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12879652 Parenteral Quality Control

12879652 Parenteral Quality Control

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In pharmaceutical manufacture, the sterility of a parenteral
product lot is checked by a statistically valid sampling proce-
dure. After years of experience, most manufacturers of paren-
teral products will sterility test 10 to 20 units of product per
lot.Thenumberofunitstestedmaybedoubledwhenthedeliv-
erable volume is 1 ml or less. The number of units sampled
depends on the number of units in the batch, the volume of
liquid per container, the method of sterilization, the use of a
biological indicator system, and the good manufacturing prac-
tice requirements of the regulatory agency for the particular
product.Forexample,ifthebatchsizeisgreaterthan500arti-
cles, a minimum of 20 units is sampled. If the final batch size
is between 100 and 500 articles, then no fewer than 10 of the
articles are sterility tested, although there are minimum re-
quirements for sterility testing of biologics. For large-volume
parenteral (LVP) products (volume 100 ml per container),
at least 2% of the batch or 10 containers, whichever is less, is
sampled. Sampling requirements as specified in the USP and
European Pharmacopeia (EP) Sterility Test Section are sum-
marized in Table 1.2.
Correct statistical sampling represents a difficult, yet vi-
tal, aspect of sterility testing. Realizing that the parenteral
product being used by the patient has itself not been tested
for sterility, it is absolutely essential that the sampling proce-
dure be as valid and representative of the whole batch as pos-

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9

Table 1.2 Minimum Number of Units Required per Medium for Performance of the USP Sterility
Test as a Function of Volume per Test Unit (Quantities for Liquid Articles)

Minimum volume of each medium

Used for membrane
or half membrane
Minimum volume Used for direct representing total
taken from each transfer of volume volume from the

Container

container for taken from each appropriate number No. of containers

content (ml)

each medium

container (ml) of containers (ml) per medium

Less than 10a

1 ml, or entire

15

100

20 (40 if each

contents if less

does not con-

than 1 ml

tain sufficient
volume for both
media)

10 to less than 5 ml

40

100

20

50a
50 to less than 10 ml

80

100

20

100a
50 to less than Entire contents

100

10

100, intended
for intravenous
administrationb
100 to 500a

Entire contents

100

10

Antibiotics

1 ml

100

10

(liquid)

a

Intended for multiple dose or nonintravenous use.

b

Intended for single dose or intravenous use.

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10

Chapter 1

sible. Realistically, this presents an impossible principle to
prove.

Pharmaceutical quality control departments employ
sampling plans called acceptance sampling for many quality
controltesting proceduresthatare notamenableto 100%final
testing. Acceptance sampling in sterility testing is based on
the establishment of operating characteristic (OC) curves,
which are plots of probability versus percentage contamina-
tion. Operating characteristic curves for sample sizes of 10
and 20 units are shown in Figs. 1.1 and 1.2, respectively (9).
These curves are drawn from a series of government-spon-
sored sampling plans called MIL-STD-414 (10). The shape of
the curve depends on five criteria:

1. An acceptable quality level (AQL), which is the highest
percentage of defective (nonsterile) units that is accept-
able

2. Anunacceptablequalitylevel(UQL),whichisthepercent-
age of nonsterile units for which there is a low probability
of acceptance
3. The alpha (α) factor, which is the probability of rejecting
a good (sterile) batch
4. The beta (β) error, which is the probability of accepting a
bad (nonsterile) batch
5. The sample size

With all criteria (1) through (5) being constant, the slope
of the OC curve will become steeper as the sample size is in-
creased. Similarly, with the criteria being constant, the slope
of the curve will become steeper as the AQL is decreased or as
theUQLisdecreased.AnexampleofanOCcurveforsampling
plans at AQL 1% for different sample sizes is seen in Fig.
1.3 (11). At a given AQL level, the larger the sample size, the
greater is the probability of accepting a sterile lot and re-
jecting a nonsterile lot. Each pharmaceutical manufacturer
for each type of parenteral product assumes a given AQL or
rate of contamination, thus fixing the point of reference on the
abscissa of the OC curve.

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Sterility Testing

11

Fig. 1.1 Operation characteristic curves for a sample size of 10
units; n sample size; N lot size. (From Ref. 9.)

Sampling plans and concomitant OC curves are prepared
on the assumption that the samples are selected at random.
By random sampling, it is inferred that any one of the re-
maining uninspected units of the same lot of product has an
equal chance of being selected (12). This is not always easily
accomplished. Random sampling often is inconvenient and
may not be appreciated by production workers responsible for
many other important duties during the production process.
Random samples are optimally selected every kth

unit, where

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12

Chapter 1

Fig. 1.2 Operating characteristic curves from a sample size of 20
units; n sample size, N lot size (From Ref. 9.)

k the total units in the batch per the number of samples
required. For example, if the batch size of an aseptically filled
product is 10,000 units and 20 samples are required for the
sterility test, then samples are taken every 500 units includ-
ing the first and last unit filled.*

* Some manufacturers also take sterility test samples immediately after a halted
sterile (aseptic) production process has been re-started.

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Sterility Testing

13

Fig. 1.3 Operating characteristic curve for sampling plans at an
acceptable quality level of 1% for different sample sizes N. (From
Ref. 11.)

Additional discussion of sampling with regard to its lim-
iting the interpretation of the results of the sterility test is
presented in this chapter in the section, “Limitations of the
USP/NF Referee Sterility Test.”
A major consideration in sampling for sterility testing is
propertreatmentofthepackagesystemtopreventcontamina-
tion of the sample when it is taken out of the package for test-
ing. For example, parenteral products packaged in ampules,
vials, or bottles must be aseptically sampled using sterile ma-
terials and aseptic techniques. The neck of the ampule or the
surface of the rubber closure must be disinfected with a liquid
disinfectant solution before breaking the ampule or penetrat-
ing the closure with a needle. Special procedures must be im-
plemented to sample products contained in aluminum foil, pa-
per, or plastic outer bags. For example, bulk solid chemicals
sterilized by ethylene oxide prior to aseptic compounding are
contained in gas-permeable paper or plastic bags. The chemi-
cals must be sampled by tearing open the package, which is
not easy to do because of the potential for accidental contami-
nation. Sutures are contained in glass or aluminum foil enclo-

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14

Chapter 1

sures that must be disinfected before the product is removed.
Sampling of devices without contaminating the sample also is
avery difficultprocedure toaccomplish. Althoughthe package
may be designed to maintain the sterility of the product in-
definitely, it is obviously of no value if the inner contents can-
not be removed without contaminating the product and in-
terfering with the performance of certain essential tests (3).

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