905UNIFORMITY OF DOSAGE UNITS(1), chemical structure, molecular formula, Reference Standards

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á905ñUNIFORMITY OF DOSAGE UNITS

[NOTE—In this chapter,unit and dosage unitare 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.Dosage units are defined as dosage forms containing a single dose or a part of a dose of drug substance in each unit.

The term “uniformity of dosage unit”is defined as the degree of uniformity in the amount of the drug substance among dosage units.Therefore,the requirements of this chapter 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 Uniformityor Weight Variation(see 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 Content Uniformitymethod may be applied in all cases.The test for Content Uniformityis required for those dosage forms described in (C1)–(C6)below:

(C1)	coated tablets,other than film-coated tablets containing 25mg or more of a drug substance that comprises 25%or more (by weight)of one tablet;
(C2)	transdermal systems;
(C3)	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);
(C4)	inhalations (other than solutions for inhalation packaged in glass or plastic ampuls and intended for use in nebulizers)packaged in premetered dosage units.For inhalers and premetered dosage units labeled for use with a named inhalation device,also see Aerosols,Nasal Sprays,Metered-Dose Inhalers,and Dry Powder Inhalers á601ñ;
(C5)	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 Variationmay be applied in the special situations stated in (W2)and(W3)below;and
(C6)	suppositories.

The test for Weight Variationis applicable for the following dosage forms:

(W1)	solutions for inhalation that are packaged in glass or plastic ampuls and intended for use in nebulizers,and oral solutions packaged in unit-dose containers and into soft capsules;
(W2)	solids (including sterile solids)that are packaged in single-unit containers and contain no added substances,whether active or inactive;
(W3)	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 labeled to indicate this method of preparation;and
(W4)	hard capsules,uncoated tablets,or film-coated tablets,containing 25mg 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 Content Uniformityrequirements.

The test for Content Uniformityis required for all dosage forms not meeting the above conditions for the Weight Variation test.Alternatively,products listed in item (W4)above that do not meet the 25mg/25%threshold limit may be tested for uniformity of dosage units by Weight Variation instead of the Content Uniformity test if the concentration relative standard deviation (RSD)of the drug substance in the final dosage units is not more than 2%,based on process validation data and development data.The concentration RSDis the RSDof 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 RSDformula in Table 2.

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

			Dose &Ratio of Drug Substance
Dosage Form	Type	Subtype	³25mg & ³25%	<25mg or <25%
Tablets	Uncoated		WV	CU
	Coated	Film	WV	CU
	Coated	Others	CU	CU
Capsules	Hard		WV	CU
	Soft	Suspension,emulsion, or gel	CU	CU
	Soft	Solutions	WV	WV
Solids in single-unit containers	Single component		WV	WV
	Multiple components	Solution freeze-dried in final container	WV	WV
	Multiple components	Others	CU	CU
Suspension,emulsion,or gel for systemic use only, packaged in single-unit containers			CU	CU
Solutions for inhalation packaged in glass or plastic ampuls andintended for use in nebulizers, and oral solutions packaged in unit-dose containers and into soft capsules			WV	WV
Inhalations (other than solutions for inhalation packaged in glass or plastic ampuls and intended for use in nebulizers)packaged in premetered dosage units			CU	CU
Transdermal systems			CU	CU
Suppositories			CU	CU
Others			CU	CU

CONTENT UNIFORMITY

Select not less than 30units,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 Assayprocedure;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 (see Titrimetry á541ñ);see also Proceduresunder Tests and Assaysin the General Notices and Requirements.If any such modifications are made in the Assayprocedure set forth in the individual monograph,make the appropriate corresponding changes in the calculation formula and titration factor.

Where a special Procedure for content uniformityis specified in the test for Uniformity of dosage unitsin the individual monograph,make any necessary correction of the results obtained as follows.

Prepare a composite specimen of a sufficient number of dosage units to provide the amount of specimen called for in the Assayin the individual monograph plus the amount required for the special Procedure for content uniformityin 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.

Assay separate,accurately measured portions of the composite specimen 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 uniformityin the monograph.

Calculate the weight of drug substance equivalent to 1average dosage unit,by (a)using the results obtained by the Assayprocedure,and by (b)using the results obtained by the special procedure.

Calculate the correction factor,F,by the formula:

F=W/P,

in which Wis the weight of drug substance equivalent to 1average dosage unit obtained by the Assayprocedure,and Pis the weight of drug substance equivalent to 1average dosage unit obtained by the special procedure.If

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

The correction factor is to be applied only if Fis not less than 1.030nor greater than 1.100,or not less than 0.900nor greater than 0.970.If Fis between 0.970and 1.030,no correction is required.

If Flies between 1.030and 1.100,or between 0.900and 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 Single-Unit Containers,and Solids (including Sterile Solids)in Single-Unit Containers— Assay 10units individually as directed in the Assayin the individual monograph,unless otherwise specified in the Procedure for content uniformityin 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 Assayon the amount of well-mixed material that drains from an individual container in not more than 5seconds,or for highly viscous products,conduct the Assayon 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.

Table 2

Variable	Definition	Conditions	Value
bar(X)	Mean of individual contents (c1,c2,…,cn),expressed as a percentage of the label claim
c1,c2,…,cn	Individual contents of the units tested,expressed as a percentage of the label claim
n	Sample size (number of units in a sample)
k	Acceptability constant	If n=10,then k=	2.4
		If n=30,then k=	2.0
s	Sample standard deviation
RSD	Relative standard deviation (the sample standard deviation expressed as a percentage of the mean)
M(case 1)to be applied when T£101.5	Reference value	If 98.5%£bar(X)£101.5%,then	M=bar(X) (AV=ks)
		If bar(X)<98.5%,then	M=98.5% (AV=98.5–bar(X)+ks)
		If bar(X)>101.5%,then	M=101.5% (AV=bar(X)–101.5+ks)

M(case 2)to be applied when T>101.5	Reference value	If 98.5£bar(X)£T,then	M=bar(X) (AV=ks)
		If bar(X)<98.5%,then	M=98.5% (AV=98.5–bar(X)+ks)
		If bar(X)>T,then	M=T% (AV=bar(X)–T+ks)
Acceptance value (AV)			general formula: (Calculations are specified above for the different cases.)
L1	Maximum allowed acceptance value		L1=15.0unless otherwise specified in the individual monograph
L2	Maximum allowed range for deviation of each dosage unit tested from the calculated value ofM	On the low side,no dosage unit result can be less than (1–L20.01)M,while on the high side no dosage unit result can be greater than (1+L20.01)M.(This is based on an L2value of 25.0.)	L2=25.0unless otherwise specified in the individual monograph
T	Target test sample amount at time of manufacture.For purposes of this Pharmacopeia,unless otherwise specified in the individual monograph,Tis 100.0%,and for manufacturing purposes,Tis the manufacturer's approved target test amount value at the time of manufacture.

Suppositories,Transdermal Systems,and Inhalations Packaged in Premetered Dosage Units— [NOTE—Acceptance value calculations are not required for these dosage forms.]Assay 10units individually as directed in the Assayin the individual monograph,unless otherwise specified in the Procedure for content uniformity.

WEIGHT VARIATION

Select not less than 30dosage units,and proceed as follows for the dosage form designated.The result of the Assay,obtained as directed in the individual monograph,is designated as result A,expressed as %of label claim (see Calculation of the Acceptance Value).Assume that the concentration (weight of drug substance per weight of dosage unit)is uniform.[NOTE—Specimens other than these test units may be drawn from the same batch for assay determinations.]

Uncoated or Film-Coated Tablets— Accurately weigh 10tablets individually.Calculate the drug substance content,expressed as %of 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 10capsules 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 %of 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 10intact 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 30minutes,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 %of 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 5seconds from each of 10individual containers.If necessary,compute the equivalent volume after determining the density.Calculate the drug substance content,expressed as %of 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 shown in Content Uniformity,except that the individual contents of the units are replaced with the individual estimated contents defined below.

c1,c2,...,cn	=	individual estimated contents of the units tested,where ci=wi×A/bar(W),
w1,w2,...,wn	=	individual weights of the units tested,
A	=	content of drug substance (%of label claim)determined as described in the Assay,and
bar(W)	=	mean of individual weights (w1,w2,...,wn).

Solutions for Inhalation Packaged in Glass or Plastic Ampuls and Intended for Use in Nebulizers— [NOTE—Acceptance value calculations are not required for these dosage forms.]Accurately weigh 10containers 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 %of 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 Single-Unit Containers,and Solids (Including Sterile Solids)in Single-Unit Containers— The requirements for dosage uniformity are met if the acceptance value of the first 10dosage units is less than or equal to L1%.If the acceptance value is greater than L1%,test the next 20units and calculate the acceptance value.The requirements are met if the final acceptance value of the 30dosage units is less than or equal to L1%,and no individual content of any dosage unit is less than (1–L2*0.01)Mnor more than (1+L2*0.01)Mas specified in the Calculation of Acceptance Valueunder Content Uniformityor under Weight Variation.Unless otherwise specified in the individual monograph,L1is 15.0andL2is 25.0.

Suppositories—

If 1unit is outside the range of 85.0%to 115.0%of label claim,and no unit is outside the range of 75.0%to 125.0%of label claim,or if the RSDis greater than 6.0%,or if both conditions prevail,test 20additional units.The requirements are met if not more than 1unit of the 30is outside the range of 85.0%to 115.0%of label claim,and no unit is outside the range of 75.0%to 125.0%of label claim and the RSDof the 30dosage units does not exceed 7.8%.

Limit B(if the average of the limits specified in the potency definition in the individual monograph is greater than 100.0percent)—

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”.

If the average value of the dosage units tested is between 100percent 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 percent 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 100.0percent 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 less than 9of the 10dosage units as determined from the Content Uniformitymethod (or,in the case of solutions for inhalation packaged in glass or plastic ampuls and intended for use in nebulizers,from either the Content Uniformityor the Weight Variationmethod)lies within the range of 85.0%to 115.0%of label claim,and no unit is outside the range of 75.0%to 125.0%of label claim,and the RSDof the 10dosage units is less than or equal to 6.0%.

If 2or 3dosage units are outside the range of 85.0%to 115.0%of label claim,but not outside the range of 75.0%to 125.0%of label claim,or if the RSDis greater than 6.0%or if both conditions prevail,test 20additional units.The requirements are met if not more than 3units of the 30are outside the range of 85.0%to 115.0%of label claim and no unit is outside the range of 75.0%to 125.0%of label claim,and the RSDof the 30dosage units does not exceed 7.8%.

Limit B (if the average of the limits specified in the potency definition in the individual monograph is greater than 100.0percent)—

USP28

(Official April 1,2006)