Practical Applications of Statistical

Methods Under 2011 FDA Process

Validation Guidance
Abe Germansderfer
Associate Director, Quality Control
Gilead Sciences
2011 Process Validation Guidance
• In January 2011, the FDA issued its new guidance regarding Process
Validation. The last guidance was issued in 1987.
• This new definition of process validation is a significant paradigm shift
from the original concept, embracing the Quality by Design concepts put
forth in ICH Q8 and Q9 as the foundation for establishing robust process
control strategies.
• The previous paradigm of 3 or 5 validation runs is being abandoned in
favor of building confidence in the process and controlling process
variability.
• Most organization will face the challenge of gathering and integrating
multiple process development and characterization studies into a usable
model that would serve as the basis for the development of process
controls and demonstration of process understating.
• Basic statistical tools will be invaluable in meeting these challenges.
Process Validation Paradigm Shift
Process Validation is Based on Three
Stages
• Stage 1: Process Design
– Defining the commercial process based on development & scale‐up
experience.
– Developing an understating of the functional relationship between materials,
equipment, process and quality attributes.
– Understanding of risks.
– Design Space estimation.
• Stage 2: Process Qualification
– Confirming that the process design is capable of reproducible commercial
manufacturing.
– Process parameters meet the acceptance criteria .
– The fluctuations in operating parameters are measured objectively.
• Stage 3: Continued Process Verification
– Gaining ongoing assurance during routine production that the process
remains in control via robust process monitoring.
– Improving process control and reducing product and process variation.
 PV Lifecycle --- Statistical Tool
Process Design
Initial Scoping Design of
Raw Materials Qualification Experiments
Process Optimization (DOE)

Process Qualification
Design Space Definition Model Building
Process Robustness And Evaluation
Develop PVACs

Continued Process Verification Simulation,

Control Systems/IPCs Statistical
Tracking and trending Process Control
Basic Statistical Tools For Process
Validation
• Building Confidence in Operating Parameter Ranges
with Regression.
• Setting Process Validation Acceptance Criteria with
Statistical Tolerance Intervals
• Adopting Acceptance Sampling Plans to Determine
Validation Sampling Requirements
• Process Monitoring via Statistical Process Control
Tools (Control Charts, Run Rules, and Capability
Indices)
Building Confidence in Operating Parameter
Ranges with Regression
• “The approach to Product Performance Qualification (PPQ)
should be based on sound science and the manufacturer’s
overall level of product and process understanding and
demonstrable control. The cumulative data from all relevant
studies (e.g., designed experiments; laboratory, pilot, and
commercial batches) should be used to establish the
manufacturing conditions in the PPQ.”
• “To understand the commercial process sufficiently, the
manufacturer will need to consider the effects of scale.“
• “In addition, we strongly recommend firms employ objective
measures (e.g., statistical metrics) wherever feasible and
meaningful to achieve adequate assurance.”
FDA’s Initiative on Quality by Design

• In a Quality‐by‐Design system:
– The product is designed to meet patient requirements
– The process is designed to consistently meet product
critical quality attributes
– The impact of process parameters on product quality is
understood and quantitated
– Critical sources of process variability are identified and
controlled

Design Space quantifies effects of OPs and PPs within a set of defined
operating conditions

8
Design Space (ICH Q8)
• Definition: The multidimensional combination and
interaction of input variables (e.g., material attributes)
and process parameters that have been demonstrated
to provide assurance of quality
• Note: Design space is a range on the Operating
Parameters. Process Validation Acceptance
Parameters (PVACs) provide a range on Performance
Parameters.

9
PAR Definitions & Design Space Claim

• From Annex to Q8 ICH Guideline

– Proven Acceptable Range (PAR) is a characterized
range of a process parameter for which operation
in this range, while keeping other parameters
constant, will result in producing a material
meeting relevant quality criteria.
– There must be an “assurance of quality” in the
defined design space.

10
A Simple Example : Build Response Model
for a Single Performance Parameter

1.5
Titer

0.5

3 3.5 4 4.5 5 5.5 6 6.5 7

Seed VCD

Linear Fit
A Simple Example : Define Acceptable
Range for a Single Performance Parameter

1.5
Titer

Spec Limit
1

0.5 Acceptable Range

3 3.5 4 4.5 5 5.5 6 6.5 7

Seed VCD

Linear Fit
A Simple Example : Build Confidence in the
Define Acceptable Range
95% Confidence Interval
2
on Individual Runs

1.5
Titer

Spec Limit
1

Acceptable Range
0.5 with 95% Confidence

3 3.5 4 4.5 5 5.5 6 6.5 7

Seed VCD

Linear Fit
A Simple Example : Adjust for Scale

Large Scale
Runs
Regression Model
Re-centered on
Large Scale Data

Spec Limit
Acceptable Range
with 95% Confidence
Basic Statistical Tools For Process
Validation
• Building Confidence in Operating Parameter Ranges
with Regression.
• Setting Process Validation Acceptance Criteria with
Statistical Tolerance Intervals
• Adopting Acceptance Sampling Plans to Determine
Validation Sampling Requirements
• Process Monitoring via Statistical Process Control
Tools (Control Charts, Run Rules, and Capability
Indices)
Setting Process Validation Acceptance
Criteria with Statistical Tolerance Intervals
“Accordingly, in-process material should be controlled
to assure that the final drug product will meet its
quality requirements. The second principle in this
regulation further requires that in-process
specifications “. . . shall be derived from previous
acceptable process average and process variability
estimates where possible and determined by the
application of suitable statistical procedures where
appropriate.” This requirement, in part, establishes
the need for manufacturers to analyze process
performance and control batch-to-batch variability.”
Ideal Specifications
• Edge of failure or clinical effect is known. Confidence in
meeting the specification is built by “stepping in” from the
edge by some multiple of measurement error.

For Internal Use Only. Amgen Confidential.

Pretty Good Specs
• In some instances, when all sources of variability are well
understood or engineering tolerances are known. Stacked
Tolerance (Variance) Analysis can be used to build robust
specification ranges.
• Recently deliverable volume specification were developed
using fill process and analytical process variability:

• Note the multiplier of 4.

For Internal Use Only. Amgen Confidential.

When all else fails…
• Historically statistically derived acceptance criteria such as specs or IPCs
were set as:
– Min and/or Max
– Mean +/‐ 3 x StDev
• This is not wrong and has a good chance of being acceptable if baseline
dataset is large.
• For example:
Statistical Tolerance Intervals
• Statistical Tolerance Intervals are very popular with folks dealing with small
datasets
• Take form of Mean +/‐ K x StDev
• K is the multiplier that is relatively larger for smaller sample sizes to account
for larger sampling error.
• In addition to N, K is specified by two parameters:
– % coverage of future observations (results)
– % confidence in specified coverage. Conventionally set at 95%
• For Example:
Relationship of Sample Size to k-value

From Juran’s Quality Handbook

Tolerance Limits based on small sample sizes utilize extremely
large k-values.
Basic Statistical Tools For Process
Validation
• Building Confidence in Operating Parameter Ranges
with Regression.
• Setting Process Validation Acceptance Criteria with
Statistical Tolerance Intervals
• Adopting Acceptance Sampling Plans to Determine
Validation Sampling Requirements
• Process Monitoring via Statistical Process Control
Tools (Control Charts, Run Rules, and Capability
Indices)
Adopting Acceptance Sampling Plans to
Determine Validation Sampling Requirements
• “In most cases, PPQ will have a higher level of sampling, additional testing, and
greater scrutiny of process performance than would be typical of routine
commercial production. The level of monitoring and testing should be sufficient to
confirm uniform product quality throughout the batch.”

• “In addition, the CGMP regulations regarding sampling set forth a number of
requirements for validation: samples must represent the batch under analysis (§
211.160(b)(3)); the sampling plan must result in statistical confidence (§
211.165(c) and (d)); and the batch must meet its predetermined specifications (§
211.165(a)).”

• “The sampling plan, including sampling points, number of samples, and the
frequency of sampling for each unit operation and attribute. The number of
samples should be adequate to provide sufficient statistical confidence of quality
both within a batch and between batches. The confidence level selected can be
based on risk analysis as it relates to the particular attribute under examination.
Sampling during this stage should be more extensive than is typical during routine
production. “
Building Confidence into Process Validation
Sample Sizes
• Choice of the number of replicate samples depends
on the amount and content of the characterization
data and risk assessment.
• Statistical confidence can be gained by sufficiently
high number of successful replicate trials.
• ANSI Z1.4 and Z1.9 provide a good baseline for the
selection of replicate samples.
• ANSI Acceptance Sampling Plans are best described
by their Operating Characteristic (OC) Curves.
Acceptable and Rejectable Quality Levels

• AQL is the small % of

defects that consumers
are willing to accept.
• RQL is the upper limit of
the percentage of
defective items
consumers are willing to
tolerate.
ASP for Validation
• When a validation or a
qualification study is performed
the use of AQL as a means of
characterizing an ASP become
less meaningful.
• The RQL must be used a
measure of lot quality in these
cases. The RQL may be
interpreted as a measure of
product quality at a prescribed
confidence level.
• FDA’s Quality System Inspection
Technique (QSIT) takes the
same approach to build
confidence into the inspection
process
ASP for Validation
• Whenever possible variables sampling plans for validation must be used to
reduce number of required samples.
• For the tests with continuous data, the probability of batch quality may be
inferred from estimates of the mean and standard deviation of the
collected sample.
• Under assumption of normally distributed measurement results, batch
quality is demonstrated with prescribed level of confidence if k number of
standard deviations lies between a specification limit and a mean estimate

Confidence Limit k‐values for the following sample sizes

.95< 30 N=60 N=120 N=300
.20 ucl 1.75 1.60 1.50 1.4
.08 ucl 2.85 2.70 2.50 2.35
.05 ucl 3.25 3.00 2.80 2.70
.03 ucl 3.85 3.60 3.35 3.20
Basic Statistical Tools For Process
Validation
• Building Confidence in Operating Parameter Ranges
with Regression.
• Setting Process Validation Acceptance Criteria with
Statistical Tolerance Intervals
• Adopting Acceptance Sampling Plans to Determine
Validation Sampling Requirements
• Process Monitoring via Statistical Process Control
Tools (Control Charts, Run Rules, and Capability
Indices)
Process Monitoring via Statistical Process
Control Tools
• “An ongoing program to collect and analyze product and process data that relate
to product quality must be established (§ 211.180(e)). The data collected should
include relevant process trends and quality of incoming materials or components,
in-process material, and finished products. The data should be statistically trended
and reviewed by trained personnel. The information collected should verify that the
quality attributes are being appropriately controlled throughout the process.”
• “We recommend that a statistician or person with adequate training in statistical
process control techniques develop the data collection plan and statistical methods
and procedures used in measuring and evaluating process stability and process
capability.”
• “Procedures should describe how trending and calculations are to be performed
and should guard against overreaction to individual events as well as against
failure to detect unintended process variability.”
• “Production data should be collected to evaluate process stability and capability.
The quality unit should review this information. If properly carried out, these
efforts can identify variability in the process and/or signal potential process
improvements.”
Role of the Control Chart
• Differentiates between special and common cause
variation
• Describe how the process will perform in the future
• See whether intentional changes in a process had
the desired result
• Monitor key processes to identify shifts or changes
quickly to take action to restore the process
Control Chart Definition
• Time ordered plot of results (just like time plots)
• Statistically determined control limits are drawn on the plot.
• Centerline calculation is typically the mean of the data.
• Control limits, upper (UCL) and lower (LCL), are calculated from the
data and provide a means of distinguishing the types of variation
present.
I C h a r t o f C y c le T im e s
40

35
C o n tr o l: Y E S
U C L= 3 6 .0 0 Upper control limit
30 A c c e p t a b le : Y E S
Goal
Individual Value

28
25
_
20
X = 2 1 .2 5 Average Performance
15

10

5
LC L= 6 .5 0 Lower control limit
04 04 04 04 05 05 05 05 05 05 05 05
pt ct v c n b ar r il ay ne ly g
Se O No De Ja Fe M Ap M Ju Ju Au
M onth

Performance
metric on the y-axis Time always on the
x-axis
Interpreting Control Charts
• The interpretation of control charts is based on the
statistical probability of a particular pattern occurring
by complete chance (or being caused by random
variation).
• All of the tests identify events that have a less than 0.3
% chance of occurring by random chance (these
events are outside of the 3σ zone, or 3σ limits)
• Many patterns may not be detected by probability
distribution analysis.
 Nelson 1
Test 1. One Point Beyond Zone A
x
UCL
A
B
C
C
B
A
LCL
x

Test 1 – the basic test

– Caused by a large change in the process.
– Requires immediate action.
 Nelson 2
Test 2. Nine Points in a Row on One Side of the
Center Line
UCL
A
B
C
C
B x
A
LCL

Test 2
– Caused by a shift in the process mean
 Nelson 3
Test 3. Six Points in a Row Steadily
Increasing or Decreasing
UCL
A
B x
C
C
B
A x
LCL

Test 3 – Trends up or down

– Mechanical wear
– Chemical depletion
– Increasing contamination
Why Include a Process Capability Analysis

• Process Capability Analysis:

– Provides a consistent quantitative measure that can be used to
objectively answer the question “How are we doing?” across products.
– Can identify improvement opportunities in a product’s manufacturing
process and/or analytical testing
– Can identify process controls and analytical methods that have a high
risk of an Out of Specification Result
– Provides industry recognized benchmarks that can be used to drive
continuous improvement
• It is, in effect, an addition to current monitoring programs as
it evaluates the ability of a product to meet its specifications
using the Ppk metric
What is Ppk?

Performance ratios
Tolerance (X-bar) - LSL USL - (X-bar)
Pp = Ppk = Min. of
3σ 3σ
OR
6σ

tolerance LSL X USL

Pp = 1.00 Ppk = 1.00

Ppk measures the probability of having a result outside of specification based
upon the process mean and process/measurement variability
Basic Statistical Tools For Process
Validation
• Building Confidence in Operating Parameter Ranges with
Regression.
• Setting Process Validation Acceptance Criteria with
Statistical Tolerance Intervals
• Adopting Acceptance Sampling Plans to Determine
Validation Sampling Requirements
• Process Monitoring via Statistical Process Control Tools
(Control Charts, Run Rules, and Capability Indices)
• Other useful tools are DOE and Process Modeling,
Simulation, Multivariate SPC, Hypothesis and
Equivalency Testing, etc.
References and Additional Resources
• FDA's Process Validation Guideline

• “Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding” (43 FR 45013 at 45052, September
29, 1978)

• ISPE Guide: Science and Risk‐Based Approach for the Delivery of Facilities, Systems, and Equipment

• ICH: PHARMACEUTICAL DEVELOPMENT Q8(R2)

• ICH: Quality Risk Management (ICH Q9)

• Process Validation Lifecycle Approach, Grace E. McNally

• Process Validation Guidance ‐‐ What Does ‘Statistical Confidence’ Mean?, Francis Godwin

• Determination of Comparability Criteria, K.M. Bower, A. Germansderfer, GEN Nov 1, 2010 (Vol. 30, No. 19)

• Using Statistical Analysis for Setting Process Validation Acceptance Criteria for Biotech Products, X. Wang, A.
Germansderfer, J. Harms, A. S. Rathore, Biotechnology Progress, Volume 23, Issue 1, pages 55–60, 2007

• Pharmaceutical Process Validation: Third Edition, Revised and Expanded (I. R. Berry, R. A. Nash, eds.), 2003.

• Validation by Design®, The Statistical Handbook for Pharmaceutical Process Validation, Lynn Torbeck.

• Juran’s Quality Handbook, 5th Edition, Joseph M. Juran

Thank You!
• Questions…
• Comments…