch using an appropriate analytical method. This value is expressed as percentage of label claim and assumes that the concentration (weight of drug substance per weight of dosage unit) is uniform. Then accurately weigh 10 tablets individually. Calculate the content, expressed as percentage of label claim, of each tablet from the weight of the individual tablet and the result of the Assay. Calculate the acceptance value as weight variation for uniformity of dosage unit determination.

10.  Accurately weigh 10 capsules individually, taking care to preserve the identity of each capsule. Remove the contents of each capsule by a suitable means. Accurately weigh the emptied shells individually, and calculate for each capsule the net weight of its contents by subtracting the weight of the shell from the respective gross weight Calculate the drug substance content of each capsule from the net weight of the individual capsule content and the result of the Assay. Calculate the acceptance value as weight variation for uniformity of dosage unit determination.

11.  Acceptance value for content uniformity (AV) = (98.5 –+ks)

12.  Acceptability constant: If n = 10, then k =2.4; If n = 30, then k =2.0

13.  Maximum allowed acceptance valueL1 is 15.0 and L2 is 25.0.

14.  The requirements for dosage uniformity are met if the acceptance value of the first 10 dosage units is less than or equal to L1%. If the acceptance value is > L1%, test the next 20 units, and calculate the acceptance value. The requirements are met if the final acceptance value of the 30 dosage units is ≤ L1%, and no individual content of any dosage unit is less than [1 − (0.01)(L2)]M nor more than [1 + (0.01)(L2)]M as specified in the Calculation of Acceptance Value under Content Uniformity or under Weight Variation.

15.  If appropriate, these tests may be performed in-process; the acceptance criteria should be included in the specification.  When weight variation is applied for new drug products exceeding the threshold value to allow testing uniformity by weight variation, applicants should verify during drug development that the homogeneity of the product is adequate.

 

References:

  •          USP-NF {905}
  •       ICH Q6A