7/5/2017 Process Verification vs.

Process Validation: What You Need to Know

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For Life Science Professionals

Process Veri cation vs. Process Validation: What You
Need to Know

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by Andrew Snow, Momentum Solutions, LLC and Walt Murray, MasterControl, Inc.

May 10, 2012 | Free Downloads | (mailto:?subject=MasterControl Link&body=http://www.mastercontrol.com/fda/process-veri cation-vs-process-validation.html) |

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Note: The views expressed in this article are those of the authors and do not necessarily represent those of their respective employers, GxP Lifeline, its editor or MasterControl,
Inc.

Process validation o cially became part of the FDA's Quality Systems Regulation in 1997. Fifteen years later medical device manufacturers still struggle with
determining which processes require validation. The confusion traces back to two words, "fully veri ed." What does "fully veri ed" mean? What do I do if I determine
that process can't be "fully veri ed?" And, equally important, what are the FDA's expectations when I can't?

The answer to the "fully verify" question can have big consequences. Failure to identify a process that requires validation can cause compliance issues, including
warning letters, delays in pre-market submissions and eld actions. A conservative approach of validating everything can be costly. And worse yet, some people
erroneously think that if they can fully verify something, the veri cation has to be 100%. This approach, unless automated, may be a statistically invalid approach
because even manual 100% inspection is statistically not 100% e ective.

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A clear intent of the regulation is that quality cannot be inspected into a product. This has been rmly established in quality thinking. In essence, this
requirement is stating that for some processes, inspection alone may not be su cient.

The goals of this article are:

To clarify how to determine if something can be fully veri ed

How to plan validation and process controls for those that can't be fully veri ed; and
How to monitor and control processes using a risk-based approach

This will be accomplished by:

Revisiting some de nitions of key terms and the regulatory requirements

Describing how we determine what's critical to quality (CTQ)
Dissecting the terms "fully veri ed" and describing the criteria for determining if something is fully veri able
Describing how to plan validation for processes that can't be fully veri ed
Outlining a risked-based approach for controlling processes that can be fully veri ed

De nitions and Regulatory Requirements

The requirements for process validation established in the FDA's Quality Systems Regulation states in Part 820.75 (a)1:

"Where the results of a process cannot be fully veri ed by subsequent inspection and test, the process shall be validated with a high degree of assurance and
approved according to established procedures."

A clear intent of the regulation is that quality cannot be inspected into a product. This has been rmly established in quality thinking. In essence, this requirement is
stating that for some processes, inspection alone may not be su cient. This is particularly true when the defect only becomes apparent or manifests after the
product is in distribution or use. This could be because veri cation is not possible (e.g., reliability or durability) or it is not su cient (e.g., requires destructive testing).
The core of this requirement is that in order to gain con dence that the likelihood of these types of defects is small, we must use the capabilities of a process. This is
clari ed when we look at the de nition of process validation in the regulation which states process validation is2:

"...establishing by objective evidence that a process consistently produces a result or product meeting its predetermined speci cations."

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7/5/2017 Process Verification vs. Process Validation: What You Need to Know
Thus, we'll see that this requires understanding the sources of variation, reduction and control of variation to establish a process that is capable of consistently
meeting speci cations. Such speci cations and their associated acceptance criteria are determined using adequate design controls.

Design Controls and Process Validation

Before we dissect the term fully veri ed we need to go back and see how we determine what speci cations are of concern. This determination should be established
using e ective design controls. Most professionals typically make the connection between design transfer and process validation while they overlook essential design
outputs, which are the key design outputs that we must produce. So, one of the critical connections between process validation and design controls is that design
outputs de ne the "predetermined speci cations" or the results a process needs to meet.

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One of the requirements for documenting design outputs is that they contain or reference acceptance criteria. These are sometimes referred to as critical to quality
(CTQ) characteristics. In this sense, quality is de ned as "the totality of features and characteristics that bear on the ability of a device to satisfy tness for-use,
including safety and performance."3 These features and characteristics form the basis for acceptance criteria.

While there are many tools that can be used for developing CTQs, such as Design for Six Sigma (DFSS), Quality Function Deployment (QFD), and focus groups, from an
FDA perspective a risk-based approach is imperative. Using such process tools as Fault Tree Analysis (FTA) or Design Failure Mode E ects Analysis (DFMEA) when
linking product hazards to speci cations is a thorough approach to e ective post-control measures. So, for example, in DFMEA we ask: what are the e ects of a
design failing to meet its design requirements? If the failure results in a safety hazard to a patient or end user, then that speci cation becomes a CTQ. It is these
characteristics that we'll focus on when asking if they can be fully veri ed.

Dissecting Fully Veri ed

To help understand the term "fully veri ed," we can go to the Global Harmonization Task Force's (GHTF) Process Validation Guidance document4. This document
shows a decision tree which may be helpful in determining which process should be validated. When we look at Figure - 1, there are two fundamental questions to be
answered: is the output (CTQ) veri able and is veri cation su cient and cost e ective?

Most quality characteristics can be veri ed. Veri cation methods run the gamut from chemical tests such as pH or conductivity, physical tests such as tensile
strength, dimension, or hardness, to electrical measurements such as voltage and impedance. In some cases, the measurements can't easily be done on routine
production. Thus such dimensions are not e ectively "detectable" and therefore, not capable of reliability or durability. This is the main concern for detectability as a
key component of an FMEA. In other cases, the veri cations are not su cient because the method is destructive and reasonable sampling schemes may not be
su cient. One simple test to apply is asking if sampling "could be" 100% and in the case of destructive method the answer would be no. Finally, some tests
(detection) lack the sensitivity to be e ective as part of routine production.

Figure 1 - GHTF Process Validation Decision Tree

The cost e ectiveness of the veri cation can also be an important consideration. In many cases, it may be more prudent to validate the process upfront to
understand and control variation, thereby improving process capabilities, increasing yields and lowering scrap. These factors generally will outweigh even reducing
the cost of inspection, making a strong business case for validation.

The GHTF Guidance gives us several examples of processes that should be validated, including:

Sterilization processes
Aseptic lling
Sterile package sealing
Lyophilization
Heat treating
Plating processes
Plastic injection molding

It's worth noting that the guidance says "should be." It is incumbent upon the manufacturer to understand the CTQs for its product through Quality by Design (QbD)
and assess whether veri cation is su cient. However, the FDA will be expecting that these processes will be validated, so if you determine that veri cation is
su cient, your rationale will need to provide appropriate documentation.

Planning for Validation

The best place to document your validation decisions is in the Master Validation Plan (MVP). While not required, it is best practice to document your decisions and
outline the plan for processes that will need to be validated accordingly. The plan should scope out the validation e ort, including the facilities, processes, and
products covered by the plan. All the equipment under that scope of the plan should be identi ed, including any utilities such as electrical, water, and air
compressors. It should also include the process equipment and any environmental controls such as clean rooms or Electro-static Discharge (ESD) controls. It is also
common to include test methods and software used to automate processes . Plans will spell out the Installation, Operational and Performance Quali cations (i.e., IQ,
OQ and PQ) to be done for each process. It is also common to see test methods and software used to automate processes included in the lifecycle of the product,
although these may not be stated as IQ, OQ or PQ requirements.

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The installation quali cation shows that the equipment is installed according to its speci cations. This document is typically comprised of checklists and simple
veri cations such as xture inspections, gauge calibration or preventive maintenance checks. If automated software is used in the process, the IQ will check to make
sure the right version is installed and validated. One can look at the requirements in Production and Process Controls Part 820.705 to use as a basis for making a
good IQ checklist.

The OQ and PQ are the heart and soul of process validation. Once assured that the equipment is installed to speci cation, the manufacturer has greater con dence
that the equipment is operating properly and can start to use the equipment to understand the sources of variation and work towards establishing a capable
process. The goal of process characterization during the OQ is to understand the e ects process inputs (e.g., temperature, time, and pressure) have on the outputs
(e.g., burst strength for a sterile package seal).

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GHTF Guidance Figures 4, 5, and 6 help illustrate the concepts. These are adopted below in Figures 2 and 3.

Figure 2 - Moving from an Unstable to a Stable Process during the OQ

The goal of the OQ is to understand what causes the instability in GHTF Figure 4 and reduce and control that variation to produce the stable process on the right. We
should conclude through conformation runs that the stable process has the potential to meet our capability requirements. These results are typically achieved
through designed experiments which seek to explore a wide range of possible input variables through screening experiments and then re ne and optimize the most
signi cant variables to produce a stable process with acceptable process potential capabilities. While it is tempting to cut straight to the vital few variables based on
knowledge and experience to eliminate some of the experimental steps, these assumptions should be carefully documented in a risk-based process model and
supported by scienti c and historical data that clearly shows the relationships between input and output variables. A high-risk consequence condition can trump a
Pareto approach.

The goal of the PQ is to show that process is capable under conditions anticipated during manufacturing. These conditions may include multiple shifts, operators,
material lots and other factors that represent potential sources of uncontrollable variation. The purpose of process validation is not so much to show you have
excellent process capabilities but to demonstrate you know why you have excellent process capabilities.

Once process validation is completed, the manufacturer is required to establish monitoring and control to ensure the validated state of control is maintained (Part
820.75(b)6). The manufacturer should document that the validated process was performed by quali ed operators and note the monitoring and control methods,
data, date performed, the individuals performing the process, and the major equipment used.

Figure 3 - Demonstrating a Capable Process during the PQ

Risk-Based Approaches to Monitoring and Controlling Processes

Whether you have validated a process or determined that veri cation is su cient process, monitoring and control are required. For validated processes, this is
established in Part 820.75(b) and for all processes it is established in Part 820.70(a):

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"Where deviations from device speci cations could occur as a result of the manufacturing process, the manufacturer shall
establish and maintain process control procedures that describe any process controls necessary to ensure conformance to
speci cations. Where process controls are needed they shall include among other things 'monitoring and control of device
parameters and component and device characteristics during production.'"

Fundamental validation concepts are the same, while additional requirements may be commensurate with a validated process during monitoring and control. A risk-

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based approach is used for such special requirements which can then be developed as part of a control plan based on a process FMEA.

If you don't validate, do you have to do 100% inspection in order to fully verify? No - the regulation doesn't say this. It does say (820.70) "Where deviations from
device speci cations could occur as a result of the manufacturing process, the manufacturer shall establish and maintain process control procedures that describe
any process controls necessary to ensure conformance to speci cations." Where process controls are needed, they shall include, among other things, "monitoring
and control of device parameters and component and device characteristics during production." It also tells us in 820.80 that we need to establish in-process and
nal acceptance activities. Finally in 820.250, statistical techniques are delineated - "Where appropriate, each manufacturer shall establish and maintain procedures
for identifying valid statistical techniques required for establishing, controlling, and verifying the acceptability of process capability and product characteristics."

There has been at least one warning letter for not 100% testing if not validating but interpreting requirements based on one or two warning letters is di cult. In
2009, the Cincinnati District o ce of the FDA issued a warning letter to Hammill. The warning letter states that Hammill's response to not validating certain cleaning,
passivation processes and CNC equipment because they did in-process and nal inspections/test was "inadequate because you are not testing every device to assure
it meets speci cations."7 Of course. Reading the warning letter without the 483, let alone the Establishment Inspection Report, is di cult. We don't know about the
acceptance criteria (CTQs), how they were measured, whether the testing was destructive and hence, whether subsequent inspection or tests were su cient. So it is
di cult to make the leap to a requirement that all processes that are not validated must be 100% tested. In the end the regulation clearly states that process controls
should be based on appropriate statistics, which require some knowledge of risks in order to be applied properly.

An example will help illustrate how to establish controls based on risk and the signi cant role validation plays in establishing the basis for control. For example, the
CTQ for burst strength is tied to the risk associated with non-sterile packaging due to package seal failure as shown in Figure - 4. To achieve an acceptable risk level,
we had to establish better than six sigma process capabilities during process validation. The trick is to establish process monitoring that has a low risk of not
detecting a shift to an unacceptable level of process capabilities of ve sigma, or a greater likelihood of generating defective seals. Using statistical process control
(SPC) we establish a control plan that indicates an e ective control measure of burst tests will be performed on a sample of 25 units every hour of production. We are
concerned with a 1.0 sigma shift in the process average burst strength as this would reduce risk to an unacceptable level. We can calculate the beta risk or risk of not
detecting the shift using the beta risk formula below8

β = φ(L-kûn) - φ(-L-kûn)

Where:

β = Beta Risk
L = The number of sigma in the lower and upper control limits, typically 3
φ() = Cumulative Standard Normal Distribution
k = Process shift in sigma unitsû = square root ofn = Sample size

For our example above, if we assume the typical binomial three sigma limits for the control limits and a desire to detect a 1.0 sigma shift, the beta risk is estimated at
0.002, giving us high probability of detection or 2 versus a 1 almost certain to detect. This, along with the occurrence ranking of 1, gives us acceptable risk. From this
we can see that the combination of acceptable process capabilities and process monitoring are required to make risk acceptable.

This is just one example of how to estimate the beta risk and set SPC control measures. Average run length, or the average number of samples necessary to detect a
shift can also be used, which helps bring sample frequency into the equation.

Figure 4 - Example Risk-based Control Plan for Burst Strength

Conclusion
The key to understanding whether a process requires validation (http://www.mastercontrol.com/validation/) is to understand if it is veri able and assessing the
su ciency of veri cation. It is best practice to document these decisions and plan the validation e ort. Some tests cannot be done on a routine basis, are destructive
or lack the sensitivity to be su cient. The heart of validating a process is ensuring it is installed to speci cation, while characterized and optimized to be under

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7/5/2017 Process Verification vs. Process Validation: What You Need to Know
control and capable of consistently meeting speci cations. The risk-based approach shows that understanding how to achieve excellent process capabilities reduces
the likelihood of defects in the rst place. In addition, process monitoring with low beta risk assures detectability if there are problems to be addressed as necessary.
Veri cation alone may not be su cient to produce acceptable levels of risk.

References
1. Medical Devices; Current Good Manufacturing Practice (CGMP) Final Rule; Quality System Regulation, Federal Register, Vol. 61, No. 195, Monday, October 7,
1996, Rules and Regulations, p52659

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2. Medical Devices; Current Good Manufacturing Practice (CGMP) Final Rule; Quality System Regulation, Federal Register, Vol. 61, No. 195, Monday, October 7,
1996, Rules and Regulations, p52656
3. Id.
4. Quality Management Systems - Process Validation Guidance, GHTF/SG3/N99-10:2004 (Edition 2)
5. Medical Devices; Current Good Manufacturing Practice (CGMP) Final Rule; Quality System Regulation, Federal Register, Vol. 61, No. 195, Monday, October 7,
1996, Rules and Regulations, p52658
6. Supra note 1.
7. Food and Drug Administration, Warning Letter, Hammill Manufacturing Company, 01/06/09
8. Introduction to Statistical Quality Control, 5th Ed., Douglas C. Montgomery, John Wiley & Sons, 2005, p 217.

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Andrew Snow has more than 25 years' experience directing and leading operations, quality, and process design-development for medical device companies, contract
manufacturers, suppliers and several successful start-up ventures. He is president of Momentum Solutions, LLC a consulting rm specializing in solutions for design control,
risk management and process validation for medical device companies.

Andrew has championed several lean and Six Sigma programs reducing cycle time, improving process capability, reliability, order delivery and customer satisfaction. He is an
instructor with the Association for the Advancement of Medical Instrumentation (AAMI) and was recently the subject matter expert for revisions to their process validation
course. He is a graduate of Northwestern University where he obtained a master's degree from the School of Industrial Engineering and University of Arizona with a certi cate
in Systems Engineering.

Walt Murray is MasterControl's director of quality and compliance services. He is a specialist in the quality and regulatory professions with more than 25 years' experience to
his credit, working with nationally-recognized organizations including Aventis-Pasteur, Merck, P zer, Stryker, USANA, Del Monte Foods and the American Red Cross National
Labs. He is certi ed in quality systems auditing, problem solving, and process control using Six Sigma principles that support lean enterprise, including kaizen improvement
and advanced planning principles. His extensive audit experience covers several industries and he's successfully brought several medical device companies to full registration
under the ISO process model standard. Murray has also worked extensively in risk and supplier management.

A graduate of the University of Richmond, Murray is a member of the Society for Manufacturing Engineers (SME); Regulatory A airs Professions (RAPS); the American Society for
Quality (ASQ); and the Intermountain Biomedical Association (IBA).

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