Process controls involved in the

manufacturing process of pharmaceutical

dosage forms
And
statistical quality control charts and its application in
process control

Presented by,
Y.Maheshwara prasad
M pharmacy (Pharmaceutics) 1st semester
Care college of pharmacy,warangal
 Contents:
• Introduction to process controls involved in the
manufacturing of pharmaceutical dosage forms
• Statistical process control
• Control charts
• Control charts for attributes
• Control charts for variables
• Control chart patterns
• Applications in pharmacuticals

3-2
Process controls involved in the manufacturing process of
pharmaceutical dosage forms

• The in-process checking during manufacturing plays an

important role in the auditing of the quality of the product
at various stages of production. duties of the control
inspector consisting of checking, enforcing and reviewing
procedures and suggesting the change for upgrading the
procedures when necessary
The aim of in process quality control system is to
monitor all the features of a product that may affect its
quality and to prevent errors during processing
 process controls involved in the
manufacturing process of parental
• Checking the bulk solution before filling for drug
content,pH,color,clarity, and completeness of solutions
• Checking the filled volume of liquids or the filled weight
of sterile powders for injection in the final containers at
predetermined intervals during filling
• Testing for leakage of flame sealed ampoules
• Subjecting the product to physical examination
• Examining the sterility indicator placed in various areas
of the sterilizer for each sterilization operation
 Process controls involved in the manufacturing
process of solid dosage forms

• Determining the drug content of the formulation

• Checking the weight variation for tablets and
capsules at pre determined intervals during
manufacturing
• Checking the disintegration and dissolution time
,hardness and friability
at least during the beginning, middle, and end of
production or at prescribed intervals during
manufacturing
 Process controls involved in the manufacturing of
the semisolid dosage forms
• Checking for the uniformity and homogeneity of drug
content prior to the filling operations
• Determining the particle size of the preparation when
appropriate
• Checking the appearance ,viscosity, specific gravity
,sediment volume and other physical parameters at
prescribed intervals
• Testing for filling weight during the filling operation
• Testing for leakage on the finished jars or tubes
 Introduction:
• The term statistical means collecting the data,tabulating and
summarizing using prescribed statistical tools for purpose of
analysis and reporting.
• SQC is important for
improving the quality.
• Identifies any decline in quality during
initial stages of production and taking immediate corrective
steps instead of identifying defectives after the damage has
been done.
• One of the methods used for identifying defects is
“SAMPLING”.
• Sampling always shows defects as well as 100%inspection.
 Statistical quality control:
• Statistical quality control (SQC) is the term
used to describe the set of statistical tools used
by quality professionals. Statistical quality
control can be divided into three broad
categories:
1. Descriptive statistics are used to describe
quality characteristics and relationships.
• Included are statistics such as the mean,
standard deviation, the range,and a measure of
the distribution of data.
• 2. Statistical process control (SPC) involves inspecting
a random sample of the output from a process and
deciding whether the process is producing products with
characteristics that fall within a predetermined range.
SPC answers the question of whether the process is
functioning properly or not.
• 3. Acceptance sampling is the process of randomly
inspecting a sample of goods and deciding whether to
accept the entire lot based on the results. Acceptance
sampling determines whether a batch of goods should
be accepted or rejected.
 General terms used in statistical
analysis:
• Mean: A statistic that measures the central
tendency of a set of data. (average)
• Range: The difference between the largest
and smallest observations in a set of data.
• Standard deviation: A statistic that
measures the amount of data dispersion
around the mean.
 Causes of variation:
• Common causes: Random causes that
cannot be identified.
• Assignable causes: Causes that can be
identified and eliminated.
 Normal Distribution:
“shewhart chart”

95%
99.74%
-3σ -2σ -1σ µ =0 1σ 2σ 3σ

3-12
 Process Control Chart
Out of control
Upper
control
limit

Process
average

Lower
control
limit

1 2 3 4 5 6 7 8 9 10
Sample number

3-13
A Process Is in Control If …

1. … no sample points outside limits

2. … most points near process average
3. … about equal number of points above
and below centerline
4. … points appear randomly distributed

3-14
 Types of Control Charts:
• Control charts are one of the most commonly
used tools in statistical process control.
• They can be used to measure any characteristic
of a product, such as the weight of a cereal box,
the number of chocolates in a box, or the volume
of bottled water.
• The different characteristics that can be
measured by control charts can be divided into
two groups: variables and attributes.
 A control chart for variables:
• A control chart for variables is used to monitor
characteristics that can be measured and have a
continuum of values, such as height, weight, or
volume.
• EG: Syrup solution bottling operation is an
example of a variable measure, since the
amount of syrup solution in the bottles is
measured and can take on a number of different
values.
• Other examples are the weight of a bag of
paracetamol powder, the temperature of a Hot
air oven, or the diameter of plastic tubing.
 A control chart for attributes:
• A control chart for attributes, on the other hand, is used
to monitor characteristics that have discrete values and
can be counted. Often they can be evaluated with a
simple yes or no decision.
• Examples include color, taste, or smell.
• The monitoring of attributes usually takes less time than
that of variables because a variable needs to be
measured.
• An attribute requires only a single decision, such as yes
or no, good or bad, acceptable or unacceptable
• e.g., the apple is good or rotten, the meat is good or
stale, or counting the number of defects e.g., the number
of broken cookies in the box, the number of dents in the
car, the number of barnacles on the bottom of a boat.
 A control chart for variables:
• Two of the most commonly used control
charts for variables monitor both the
central tendency of the data (the mean)
and the variability of the data (either the
standard deviation or the range).
• Mean (x-Bar) Charts
• Range (R) Charts
 Mean (x-Bar) Charts:
• A mean control chart is often referred to
as an x-bar chart. It is used to monitor
changes in the mean of a process.
• This chart serves mainly in validation.
• Changes in the process can be detected
by these charts.
• Accuracy may also be monitored to some
extent.
 Construction of x-bar Chart:

UCL = x=+ zσ x LCL = x=- zσ x

= x1 + x2 + ...
x
xn
=
Where, x = average of sample means.
n
z =standard normal variable (2 for
95.44% confidence, 3 for
99.74%confidence).
=
n = sample size.
σ x = σ /√n, σ =population (process) SD.
3-20
 x-bar Chart Example:
Standard Deviation Known (cont.)

3-21
 x-bar Chart Example:
Standard Deviation Known (cont.)

3-22
 x-bar Chart Example:
Standard Deviation Unknown

=A R
UCL = x + LCL =
= x - A22R
2
2

Where, A2 == factor(dependant on sample size),

R = average range of samples,
x == average
average ofof sample
sample means.
means.

3-23
Control
Limits

3-24
 x-bar Chart Example:
Standard Deviation Unknown
OBSERVATIONS (RING DIAMETER, CM)
SAMPLE k 1 2 3 4 5 x R
1 5.02 5.01 4.94 4.99 4.96 4.98 0.08
2 5.01 5.03 5.07 4.95 4.96 5.00 0.12
3 4.99 5.00 4.93 4.92 4.99 4.97 0.08
4 5.03 4.91 5.01 4.98 4.89 4.96 0.14
5 4.95 4.92 5.03 5.05 5.01 4.99 0.13
6 4.97 5.06 5.06 4.96 5.03 5.01 0.10
7 5.05 5.01 5.10 4.96 4.99 5.02 0.14
8 5.09 5.10 5.00 4.99 5.08 5.05 0.11
9 5.14 5.10 4.99 5.08 5.09 5.08 0.15
10 5.01 4.98 5.08 5.07 4.99 5.03 0.10
50.09 1.15

3-25
 x-bar Chart Example:
Standard Deviation Unknown
(cont.)
∑R 1.15
R= = =
0.115k 10

= ∑x 50.09
x= = = 5.01 cm
k 10

=
UCL = x + A2R = 5.01 + (0.58)(0.115) = 5.08
=
LCL = x - A2R = 5.01 - (0.58)(0.115) = 4.94
Retrieve Factor Value A2
3-26
 5.10 –

5.08 –
UCL = 5.08
5.06 –

5.04 –

5.02 – x= = 5.01
Mean

5.00 –

x- bar 4.98 –

Chart 4.96 –
LCL = 4.94
Example 4.94 –

(cont.) 4.92 –
| | | | | | | | | |
1 2 3 4 5 6 7 8 9 10
Sample number

3-27
 Range (R) chart:
• Range (R) chart a control chart that monitors
changes in the dispersion or variability of
process. Whereas x-bar charts measure shift in
the central tendency of the process.
• The method for developing and using R-charts is
the same as that for x-bar charts.
• The center line of the control chart is the
average range, and the upper and lower control
limits are computed as follows:
 R- Chart

UCL = D4R LCL = D3R

∑R
R=
k
where
R = range of each sample
k = number of samples

3-29
 R-Chart Example
OBSERVATIONS (RING DIAMETER, CM)
SAMPLE k 1 2 3 4 5 x R
1 5.02 5.01 4.94 4.99 4.96 4.98 0.08
2 5.01 5.03 5.07 4.95 4.96 5.00 0.12
3 4.99 5.00 4.93 4.92 4.99 4.97 0.08
4 5.03 4.91 5.01 4.98 4.89 4.96 0.14
5 4.95 4.92 5.03 5.05 5.01 4.99 0.13
6 4.97 5.06 5.06 4.96 5.03 5.01 0.10
7 5.05 5.01 5.10 4.96 4.99 5.02 0.14
8 5.09 5.10 5.00 4.99 5.08 5.05 0.11
9 5.14 5.10 4.99 5.08 5.09 5.08 0.15
10 5.01 4.98 5.08 5.07 4.99 5.03 0.10
50.09 1.15

3-30
R-Chart Example (cont.)

UCL = D4R = 2.11(0.115) = 0.243

LCL = D3R = 0(0.115) = 0

Retrieve Factor Values D3 and D4

3-31
R-Chart Example (cont.)

0.28 –
0.24 – UCL = 0.243
0.20 –
Range

0.16 – R = 0.115
0.12 –
0.08 –
0.04 – LCL = 0
| | | | | | | | | |
0–
1 2 3 4 5 6 7 8 9 10
Sample number

3-32
Control Charts for Attributes

 p-chart
 uses portion defective in a sample
 c-chart
 uses number of defective items in
a sample

3-33
 P-charts:
• P-charts are used to measure the proportion of
items in a sample that are defective. Examples
are the proportion of broken vials in a batch .
• P-charts are appropriate when both the number
of defectives measured and the size of the total
sample can be counted.
• The center line is computed as the average
proportion defective in the population, . This is
obtained by taking a number of samples of
observations at random and computing the
average value of p across all samples.
 p-Chart

UCL = p + zσ p

LCL = p - zσ p

z = number of standard
deviations from process average
p = sample proportion
defective; an estimate of process average
σ p = standard deviation of sample
proportion

p(1 - p)
σ =
p
n

3-35
Construction of p-Chart
NUMBER OF PROPORTION
SAMPLE DEFECTIVES DEFECTIVE
1 6 .06
2 0 .00
3 4 .04
: : :
: : :
20 18 .18
200

20 samples of 100 pairs of jeans

3-36
Construction of p-Chart (cont.)

total defectives
p= = 200 / 20(100) = 0.10
total sample observations

p(1 - p) 0.10(1 - 0.10)

UCL = p + z = 0.10 + 3
n 100
UCL = 0.190

p(1 - p) 0.10(1 - 0.10)

LCL = p - z = 0.10 - 3
n 100
LCL = 0.010

3-37
 0.20

0.18 UCL = 0.190

0.16

0.14
Proportion defective

0.12

p = 0.10
0.10

0.08

0.06

0.04

0.02 LCL = 0.010

2 4 6 8 10 12 14 16 18 20
Sample number
3-38
 C-charts:
• C-charts are used to monitor the number of
defects per unit.
• Examples are the number of recalled products in
an industry in a month, and the number of
bacteria in a milliliter of water.
• Note that the types of units of measurement we
are considering are a period of time, or a volume
of liquid.
• The average number of defects, is the center
line of the control chart. The upper and lower
control limits are computed as follows:
 c-Chart

UCL = c + zσ c
σ = c
LCL = c - zσ c
c

where
c = number of defects per sample

3-40
 c-Chart (cont.)
Number of defects in 15 sample rooms
NUMBER
SAMPLE OF
DEFECTS
190
1 12 c= = 12.67
15
2 8
UCL = c + zσ c
3 16
= 12.67 + 3 12.67
: : = 23.35
: : LCL = c - zσ c
15 15 = 12.67 - 3 12.67
190 = 1.99

3-41
 24
UCL = 23.35
21

18

Number of defects
c-
c = 12.67

15

Chart 12

(cont.) 9

3 LCL = 1.99

2 4 6 8 10 12 14 16
Sample number

3-42
Contol chart for capsule weight
data
 Application to pharmaceuticals
• Drug potency
• Tablet or capsule inprocess characteristics
• Powder chcharacteristics like mean particle size
• Microbial count
• Drug content application (nasal spray )
• Fill weight and fill volume
• Liquid charecteristics like viscosity and refractive index
• Consumer complaints and industrial safety
measurements
 Conclusion
• statistical process control improve the quality
of the processes
• Statistical process control provides a
statistical approach for evaluating process
• When statistical process controls
implemented benefits can be derived through
a reduced cost of manufacture, improved
quality ,reduced trouble shooting crises
 References:
• Quality assuarance and quality management in
pharmaceutical industry by Anjaneyelu.
• Encyclopedia of pharmaceutical technology
volume -6 by James Warrick
• Theory and practice of industrial pharmacy
by Leon Lachlan
.