12 views

Uploaded by zombiecorp

Risk-based Methodology for Validation of Pharmaceutical Batch Processes.

- Statistics in Anaesthesia - Part 1
- notes on normal distribution
- Session 3
- Statistics 3 Questions
- Brm- Determination of Sample Size
- The Effects of Economic Stimulus - Cash for Clunkers
- Commercial Buildings
- Lecture 3 (Confidence Intervals)
- Statistical Methods for Material Characterization and Qualification
- Application of Statistical Concepts in the Determination of Weight Variation in Samples
- 120 eBook Elementos Basicos 2016 POSADAS Co 159pp (1)
- PPCh09mod
- Linear Correlation.docx
- term project s16 eportfolio
- math 1040 skittles project hayden christensen
- midsem_soln.pdf
- Confidence Intervals for the Exponential Hazard Rate
- Interpreting Interval Estimate of a Population Proportion
- 8[1].Basic Stat Inference
- Introduction to Statistics

You are on page 1of 14

Batch Processes

Frederick Wiles

Access the most recent version at doi:10.5731/pdajpst.2013.00923

Downloaded from journal.pda.org on June 7, 2014

TECHNOLOGY/APPLICATION

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.

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-

Downloaded from journal.pda.org on June 7, 2014

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

Downloaded from journal.pda.org on June 7, 2014

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-

Downloaded from journal.pda.org on June 7, 2014

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)

Downloaded from journal.pda.org on June 7, 2014

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

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.

Downloaded from journal.pda.org on June 7, 2014

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

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

冑

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

3ˆ LT

,

3ˆ LT

册 (1)

with probability ␥, the statistical confidence

obtained from the matrix in Table V

mal distribution found by iteration of eq 4:

冕

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

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

Downloaded from journal.pda.org on June 7, 2014

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.

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

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-

Downloaded from journal.pda.org on June 7, 2014

TABLE VI

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

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.

Downloaded from journal.pda.org on June 7, 2014

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

Downloaded from journal.pda.org on June 7, 2014

TABLE VII

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

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

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

Downloaded from journal.pda.org on June 7, 2014

Figure 4

Graphical representation of simulated PPQ capability analysis showing the relationship between PPK, LCCB,

and k2 with respect to the minimum capability criterion.

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

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

batches needed to achieve an LCCB above the mini-

mum capability specification.

1. FDA. Guidance for Industry. Process Validation:

General Principles and Practices. Office of Com-

While the methodology outlined in this paper was munications, Division of Drug Information, Silver

designed specifically for application with liquid Spring, MD, 2011.

batch pharmaceutical processes in which the mea-

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-

with discrete processes by substituting control quirements Task Force. Fundamental Statistical

charts and formulas for P pk and LCCB based on Process Control: Reference Manual. AIAG:

attribute data. Southfield, MI, 1991.

Downloaded from journal.pda.org on June 7, 2014

mark Publishing, Inc.: Cedarburg, WI, 2001. 2012.

4. Wald, A; Wolfowitz, J. (1946). Tolerance limits for a 6. Pyzdek, T. The Six Sigma Handbook. McGraw-

normal distribution. Annals of Mathematical Statistics Hill Companies, Inc.: New York, 2000.

1946, 17 (2), 208 –215; http://projecteuclid.org/

euclid.aoms/1177730981, retrieved October 30, 2012. 7. NIST/SEMATECH e-Handbook of Statistical

Methods; http://www.itl.nist.gov/div898/hand-

5. NIST/SEMATECH e-Handbook of Statistical Meth- book/pmc/section3/pmc32.htm, retrieved Septem-

ods; http://www.itl.nist.gov/div898/handbook/prc/ ber 7, 2012.

Downloaded from journal.pda.org on June 7, 2014

Technology (the PDA Journal) is a PDA Member in good standing. Authorized Users are

permitted to do the following:

·Download a single article for the individual use of an Authorized User

·Assemble and distribute links that point to the PDA Journal

·Print individual articles from the PDA Journal for the individual use of an Authorized User

·Make a reasonable number of photocopies of a printed article for the individual use of an

Authorized User or for the use by or distribution to other Authorized Users

·Except as mentioned above, allow anyone other than an Authorized User to use or access the

PDA Journal

· Display or otherwise make any information from the PDA Journal available to anyone other

than an Authorized User

·Post articles from the PDA Journal on Web sites, either available on the Internet or an Intranet,

or in any form of online publications

·Transmit electronically, via e-mail or any other file transfer protocols, any portion of the PDA

Journal

·Create a searchable archive of any portion of the PDA Journal

·Use robots or intelligent agents to access, search and/or systematically download any portion

of the PDA Journal

·Sell, re-sell, rent, lease, license, sublicense, assign or otherwise transfer the use of the PDA

Journal or its content

·Use or copy the PDA Journal for document delivery, fee-for-service use, or bulk reproduction or

distribution of materials in any form, or any substantially similar commercial purpose

·Alter, modify, repackage or adapt any portion of the PDA Journal

·Make any edits or derivative works with respect to any portion of the PDA Journal including any

text or graphics

·Delete or remove in any form or format, including on a printed article or photocopy, any

copyright information or notice contained in the PDA Journal

- Statistics in Anaesthesia - Part 1Uploaded bynot here 2make friends sorry
- notes on normal distributionUploaded byAnonymous 7HfJimv
- Session 3Uploaded bychanlal
- Statistics 3 QuestionsUploaded byHemu Jain
- Brm- Determination of Sample SizeUploaded byN C Abhijith
- The Effects of Economic Stimulus - Cash for ClunkersUploaded byatthemoney
- Commercial BuildingsUploaded byalwathaifi19
- Lecture 3 (Confidence Intervals)Uploaded byKismet
- Statistical Methods for Material Characterization and QualificationUploaded byGunner92
- Application of Statistical Concepts in the Determination of Weight Variation in SamplesUploaded byIan Paguigan
- 120 eBook Elementos Basicos 2016 POSADAS Co 159pp (1)Uploaded byorlando paez
- PPCh09modUploaded bypkj009
- Linear Correlation.docxUploaded byFlavian Tutuianu
- term project s16 eportfolioUploaded byapi-259634792
- math 1040 skittles project hayden christensenUploaded byapi-388376823
- midsem_soln.pdfUploaded byRodolfo Young
- Confidence Intervals for the Exponential Hazard RateUploaded byscjofyWFawlroa2r06YFVabfbaj
- Interpreting Interval Estimate of a Population ProportionUploaded byLawrenceB.Basilio
- 8[1].Basic Stat InferenceUploaded byManish Mahabir
- Introduction to StatisticsUploaded bydzzz
- Estimation and Testing of Population ParametersUploaded bythrphys1940
- Chapter_03_Revised(1).pptUploaded byMeth
- six sigmaUploaded byShruti Gaind
- RegressionUploaded bypaliwalmanoj
- Statistics Assignment 05Uploaded byMila Anjum
- The Employment Situation, Aug. 2011Uploaded byTexas Watchdog
- Web Intervalos de ConfianzaUploaded byCaesar Almaguer
- Madison, GuyUploaded byMarshall Berg
- SAMPL-Guidelines-3-13-13 (1).pdfUploaded byLuis Luengo Machuca
- 03-errorUploaded byGabi Levente

- Revision Batch Records AUploaded byzombiecorp
- Knapp TestUploaded byzombiecorp
- modulovgmercado INVIMAUploaded byzombiecorp
- Pharmaceutical Quality SystemUploaded bydipaknp
- Catalogo ono DesignUploaded byzombiecorp
- IMPORTANTE - Valoracion de sistemas de impacto directo.pdfUploaded byzombiecorp
- pi032-2technicalinterpretationofannex1togmpguide-copy1Uploaded bymokhzanni
- Filtro HEPA 22x22x3Uploaded byzombiecorp
- sterilizationUploaded byFenil Desai
- ASS-AYC-GU015 Validacion de ProcesosUploaded byzombiecorp
- Quality ManualUploaded byzombiecorp
- jresv13n1p1_a2bUploaded byzombiecorp
- Guideline Sterilisation Medicinal Product Active Substance Excipient Primary Container EnUploaded byzombiecorp
- Corrective Action NASAUploaded byzombiecorp
- 2015 GMP Validation Forum D2.T4.1.1 Ashley Isbel Writing an Effective FSE URS 2Uploaded byzombiecorp
- Smoke StudiesUploaded byzombiecorp
- FDA Guidance Document for GLPsUploaded byRamesh Damani
- Spreadsheetvalidation101 - Createandvalidatefda-compliantms ExcelspreadsheetsUploaded byzombiecorp
- 014 Can OMS 130728 Trigger Insides EsUploaded byzombiecorp
- Anova SimpleUploaded byJuan Perez
- ASTM-E-29-yr-13Uploaded byzombiecorp
- Stability MaintainanceUploaded byveeru_1319
- IMPORTANTE - Valoracion de sistemas de impacto directo.pdfUploaded byzombiecorp
- Cmg p ReportUploaded byChelsea Valdez
- Casos de Estudio CGMPUploaded byzombiecorp
- Inspecciones - casosUploaded byzombiecorp
- Empaque y EtiquetadoUploaded byzombiecorp
- EstaBiliDad fdaUploaded byzombiecorp
- FDA QSIT GuidelineUploaded byTim Sandle

- Exp 108 Transverse WavesUploaded byJohn Andrae Manglo
- ISA 75.19.01 Hydro Static Testing of Control ValvesUploaded byJosé Wero Ayala
- Health professionals of NY letter to Governor CuomoUploaded byAlexander Knight
- Assembler p6Uploaded byAyad M Al-Awsi
- MarshmallowUploaded byMaster Mind
- en.DM00108832Uploaded bysvm86
- Ligament Pressure Vessel AnalysisUploaded byAnnie Hill
- 3G RAN 12 Huawei - Recommended KPIs_v1.0Uploaded byangicar
- Finals Cs461Uploaded byt151848p
- Design manual for high voltage transmission linesUploaded byRoco3D
- IJNGNUploaded byijngn
- SFF PerformanceUploaded byVijay Bhan
- NIEM IEPD XML Code Generation in JavaUploaded byIJIS Institute
- Comparison of Simulation Tools Atp Emtp and Matlab Simulink for Time Domain Power System Transient StudiesUploaded byramonenrique
- Configuring Wamp Server and JcreatorUploaded byeddiey01
- Final C ManualUploaded bysonu1070
- Manrose BrochureUploaded byVijaya Raghavan
- WIM Controller SPP GuideUploaded byJosé Sánchez B
- مستند نص منسق جديد (6).rtfUploaded byحسامالدينالاسطل
- Dimension-9150 Service Manual en-usUploaded byBigKat
- 10.1.1.115.1978dgsdgUploaded byankitsarvaiya
- Samsung ProtocolUploaded byBet C Hai
- Site AssessmentUploaded byhmaisano1
- PPL-Electric-Utilities-Corp-RTS(R)---Residential-Service---Thermal-StorageUploaded byGenability
- VolumeCUploaded byTheodorus Ivan Kurniawan
- CSC 3110_Study GuideUploaded byanon_29869256
- Square Keyway Tolerances AGMA 9002A86.pdfUploaded byGhostGod
- [Xxxx] Syllabus - Uji Kompetensi Administrasi Database Oracle 11g I - 060614Uploaded byHerman Hartanto
- Manoeuvring Simulation of the MUN Explorer AUV Based on the Empirical Hydrodynamics of Axi-symmetric Bare HullsUploaded byali_naghedifar
- gdxutilsUploaded byOmid Alizadeh Mousavi