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Risk-based Methodology for Validation of Pharmaceutical


Batch Processes
Frederick Wiles

PDA J Pharm Sci and Tech 2013, 67 387-398


Access the most recent version at doi:10.5731/pdajpst.2013.00923
Downloaded from journal.pda.org on June 7, 2014

TECHNOLOGY/APPLICATION

Risk-based Methodology for Validation of Pharmaceutical


Batch Processes
FREDERICK WILES, ASQ CQE*

ProPharma Group, Inc., 10975 Benson Dr. Suite 330, Corporate Woods Bldg. 12, Overland Park, Kansas 66210
©PDA, Inc. 2013

ABSTRACT: In January 2011, the U.S. Food and Drug Administration published new process validation guidance for
pharmaceutical processes. The new guidance debunks the long-held industry notion that three consecutive validation
batches or runs are all that are required to demonstrate that a process is operating in a validated state. Instead, the
new guidance now emphasizes that the level of monitoring and testing performed during process performance
qualification (PPQ) studies must be sufficient to demonstrate statistical confidence both within and between batches.
In some cases, three qualification runs may not be enough. Nearly two years after the guidance was first published,
little has been written defining a statistical methodology for determining the number of samples and qualification runs
required to satisfy Stage 2 requirements of the new guidance. This article proposes using a combination of risk
assessment, control charting, and capability statistics to define the monitoring and testing scheme required to show
that a pharmaceutical batch process is operating in a validated state. In this methodology, an assessment of process
risk is performed through application of a process failure mode, effects, and criticality analysis (PFMECA). The
output of PFMECA is used to select appropriate levels of statistical confidence and coverage which, in turn, are used
in capability calculations to determine when significant Stage 2 (PPQ) milestones have been met. The achievement
of Stage 2 milestones signals the release of batches for commercial distribution and the reduction of monitoring and
testing to commercial production levels. Individuals, moving range, and range/sigma charts are used in conjunction
with capability statistics to demonstrate that the commercial process is operating in a state of statistical control.

KEYWORDS: Process capability, Statistical confidence, Statistical coverage, Control chart, PFMECA, Process
validation, Risk-based.

LAY ABSTRACT: The new process validation guidance published by the U.S. Food and Drug Administration in
January of 2011 indicates that the number of process validation batches or runs required to demonstrate that a
pharmaceutical process is operating in a validated state should be based on sound statistical principles. The old rule
of “three consecutive batches and you’re done” is no longer sufficient. The guidance, however, does not provide any
specific methodology for determining the number of runs required, and little has been published to augment this
shortcoming. The paper titled “Risk-based Methodology for Validation of Pharmaceutical Batch Processes” describes
a statistically sound methodology for determining when a statistically valid number of validation runs has been
acquired based on risk assessment and calculation of process capability.

Introduction tical industry about the number of runs required to satisfy


process performance qualification (PPQ) as described in
Although published more than 2 years ago, there is still the latest U.S. Food and Drug Administration guidance
a considerable amount of uncertainty in the pharmaceu- on process validation. The old rule of three process
validation runs is out and has now been replaced by a
more robust statistical methodology. The new Guidance
for Industry. Process Validation: General Principles and
* Corresponding Author: ProPharma Group, Inc.,
Practices (1), published in January 2011, in part states
10975 Benson Dr. Suite 330, Corporate Woods Bldg.
that
12, Overland Park, Kansas 66210, E-mail: fred.wiles@
propharmagroup.com
in most cases, PPQ will have a higher level of
doi: 10.5731/pdajpst.2013.00923
sampling, additional testing, and greater scru-

Vol. 67, No. 4, July–August 2013 387


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tiny of process performance than would be pressed using capability statistics. Organizations
typical of routine commercial production. The adopting this methodology should consult with a stat-
level of monitoring and testing should be istician or other professional possessing expertise and
sufficient to confirm uniform product quality experience in statistical process control to determine
throughout the batch (emphasis mine). the applicability of this methodology for their specific
process.
The guidance goes on to recommend that the PPQ
protocol discuss Risk-based PPQ Methodology for Pharmaceutical
Batch Processes
the sampling plan, including sampling points,
number of samples, and the frequency of sam- The first step in any risk-based process validation
pling for each unit operation and attribute. strategy is to identify and quantify the risks associated
The number of samples should be adequate to with each process step. This is best accomplished
provide sufficient statistical confidence of through the application of a process failure mode,
quality both within a batch and between effects, and criticality analysis (PFMECA). A
batches. The confidence level selected can be PFMECA is a systematic approach for identifying,
based on risk analysis as it relates to the categorizing, and rating failures associated with a
particular attribute under examination. Sam- manufacturing process based on their effect on the
pling during this stage should be more exten- process output. PFMECAs are usually prepared by a
sive than is typical during routine production cross-functional team consisting of representatives
(emphasis mine). from at least the research and development, manufac-
turing, and quality functions. Other functions such as
The guidance also recommends engineering and quality control may be included in the
team as well.
continued monitoring and sampling of pro-
cess parameters and quality attributes at the Prior to developing the PFMECA, a map of the pro-
level established during the process qualifica- cess illustrating the process steps in the order that they
tion stage until sufficient data are available to occur should be created. The process map can be a
generate significant variability estimates (em- simple block diagram, but should identify process
phasis mine). inputs such as the equipment used, raw materials, and
process parameters required for manufacture of the
The guidance states that the number of samples should product. In addition to the process inputs, the pro-
be adequate to provide sufficient statistical confidence, cess flow diagram should identify key process out-
but it does not provide any specific methodology to be puts which, for pharmaceutical batch processes,
used to determine the number of samples required. take the form of in-process and batch release test-
Pharmaceutical companies are left to their own de- ing. Once created, the process flow diagram will be
vices to develop methods and procedures that yield a used as a reference for constructing the PFMECA.
statistically valid number of PPQ runs and sample An example of a simple process flow diagram is
sizes. Unfortunately, there is little published literature provided in Figure 1.
that goes into depth on this subject. This article de-
scribes a specific methodology for deriving PPQ sam- After finalizing the process flow diagram, the next step
pling plans under the new guidance. This methodology in the development of the PFMECA is to procure data
is risk-based and provides a mathematical approach that can be used to identify potential risks to the
for determining when a sufficient number PPQ batches process output. Primary sources of data for input to the
have been acquired to demonstrate adequate statistical PFMECA are process characterization studies. Process
confidence in the process validation results. characterization involves challenging the process un-
der varying manufacturing conditions and process pa-
The methodology described herein was developed spe- rameter settings in order to gain first-hand knowledge
cifically for process performance qualification of liq- of how a process will perform under different stresses.
uid batch pharmaceutical processes. However, the The output of process characterization can be used to
concepts outlined in this article may be adapted to suit identify key process inputs affecting product quality
any process where process performance can be ex- and yield. Evaluation of process performance at input

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Figure 1

Example process flow diagram for a simple pharmaceutical batch compounding process.

extremes expose weak points in the process where screening studies, response surface analysis, and anal-
additional controls may be needed to reduce the risk to ysis of variance (ANOVA), to name a few, can be used
the finished product and defines process limits beyond to quantify the effect of input variation on the process
which the process is no longer viable. Tools such as outputs. Other data sources such as product develop-

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TABLE I
Example PFMECA Matrix. The RPN Value in the Rightmost Column Is the Product of the Ratings of the
Three Risk Categories, Severity, Occurrence, and Detection

CONTROLS IN PLACE
FAILURE MODE
FUNCTION
ITEM NO.

PROCESS

EFFECTS

CAUSE

OCC

DET

RPN
SEV
List controls
List List in place to
List specific effect(s) of List causes mitigate the
Description process failure each failure for each probability of
of process functions modes mode failure mode occurrence 1–3 1–5 1–5 1–75

ment and past production history also provide useful coverage, p, required for the PPQ study of interest.
input to the PFMECA. Confidence and coverage values are chosen based on
the highest RPN value exhibited by the process. A
In preparing the PFMECA, the risks associated with matrix may be created for this purpose where specific
each process step are quantified to produce a risk RPN ranges correspond to predetermined combina-
priority number (RPN). Quantization is achieved by tions of confidence and coverage. Such a matrix
categorizing and rating the individual risks on a nu- should be documented in the company’s validation
merical scale. The risk categories rated are arbitrary and/or risk assessment procedures. Example risk rat-
but are usually chosen as the severity of the risk, the ing system matrixes are provided in Tables II, III, IV,
probability of detection, and the probability of occur- and V. Only after completing the PFMECA and es-
rence. The RPN value is the product of the ratings tablishing appropriate levels of statistical confidence
from each of the risk categories. An example and coverage can the process progress to PPQ.
PFMECA matrix is provided in Table I.
PPQ is performed in two phases reflecting recom-
RPN values established in the PFMECA are used to mendations put forth in Stage 2 and Stage 3 of the
determine the levels of statistical confidence, ␥, and process validation guidance. In the first phase of

TABLE II
Example Ranking Scale for Probability of Occurrence. The Probability of Occurrence Is Measured on a
Scale of 1 to 3. The Highest Ranking Is Used When the Probability Is Unknown

Probability of Occurrence
Ranking Description Comments
1 Low Not likely to occur (Probability ⬍ 0.001)
2 Moderate Could occur (0.1 ⬎ Probability ⬎ 0.001)
3 High Likely to occur at some time (Probability ⬎ 0.1)

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TABLE III
Example Ranking Scale for Severity of Effect. The Severity of Effect of a Failure Is Measured on a Scale of
1 to 5. The Highest Ranking Is Used When Severity Is Unknown

Severity of Effect
Ranking Description Comments
Unreasonable to expect any real or measurable effect on the safety and
efficacy of the finished product. The failure is unlikely to result in a
1 Minor customer complaint.
Failure could lead to a slight deterioration of the product appearance but
2 Low is not likely to affect the safety or efficacy of the product.
Failure that easily affects a product or process. Product deterioration
is likely and some customer dissatisfaction and/or annoyance is
3 Moderate expected
Failure resulting in a high degree of product non-performance and
extreme customer dissatisfaction. Safety or efficacy of the product may
4 High be impacted. Immediate corrective actions are required.
Failure seriously affects the safety or efficacy of the product resulting in
5 Very High product destruction, recall, or other regulatory action.

PPQ, a number of initial runs or batches are exe- usually taken from different levels within the blend-
cuted. Data collected in the first PPQ phase are used ing vessel to demonstrate bulk product uniformity.
to establish preliminary estimates of process control However, unlike a discrete manufacturing process
and capability. Product batches undergoing PPQ are such as a filling operation where items are produced
not released until successful completion of this one at a time, a bulk pharmaceutical batch is man-
phase. The second phase of PPQ is a continuation of ufactured as a whole at one time. Thus, the within-
the PPQ sampling and testing plan, but allowing for batch variation in a batch process is usually so much
release of PPQ batches for commercial distribution. smaller than the between-batch variation; the con-
The purpose of the second phase PPQ testing is to trol limits on a standard X-bar and R/S chart will be
acquire additional data to bolster the initial capabil- too close together (2). In an I-MR-R/S chart, the
ity assessment and to show long-term statistical average of each batch characteristic charted is con-
control of the process. sidered a single data point. The control limits are
based on the batch-to-batch variation (as indicated
Statistical control is best demonstrated through the by the MR chart) rather than the subgroup variation
use of a control chart. For pharmaceutical batch as in a standard X-bar and R or X-bar and S chart,
processes, the most appropriate chart is the individ- thus providing a more reasonable representation of
uals, moving range, and range/sigma (I-MR-R/S) the batch-to-batch control. The R/S portion of the
chart. In a bulk pharmaceutical batch, samples are I-MR-R/S chart captures the within-batch varia-

TABLE IV
Example Ranking Scale for Probability of Detection. The Probability of Detection Is Measured on a Scale
of 1 to 5. The Highest Ranking Is Used When Severity Is Unknown

Ranking Description Comments


1 Very High Will catch failure every time.
2 High Has a good chance of catching failure.
3 Moderate May catch failure.
4 Low Poor chance of finding failure.
5 Very Low Very poor or no chance of finding failure.

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TABLE V
Example Matrix Associating RPN Ranges with Values of Statistical Confidence and Coverage. Values
Populating the Matrix Should Be Consistent with Each Company’s Internal Risk Management Procedures

RPN Risk Rating Statistical Confidence (␥) Statistical Coverage (p)


1–25 Low 0.90 0.950
26–50 Medium 0.95 0.990
51–75 High 0.99 0.999

tion. An example I-MR-R/S chart is provided in fowitz (4) to calculate approximate two-sided toler-
Figure 3. ance limits. This formula is expressed as


The within- and between-batch variation should be
mn ⫺ 1
monitored using the I-MR-R/S chart throughout both k2 ⫽ r (3)
␹␥,mn⫺1
2
phases of the PPQ. In fact, the new process validation
guidance strongly encourages control chart monitoring
throughout the life of the product in order to rapidly where
detect changes in the state of process control.
n is the batch sample size
Upon completion of the second and all subsequent
PPQ batches, process performance capability is calcu- m is the number of validation batches
lated. Process performance capability is expressed us-
ing the PPK (long term) index (3): ␹␥,mn⫺1
2
is the critical value of the chi-square distribu-
tion with mn –1 degrees of freedom surpassed

P pk ⫽ Min 冋 USL ⫺ X X ⫺ LSL


3␴ˆ LT
,
3␴ˆ LT
册 (1)
with probability ␥, the statistical confidence
obtained from the matrix in Table V

where r is the interval covering p percent of the nor-


mal distribution found by iteration of eq 4:


X is the grand mean of the process data 1
1 ⫹r
冑 mn
p ⫽ e⫺t / 2 dt
2
(4)
USL is the upper specification limit 冑2␲ 1
⫺r
冑 mn
LSL is the lower specification limit
where p is the statistical coverage obtained from the
␴ˆ LT is the long term process sigma matrix in Table V.

Historically, statistics practitioners have required at The NIST/Sematech e-Handbook of Statistical Methods
least 25 subgroups before attempting to calculate pro- (5) provides an example of how eq 4 can be easily
cess capability. However, due to the limited number of evaluated using the NORMDIST function in Microsoft
runs associated with batch pharmaceutical processes, Excel. In a spreadsheet enter the following cell informa-
capability indices in this methodology are calculated tion:
using a variable multiple of sigma rather than the
standard ⫾3 sigma typically used for time-ordered Cell A1 ⫽ 0 (starting value for r)
processes. Substituting the variable, k2, for the multi-
ple of sigma in eq 1 gives Cell A2 ⫽ Sample size, n, times the number of vali-
dation batches, m

P pk ⫽ Min 冋
USL ⫺ X X ⫺ LSL
k2 ␴ˆ LT
,
k2 ␴ˆ LT
册 (2) Cell A3 ⫽ the desired statistical coverage, p

One way to determine the value of k2 in eq 2 utilizes Cell A4 ⫽ NORMDIST(1/SQRT(A2)⫹A1,0,1,TRUE)-


a variation of a formula proposed by Wald & Wol- NORMDIST(1/SQRT(A2)-A1,0,1,TRUE)

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The value of p, then, is found by iteration using the the value 9 in the denominator of the first term under
Microsoft Excel Solver add-in. Using Solver; the cell the square root is replaced with k22, the square of the
containing the value for r (Cell A1) is repeatedly coverage factor found using eq 3. The LCCB, then, is
changed until the calculated p (Cell A4) matches the defined as
desired p (Cell A3). The value of r yielding the desired
p is the value of r used in eq 3.

Equation 3 takes into account the statistical degrees of


LCCB ⫽ PPK ⫺ Z1⫺␣/ 2 冑 1
2
2

2
PPK
k mn 2共mn ⫺ 1兲
(6)

freedom provided by the sample size and number of If the process is capable and in a state statistical
PPQ batches to yield the factor, k2, covering the de- control, at some number of PPQ runs the increasing
sired proportion of the distribution at the desired con- value of PPK and decreasing span of the capability
fidence. Because the value ␹␥,mn⫺1
2
increases with increas- confidence interval will yield a LCCB greater than the
ing degrees of freedom, k2 decreases as the number of pre-established minimum. At this point PPQ runs can
PPQ runs increases. Consequently, even though a pro- cease and sampling can drop to normal production
cess may initially yield a PPK lower than desired, the levels.
decreasing values of k2 on subsequent PPQ runs will
yield successively improved PPK values. Because the value for k2 is dependent on the number of
samples pulled from individual validation batches, the
The first phase of PPQ is considered acceptable when number of validation batches needed to achieve an
the calculated PPK indices for the product character- LCCB greater than the minimum capability specifica-
istics examined are greater than a pre-established min- tion can be reduced by selecting a larger batch sample
imum capability. Upon successful completion of size. Most commercial statistical software packages
Phase 1, PPQ batches may be released, but sampling provide sample size calculators that can be used to
and testing must continue at PPQ established levels as estimate an appropriate sample size for individual
the PPQ study progresses into Phase 2. In any event, PPQ batches.
the minimum number of PPQ runs prior to product
release regardless of the capability estimate should be Simulation
no less than three in order to demonstrate a prelimi-
nary state of statistical control. A study was conducted using simulated PPQ data to
demonstrate the PPQ methodology described above.
During Phase 2, PPK indices are continually recalcu- The simulated PPQ data are listed in Table VI. The
lated as data for each new PPQ batch becomes avail- data were calculated about a mean of 60 and a
able. The number of runs required to satisfy Phase 2 is standard deviation of 1.275 using the random nor-
determined based on a calculation of a confidence mal distribution function in Minitab ® statistical
interval around the PPK index. This interval is approx- software.
imated below by eq 5 (3):
Prior to assessing the simulated data statistically, a

冋 P PK ⫺ Z1⫺␣/ 2 冑1

P 2
PK

9mn 2共mn ⫺ 1兲 册 ⱕ PPK


probability plot was prepared using Minitab® statisti-
cal software to test the assumption of normally dis-

冋 冑 册
tributed data (Figure 2). The probability plot shows
2
1 PPK graphically how well the data conforms to the normal
ⱕ PPK ⫹ Z1⫺␣/ 2 ⫹ (5)
9mn 2共mn ⫺ 1兲 distribution. On a probability plot, the y-axis repre-
sents the cumulative percentage of the data distribu-
Similar to PPK, the span of the capability confidence tion while the x-axis represents the value of the char-
interval will generally decrease as the number of PPQ acteristic being measured. Data that are normally
runs increases. distributed will fall on or very close to a straight line
on the graph, with the majority of the data clustered
For PPQ, we are interested only in the lower capability symmetrically about the 50th percentile. Looking at
confidence interval bound (LCCB) represented by the Figure 2, one can see that the simulated data plot
left-most bracketed term in eq 5. Also, because a closely follows a straight line. Another way to test the
variable coverage factor is used to determine the mul- assumption of normality is to apply the Anderson-
tiple of sigma required in the capability calculation, Darling test. The Anderson-Darling test yields a P-

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TABLE VI
Normally Distributed Data for Fifteen Simulated Batches; Mean ⴝ 60, Standard Deviation ⴝ 1.275

Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Sample 6


Batch 1 61.98599 59.54588 60.86150 59.79496 59.23867 58.33622
Batch 2 62.73705 59.91604 61.84170 59.27713 56.93497 59.19581
Batch 3 60.47101 61.75766 60.82654 61.78138 61.06394 61.21538
Batch 4 61.88888 59.84157 59.63065 57.99141 60.29579 58.58291
Batch 5 62.37012 60.48514 61.56628 58.71746 61.63891 57.30216
Batch 6 60.26066 59.57322 61.09212 59.84095 59.46014 59.61616
Batch 7 61.31893 59.59596 61.44147 60.54807 60.99950 59.92599
Batch 8 59.81401 59.39050 60.70978 58.99141 62.79123 60.36888
Batch 9 60.58472 61.95316 59.83788 58.73686 61.44967 58.41934
Batch 10 60.20420 59.52094 60.04476 59.56099 58.92952 59.67628
Batch 11 61.12075 61.36394 61.99651 57.59433 63.60003 59.75626
Batch 12 61.79105 58.50612 60.76354 60.66932 60.46674 61.08246
Batch 13 60.60140 59.97265 61.91600 61.41712 59.38803 59.11069
Batch 14 59.87057 59.95486 61.56102 59.14503 60.09704 59.81568
Batch 15 62.18290 59.07597 60.07380 59.55689 61.47939 59.10225

value that, when compared to the chosen significance Normally distributed data are crucial if a reliable assess-
level, determines whether or not the assumption of ment of process capability is to be obtained. In the event
normality should be rejected. The significance level, that the assumption of normality is rejected, the cause of
␣, chosen in this case is 0.05. Any value for P greater the non-normal variation should be investigated and
than the significance level indicates that the data are eliminated prior to continuing with further PPQ runs.
likely normally distributed. The probability plot pre-
pared for the simulated data in Table VI yielded a There are situations where non-normal data cannot be
P-value of 0.420; therefore, we would not reject the avoided and, indeed, may even be desired. Consider a
assumption that the data are normally distributed. product characteristic for which the total improvement

Figure 2

Normal probability plot of the simulated PPQ data created using Minitab® statistical software. The P-value is
greater than 0.05; therefore the assumption of normality cannot be rejected.

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Figure 3

Control charts for simulated PPQ data plotted using Minitab® statistical software. All data points are within
statistical control limits. Note that the lower chart is an S chart. For subgroup sample sizes less than 10, an R
chart may be displayed instead.

achievable is constrained due to a physical limit of the that of the normal distribution. For example, if the
characteristic. Such a characteristic will often exhibit data distribution exhibits a long tail to the right as is
an increasingly skewed distribution as the physical characteristic of a log-normal distribution, taking the
limit is approached (3). One example of this situation logarithm of the data in many cases will yield a normal
is microbial testing. Process improvements may re- distribution (6). There are many functions available
duce the microbial load of a product, but the load can for transforming non-normal data. The Johnson Trans-
never be less than zero. A steadily improving process formation or Box-Cox families of transformation
yields successively lower microbial counts, but as the functions are popular examples. Whatever methodol-
average number of counts approaches zero, the distri- ogy is chosen, it is important to remember to transform
bution of counts becomes more asymmetric about the any specification limits along with the process data in
average with the shorter tail being truncated at zero order to maintain a consistent scale.
and the longer tail trailing off in the positive direction
without limit. After testing the assumption that the simulated PPQ
data are normally distributed, an I-MR-R/S chart (Fig-
Fortunately, if the deviation from a normal distribu- ure 3) was prepared to verify that the data met statis-
tion is not too severe, there are transformations that tical control criteria. Whether or not a control chart
can be applied to make the data emulate a normal indicates that a process is in statistical control is
distribution. Transformation involves finding a math- usually determined by applying tests for special causes
ematical function that, when applied to the non-normal of variation. The most commonly known tests for
data, yields a data distribution more closely following special causes of variation are the Western Electric

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TABLE VII
The Process Is Considered Out of Statistical Control if Any of These Test Conditions Are True

Test 1 One point more than 3 ␴ from center line


Test 2 Six points in a row, all increasing or all decreasing
Test 3 Fourteen points in a row, alternating up or down
Test 4 Eight points in a row on the same side of the center line
Test 5 Two out of three points more than 2 ␴ from the center line (same side)
Test 6 Four out of five points more than 1 ␴ from the center line (same side)

Company (WECO) Rules (7). The WECO Rules con- In Figure 4, one can see the asymptotic decrease in k2 is
sist of a number of tests or conditions that indicate roughly mirrored by the simultaneous increase in PPK
when a process has become unstable. The WECO rules and the LCCB. A narrowing of the gap between the
are summarized in Table VII. capability estimate and the LCCB can also be seen as the
chart progresses to the right. This narrowing is the result
Table VIII provides a summary of the capability sta- of increasing sample size as additional PPQ runs are
tistics calculated for the simulated PPQ data. The added, which in turn yields ever tighter estimates of PPK.
minimum capability criterion chosen for the simulated Although only seven PPQ batches were required to sat-
PPQ is 1.00. The coverage factor, k2, was calculated isfy the minimum capability criterion, Figure 4 shows data
for each batch using the values 0.95 for ␥ and 0.99 for from 15 batches to illustrate the concepts described above.
p. With a specification range of 54 – 66, the initial The actual number of batches required will ultimately be
capability estimate shows the simulated process to be determined by the number of samples pulled from each
just barely capable at PPQ run 3. Additional runs were batch and the capability of the process under study.
required to establish the LCCB above the minimum
capability criterion. At run 7, the LCCB also rises Conclusion
above the minimum capability criterion, thus complet-
ing the second PPQ phase. Figure 4 illustrates graph- The methodology presented in this paper provides a
ically the relationship between PPK, the LCCB, and k2 statistically sound approach for determining the num-
relative to the minimum acceptable capability. ber PPQ runs required to demonstrate that a process is

TABLE VIII
Capability Results for Simulated Batch Data

Batch Number k2 PPK LCCB


1 5.77 0.80 0.29
2 4.15 0.88 0.49
3 3.70 1.03 0.66
4 3.48 1.15 0.80
5 3.35 1.13 0.82
6 3.26 1.26 0.95
7 3.19 1.34 1.04
8 3.14 1.37 1.08
9 3.10 1.40 1.12
10 3.07 1.48 1.20
11 3.04 1.39 1.14
12 3.01 1.42 1.18
13 2.99 1.45 1.21
14 2.97 1.50 1.26
15 2.96 1.52 1.28

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Figure 4

Graphical representation of simulated PPQ capability analysis showing the relationship between PPK, LCCB,
and k2 with respect to the minimum capability criterion.

capable and in a state of statistical control regardless Acknowledgements


of the availability of historic process data. Further-
more, this methodology allows the number of PPQ The author thanks Dr. Christopher Holloman of Ohio
runs to be derived mathematically based on an assess- State University and Dr. Ramon Burns of ProPharma
ment of the risks associated with the manufacturing Group, Inc. for their timely review and invaluable
process, thereby satisfying agency expectations for suggestions, and Bob Beall of ProPharma Group, Inc.
process validation under the new process validation for helping to pull it all together.
guidance.
Conflict of Interest Declaration

In most cases where a process is highly capable and


The author is a provider of validation consulting ser-
the process is in a state of statistical control, the LCCB
vices to the pharmaceutical, medical device, and bio-
will rise above the minimum capability specification
logics industries.
after only a few PPQ batches. Selecting a larger batch
sample size can also help reduce the number of PPQ
References
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mum capability specification.
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General Principles and Practices. Office of Com-
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designed specifically for application with liquid Spring, MD, 2011.
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sured variables are continuous, the concepts dis- 2. Automotive Industry Action Group, American So-
cussed in this paper can be easily adapted to work ciety for Quality Control, Supplier Quality Re-
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