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Uniformity of Dosage Units

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Title: Uniformity of Dosage Units


1
  • Uniformity of Dosage Units
  • Ms. Witinee Kongsuk
  • Bureau of Drug and Narcotic
  • Department of Medical Sciences
  • July 25, 2008

2
  • Uniformity of Dosage Units
  • Outline
  • USP 28
  • BP 2004
  • Harmonized Uniformity of Dosage Units
  • USP 29, BP 2007
  • Examples
  • Frequently asked questions

3
  • 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.

4
  • Uniformity of Dosage Units
  • Can be demonstrated by either of 2 methods
  • 1. Content Uniformity (CU)
  • 2. Mass/Weight Variation (MV)/(WV)

5
  • Uniformity of Dosage Units
  • - The United States Pharmacopeia (USP)
  • - British Pharmacopoeia (BP)

6
  • The United States Pharmacopeia

7
  • The United States Pharmacopeia

8
  • lt905gt Uniformity of Dosage Units
  • USP 28

9
Application of Content Uniformity (CU) and Weight
Variation (WV) Tests for Dosage Forms (USP28)
10
Application of Content Uniformity (CU) and Weight
Variation (WV) Tests for Dosage Forms (USP28)
11
  • 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

12
  • 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

13
  • 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

14
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
15
Criteria
16
Criteria USP28
17
  • British Pharmacopoeia

18
British Pharmacopoeia
19
  • 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)

20
  • 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

21
  • 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

22
  • 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

23
  • 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

24
  • 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

25
  • 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

26
  • 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

27
  • 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

28
  • 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

29
  • 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

30
  • 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

31
  • 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

32
  • 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

33
  • 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

34
  • 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

35
  • 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
    ?????

36
  • lt905gt Uniformity of Dosage Units
  • USP 29, USP 30

37
Application of Content Uniformity (CU) and Weight
Variation (WV) Tests for Dosage Forms (USP29)
38
Application of Content Uniformity (CU) and Weight
Variation (WV) Tests for Dosage Forms (USP29)
39
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

40
USP29 Calculation of Acceptance Value
41
(No Transcript)
42
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)
43
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
44
Criteria
45
USP29 (10 units)
46
USP29 (30 units)
47
  • Example 1 Pass on First

48
  • Example 2 Fail-Pass

49
  • Example 2 Fail-Pass (Cont.)

50
  • Example 3 Fail-Fail

51
  • Example 3 Fail-Fail (Cont.)

52
  • Appendix XII N. Uniformity of Dosage Units
  • BP 2007

53
Application of Content Uniformity (CU) and Mass
Variation (MV) Tests for Dosage Forms (BP2007)
54
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

55
  • 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

56
  • 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

57
Calculation of individual estimated content
xi wi x A / w
58
  • 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

59
BP2007 Calculation of Acceptance Value (AV)
60
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
61
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
62
(No Transcript)
63
  • 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.

64
  • 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.

65
  • 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.

66
  • 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. )

67
  • 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.

68
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