Escolar Documentos
Profissional Documentos
Cultura Documentos
Ot,l.
Accept.
Prob. 5
I
6 7 8 9 10 11 12 13
Sample Sizc
14 15 18 20 25 30 50
--
60 100
0 0.95 1 0.9 0.8 0.7 0.6 0.5 0.5 0.4 0.4 0.4 0 . 3 0.27 0.25 0.20 0.17 0.10 0.09 0.05
0.10 37 32 28 25 23 21 19 17 16 15 14 12 11 9 7.5 4.5 3.8 2.5
0.05 45 39 35 31 28 26 24 22 21 19 18 15 14 11 9.5 6 5 3
1 0.95 8 6 5 4.5 4 3.5 3.3 3 2.8 2.5 2.5 2.2 2 1.5 1 0.7 0.6 0.35
0.10 58 51 45 41 37 34 31 29 27 25 24 20 18 15 12.5 8 6.5 4
0.05 66 58 52 47 43 39 36 34 32 30 28 24 22 18 15 9.5 8 4.5
2 0.95 19 15 13 11 10 9 8 7 7 6 5.55 4.5 3.5 2.5 1.5 1.4 0.8
0.10 75 67 60 54 49 45 42 39 36 34 32 27 24.5 20 17 10.5 9 5.5
0.05 81 73 66 60 55 51 47 44 41 39 36 31 28 23 20 12.5 10.5 6.5
3 0.95 34 27 23 19 17 15 14 12 11 10 9. 5 7 . 5 7 5.5 4.5 2.5 2.3 1.5
0.10 89 80 72 66 60 55 51 48 45 42 39 33 30.5 25 21 13.5 11.1 6.5
0.05 92 85 77 71 66 61 56 53 49 47 44 38 34 28 24 15.5 13 8
4 0.95 42 34 29 25 22 20 18 17 15 14 12 10.5 8.5 7 4 3.3 2
0.10 83 76 70 65 60 55 52 49 46 40 36 30 25 16 13.3 8
0.05 87 81 75 70 65 61 57 54 51 44 40 33 28 18.5 15.3 9
5 0.95 40 34 30 27 25 22 21 19 16 14 11 9 5 4.4 2.5
0.10 79 73 68 63 59 56 53 46 41 34 29 18.5 15.5 9.5
0.05 83 78 73 68 64 61 58 50 46 38 32 21 17.5 10.5
6 0.95 35 32 29 26 24 20 18 14 12 6.5 5.5 3.5
0.10 63 60 51 46 38 33 21 17.6 10.5
0.05 67 64 55 51 42 36 23.5 19.7 12
7 0.95 33 30 24 22 17 14 8 6.6 4
0.10 56 51 43 36 23.5 19.6 12
0.05 61 56 46 39 26.5 22 13
8 0.95 29 26 21 17 9.5 7.8 4.5
0.10 56 47 40 26 21.7 13
0.05 61 50 43 29 24.1 14.5
9 0.95 30 24 19 11 9 5.5
0.10 50 43 28.5 23.7 14
0.05 54 47 31.5 26.2 15.5
10 0.95 27 22 12.5 10.3 6
0.10 55 47 31 25.7 15.5
0.05 58 50 34 28.3 17
11 0.95 31 25 14 11.5 7.0
0.10 50 33 27.7 16.5
0.05 53 36.5 30.3 18.0
-
12 0.95 28 15.5 12.8 7.5
0.10 35.5 29.6 18
0.05 39 32.4 19.5
average consumer, or in outgoing quality inspection of the pro- ANALYSIS OF THE UNIFORMITY
ducer. This obstacle may be overcome assuming a normal distribu- SPECIFICATIONS OF PHARMACOPEIAS
tion. But the variables involved do not always conform to the normal
distribution, since sometimes they are truncated normal, skew, With the exception of the PharmacopCe Franqaise (1 I), the
lepto- or platy-curtic, or bimodal, etc. (8-10). Nevertheless, a normal most important recent pharmacopeias demand the compliance with
distribution is very frequent, and therefore it is still meaningful to uniformity tests for several dosage forms. In the present study
assume it for analyzing uniformity specifications and for comparing the pharmacopeias listed in Table 111 were examined, their uni-
those of different official codexes. Obviously this assumption must formity tests analyzed, and the percentages of outsiders calculated
be kept in mind in critical situations and in borderline conditions. with the aid of Table I at the acceptance probability levels of RP =
In these cases the distribution type ought to be checked with large 95% and of RC = 10% and then converted into C V values using
samples before drawing final conclusions. Table 11.
Table 11-Factors (u) for Calculating CV in Relation to the Per- Table In-Pharmacopeias Examined and Abbreviations Used
centage of Outsiders
Year of
Out- Pharmacopeias Issue Abbreviation
siders,
Zb 0 1 2 3 4 5 6 7 8 9 British Pharmacopoeia 1968 BP
Deutsches Arzneibuch 7 (of the DDR) 1964 DA-E
0 c 39 43 46 49 51 53 55 57 59 Deutsches Arzneibuch 7 (of the BR) 1968 DA- W
10 61 63 64 66 68 69 71 73 75 76 Farmacopea Ufficiale delta Repubblica
20 78 80 81 83 85 87 89 91 93 95 Italiana 7 1965 FU
30 97 99 101 103 105 107 109 112 114 116 Osterreichisches Arzneibuch 9 1960 OA
40 119 121 124 127 130 132 135 138 142 145 Pharmacopde Belge 5 1962 PB
Pharmacopoeia of Japan 7 1961 PJ
Pharmacopoea Nordica 1964 PN
Q CV = u . L; L is the limit about the mean and expressed as fraction State Pharmacopoeia of the USSR 9 1961 PUSSR
of the mean. b E.g., for 22 % outsiders, u = 81. c Factors for percentages SpCcificationspour le ContrSle de la
between 0.05 and 0.90: Qualitd des PrCparations Pharmaceu-
Percent 0.05 0.10 0.20 0.25 0.30 0.40 tiques (WHO) 1967 WHO
Outsiders, % 29 30 32 33 34 35 United States Pharmacopeia XVII 1965 USP
Percent 0.50 0.60 0.70 0.80 0.90 National Formulary XI1 1965 NF
Outsiders, % 36 36 37 38 38
Sample
7
---- -Acceptance
I Condition---
Conditionsa--------
----- I1 Condition-----
- --
-Producer--
CF-
--Consumer---
-
Codex Size Plan Limits Op OC Plan Limits OP oc I I1 I I1
BP 20 2/20 m fL 4.5 24.5 0120 m f L 0.25 11.0 2.5-5.0 3.3-5.0 4.3- 8 . 6 6.3- 9 . 5
DA-Ec 10 1/10 m fL 3.5 34.0 0110 m =k 2 L 0.50 21.0 2.4-7.2 3.6-10.85.2-15.7 8.&24.0
DA- W 20 2/20 m+L 4.5 24.5 0/20 m i 2L 0.25 11.0 2.5-7.5 3.3-9.9 4.3-12.9 6.3-18.9
FU 20 2/20 mf L 4.5 24.5 0120 m f 2L 0.25 11.0 2.5-5.0 3.3-6.6 4.3- 8 . 6 6.3-12.6
OA 20 2/20 m=t L 4.5 24.5 0120 m + 1.5L 0.25 11.0 2.5-5.0 2.5-4.9 4.3- 8 . 6 4.7- 9 . 5
PB 20 2/20 m f L 4.5 24.5 0120 m f 2 L 0.25 11.0 2.5-7.5 3.3-9.9 4.3-12.9 6.3-18.9
PJ 20 2/20 m i L 4.5 24.5 0120 m f 2 L 0.25 11.0 2.5-5.0 3.3-6.6 4 . 3 - 8 . 6 6.3-12.6
PN 100, 30 3/30 Md*L 4.5 21.0 0130 Md=k2L 0.17 7.5 2.9-5.0 3.8-6.4 4.6- 8 . 0 6.5-11.2
PUSSR 10 0110 mf L 0.5 21.0 1.8-3.6 4.0- 8 0
WHO 20 2/20 m f L 4.5 24.5 0120 m+2L 0.25 11.02.5-7.5 3.3-9.94.3-12.96.3-18.9
USP-NF 20 2/20 m f L 4.5 24.5 0120 m 31 2 L 0 25 11.0 2.5-5.0 3.3-6.6 4.3- 8 . 6 6 3-12.6
a The actual values o f L are given in Table V. 6 The ranges shown reflect the ranges of L values for different tablet weights. c Cf.Footnotea of Table
V. dCf.Footnotch of Table V.
OC
7---
--Producer--
I I1
-Consumer--
I I1
BPC A 20 2/20 rn f L 4.5 24.5 0120 m i 2 L 0.25 11.0 3.8-5.0 4.9- 6 . 6 6.4- 8 . 6 9.5-12.6
B 10 1/10 m + 0.075m 3.5 34.0 0/10 m =k 0 . 1 5 m 0.5 21.0 3.6 5.4 7.9 12.0
DA-E 10 1/10 m f Ld 3.5 34.0 0/10 m i 2 L d 0.5 21.0 2.4-7.2 3.6-10.8 5.3-15.7 8.0-24.0
DA-W
PB
20
20
2/20
2/20
m f 0.10m
m + ~e
4.5
4.5
24.5
24.5
0120 m *
0 . 1 5 ~ 10.25
0120 m f 2 L 0.25
11.0 5.0
11.0 3.0-7.5
5.1 8.6 9.5
4.0- 9 . 9 5.2-12.9 7.6-18.9
PN 20 2/20 miO.10m 4.5 24.5 0120 m f 0 . 2 0 m 0.25 11.0 5.0 6.6 8.6 12.6
WHO, A 20 0120 m 4 0.1Om 0.25 14.0 3.3 6.8
B 20 2/20 m f 0.10m 4.5 24.5 0/20 m f 0.20rn 0.25 11.0 5.0 6.6 8.6 12.6
USP-NFO A 20 0/20 m + 0.10m 0.25 14.0 3.3 6.8
B1 20 2/20 m f 0.10m 4 . 5 24.5 0120 m f 0 . 2 5 m 0.25 11.0 5.0 8.2 8.6 15.8
B2 60 6/60 m + 0.10m 5 . 5 17.6 0160 rn *0 . 2 5 m 0.09 3.8 5.2 7.5 7.4 12.0
The actual values of L are given in Table VII. 6 The ranges shown reflect the ranges of L values for different capsule weights. c Cf.Note (a) in Table
VII. d Cf.Note ( b ) in Table VII. e Cf.Note ( c ) in Table VII. f Cf.Note ( d )in Table VII. 9 Cf,Note ( e ) in Table VII.
7
7
-
I Condition
Acceptance Conditions
I1 Condition--
, -
--Producer--
-c V-
--Consumery
-
Dosage Form Plan Limits OP Oc Plan Limits OP oc I I1 I I1
DA-E
Dragees 1/10 m f 0 .1 5 m 3.5 3 4 .0 7.2 15.8
Pills. 2/20 m+O.lOm 4.5 2 4 .5 0/20 mf0.15m 0 .2 5 11.0 5.0 5.0 8.6 9.5
DA-W
Pills 3/30 rnf0.10~1 4.5 2 1 .0 0/30 mf0.30rn 0 .1 7 7.5 5.0 9.6 8.0 16.8
OA
~~~
Pills 3/30 m+O.lOm 4.5 2 1 .0 0/30 m=t0.30m 0 .1 7 7.5 5.0 9.6 8.0 16.8
Divided powders O/lO m f Lb 0.5 2 1 .0 2 .9 - 5 .4 6.4-12.0
PB
~-
Cachet-gelules 2/20 m f Lc 4.5 24.5 020 m f 2Lc 0 .2 5 11.0 2.8-5.0 3 .7 - 6 .6 4.8- 8 . 6 7.1-12.6
_N_ .
P
Pills 3/30 Mdf 0.15 M 4.5 2 1 .0 7.5 1 5 .0
Drageesandboles 2/20 m f 0.10m 4.5 24.5 020 m f 0 . 2 0 ~ 1 0.25 11.0 5.0 6.6 8.6 12.6
~~~
L values given in Table V for weights of different tablets. Remark- and VII show the weight uniformity specification for capsule
able differences may be noted between the uniformity levels required weights, Table VITI shows those for miscellaneous oral dosage
by the different codexes. forms, and Table 1X shows those for suppositories.
The following example, based on the BP uniformity specifica- These tables were prepared following the same criteria adopted
tions for tablets greater than 250 mg., shows how the CV values for tablets and, as for tablets, there is little similarity between the
were obtained. The sampling pIan is defined by n = 20 and c = 2 different sampling plan strategies and procedures.
(Table IV). According t o Table I there is a 9 5 z probability of Specifications for Uniformity of Injectables-Tables X and XI
accepting the submitted lot if 4.5 (OP)of the items of the lot are summarize the specifications for weight uniformity of sterile solids.
outside the limits, which are m i0.05 m (Table V). From the table There are large differences with regard t o the allowed CV values
of the normal distribution, it is found that 4 . 5 z outsiders (OP), and still more with regard to the weight classes for which the
namely, 2.25% at each end, lie beyond the limits m =k 2 S D . sizes of limits change (Table XI).
Therefore, 2 SD = 0.05 m, so that CV = 100S D f m = 2.5. The specifi.cations for uniformity of volume of injectables are
The CV values may be obtained using the factors of Table 11: more regular (Table XII). These specifications are given in four of
the examined pharmacopeias.
CV = u .L = 50 . 0.05 = 2.5 (Eq. 2) Content Uniformity-USP-NF are the first pharmacopeias t o
introduce a specification on content uniformity. The prescribed
Specification for Uniformity of Capsule Weights, for Weights of two-step procedure is summarized in Table XI1 and the operating
Miscellaneous Oral Forms, and for Suppository Weights-Tables VI characteristic curve is given in Fig. 1 .
Sample
--Acceptance
I I Condition 7
Conditions
, I1 Condition -7 r
-Producer-
cv--
-Consumer-
-
Codex Size Plan Limits OP OC Plan Limits OP oc I I1 I I1
cv-
Sam- _---____-
ple
Codex StepSize Plan
-----
Limits
Acceptance Conditions-
I Condition----
O p 0s Plan
11 Condition----
Limits OP
--- Oc
7 -
yProducer--
I I1
-Consumer--
I I1
BP 10 1/10 pa* L 3.5 3 4 . 0 0110 m=!=2 L 0.5 2 1 . 0 2.4- 4 . 8 3.6- 7 . 2 5.3-10.6 8 . G 1 6 . 0
DA-E5 10 O/lO m +L 0.5 21.0 2.2- 5 . 4 4.8-12.0
DA-Ec 5 I/5 m =!= L 8.0 5 8 . 0 0/5 m f . 2 L 1 . 0 3 7 . 0 2 . 8 - 8 . 6 3.9-11.7 9.1-27.1 11.2-33.6
PB 10 O/lO m fL 0.5 21.0 1.1- 3.6 2.4- 8 . 0
PJ 10 O/lO p d i L 0.5 21.0 5.0-10.8 11.2-24.0
USP-NFe120 2/20 m f 0 . 1 0 m 4.5 2 4 . 5 0/20 m = ! = O 0 . 1 5 m0 . 2 5 11.0 5.0 5.0 8.6 9.5
260 6/60 m f 0 . 1 0 m 5.5 1 7 . 6 1/60 m f 0 . 1 5 m 0.6 6.5 5.2 5.4 7.4 8.1
Table XII-Official Specifications for Uniformity of Injection Volume and for Content Uniformity
Codex
Sample
Size Plan
Acceptance Conditions
Limits OP oc
- r
Producer
cv
Consumer
7