Uniformity of Dosage Units

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• Uniformity of Dosage Units
• Ms. Witinee Kongsuk
• Bureau of Drug and Narcotic
• Department of Medical Sciences
• July 25, 2008

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• Uniformity of Dosage Units
• Outline
• USP 28
• BP 2004
• Harmonized Uniformity of Dosage Units
• USP 29, BP 2007
• Examples
• Frequently asked questions

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• Uniformity of Dosage Units
• To ensure the consistency of the dosage units
• - each unit in a batch should have an active
  substances content within a narrow range around
  the label claim
• The degree of uniformity in the amount of the
  active substance among dosage units.

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• Uniformity of Dosage Units
• Can be demonstrated by either of 2 methods
• 1. Content Uniformity (CU)
• 2. Mass/Weight Variation (MV)/(WV)

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• Uniformity of Dosage Units
• - The United States Pharmacopeia (USP)
• - British Pharmacopoeia (BP)

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• The United States Pharmacopeia

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• The United States Pharmacopeia

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• lt905gt Uniformity of Dosage Units
• USP 28

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Application of Content Uniformity (CU) and Weight
Variation (WV) Tests for Dosage Forms (USP28)
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Application of Content Uniformity (CU) and Weight
Variation (WV) Tests for Dosage Forms (USP28)
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• lt905gt Uniformity of Dosage Units, USP 28
• Weight Variation (WV)
• Select gt 30 units
• Weigh accurately 10 tablets individually
• Calculate the content of active ingredient in
  each 10 units from the result of the Assay
• Assuming homogeneous distribution of the active
  ingredient

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• lt905gt Uniformity of Dosage Units, USP 28
• Content Uniformity (CU)
• Select gt 30 units
• assay 10 tablets individually as directed in the
  individual monograph
• Unless otherwise specified in the
• Procedure for CU

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• lt905gt Uniformity of Dosage Units, USP 28
• Content Uniformity (CU)
• Special procedure for CU is specified in the
  monograph
• The correction factor, F
• F A / P
• A the weight of active ingredient eq. to 1 av.
  Dosage unit obtained by the Assay
• P the weight of active ingredient eq. to 1 av.
  Dosage unit obtained by
• special procedure (difference from assay
  procedure)
• IF 100 A P gt 10, F is not
  valid
• A
• valid F 1.030 lt F lt 1.100 or 0.900 lt F lt
  0.970
• F is between 0.970 - 1.030 , no F required
• F is between 1.030 1.100 or 0.900 0.970
  P x F

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USP28
when XT the average value of the
dosage units tested
XL the average of
the limits specified in the potency definition
in the individual
monograph
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Criteria
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Criteria USP28
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• British Pharmacopoeia

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British Pharmacopoeia
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• BP 2004
• Content of active substance
• lt 2 mg or lt 2 of the total mass
• Appendix XII H Uniformity of Content
• (Ph. Eur. Method 2.9.6)

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• BP 2004
• Appendix XII G Uniformity of Weight (Mass)
• (Ph. Eur. Method 2.9.5)
• Weigh individually 20 units
• Determine the av. Mass
• NMT 2 of the individual masses deviate from
• the av. Mass by more than twice that
  percentage

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• BP 2004
• Appendix XII G Uniformity of Weight (Mass)
• (Ph. Eur. Method 2.9.5)
• Pharmaceutical Form Average
  mass deviation
• Tablets (uncoated, film coated) lt 80 mg
  or less 10
• 
  gt 80 mg and lt 250 mg 7.5
• 
  gt 250 mg
  5
• Capsules, granules
  lt 300 mg 10
• (uncoated, single dose)
  gt 300 mg 7.5
• and powders (single-dose)
• Powder for parenteral use gt
  40 mg 10
• (single dose)
• Suppositories and pessaries All
  masses 5
• Powders for eye-drops and lt
  300 mg 10
• Powder for eye-lotions
  gt 300 mg 7.5
• (single-dose)
• Av. Mass lt 40 mg, test for uniformity of
  content

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• BP 2004
• Appendix XII H Uniformity of Content
• (Ph. Eur. Method 2.9.6)
• Content of active ingredient
• lt 2 mg or lt 2 of the total mass
• Determine the individual contents
• of active substance(s) of 10 dosage units

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• BP 2004
• Appendix XII H Uniformity of Content
• (Ph. Eur. Method 2.9.6)
• TEST A
• Tablets, powders for parenteral use, ophthalmic
  inserts,
• suspensions for injections
• 85 115 of the av. content
• If more than 1 unit is outside 85-115 of the
  av. content but within
• 75-125 of the av. content
• Determine the individual contents of another 20
  units
• NMT 1 of 30 units is outside 85-115 of the av.
  content and
• none is outside 75-125 of the av. content

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• BP 2004
• Appendix XII H Uniformity of Content
• (Ph. Eur. Method 2.9.6)
• TEST B
• Capsules, powders other than parenteral use,
  granules, suppositories,
• pessaries
• NMT 1 unit is outside 85 115 of the av.
  Content,
• none is outside 75-125 of the av. Content
• If lt 3 units are outside 85 115 of the av.
  Content but within 75-125 of the av. Content
• Determine the individual contents of another 20
  units
• NMT 3 of 30 units are outside 85-115 of the av.
  content and
• none is outside 75-125 of the av. content

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• BP 2004
• Appendix XII H Uniformity of Content
• (Ph. Eur. Method 2.9.6)
• TEST C
• Transdermal patches
• av. content of 10 units is 90-110 of the content
  stated on the
• label and if each unit is between 75-125 of the
  av. content

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• BP 2004
• Appendix XII L Uniformity of Weight (Mass) of
  Delivered Doses from Multi-dose Containers
• (Ph. Eur. Method 2.9.27)
• Oral dosage form granules powders for oral use
  and liquids for oral use, which are supplied in
  multi
• Weigh individually 20 doses from gt 1 containers
• Determine the individual and av. weights (mass)
• NMT 2 individual weight deviate gt 10 of av.
  Weight (mass)
• And none deviates gt 20

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• USP-NF General Chapter
• lt905gt Uniformity of Dosage Units
• USP 28-NF 23
• - harmonized general chapter lt905gt on page
  2505-2510
• - Implementation date April 1, 2006
• - approved by the Pharmacopeial Discussion
  Group
• (PDG)
• PDG- The United States Pharmacopeia
• - The Japanese Pharmacopeia
• - The European Pharmacopeia

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• USP-NF General Chapter
• lt905gt Uniformity of Dosage Units
• USP 29-NF 24
• the official and the revised, harmonized
  versions of lt905gt appeared
• Official Harmonized Chapter lt905gt
• official on January 1, 2007

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• USP-NF General Chapter
• lt905gt Uniformity of Dosage Units
• Harmonized Chapter Testing Requirements
• - lt905gt includes Content Uniformity and Weight
  Variation procedures and acceptance criteria to
  evaluate uniformity of dosage units.
• - Apply to both newly registered and existing
  products

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• USP-NF General Chapter
• lt905gt Uniformity of Dosage Units
• 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 greater than L1,
• test the next 20 units.
• - The requirements are met if the final
  acceptance value of the 30 dosage units is less
  than or equal to L1 and all individual dosage
  units fall within the range calculated using L2
  factor

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• Statistical Basis of the New Content Uniformity
  Criteria
• General idea for statistical tolerance intervals
  
• To use the available data to form an interval
  that
• covers a specified proportion of the
  distribution data.
• To form an interval about the label claim within
  which a specified proportion of units would fall.
• An interval is a 95 tolerance interval for 90
  of the distribution if 95 of such intervals with
  repeated sampling would cover at least 90 of the
  distribution

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• Statistical Basis
• of the New Content Uniformity Criteria
• Constructing the criteria of General Chapter
  lt905gt
• 1. The tolerance interval is modified to
  correspond to
• the standard two-stage testing of content
  uniformity.
• i.e., where 10 units are tested and then,
  if needed,
• an additional 20 are tested.
• This requires
• k1 after the first stage,
• k2 after the second stage, where the
  sample is larger

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• Statistical Basis
• of the New Content Uniformity Criteria
• Constructing the criteria of General Chapter
  lt905gt
• 2. The acceptance interval is allowed to be
  asymmetric with respect to the label claim
• where the potency range specified in the
  monograph is not symmetric
• The T of General Chapter lt905gt is the
  center of the potency range

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• Statistical Basis
• of the New Content Uniformity Criteria
• Constructing the criteria of General Chapter
  lt905gt
• 3. A 1.5 interval about the label claim is
  included
• so deviation of the mean content from the
  label claim
• count only to the extent they are greater
  than this
• percentage.
• This is reflected in calculation of M

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• Statistical Basis
• of the New Content Uniformity Criteria
• Constructing the criteria of General Chapter
  lt905gt
• 4. k
• New procedure has operating
  characteristics similar to those prior General
  Chapter lt905gt criteria.
• It does not mean that the data would pass
  by the prior criteria, it will pass by the new
  criteria and similarly for the data would fail
  ?????

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• lt905gt Uniformity of Dosage Units
• USP 29, USP 30

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Application of Content Uniformity (CU) and Weight
Variation (WV) Tests for Dosage Forms (USP29)
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Application of Content Uniformity (CU) and Weight
Variation (WV) Tests for Dosage Forms (USP29)
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Application of Content Uniformity (CU) and Weight
Variation (WV) Tests for Dosage Forms (USP29)

• if do not meet the 25 mg/ 25 threshold
  limit
• may be tested for WV
• if conc. RSD lt 2 (based on process
  validation
• data
  and development data)
• conc. RSD RSD of conc. per dosage unit (w/w
  or w/v)
• conc./dosage unit assay result per
  dosage unit individual
  dosage unit weight

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USP29 Calculation of Acceptance Value
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Acceptance Value (AV)
AV M-X ks M (case 1), T lt
101.5 T, Target test sample amount at time of
manufacture. T 100.0 unless otherwise
specified in the individual monograph If n
10, then k 2.4 If n 30, then k 2.0
X Mean of individual contents (
label claim)
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Acceptance Value (AV)
AV M-X ks M (case 2),
T gt 101.5 T, Target test sample amount at time
of manufacture. T 100.0 unless otherwise
specified in the individual monograph If n
10, then k 2.4 If n 30, then k 2.0
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Criteria
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USP29 (10 units)
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USP29 (30 units)
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• Example 1 Pass on First

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• Example 2 Fail-Pass

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• Example 2 Fail-Pass (Cont.)

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• Example 3 Fail-Fail

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• Example 3 Fail-Fail (Cont.)

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• Appendix XII N. Uniformity of Dosage Units
• BP 2007

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Application of Content Uniformity (CU) and Mass
Variation (MV) Tests for Dosage Forms (BP2007)
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Application of Content Uniformity (CU) and Mass
Variation (MV) Tests for Dosage Forms (BP2007)

• if do not meet the 25 mg/ 25 threshold
  limit
• may be tested for MV
• if conc. RSD lt 2 (based on process
  validation
• data
  and development data)
• conc. RSD RSD of conc./dosage unit (m/m
  or m/v)
• conc./dosage unit assay result per
  dosage unit individual
  dosage unit mass

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• Mass Variation (MV)
• Assay for the active
  substance(s)
• Result A ( label
  claim)
• Assume that the concentration
• (mass of active substance per mass of dosage
  unit)
• is uniform
• Select NLT 30 dosage units

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• Mass Variation (MV)
• Accurately weigh 10 units individually
• calculate active substance content
• ( label claim)
• from the Assay result and mass of each unit
• Calculate the acceptance value

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Calculation of individual estimated content
xi wi x A / w
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• Content Uniformity (CU), BP 2007
• select NLT 30 units and
• proceed as follows for the dosage form designated
  
• assay 10 units individually
• calculate the acceptance value

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BP2007 Calculation of Acceptance Value (AV)
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Acceptance Value (AV)
AV M-X ks M (case 1), T
lt 101.5 T, Target test sample amount at time of
manufacture. T 100.0 unless otherwise
specified in the individual monograph If n
10, then k 2.4 If n 30, then k 2.0
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Acceptance Value (AV)
AV M-X ks M (case 2),
T gt 101.5 T, Target test sample amount at time
of manufacture. T 100.0 unless otherwise
specified in the individual monograph If n
10, then k 2.4 If n 30, then k 2.0
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• Frequently asked questions
• Q What is meant by the term special procedure
  as
• found under Content Uniformity in the
  official chapter?
• A Typically, CU determination is made on
  individual
• dosage units using the procedure found in
  the Assay.
• For certain products, a separate procedure
  is given in the
• monograph for CU determination.
• Theophylline Extended-Release Capsule is an
  example.

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• Frequently asked questions
• Q The Harmonized lt905gt became official on Jan 1,
  2007.
• Does the harmonized chapter completely
  replace the
• current text?
• A Yes. As of Jan 1, 2007, only the revised,
  harmonized
• chapter text is official.

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• Frequently asked questions
• Q Existing products may be exempt from the
  requirements
• of the harmonized chapter and that it will
  only apply to
• new formulations. Will the USP allow such
• grandfathering?
• A The harmonized chapter text applies to any
  monograph,
• new or existing, that includes a test for
  Uniformity of
• Dosage Units.

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• Frequently asked questions
• Q What is the max. allowable acceptance value
  for Content
• Uniformity testing at level 2, where a
  total of 30 dosage
• units have been tested?
• The confusion is in the use of the L1
  (15.0) and L2 values
• (25.0)
• A CU testing can be performed in 2 stages.
• First stage (10 units) and Second stage
  (total 30 units)
• L1 Limit for the acceptance value for both
  stages
• L2 to calculate the allowed limits for
  individual dosage
• unit content (range for deviation
  of each dosage unit. )

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• Frequently asked questions
• Q WV is allowed for hard capsules, uncoated
  tablets, and
• film-coated tablets containing gt 25 mg of
  drug substance
• comprising gt 25 of the weight of the
  dosage unit.
• If uncoated tablet contains 2 drug
  substances but only
• one of them meets the requirement for WV,
  how can the
• requirement be met?
• A In the case of a two-component tablet, the
  Uniformity of
• Dosage Units test requirement will be met by
  the WV for
• the component gt 25 mg of drug substance
  comprising
• gt 25 of the weight of the dosage unit
  mass.
• The other component will require the CU.

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Thank you