DESIGN FOR SIX SIGMA

.i!:,',

1;,+

NOT LONG after its inception at Motorola in the mid 1980's, Six Sigma's practitioners reahzed that there is often a practical limit to how much
products or processes can be improved. This limit is sometimes referred to as the "five sigma barrier" because it is in this region of process performance that the financial gain of further improvement is frequently outweighed by the cost of implementation. At approximat ely 233 defects per

million (dp*), a five sigma process

most manufacturing processes.

is well above average when compared to

Yet a five sigma process may not be sufficient for many critical process steps. In the pharmaceutical industry, even the "world class" six sigma standar d (3.4 dp*) is inadequate with respect to some critical defects. Given this dilemma, how can we achieve an appropriate level of process performance while maintaining a competitive operating cost? And how do we make sure that we "get it right the first time" without spending extraordinary amounts of time and money in development? The answer that Six Sigma's early practitioners came up with was to develop an additional set of tools and techniques for the development cycle. These became known as Design for Six Sigma (DfSS). The fundamental premise behind DfSS is that developers must thoroughly understand the process and product such that critical material and process parameters are identified and

ON THE WEB
u+iffi

An extended version of

thisartic|e,addto''|:.:......
graphics, and references are available on PharmaQ,b.D.,com.

appropriately controlled. It's easy to recog nLZe that the underpinnings of DfSS are closely aligned with those of Quality by Design (QbD). Guidance documents published by ICH, for example, frequently refer to the need for pharmaceutical R&D teams to develop an "enhanced" level of process knowledge using sould scigntific metho:ds and experimentation. Thus, these two approaches, DfSS and QbD, complement each other well. This paper Will take a closer look at this overlap between Design for Six Sigma and Quality by Design, as well as introduce DfSS tools:.-*including Monte Carlo Simulation, Parameter (robust) Design, and Tolerance

36

FEBRUARY 2O1O

PHARMACEUTICAL IV1ANUFACTURING

WWW.PHARMAMANUFACIURING;COM

DESIGN FOR SIX SIGMA

Allocation-which
program.

can also be used to support a QbD

FMEA, the team will have an extensive list of potentially important factors. How does it determine which ones are actually "critical to quality" with respect to the performance
of the finished product? On the basis of the results of the FMEA exercise, prior knowledg. and preliminaryr experimentation, the team should be able to create a shorter list. However, they will probably not yet have enough knowledge or data to narrow the list to what Dr. |oseph ]uran referred to as the "vital few among the trivial many." Hence, additional tools are needed.

INPUTS AND OUTPUTS According to ICH Q8, "The aim of pharmaceutical development is to design a quality product and its manufacturing
process to consistently deliver the intended performance

of

the product." This objective can be attained by using an "empirical approach or a more systematic approach to product development." DfSS and QbD are very much focused on the latter. Both are founded upon the definition and understanding of the product, its performance requirements, and the processes by which it is manufactured and packaged.
The ultimate goal of most production processes is to understand the relationships between the critical inputs and outputs of each step. Although in early development teams often do not have well-defined specifications, once general performance measures have been identified, it is possible to list inputs that may affect outputs of interest. As suggested in ICH QB (Rl), development teams can use prior knowledge of similar products and the results of preliminary experimentation to create fishbone diagrams listing all potential factors which could impact each of the outputs. This initial effort should result in an exhaustive list of inputs

A statistically designed experiment, often referred to as Design of Experiments (DoE), is one way to efficiently and scientifically narrow the list of factors. There are many
a

different designs which could be used for this purpose, each

with their own pros and cons.

At a preliminary screening stage, it is best to test the maximum number of factors while performing the fewest
possible experiments. For example, a

TaguchiLlzdesign

will allow

us to evaluate the relative

importance of up

to 11 factors using just 12 experimental runs. One of the

limitations of this design is that, although it provides information regarding the relative importance of the individual factors, it does not give information on possible interactions between those factors. Nonetheless, it is a good first step towards ranking factors under investigation.

which will grow and evolve as the team learns more. Failure Mode and Effects Analysis (FMEA) and other risk management tools should be applied at all stages. As suggested by ICH QB (Rl), FMEA might be used to rank
the many factors contained within the various fishbone diagrams. There are several other ways that FMEA can be applied. Two of these that are suitable for early stages of development include a step-by-step review of the process and a component review of the formulation. When using the former approach, the team must identify the intended

TRANSFER FUNCTION Once the list of "most important" factors has been made

ffiffi'.":ff 'l::"?t1i::il:ril,,1TI#.Tfiffi:,T,",
designs can produce an empirical model which mathemati-

cally describes the relationship between the inputs and the output(s) of interest. In DfSS jargon, this mathematical

function of each process step. It must then ask what could go wrong with that step that could impair or prevent it from delivering the intended function. Similarly, using the second approach, after listing every component of the formulation, the team must ask what the intended purpose of each component is and how it could fail to perform that function. The results will be rated in terms of the severity of the failure, its likelihood of occurrence, and the probability of escaped detection. The product of these individual ratings, the Risk Priority Number (RPN), provides a priortttzedlist of problems which present the greatest risk. Like the fishbone diagrams, an FMEA is a living document which should be revisited, revised and augmented multiple times during the development cycle.

prediction equation is known as a transfer function. The transfer function is an extremely valuable piece of process knowledg.. Given specific values for the inputs, it can provide a means to predict the averagevalue of the output(s). Conversely, if the desired value or a specification range of the output is known, it can identify optimum
operational and material parameters to achieve the desired
average response.

Almost always, the team is interested in more than one output. Fortunately, it is possible collect data on multiple outputs for each experimental run, and then use all of this information to predict the best conditions that satisfy the specifications for each of the outputs. This technique is known as multiple response optim tzation. Unfortunately, there is no guarantee that a perfect solution exists. Although it is possible to mathematically
explore the experimental space described by the transfer functions, there may or may not be a location (the design space) that will consistently satisfy all of the specifications at the same time. If the development team finds itself in this situation, at least they identified this problem relatively

FINDING THE "VITAI FEWDfSS, like QbD, is based upon the development of an understanding of the relationship between specific input parameters and the performance of the finished product.

After

completing the initial versions of the fishbone diagrams and

PHARMACEUTICAL MANU FACTU RING

WWW- PHARMAMAN

FACTU

RI NG.

COM

FEBRUARY

201O

37

DESIG

N FOR SIX

SIG MA

quickly and efficiently, and the knowledge gained can help them to regroup and find solutions later in development.

MONTE CARLO SIMULATION

Figure 1. Monte Carlo Simulation
Estimated Input Distributions Predicted 0utput Distributions

Y,=bo+b,X,+b

Y, = bo + brX., = buX,
wffiffiffimffim:ffiffi

br{.,'

Transfer Functions

Monte Carlo Simulation (MCS) applies the characteristics of known or

estimated input distributions to the transfer function of each output in order to produce an estimate of the distribution of that output. lf output specifications have been developed or proposed, process capability and

A wide variety of other DfSS statistical tools can be applied using the transfer function. One is Monte Carlo Simulation (MCS), sometimes referred to as Expected Value Analysis (EVA). Among other things, MCS can be used to predict process capability-i.e., how well the process is expected to perform relative to its specification(s). In many cases, applying the average values of inputs to the transfer function will predict the average value of the output(s). Unfortunately, this approach does not consider the fact that most inputs are not perfectly constant-that is, they are not always going to be equal to the average value. Inputs may vary from one duy to the next, from lot to lot or even operator to operator. Although controls are often implemented to hold these factors constant or within a specified range, the ability to do so is sometimes limited 'by technology or cost. The advantage MCS offers is that, if the long-term distribution parameters (e.g., the mean and standard deviation of a normally distributed factor) can be estimated for each critical input, these estimates can be applied to the transfer function and used to predict what
the expected distribution of the output(s) will be over the

the associated defect rate (dpm) can also be predicted.

Figure 2: Parameter Design

long term, across many batches. "T Figure I (left) represents an Input-Process-Output (IPO) diagram which indicates that the process inputs have three different distributions. In this example, inputs
i!

ii

r*

.s

Figure 3: Tolerance Allocation

Y, = bo + b,X,, + brX, + brX,X,

j
1 a

-, iffiwffiffiffi.mffilffiffiffi

Mn*L ,
wffiffiffimffiffiffiffi has

Parameter Design explores the experimental space looking for regions

which make the process tolerant of the known variation of some difficult to control process inputs. In this example, the average value of X,
been reduced and the average value of X, has been increased (input

Tolerance Allocation evaluates the effect of individually increasrng and decreasing the standard deviation of process inputs. In this example, reducing the variation of X, (the green dashed line represents the distri-

distributions have been shifted from the blue to the green histograms).
Effectively the variability of the inputs and the average response remain

the same, but the variation around the average response has been significantly reduced (green output histogram) resulting in a process which
is

bution resulting from a tightened specification) has significantly reduced the variation of the output (green output histogram). This approach
allows the team to identify which inputs will have the greatest impact on

tolerant (robust) to the variation of the inputs. To simplify the example,

only one response has been used in this illustration, but multiple responses can be evaluated simultaneously.

the output variation and thereby helps to balance cost-benefit trade-offs

and set appropriate specifications for each of the process inputs.

FEBRUARY 201O

PHARMACEUTICAL MAN

FACTU

RI

NG

WWW, PHARIMAN/IAN

FACTU RING.CON/I

DESIGN FOR SIX SIGMA

Xr, X2, and X, appear to be normally, exponentially, and uniformly distributed. The MCS will "randomly

the inputs. Parameter Design shifts the average response of the various inputs and evaluates the effect on the output

draw" one value from each of these distributions and apply those values to the transfer function to generate a single result for the predicted value of the output(s). It will repeat this process as many as one million times. The histogram of the resulting values will provide an estimate of the output distribution which can then be compared to the specifications for that performance metric. The ability to predict process output capability not only allows the team to estimate the defect rate for the intermediate or finished product under investigation, but also allows a direct comparison of the relative performance of various formulation options, processes or products which may be under consideration. PROCESS ROBUSTNESS AND F ICATIONS Ary process should be "robust" to the
SPECI

distributions. If successful, it will find a combination of average input settings which achieve the same average output response, but with less variation around that average. If the team is not able to find any
robust regions within the design space (they may not exist), they may tighten the input specifications to reduce the

on the variation of the output(s). In contrast to Parameter Design which shifts process averages, Tolerance Allocation will evaluate the effects of

individually increasing and decreasing

the standard deviations of each of the input factors. It will estimate the expected number of defects per million (dp*) under each of these trial conditions. The resulting matrix gives the team the knowledge required to
set appropriate specifications

for each

output variation. Intuitively, many

process scientists and engineers believe

input.

that tightening the specification of an input will reduce the output defect level, and in fact this is often true. However, what is often not intuitive is the ability to identify which factors

coNcLUsroNs
DfSS and QbD share a common philosophy based upon the principle that employing a systematic and structured approach to product development will increase the amount of process knowledg. the development team obtains. This will allow the team to make better decisions and increase the probability of development success @

will have the greatest impact and to

what degree specifications need to be tighten.d. Tpically, asking suppliers or the manufacturing team to meet a tighter specification on a raw material attribute, or an operating parameter, will result in an increase of operational
cost. Consequently, it's

important

About the Author

Murray Adams
is a certified Master Black Belt

variation of process inputs which are difficult or expensive to control. Let's say the particle size distribution (PSD)
of a micron rzedactive pharmaceutical ingredient (API) is difficult to control. If PSD is an important factor

to prevent a situation where input specifications are tightened "just to be

sure." Tolerance Allocation allows the

and the Managing Director of Operational

Excellence, a consulting company that provides
Six Sigma andDlSS analysis, training, and

team to understand the effect of changing the variation of each input

coaching. He can be reached at murray. adams@rogers.com.

with respect to dosage uniformity,

rather than tightening the specification and perhaps paying a premium to the supplier, it would be preferable to find operationai conditions which are tolerant of this variation; that is, teams can identify conditions under which the dosage uniformity is relatively unaffected even in the presence of the
PSD variation. Several DoE techniques can help make a process robust to variation in certain input variables, though many of these become difficult and cumbersome to apply when dealing

ERIEZ

X-Hay lnspection Systems

Errez'E-Z Tec XR Series delivers product and packaging integrity through X-Ray Inspection. Provides advanced technology for sensitivity and speed, real-time analysis of goods, monitors packaging for count, mass and flll level and detects
metals, stone, glass and
plastics.

with multiple responses. Another DfSS

tool, Parameter Desigr, explores the experimental space looking for regions which make the process relatively insensitive to the known variation of

Eriez Magnetics
888-300-ERIEZ t37431 o www.Eriez.com

PHARMACEUTICAL MANUFACTURING

WWW.PHARMAMANUFACTURING.COM

FEBRUARY

201O

39