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4.28 UNIFORMITY OF DOSAGE UNITS

      Dosage units are defined as dosage forms containing a single dose or a part of a dose of drug substance in each unit. (Note In this appendix, unit and dosage unit are synonymous.) 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. The term “uniformity of dosage units” is defined as the degree of uniformity in the amount of the drug substance among dosage units. Therefore, the requirements of this appendix apply to each drug substance being comprised in dosage units containing one or more drug substances, unless otherwise specified in the individual monograph.

      The uniformity of dosage units can be demonstrated by either of two methods, Content Uniformity or Weight Variation (Table 1). The test for Content Uniformity is based on the assay of the individual content of drug substance(s) in a number of individual dosage units to determine whether the individual content is within the limits set. The method of Content Uniformity may be applied in all cases. The test for Content Uniformity is required for those dosage forms described below:

      (1) coated tablets, other than film-coated tablets containing 25 mg or more of a drug substance that comprises 25 per cent or more (by weight) of one tablet;

      (2) transdermal systems;

      (3) suspensions or emulsions or gels in unit-dose containers or in soft capsules that are intended for systemic administration only (not for those drug products that are intended for external, cutaneous administration);

      (4) inhalations (other than solutions for inhalation packaged in glass or plastic ampoules and intended for use in nebulizers) packaged in premetered dosage units. For inhalers and premetered dosage units labelled for use with a named inhalation device;

      (5) solids (including sterile solids) that are packaged in single-unit containers and that contain active or inactive added substances, except that the test for Weight Variation may be applied in the special situations stated in (b) and (c) below; and

      (6) suppositories.

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

      (a) solutions for inhalation that are packaged in glass or plastic ampoules and intended for use in nebulizers, and oral solutions packaged in unit-dose containers and into soft capsules;

      (b) solids (including sterile solids) that are packaged in single-unit containers and contain no added substances, whether active or inactive;

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

      (d) hard capsules, uncoated tablets, or film-coated tablets, containing 25 mg or more of a drug substance comprising 25 per cent 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 of Content Uniformity

      The test for Content Uniformity is required for all dosage forms not meeting the above conditions for the test for Weight Variation. Alternatively, products listed in item (d) above that do not meet the 25 mg/25 per cent threshold limit may be tested for uniformity of dosage units by Weight Variation instead of the test for Content Uniformity if the concentration relative standard deviation (RSD) of the drug substance in the final dosage units is not more than 2 per cent based on process validation data and development data. The concentration RSD is the RSD of the concentration per dosage unit (w/w or w/v), where concentration per dosage unit equals the assay result per dosage unit divided by the individual dosage unit weight. See the RSD formula in Table 2.

Content Uniformity

      Select not less than 30 units and proceed as follows for the dosage form designated. Where the amount of drug substance in a single dosage unit differs from that required in the Assay, adjust the degree of dilution of the solutions and/or the volume of aliquots so that the concentration of the drug substances in the final solution is of the same order as that obtained in the Assay procedure; or, in the case of a titrimetric assay, use a titrant of a different concentration, if necessary, so that an adequate volume of titrant is required. If any such modifications are made in the Assay procedure set forth in the individual monograph, make the appropriate corresponding changes in the calculation formula and titration factor.

Table 1 Application of Content Uniformity (CU) and Weight Variation (WV) Tests for Dosage Forms

      Where a special procedure is specified in the test for Content Uniformity in the individual monograph, make any necessary correction of the results obtained as follows.

      (1) Prepare a composite sample of a sufficient number of dosage units to provide the amount of specimen called for in the Assay in the individual monograph plus the amount required for the special procedure in the monograph by finely powdering tablets or mixing the contents of capsules or oral solutions, suspensions, emulsions, gels, or solids in single-unit containers to obtain a homogeneous mixture. If a homogeneous mixture cannot be obtained in this manner, use suitable solvents or other procedures to prepare a solution containing all of the drug substance, and use appropriate aliquot portions of this solution for the specified procedures. 

      (2) Assay separate, accurately measured portions of the composite sample of capsules or tablets or suspensions or inhalations or solids in single-unit containers, both (a) as directed in the Assay, and (b) using the special procedure for Content Uniformity in the monograph.

      (3) Calculate the weight of drug substance equivalent to one average dosage unit, by (a) using the results obtained by the assay procedure, and by (b) using the results obtained by the special procedure in the monograph.

      (4) Calculate the correction factor, F, by the formula:

               F = W/P

in which W is the weight of drug substance equivalent to one average dosage unit obtained by the Assay procedure, and P is the weight of drug substance

equivalent to one average dosage unit obtained by the special procedure. If

      

is more than 10, the use of a correction factor is not valid.

      (5) The correction factor is to be applied only if F is not less than 1.030 nor more than 1.100, or not less than 0.900 nor more than 0.970. If F is between 0.970 and 1.030, no correction is required.

      (6) If F lies between 1.030 and 1.100, or between 0.900 and 0.970, calculate the weight of drug substance in each dosage unit by multiplying each of the weights found using the special procedure by F.

      UNCOATED, COATED, OR MOLDED TABLETS, CAPSULES, ORAL SOLUTIONS IN SINGLE-UNIT CONTAINERS, ORAL SUSPENSIONS OR ORAL EMULSIONS OR ORAL GELS IN SINGLEUNIT CONTAINERS, AND SOLIDS (INCLUDING STERILE SOLIDS) IN SINGLE-UNIT CONTAINERS Assay 10 units individually as directed in the Assay in the individual monograph, unless otherwise specified in the procedure for Content Uniformity in the individual monograph. Calculate the acceptance value as directed below. 

      For oral solutions, oral suspensions, oral emulsions, or oral gels in single-unit containers, conduct the Assay on the amount of well-mixed material that drains from an individual container in not more than 5 seconds, or for highly viscous products, conduct the Assay on the amount of well-mixed material that is obtained by quantitatively removing the contents from an individual container, and express the results as the delivered dose.

      Calculation of acceptance value Calculate the acceptance value by the formula:

      

in which the terms are as defined in Table 2.

SUPPOSITORIES, TRANSDERMAL SYSTEMS, AND INHALATIONS PACKAGED IN PREMETERED DOSAGE UNITS

(Note Acceptance value calculations are not required for these dosage forms.) Assay 10 units individually as directed in the Assay in the individual monograph, unless otherwise specified in the procedure for Content Uniformity.

Weight Variation

      Carry out the Assay on a representative sample of the batch as directed in the individual monograph. The result of the Assay, obtained as directed in the individual monograph, is designated as result A, expressed as a percentage of the label claim as described under Calculation of Acceptance Value. Assume that the concentration (weight of drug substance per weight of dosage unit) is uniform. Select not less than 30 dosage units, and proceed as follows for the dosage form designated. (Note Specimens other than these test units may be drawn from the same batch for assay determinations.)

      UNCOATED OR FILM-COATED TABLETS Accurately weigh 10 tablets individually. Calculate the drug substance content, expressed as a percentage of the label claim, of each tablet from the weight of the individual tablet and the result of the Assay. Calculate the acceptance value.

      HARD CAPSULES 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, expressed as a percentage of the label claim, of each capsule from the net weight of the individual capsule content and the result of the Assay. Calculate the acceptance value.

      SOFT CAPSULES Accurately weigh 10 intact capsules individually to obtain their gross weights, taking care to preserve the identity of each capsule. Then cut open the capsules by means of a suitable clean, dry cutting instrument such as scissors or a sharp open blade, and remove the contents by washing with a suitable solvent. Allow the occluded solvent to evaporate from the shells at room temperature over a period of about 30 minutes, taking precautions to avoid uptake or loss of moisture. Weigh the individual shells, and calculate the net contents. Calculate the drug substance content, expressed as a percentage of the label claim, in each capsule from the net weight of product removed from the individual capsules and the result of the Assay. Calculate the acceptance value.

      SOLIDS (INCLUDING STERILE SOLIDS) IN SINGLE-UNIT CONTAINERS Proceed as directed for Hard Capsules, treating each unit as described therein. Calculate the acceptance value.

      ORAL SOLUTIONS PACKAGED IN SINGLE-UNIT CONTAINERS Accurately weigh the amount of liquid that drains in not more than 5 seconds from each of 10 individual containers. If necessary, compute the equivalent volume after determining the density. Calculate the drug substance content, expressed as a percentage of the label claim, in the liquid drained from each unit from the net weight of the individual container content and the result of the Assay. Calculate the acceptance value.

      Calculation of acceptance value Calculate the acceptance value as described under Content Uniformity, except that the individual contents of the units are replaced with the individual estimated contents defined below.

x₁, x₂, ..., x_n = individual estimated contents of the units tested, where xi = wi × A/

w₁, w₂, ..., w_n = individual weights of the units tested,

A = content of drug substance (per cent of label claim) determined as described in the Assay, and 

= mean of individual weights (w₁, w₂, ..., w_n).

      SOLUTIONS FOR INHALATION PACKAGED IN GLASS OR PLASTIC AMPOULES AND INTENDED FOR USE IN NEBULIZERS (Note Acceptance value calculations are not required for these dosage forms.) Accurately weigh 10 containers individually, taking care to preserve the identity of each container. Remove the contents of each container by a suitable means. Accurately weigh the emptied containers individually, and calculate for each container the net weight of its contents by subtracting the weight of the container from the respective gross weight. From the results of the Assay, obtained as directed in the individual monograph, calculate the drug substance content, expressed as a percentage of the label claim, in each of the containers.

Criteria

      Apply the following criteria, unless otherwise specified in the individual monograph.

      UNCOATED, COATED, OR MOLDED TABLETS, CAPSULES, ORAL SOLUTIONS IN SINGLE-UNIT CONTAINERS, ORAL SUSPENSIONS OR ORAL EMULSIONS OR ORAL GELS IN SINGLEUNIT CONTAINERS, AND SOLIDS (INCLUDING STERILE SOLIDS) IN SINGLE-UNIT CONTAINERS 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 more than 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 less than or equal to L1, and no individual content of any dosage unit is less than (1 – L2 × 0.01)M nor more than (1 + L2 × 0.01)M as specified in the Calculation of Acceptance Value under Content Uniformity or under Weight Variation. Unless otherwise specified in the individual monograph, L1 is 15.0 and L2 is 25.0.

      SUPPOSITORIES

      Limit A (if the average of the limits specified in the potency definition in the individual monograph is 100.0 per cent or less) Unless otherwise specified in the individual monograph, the requirements for dosage uniformity are met if the amount of the drug substance in each of the 10 dosage units as determined from the method of Content Uniformity lies within the range of 85.0 per cent to 115.0 per cent of the label claim, and the RSD is less than or equal to 6.0 per cent.

      If one unit is outside the range of 85.0 per cent to 115.0 per cent of the label claim, and no unit is outside the range of 75.0 per cent to 125.0 per cent of the label claim, or if the RSD is more than 6.0 per cent, or if both conditions prevail, test 20 additional units. The requirements are met if not more than one unit of the 30 is outside the range of 85.0 per cent to 115.0 per cent of the label claim, and no unit is outside the range of 75.0 per cent to 125.0 per cent of the label claim and the RSD of the 30 dosage units does not exceed 7.8 per cent.

      Limit B (if the average of the limits specified in the potency definition in the individual monograph is more than 100.0 per cent)

      (1) If the average value of the dosage units tested is 100.0 per cent or less, the requirements are as in Limit A.

      (2) If the average value of the dosage units tested is greater than or equal to the average of the limits specified in the potency definition in the individual monograph, the requirements are as specified under Limit A, except that the words “label claim” are replaced by the words “label claim multiplied by the average of the limits specified in the potency definition in the monograph divided by 100”.

      (3) If the average value of the dosage units tested is between 100 per cent and the average of the limits specified in the potency definition in the individual monograph, the requirements are as specified under Limit A, except that the words “label claim” are replaced by the words “label claim multiplied by the average value of the dosage units tested (expressed as a per cent of label claim) divided by 100”.

      TRANSDERMAL SYSTEMS AND INHALATIONS PACKAGED IN PREMETERED DOSAGE UNITS

      Limit A (if the average of the limits specified in the potency definition in the individual monograph is 100.0 per cent or less) Unless otherwise specified in the individual monograph, the requirements for dosage uniformity are met if the amount of the drug substance in not fewer than 9 of the 10 dosage units as determined from the method of Content Uniformity (or, in the case of solutions for inhalation packaged in glass or plastic ampoules and intended for use in nebulizers, from either the method of Content Uniformity or the Weight Variation) lies within the range of 85.0 per cent to 115.0 per cent of label claim, and no unit is outside the range of 75.0 per cent to 125.0 per cent of the label claim, and the RSD of the 10 dosage units is less than or equal to 6.0 per cent.

      If two or three dosage units are outside the range of 85.0 per cent to 115.0 per cent of the label claim, but not outside the range of 75.0 per cent to 125.0 per cent of the label claim, or if the RSD is more than 6.0 per cent or if both conditions prevail, test 20 additional units. The requirements are met if not more than 3 units of the 30 are outside the range of 85.0 per cent to 115.0 per cent of the label claim and no unit is outside the range of 75.0 per cent to 125.0 per cent of the label claim, and the RSD of the 30 dosage units does not exceed 7.8 per cent.

      Limit B (if the average of the limits specified in the potency definition in the individual monograph is more than 100.0 per cent)

      (1) If the average value of the dosage units tested is 100.0 per cent or less, the requirements are as in Limit A.

      (2) If the average value of the dosage units tested is more than or equal to the average of the limits specified in the potency definition in the individual monograph, the requirements are as specified under Limit A, except that the words “label claim” are replaced by the words “label claim multiplied by the average of the limits specified in the potency definition in the monograph divided by 100”.

      (3) If the average value of the dosage units tested is between 100 per cent and the average of the limits specified in the potency definition in the individual monograph, the requirements are as specified under Limit A, except that the words “label claim” are replaced by the words “label claim multiplied by the average value of the dosage units tested (expressed as a percentage of label claim) divided by 100”.