Quality Management

QA-GMP-QC

QA/QC 1
 What is Quality ?

 Fitness for use

 Freedom from defects

 Degree of excellence

 Customer/Buyer’s satisfaction

 Compliance with specified/official requirements

QA/QC 2
 What is Quality ?

 US-FDA
A measure of a product’s or service’s ability to
satisfy the custmor’s stated or implied needs
 Swiss Standard Association:-

The degree to which the product characteristics

conform to the requirement placed upon that
product including reliability, maintainability and
safety.

QA/QC 3
 What is Quality ?

 Quality of a pharmaceutical product is

measured by it’s fitness for intended use.
Safety and efficacy are part of quality & not
separable from Quality.

QA/QC 4
Relation Between QM, QA, QC &
GMP

QA/QC 5
 What is Quality Management?

 WHO Definition :
 The aspect of management functions that
determines and implements the ‘quality policy’
 Responsible quality of pharm. product
 Product must comply with basic requirements
 Identity, Strength/ potency, Purity
 Bioavailabity and Biopharmaceutical parameters
 Basic Elements of QM
 Quality system infrastructure & systematic actions
QA/QC 6
 What is Quality Assurance?

 WHO definition :
It is a wide-ranging concept covering all matters
that individually or collectively influence the
quality of a product. It is the totality of the
arrangements made with the object of ensuring
that pharm. products are of quality required for
their intended use.

QA/QC 7
 What is GMP?

 GMP is that part of QA which ensures that

products are consistently produced and
controlled to the quality standards
appropriate to their intended use and as
required by the Marketing Authorization or
product specification.

QA/QC 8
 What is Quality Control?

 Is that part of GMP concerned with

sampling, specification & testing,
documentation & release procedures
which ensure that the necessary &
relevant tests are performed & the product
is released for use only after ascertaining
it’s quality

QA/QC 9
 What is difference?

 Q.A.  Q.C.

 sum total of organized  concerned with

arrangements made
with the object of
ensuring that product
will be of the Quality
required by their
intended use.
sampling,specifications,
testing and with in the
organization,
documentation and
release procedures
which ensure that the
necessary and relevant
tests are carried out

QA/QC 10
 What is difference?
 Q.A.  Q.C.
 Systematic actions  Operational laboratory
necessary to provide techniques and activities
adequate confidence that used to fulfill the
a product will satisfy the requirement of Quality
requirements for quality
 QA is ORGNIZATION  QC is lab based
based
 Responsible for assuring  Responsible for day to
adopted quality policies day quality within org.

QA/QC 11
 Total Quality Control

 Process of striving to produce a perfect

product by a series of measures requiring an
organized effort to prevent or eliminate errors
at every stage in production

QA/QC 12
 Sources of Quality
Variation and its Control

Quality Control
Variation

 There is no two natural items in any

category are the same.
 Variation may be quite large or very small.
 If variation very small, it may appear that
items are identical, but precision
instruments will show differences.
Categories of variation
 Within-piece variation
 One portion of surface is rougher than
another portion.
 A piece-to-piece variation
 Variation among pieces produced at the

same time.
 Time-to-time variation
 Service given early would be different
from that given later in the day.
Sources of variation

 Equipment
 Tool wear, machine vibration, …
 Material
 Raw material quality
 Environment
 Temperature, pressure, humadity
 Operator
 Operator performs- physical & emotional
Control of Quality Variation

 Raw Materials
 Q.A. monograph
 In process Quality Control
 Q.A. before startup
1. Environmental and microbiologic control,
sanitation
2. MWFP
3. Raw materials
4. Mfg. equipment

QA/QC 17
Control of Quality Variation

 In process Quality Control

 Q.A. at startup
1. Raw materials processing
2. Compounding
3. Labels Control
4. Finished product control

QA/QC 18
Statistical Quality Control

 Monitoring quality by application of statistical

methods in all stages of production

QA/QC 19
Control Chart Viewpoint

 Variation due to
 Common or chance causes
 Assignable causes

 Control chart may be used to discover

“assignable causes”
Control chart functions

 Control charts are powerful aids to

understanding the performance of a process
over time.

Input Output

PROCESS

What’s causing variability?

Control charts identify variation

 Chance causes - “common cause”

 inherent to the process or random and not
controllable
 if only common cause present, the process is
considered stable or “in control”
 Assignable causes - “special cause”
 variation due to outside influences
 if present, the process is “out of control”
Control charts help us learn more
about processes
 Separate common and special causes of
variation
 Determine whether a process is in a state of
statistical control or out-of-control
 Estimate the process parameters (mean,
variation) and assess the performance of a
process or its capability
Control charts to monitor
processes
 To monitor output, we use a control chart
 we check things like the mean, range, standard
deviation
 To monitor a process, we typically use two
control charts
 mean (or some other central tendency measure)
 variation (typically using range or standard
deviation)
Types of Data
 Variable data
 Product characteristic that can be measured
 Length, size, weight, height, time, velocity

 Attribute data
 Product characteristic evaluated with a discrete choice
 Good/bad, yes/no
Control chart for variables

 Variables are the measurable

characteristics of a product or service.
 Measurement data is taken and
arrayed on charts.
Control charts for variables
 X-bar chart
 In this chart the sample means are plotted in order to
control the mean value of a variable (e.g., Fill vol. of
liquid , hardness of tablet, etc.).
 R chart
 In this chart, the sample ranges are plotted in order to
control the variability of a variable.
 S chart
 In this chart, the sample standard deviations are plotted
in order to control the variability of a variable.
 S2 chart
 In this chart, the sample variances are plotted in order
to control the variability of a variable.
X-bar and R charts

 The X- bar chart is developed from the

average of each subgroup data.
 used to detect changes in the mean between
subgroups.
 The R- chart is developed from the ranges of
each subgroup data
 used to detect changes in variation within
subgroups
Control chart components

 Centerline
 shows where the process average is centered or
the central tendency of the data
 Upper control limit (UCL) and Lower control
limit (LCL)
 describes the process spread
The Control Chart Method
X bar Control Chart:
UCL = XDmean + A2 x Rmean
LCL = XDmean - A2 x Rmean
CL = XDmean

R Control Chart:
UCL = D4 x Rmean
LCL = D3 x Rmean
CL = Rmean
Control Chart Examples

UCL
Variations

Nominal
LCL

Sample number
How to develop a control chart?
Define the problem

 Use other quality tools to help determine the

general problem that’s occurring and the
process that’s suspected of causing it.

Select a quality characteristic to be measured

 Identify a characteristic to study - for
example, angle of repose or any other
variable affecting performance.
Choose a subgroup size to be
sampled
 Choose homogeneous subgroups
 Homogeneous subgroups are produced under the
same conditions, by the same machine, the same
operator, the same mold, at approximately the
same time.
 Try to maximize chance to detect differences
between subgroups, while minimizing chance
for difference with a group.
Collect the data

 Generally, collect 20-25 subgroups (100 total

samples) before calculating the control limits.
 Each time a subgroup of sample size n is
taken, an average is calculated for the
subgroup and plotted on the control chart.
Determine trial centerline

 The centerline should be the population

mean, 
 Since it is unknown, we use X Double bar, or
the grand average of the subgroup averages.
m

X i

X  i 1
m
Determine trial control limits - Xbar
chart
 The normal curve displays the distribution of
the sample averages.
 A control chart is a time-dependent pictorial
representation of a normal curve.
 Processes that are considered under control
will have 99.73% of their graphed averages
fall within 3.
UCL & LCL calculation

UCL X  3
LCL X  3
  standarddeviation
Determining an alternative value
for the standard deviation
m

 R i
R  i 1

UCL  X  A 2 R

LCL  X  A 2 R
Determine trial control limits - R chart

 The range chart shows the spread or

dispersion of the individual samples within
the subgroup.
 If the product shows a wide spread, then the
individuals within the subgroup are not similar to
each other.
 Equal averages can be deceiving.
 Calculated similar to x-bar charts;
 Use D3 and D4
 Example: Control Charts for Variable Data
Tablet thickness (mm)
Sample 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
Calculation
From Table above:
 Sigma X-bar = 50.09

 Sigma R = 1.15

 m = 10

Thus;
 X-Double bar = 50.09/10 = 5.009 mm

 R-bar = 1.15/10 = 0.115 mm

Note: The control limits are only preliminary with 10 samples.

It is desirable to have at least 25 samples.
Trial control limit
 UCLx-bar = X-D bar + A2 R-bar
= 5.009 + (0.577)(0.115)
= 5.075 mm
 LCLx-bar = X-D bar - A2 R-bar
= 5.009 - (0.577)(0.115)
= 4.943 mm
 UCLR=D4R-bar=(2.114)(0.115)=0.243 mm
 LCLR = D3R-bar = (0)(0.115) = 0 cm
3-Sigma Control Chart Factors

Sample size X-chart R-chart

n A2 D3 D4
2 1.88 0 3.27
3 1.02 0 2.57
4 0.73 0 2.28
5 0.58 0 2.11
6 0.48 0 2.00
7 0.42 0.08 1.92
8 0.37 0.14 1.86
X-bar Chart

5.10
UCL
5.08
5.06
5.04
X bar

5.02
5.00 CL
4.98
4.96 LCL
4.94
0 1 2 3 4 5 6 7 8 9 10 11

Subgroup
R Chart

0.25 UCL

0.20
Range

0.15
CL

0.10

0.05
LCL
0.00
0 1 2 3 4 5 6 7 8 9 10 11
Subgroup
Run Chart
6.70
6.65
6.60

Mean, X-bar
6.55
6.50
6.45
6.40
6.35
6.30
0 5 10 15 20 25
Subgroup number
0.35
0.3
0.25
Range, R

0.2
0.15
0.1
0.05
0
0 5 10 15 20 25
Subgroup number
Another Example
of X-bar & R chart
 Given Data (Table 5.2)
Subgro
up X1 X2 X3 X4 X-bar UCL-X-bar X-Dbar LCL-X-bar R UCL-R R-bar LCL-R
1 6.35 6.4 6.32 6.37 6.36 6.47 6.41 6.35 0.08 0.20 0.0876 0
2 6.46 6.37 6.36 6.41 6.4 6.47 6.41 6.35 0.1 0.20 0.0876 0
3 6.34 6.4 6.34 6.36 6.36 6.47 6.41 6.35 0.06 0.20 0.0876 0

4 6.69 6.64 6.68 6.59 6.65 6.47 6.41 6.35 0.1 0.20 0.0876 0
5 6.38 6.34 6.44 6.4 6.39 6.47 6.41 6.35 0.1 0.20 0.0876 0
6 6.42 6.41 6.43 6.34 6.4 6.47 6.41 6.35 0.09 0.20 0.0876 0
7 6.44 6.41 6.41 6.46 6.43 6.47 6.41 6.35 0.05 0.20 0.0876 0
8 6.33 6.41 6.38 6.36 6.37 6.47 6.41 6.35 0.08 0.20 0.0876 0
9 6.48 6.44 6.47 6.45 6.46 6.47 6.41 6.35 0.04 0.20 0.0876 0
10 6.47 6.43 6.36 6.42 6.42 6.47 6.41 6.35 0.11 0.20 0.0876 0
11 6.38 6.41 6.39 6.38 6.39 6.47 6.41 6.35 0.03 0.20 0.0876 0
12 6.37 6.37 6.41 6.37 6.38 6.47 6.41 6.35 0.04 0.20 0.0876 0
13 6.4 6.38 6.47 6.35 6.4 6.47 6.41 6.35 0.12 0.20 0.0876 0
14 6.38 6.39 6.45 6.42 6.41 6.47 6.41 6.35 0.07 0.20 0.0876 0
15 6.5 6.42 6.43 6.45 6.45 6.47 6.41 6.35 0.08 0.20 0.0876 0
16 6.33 6.35 6.29 6.39 6.34 6.47 6.41 6.35 0.1 0.20 0.0876 0
17 6.41 6.4 6.29 6.34 6.36 6.47 6.41 6.35 0.12 0.20 0.0876 0

18 6.38 6.44 6.28 6.58 6.42 6.47 6.41 6.35 0.3 0.20 0.0876 0
19 6.35 6.41 6.37 6.38 6.38 6.47 6.41 6.35 0.06 0.20 0.0876 0
20 6.56 6.55 6.45 6.48 6.51 6.47 6.41 6.35 0.11 0.20 0.0876 0

21 6.38 6.4 6.45 6.37 6.4 6.47 6.41 6.35 0.08 0.20 0.0876 0
22 6.39 6.42 6.35 6.4 6.39 6.47 6.41 6.35 0.07 0.20 0.0876 0
23 6.42 6.39 6.39 6.36 6.39 6.47 6.41 6.35 0.06 0.20 0.0876 0
24 6.43 6.36 6.35 6.38 6.38 6.47 6.41 6.35 0.08 0.20 0.0876 0
25 6.39 6.38 6.43 6.44 6.41 6.47 6.41 6.35 0.06 0.20 0.0876 0
Calculation
From Table 5.2:
 Sigma X-bar = 160.25

 Sigma R = 2.19

 m = 25

Thus;
 X-double bar = 160.25/29 = 6.41 mm

 R-bar = 2.19/25 = 0.0876 mm

Trial control limit
 UCLx-bar = X-double bar + A2R-bar = 6.41 +
(0.729)(0.0876) = 6.47 mm
 LCLx-bar = X-double bar - A2R-bar = 6.41 –
(0.729)(0.0876) = 6.35 mm

 UCLR = D4R-bar = (2.282)(0.0876) = 0.20

mm
 LCLR = D3R-bar = (0)(0.0876) = 0 mm
X-bar Chart
R Chart
 Revised CL & Control Limits

 Calculation based on discarding subgroup 4 & 20 (X-

bar chart) and subgroup 18 for R chart:


XnewXX d = (160.25 - 6.65 - 6.51)/(25-2)
mm
d = 6.40 mm


R RR d = (2.19 - 0.30)/25 - 1
mm = 0.079 = 0.08 mm
new
d
New Control Limits

New value:
X
oX, R
new oR, 
newo
R
O
d
2
 Using standard value, CL & 3 control limit obtained
using formula:

X

UCLX
o
A 
, LCL
o X
X
o
Ao

R
UCL
D
2 ,
o 
LCL
R 
D
1o
From Table B:
 A = 1.500 for a subgroup size of 4,

 d2 = 2.059, D1 = 0, and D2 = 4.698

Calculation results:

XoX 6
new .40 
RR 0
.
079
mmo new , 
o
R
o 0

.
079

0.
038
m


d
2 2
.
059


X
UCLA6.
40(
1
.500
)(
0. 
038
)6
.46
m

X o o


X
LCL
A6
.
40(
1
.500
)(
0. 
038
)6
.34
m

X o o


UCL
RD2o(
4.
698
)(
0. 
038
)0.
18mm

R
LCLD
1o(
0)(
0
. 

038
) 0
mm
Trial Control Limits & Revised Control Limit
6.65

6.60 Revised control limits

6.55
Mean, X-bar

UCL = 6.46
6.50

6.45

6.40
CL = 6.40
6.35

6.30 LCL = 6.34

0 2 4 6 8
Subgroup

0.20
UCL = 0.18

0.15
Range, R

0.10 CL = 0.08

0.05

0.00
0 2 4 6 8 LCL = 0
Subgroup
Revise the charts

 In certain cases, control limits are revised

because:
 out-of-control points were included in the
calculation of the control limits.
 the process is in-control but the within
subgroup variation significantly
improves.
Revising the charts

 Interpret the original charts

 Isolate the causes
 Take corrective action
 Revise the chart
 Only remove points for which you can determine an
assignable cause
Process in Control

 When a process is in control, there occurs a

natural pattern of variation.
 Natural pattern has:
 About 34% of the plotted point in an imaginary
band between 1 on both side CL.
 About 13.5% in an imaginary band between 1
and 2 on both side CL.
 About 2.5% of the plotted point in an imaginary
band between 2 and 3 on both side CL.
The Normal
Distribution
 = Standard deviation

Mean
-3 -2 -168.26%
+1 +2 +3
95.44%
99.74%
LSL USL

-3 +3
CL
Normal Distribution Review

 Define the 3-sigma limits for sample means as follows:


3 3(0
.05
)
 5
Upper
Limit 
.01 5
.077
n 5

3 3(0
.05
)
 5
Lower
Limit 
.01 4
.943
n 5
 What is the probability that the sample means will lie
outside 3-sigma limits?
 Note that the 3-sigma limits for sample means are
different from natural tolerances which are at
3
Process Out of Control

 The term out of control is a change in the

process due to an assignable cause.
 When a point (subgroup value) falls outside
its control limits, the process is out of control.
Assignable Causes
Average (a) Mean

Grams
Assignable Causes
Average
(b) Spread

Grams
Assignable Causes
Average
(c) Shape

Grams
 Assignable
Control Charts causes
likely

UCL

Nominal

LCL

1 2 3
Samples
Control Chart Examples

UCL
Variations

Nominal
LCL

Sample number
Achieve the purpose

 Our goal is to decrease the variation inherent

in a process over time.
 As we improve the process, the spread of the
data will continue to decrease.
 Quality improves!!
Improvement
Examine the process

 A process is considered to be stable and

in a state of control, or under control,
when the performance of the process
falls within the statistically calculated
control limits and exhibits only chance, or
common causes.
Consequences of misinterpreting
the process
 Blaming people for problems that they cannot
control
 Spending time and money looking for problems that
do not exist
 Spending time and money on unnecessary process
adjustments
 Taking action where no action is warranted
 Asking for worker-related improvements when
process improvements are needed first
Process variation

 When a system is
subject to only
chance causes of
variation, 99.74% of
the measurements
will fall within 6
standard deviations Mean
-3 -2 -1 +1 +2 +3
 If 1000 subgroups are 68.26%
measured, 997 will 95.44%
fall within the six 99.74%
sigma limits.
Chart zones
 Based on our knowledge of the normal curve, a
control chart exhibits a state of control when:
♥ Two thirds of all points are near the center

value.
♥ The points appear to float back and forth

across the centerline.

♥ The points are balanced on both sides of the

centerline.
♥ No points beyond the control limits.

♥ No patterns or trends.
Quality should be built
into product and
testing alone can not
relied on to ensure
product quality
QA/QC 75