Monthly Archives: July, 2011

On Validation and Verification

The intent underlying validation or verification activities is to answer the question “How do you know?”. How do you know the product you designed meets the requirements for its intended use? How do you know a given unit you manufactured, based on that design, will perform as expected in the field? Objective evidence is needed to demonstrate that requirements of a given product that define its fitness for a specific purpose will be consistently fulfilled. For industries whose products can have a harmful impact on life, the requirement to perform validation and verification activities is codified in regulations.

For the purposes of this discussion, let’s assume that the product’s design fulfills the requirements of its intended use. This will allow us to focus on just its manufacturing process. How can you show that an output of the manufacturing process meets the requirements that define its fitness for use? One mechanism is to inspect and test every manufactured unit. And, so long as such activities do not destroy the manufactured unit in the process, it is a perfectly acceptable method to show its fitness for use. This sort of check is referred to as product verification.

However, inspection and testing of certain performance characteristics of a manufactured unit do destroy the unit in the process. Verifying such characteristics of each manufactured unit would not leave any units for use or sale. To address this issue, we have to look at data from samples of manufactured units, viewed through the lens of statistical theory, to draw conclusions about their overall population. This is the basis of process validation.

As long as the distribution of data points describing a particular performance characteristic of the product, collected from samples of manufactured units, falls within the limits that define the performance requirements for that particular product characteristic, we can be confident that the rest of the population of manufactured product meets those performance requirements as well. The theory of statistics provides us with a mechanism by which to quantitatively express the degree of our confidence that untested units will perform as expected.

An implicit point made in my assertion is that the manufacturing process is subjected to the range of variability present in its inputs. Each input to the manufacturing process has a distribution that describes its center and variation. These inputs interact with the manufacturing process and with each other as they are transformed into the output with its own distribution. However, the shape, location and spread of the output distribution is only revealed after significant data has been collected over time. And, it is the boundaries of this distribution when compared against requirements that demonstrates whether the manufacturing process can consistently produce units that are fit for use.

Companies do not have unlimited time or money to collect such data by conducting large numbers of manufacturing runs. And, such a large data set isn’t necessary either. Subjecting the manufacturing process to extreme values of each input will yield output values that represent the boundaries of the manufactured product. It is reasonable to expect that if the inputs are within their extreme values, the output will be within its boundary values. If the boundary values of the output are within the limits that define performance requirements, we can rest assured that the manufacturing process will produce units that are fit for the intended purpose. And, this manufacturing process can then be said to have been validated to produce the particular part.

A final thought: manufacturing processes have several inputs. It is not efficient to vary them one at a time. In fact, varying them one at a time doesn’t give you the complete picture of how they interact with the manufacturing process or with each other. Running controlled experiments that are properly designed can paint a more full picture. The science of the design of experiments should be the tool of choice when validating a process.

A [Breakdown in] Validation of Quality

Recently MD+DI (Medical Device and Diagnostic Industry) published “A Validation of Quality”. I would like to think it was motivated by a desire to inform and educate the readers of the value of conducting proper process validations. But, instead the author, Jean Mattar, misinforms the readers and perpetuates validation mythology. And, it seems no one at MD+DI bothered to do a spelling or grammar check, much less fact check what they were publishing. This is particularly troublesome as many medical device industry professionals use such articles in MD+DI as reference when setting up their quality systems or performing various quality assurance activities like process validation.

My aim is to march through the article, quoting the author and pointing out the misinformation. Hopefully this will help you understand process validation correctly or at least prevent you from learning the wrong things.

Because it is a repeatable process, laser welding can be statistically proven and easily validated.

Nothing about the laser welding process suggests that it is inherently a repeatable process. Like any process, if the inputs to the laser welding process vary, so will its output. That is why you need to perform a process validation: to demonstrate that expected variation in inputs to the process will still yield an output that meets performance requirements. There is nothing easy about this effort. It must be properly planned, executed with greatest care, and the resultant data analyzed with the objectivity of statistical tools. In doing so, nothing is proved statistically. Statistical analysis merely details the probabilities of occurrence. Those probabilities must then be evaluated in the context of business goals as either acceptable or not.

In a perfect world, you’d have the time to validate 100% of your samples.

It is obvious that the author does not understand the concept of sampling or sample size nor the difference between verification and validation. If you’re “validating 100% of your samples” i.e. inspecting every piece, you are performing verification and you’re not sampling.

When your company is faced with a validation issue, you’ve got a host of problems to deal with, from embarrassing to expensive.

Seriously? Embarrassment is the problem? Expense of the fallout of a validation issue is the problem? How about patient safety? Where does that fall in the spectrum of problems? Failure to validate a process that cannot be verified means you have no idea whether your product will perform as expected or whether it will fail at the most inopportune time e.g. in the middle of surgery. Just as the primary duty of a physician is to do no harm, the primary motivation of a medical device manufacturer should be to ensure that their product will perform as expected. That assurance is partly obtained through performing a manufacturing process validation and partly through continuing quality control activities. Embarrassment can be overcome and reputations can be rebuilt. Patients’ lives remain forever changed.

In the best-case scenario, your customers will require validation as part of the complete manufacturing process and will audit it closely.

If Tegra Medical truly believes this, then its customers need to reevaluate their relationship with the company. It is not your customers’ responsibility to ensure you are manufacturing good product. That responsibility is entirely yours. It should be your company’s culture to ensure that production is done properly such that your product performs as expected. So, the best-case scenario is that regardless of customer requirements you should perform process validation as part of your quality assurance activities.

When processes or parts are especially complex, validation provides a way to help control them. It enables real-time monitoring and process adjustments so you can improve processes statistically and evaluate your performance daily.

What nonsense! Process validation has nothing to do with the complexity of a part. The benefit of process validation is identical whether you are manufacturing a simple part or a complex one: assurance that it will function as expected.

Just what exactly is the author referring to when saying “validation provides a way to help control them.” Control what? If we’re talking about controlling process parameters, then quality control tools such as statistical process control (SPC) and run-rules are necessary.

Validation does not “enable real-time monitoring and process adjustments”. More importantly, when you’re conducting a process validation, process parameters should not be adjusted at all or you will contaminate the result you’re trying to validate. Process parameters’ operating windows should be established during process design; not during process validation.

The Quality System Regulation (QSR) known as 21 CFR Part 820 and ISO 13485:2003 require that validation include installation qualification (IQ), operational qualification (OQ), and process qualification (PQ).

No, they don’t. Neither 21 CFR Part 820 nor ISO 13485:2003 require that validations include IQ, OQ, and PQ. The regulations state:

Sec. 820.75 Process validation.

(a) Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures. The validation activities and results, including the date and signature of the individual(s) approving the validation and where appropriate the major equipment validated, shall be documented.

(b) Each manufacturer shall establish and maintain procedures for monitoring and control of process parameters for validated processes to ensure that the specified requirements continue to be met.

(1) Each manufacturer shall ensure that validated processes are performed by qualified individual(s).

(2) For validated processes, the monitoring and control methods and data, the date performed, and, where appropriate, the individual(s) performing the process or the major equipment used shall be documented.

(c) When changes or process deviations occur, the manufacturer shall review and evaluate the process and perform revalidation where appropriate. These activities shall be documented.

ISO 13485:2003 states:

7.5.2 Validation of processes for production and service provision General requirements

The organization shall validate any processes for production and service provision where the resulting output cannot be verified by subsequent monitoring or measurement. This includes any processes where deficiencies become apparent only after the product is in use or the service has been delivered. Validation shall demonstrate the ability of these processes to achieve planned results. The organization shall establish arrangements for these processes including, as applicable

a) defined criteria for review and approval of the processes,

b) approval of equipment and qualification of personnel,

c) use of specific methods and procedures,

d) requirements for records (see 4.2.4), and

e) revalidation.

The organization shall establish documented procedures for the validation of the application of computer software (and changes to such software and/or its application) for production and service provision that affect the ability of the product to conform to specified requirements. Such software applications shall be validated prior to initial use.

Records of validation shall be maintained (see 4.2.4) Particular requirements for sterile medical devices

The organization shall establish documented procedures for the validation of sterilization processes. Sterilization processes shall be validated prior to initial use. Records of validation of each sterilization process shall be maintained (see 4.2.4).

The Global Harmonization Task Force (GHTF) does recommends that validation activities be broken up into installation qualification, operational qualification and performance qualification. But, it is not required. And, yes, PQ stands for performance qualification; not process qualification as the author writes.

…all data are maintained in the company’s design history record (DHR)…

Obviously the author has confused a device history record (DHR) – a compilation of records containing the production history of a finished device – with a design history file (DHF) – a compilation of records which describes the design history of a finished device.

The entire section on laser welding IQ talks about equipment IQ. It does not address process IQ. An equipment qualification (equipment IQ, OQ, and PQ) is a portion of a process IQ which also includes, among other things, operator training for running the process, standard operating procedures for the process, a process risk analysis (FMEA), ensuring all process equipment are laid out properly, etc. A discussion of a proper process IQ is beyond the scope of this essay.

The author completely mischaracterizes the activity performed during process OQ. Suffice it to say that you shouldn’t be developing or designing your process (i.e. establishing operating windows) during validation. The process OQ is where you challenge the process by operating it at its inputs’ maximum and minimum values. These runs, performed most efficiently through the use of a properly designed experiment, should demonstrate that the process will yield an output that meets expectations even when the inputs are operating off their nominal values and at their extremes. Again, a discussion of proper process OQ is beyond the scope of this essay.

…process capability studies (known as gage repeatability and reproducibility (GR&R) or measurement systems evaluation…

Process capability studies are not GR&R studies. Process capability studies typically reflect the manufacturing process’s ability to make product within specification limits. GR&R studies are done on the measurement process, and do not have direct relationship to the manufacture of any given product.

This test uses a statistically significant sample plan such as a size of 60 parts based on a reliability and confidence level of 95%

Where does this sample size of 60 come from? For the life of me, I can’t figure it out.

The outcome of the test is torque or tensile data that shows with 100% accuracy how the material will hold up under different conditions.

There is no such thing as 100% certainty in the real world. Only degrees of confidence.

The author does a similar hack job in discussing laser welding PQ as he did with the IQ and OQ sections. Process performance qualification should be a final check of the process by running it at nominal levels of the process inputs. That is, during PQ you’re running production! Consider the initial batches as “risk production” if you will. The process performance here on out is monitored using statistical process control tools. Alas, a discussion of proper process PQ is also beyond the scope of this essay.

…run your laser welding parameters at the nominal condition three times in a row…

What is the statistical basis of running the process three times or whether those runs are consecutive? This is an industry myth that keeps being perpetuated over and over with no basis in fact.

I hope that I’ve successfully detailed where this article misinforms. It is throughout the entire body. Based on the type and scope of the misinformation, I can infer only that the author does not have a good understanding of process validation, how to perform it or what it is intended to achieve. Worse, his focus does not appear to be aligned with that of the FDA: patient safety. The fact that he is the vice president, quality assurance and regulatory affairs at Tegra Medical should give all of us pause. Additionally, we should all wonder about the vetting process MD+DI uses in deciding what to publish.



Correction: The gender of the author was corrected in the sentence “The author does a similar hack job in discussing laser welding PQ as she did with the IQ and OQ sections.” from “she” to “he”. The author is a man, not a woman. (11:10 AM, 25 Oct, 2011)

On the Purpose of Performing the Operational Qualification (OQ) for an Equipment

A company I worked for believes that the purpose of performing an operational qualification of an equipment is to demonstrate that the equipment functions at the settings expected to be used in production. As such, it does not feel it is necessary to validate the manufacturer’s claims about its product’s greater functional range. I wholly disagree with this limited perception.

Consider a simple hypothetical example wherein I intend to make bread. The recipe calls for the bread to be baked in an oven at 400 F for 25 minutes. Applying this company’s point of view, the operational qualification of my oven would require only demonstrating that it functions at 400 F for 25 minutes. There is no need to validate that the oven is capable of functioning to its manufacturer’s claim of 170 F to 550 F. I believe this model for conducting an equipment operational qualification to be shortsighted at best and a total misunderstanding of what an operational qualification is at worst.

While such an approach fulfills the immediate need to demonstrate that my oven is capable of generating 400 F, such a limited test does not take into account my future potential needs. Perhaps better bread might be made by baking it at 350 F for 35 minutes. Or, I might want to make pizza – that requires my oven to operate at 550 F, the hottest it gets. Or, I might want to keep food warm in the oven at 170 F. An operational qualification of this type precludes me from using my oven at temperatures that haven’t been tested. I would have to repeat the operational qualification at other temperatures before use.

But, I believe that this approach to performing an operational qualification is actually more than just shortsighted. It is wrong. It is an incorrect interpretation of what a proper operational qualification is intended to demonstrate: that the equipment is capable of performing to its manufacturer’s claims. A proper operational qualification should be done such that the functionality of the equipment is evaluated at a minimum at the high & low settings of all its critical input controls. The design of experiments provides a statistically robust and cost efficient method to do this.

In an abstract sense an operational qualification is part of the receiving inspection process, albeit a complex one. And just as in the typical receiving inspection process, it is better to find defects or deficiencies in the equipment at this stage (even those that don’t directly impact our immediate application) than to discover them during production. Defects, like cracks, tend to migrate into the production operating zone over time.

At its most basic level an operational qualification has very little, if anything, to do with using the equipment for any given application. Operational qualification of my oven has very little to do with me using the oven to bake bread, make pizza or keep food warm. Validating that the equipment will perform as expected for a given application is done as part of a performance qualification (PQ) of the equipment. So, when my former employer performed an operational qualification of a tool at an application specific setting, it was actually performing a performance qualification; bypassing operational qualification.

When a proper operational qualification has been performed for a piece of equipment, it does not need to be repeated until the equipment undergoes some sort of preventive or breakdown maintenance when consumable or broken parts are replaced. As such, a company that intends to extend the use of a piece of equipment to multiple applications needs to only perform a performance qualification of the equipment for a given application’s settings before releasing the tool to run that new application.

It is disturbing when quality managers do not take the time to understand the purpose of a particular assurance activity. As you can imagine, this leads to wrong tests being run, wrong data being collected and wrong conclusions being drawn. The problem is compounded by their willingness to take shortcuts. Is getting to the wrong place faster better? It doesn’t make any sense to me why a company would not perform a check of the manufacturer’s claims when the effort required isn’t any greater and the long term benefits are significant.