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in Pharmaceutical Manufacturing

Senior Policy Advisor

CDER/OC/OMPQ

March 9th, 2012

AOAC Conference

* This presentation reflects the views of the author and should not

be construed to represent FDAs views or policies.

Agenda

CGMP References

ASTM Standards

Conclusions

Examples involving

Incorrect application of sampling plans

Equipment changes and process

capability

Container closure - determining baseline

defect rates

Recall example application of ASTM

E2709

3

Pooled X vials, used only 1 reportable value, but used

n=X in sampling plan.

criteria on a single reportable value averaged from a

pooled sample.

= 10 vials). This equates to a lot disposition action on

3 reportable values with corresponding AQL of X%

and LQ of X% respectively. This is not equivalent to

an X or X plan as claimed in your SOP.

4

Response to 483 indicated firm did not know

how to use and interpret sampling plans

correctly.

Firm did not understand concepts of

Acceptable Quality Level (AQL) and Limiting

Quality (LQ) and Operating Characteristic

Curve (OC) of a specific sampling plan.

capability

Initial process qualification used a single-sided tablet

press. During routine production, however, these

products were also being manufactured using a

double-sided tablet press.

Compression using the double sided press was not

qualified.

Firms response to the FDA 483 attempted to show

statistical equivalence between the single and double

sides presses.

6

capability

The firms written response referenced the Cpk values for processes

using a double-sided tablet press and the single-sided tablet press.

FDA evaluation of the FDA 483 response

The Cpk value alone was not an appropriate metric to demonstrate

statistical equivalence. Cpk analysis requires a normal underlying

distribution and a demonstrated state of statistical process control. The

firm did not address these issues in their response.

Statistical equivalence between the two presses could have been

shown by using either parametric or non-parametric (based on

distribution analysis) approaches and comparing means and variances.

Neither of these approaches was employed. Firm did not use the

proper analysis to support their conclusion that no significant differences

existed between the two compression processes.

capability

Issues

Data did not support proper statistical

conclusions.

Firm did not understand underlying

assumptions required to conduct Process

Capability calculations.

Firm did not conduct proper statistical

analysis to demonstrate equivalence between

two operations.

8

baseline defect rates

Numerous complaints of leaks, bursts, and premature activation

during 2 year period.

Root cause - variability in the film thickness that influenced the

sealing of the bags. Bags have two seals and their strength (or

weakness) relative to each other led to different failure modes.

Critical defects compromising sterility and stability.

system.

Incoming acceptance activities, as well as in-process

and finished product release activities, were found

inadequate.

9

baseline defect rates

Issues

In responding to the 483, the firm equated customer

complaints to true manufacturing defect rate. They did

not understand that market incident data may not

track with the quality of the product prior to release.

The proposed sampling plans to identify these known

potential defects were not based on appropriate

statistics.

Firm did not understand sampling plan used for lot

release.

Firm could not justify using a riskier sampling plan

(higher probability of accepting bad product).

10

to Comply with an Acceptance Procedure.

Tablets,

Q value: 70%

stability. Dissolution data was analyzed using ASTM 2709. Sample data

below shown for 2 lots (Each row is a different lot). If evaluated correctly,

these lots would have been flagged as high risk for failure.

Unit

6

Unit

7

Unit

8

Unit

9

Unit

10

Unit

11

Unit

12

USP PASS

or

FAIL

ASTM E2709

Probability @

95%

confidence

Unit

1

Unit

2

Unit

3

Unit

4

Unit

5

96%

72%

82%

74%

102%

70%

97%

63%

71%

78%

74%

60%

78%

14%

17%

Pass

0.14%

77%

73%

90%

95%

92%

59%

73%

94%

60%

72%

62%

85%

78%

13%

17%

Pass

0.14%

Mean

SD

RSD

11

CGMP References

211.165(d)

211.180(e)

Preamble for 21 CFR 210, 211

12

Control procedures

Monitor the output

Performance

Variability in the characteristics of in-process

material and the drug product

.derived from previous acceptable process

average and process variability estimates

(where possible)

.determined by...suitable statistical

procedures (where appropriate)

13

Statistics

Can sample tablets at any stage of process and analyze for:

Weight.

Content Uniformity.

Dissolution.

Other critical quality attributes and or parameters of interest.

Ability for a lot to pass USP UDU and or Dissolution tests in the future.

(ASTM E2709)

Confidence in sampling. (ASTM E2334 & ASTM E122)

Capability and Performance analysis. (ASTM E2281)

Statistical Process Control Charts. (Monitor Variation, ASTM E2587)

a particular attribute, variable and or parameter with respect to

sample size and an associated confidence.

14

US Government Agencies

OMB Circular A119

Federal Participation in the Development and Use of

Voluntary Consensus Standards and in Conformity

Assessment Activities (Rev. Feb 10, 1998)

directs agencies to use voluntary consensus

standards in lieu of government-unique standards

except where inconsistent with law or otherwise

impractical

intended to reduce to a minimum the reliance by

agencies on government-unique standards.

http://www.whitehouse.gov/omb/circulars/a119/a119.html

15

ASTM E2709

7.00

Capability to Comply with an Acceptance

Procedure

n=10

5.00

RSD

n=20

4.00

n=30

n=100

3.00

n=500

2.00

n=1000

1.00

0.00

85.1

87.5

90

92.5

95

97.5

100

102.5

105

107.5

110

112.5

114.9

Sample Mean

7.00

6.00

5.00

RSD

Uniformity of Dosage

Units

6.00

n=10

n=20

4.00

n=30

n=100

3.00

n=500

2.00

n=1000

1.00

0.00

85.1

87.5

90

92.5

95

97.5

100

102.5

Sample Mean

105

107.5

110

112.5

114.9

16

Standard Practice for Demonstrating Capability

to Comply with an Acceptance Procedure

tolerance for variability. As sample size increases, so does

the tolerance for variability.

The analysis was performed using ASTM E2709-10. The

RSD limits on the y-axis represent the maximum variability a

lot can possess to ensure with 95 or 99% confidence that

there is at least a 95 or 99% probability a lot will comply with

the USP Uniformity of Dosage Units test based upon a given

sample size, confidence level, and sample mean.

For example: If you sampled 30 units and had a sample

mean of 95%, then the maximum RSD value for those 30

units would be ~3.0% to be 95% confident that there is at

least a 95% probability a future sample from the lot would

pass the USP UDU test.

17

ASTM E2334

Setting an Upper Confidence Bound For a Fraction or

Number of Non-Conforming items, or a Rate of Occurrence

for Non-conformities, Using Attribute Data, When There is a

Zero Response in the Sample

100

90

80

Confidence

70

60

Pd=1%

50

Pd=0.5%

40

Pd=0.065%

30

20

10

0

6

10

12

24

30

100

150

300

500

1000

Sample Size

18

Setting an Upper Confidence Bound For a Fraction or

Number of Non-Conforming items, or a Rate of Occurrence

for Non-conformities, Using Attribute Data, When There is a

Zero Response in the Sample

Sample Size. As sample size increases, so does

confidence demonstrated.

The analysis was performed using ASTM E2334-09.

Keeping the maximum percent defective constant (1,

0.5, and 0.065%) a line was generated to show how

sample size effects the confidence demonstrated in

having no more than the maximum percent defective. A

zero response was assumed (that is zero defects in the

sample) and a binomial distribution was used.

For example: If you desire a percent defective of no more than

0.5% and sample 30 units, then you are only ~15% confident

that your lot has no more than 0.5% defects.

19

ASTM E2334

Setting an Upper Confidence Bound For a Fraction or

Number of Non-Conforming items, or a Rate of Occurrence

for Non-conformities, Using Attribute Data, When There is a

Zero Response in the Sample

40

35

30

25

20

99%

Confidence

15

95%

Confidence

10

5

0

10

20

30

50

500

1000

20

Setting an Upper Confidence Bound For a Fraction or

Number of Non-Conforming items, or a Rate of Occurrence

for Non-conformities, Using Attribute Data, When There is a

Zero Response in the Sample

confidence bound on percent defects and sample size.

As sample size increases the upper confidence bound

on percent defects decreases.

The analysis was performed using ASTM E2334-09.

Keeping the confidence level constant (95 and 99%) a

line was generated to show how sample size effects the

upper confidence bound percent defects. A zero

response was assumed (that is zero defects in the

sample) and a binomial distribution was used.

For example: If you want to be 99% confident that there is no

more than 1% defective units in your lot, then you must sample

~460 units with a zero response.

21

ASTM E122

Standard Practice for

Calculating Sample Size to Estimate, With Specified

Precision, the Average for a Characteristic of a Lot or

Process

10.00

9.00

Precision Range

8.00

7.00

=1.0

6.00

=3.0

5.00

=5.0

4.00

=6.0

3.00

=10.0

2.00

1.00

0.00

10

20

30

50

Sample Size

500

1000

22

Standard Practice for

Calculating Sample Size to Estimate, With Specified

Precision, the Average for a Characteristic of a Lot or

Process

size and precision. As sample size increases,

so does your estimate precision.

The analysis was done using ASTM E122-09.

Lines were generated using different sample

sizes to show the effect it has on your estimate

precision.

For example: If you sampled 30 units and your sigma

value was 6, then your sample average is ~ +/-3.5%

of your true population average.

23

ASTM E2281

Standard Practice for

Process and Measurement Capability Indices

3.50

Manufacturing Capability

3.00

2.50

2.00

95% Confidence

99% Confidence

1.50

1.00

0.50

0.00

6

10

12

20

24

30

50

Sample Size

100

250

500

1000

24

Standard Practice for

Process and Measurement Capability Indices

Process Capability Index (Cpk (3.14)) and

sample size. As sample size increases, so does

the reported Cpk.

When reporting a Cpk, a lower 95 or 99%

confidence bound should always be the value

reported. As this value accounts for the sample

size in which the Cpk was estimated.

a Cpk of 3.14, then the value reported should be ~2.5

(that is I am 99% confident that the Cpk for my

process is at least 2.5). The analysis was done using

ASTM E2281-08.

25

ASTM E2281

Standard Practice for

Process and Measurement Capability Indices

3.50

Manufacturing Performance

3.00

2.50

2.00

95% Confidence

99% Confidence

1.50

1.00

0.50

0.00

6

10

12

20

24

30

50

Sample Size

100

250

500 1000

26

Standard Practice for

Process and Measurement Capability Indices

Process Performance Index (Ppk (2.79)) and

sample size. As sample size increases, so does

the reported Ppk.

When reporting a Ppk, a lower 95 or 99%

confidence bound should always be the value

reported. As this value accounts for the sample

size in which the Ppk was estimated.

a Ppk of 2.79, then the value reported should be ~2.2

(that is I am 99% confident that the Ppk for my process

is at least 2.2). The analysis was done using ASTM

E2281-08.

27

ASTM E2587

collection of very effective statistical-graphical

tools which can be used to:

Track performance to identify problems, or shifts in

performance (good or bad).

Control or adjust the process to maintain desired

performance.

Can be applied for data based on Incoming, Inprocess, or Lot release samples.

28

ASTM E2587

Variable X-bar-R chart

Sample Mean

2 5

103

UCL=103.048

5 5

_

_

X=101.868

102

101

LCL=100.689

1

100

11

21

31

41

51

Sample

61

71

81

91

Sample Range

4.5

UCL=4.326

3.0

_

R=2.046

1.5

0.0

LCL=0

1

11

21

31

41

51

Sample

61

71

81

91

29

ASTM E2587

Standard Practice for Use of Control Charts in Statistical Process Control

variation during manufacturing.

Control is determined against standard 8

rules established by Dr. Walter Shewhart.

Preceding chart is called X-bar-Range with

Subgroup size of 5 tablets (each point is

an average of 5 individual results).

Control limits reveal true variability of the

process.

30

ASTM E2587

Attribute nP chart

The tablet bottle is either pass or fail (Binary response)

Sample 100 bottles per incoming lot

12

UCL=11.38

Sa mple Count

10

8

6

__

NP=4.9

4

2

0

LCL=0

1

10

13

16

19

22

25

28

Sample

Here we assume the failure rate is 5 bottles/100 bottles

Need to know historical defect rate from supplier

31

Conclusions

What have we covered?

Enforcement action examples and CGMP references.

Use of statistics to quantify relationship between

confidence associated with attribute, variable and or

parameter of interest with respect to the sample size

collected.

To make inferences on untested units.

Can be applied to In-coming, In-process, or Finished

samples.

Can be used for real time manufacturing and or

annual/periodic product reviews.

32

Conclusions

Other Statistical Tools

Sampling plans

Do they describe Consumers Risk?

How are true defect rates calculated to use a particular

sampling plan?

right analysis?

Do the tools help answer questions about

product quality and process performance?

33

Conclusions

The specific statistical tools and analysis

depends on what variables, attributes,

parameters are being used to monitor process

performance and product quality.

The preceding example is just one set of

statistical methods available to monitor process

performance and product quality.

Statistics is a tool to elicit information to confirm

that a specific manufacturing process is

producing quality product.

34

Acknowledgements

Alex Viehmann CDER/OPS

Grace McNally CDER/OC

35

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