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CDRH Learn; Process Validation Module Script

Slide 1

Hello, my name is Joseph Tartal and I am the Postmarket and Consumer Branch Chief in the 

Division of Industry and Consumer Education. There is a lot of great educational material 

available on quality systems, including how to design the right device so it will meet user needs 

and how to qualify your suppliers so the products and services received meet your needs to 

manufacture that device. These efforts require your valuable resources such as time and money. 

The last thing you want now is to have problems during manufacturing such as device failures. 

This is where process validation comes into play. During my years in industry I spent time 

performing process validation work and it felt good to know that when done correctly the 

devices manufactured were going to meet their predetermined specifications every time. At the 

end of the day this is what you want, your customers want and we at FDA want; working devices 

that meet specifications.

Slide 2

By the time I am finished I want you to know the following learning objectives:

Understand the background and definitions in regards to process validation such as where did 

process validation come from in the 1996 Regulation and what are the key terms used. 

Understanding these definitions is important so that everyone is using the same terms and those 

terms are used correctly.

Recognize when process validation is required and also when it may be a good idea even if not 

required.

Know process validation regulatory requirements, these are the shalls and musts per the 

regulation. You have to do these.

Identify guidance and best practice information such as Installation, Operational and 

Performance Qualifications.

Be aware of Process Monitoring, Process Changes and when to Revalidate; once completed 

process validation does not go into a file never to reviewed again. One thing I can guarantee is at 

some point change will occur, how do you plan to handle that change?

Slide 3

The requirements for process validation can be found in 21 CFR 820, otherwise known as the 

Quality System Regulation, which was published in the Federal Register in October 1996. Also 

there was a lot of good discussion between the FDA and all stakeholders when the draft rule 

went out for public comment. These comments and the agency responses can be found in the 

preamble of the regulation and are useful to review in order to understand the FDA's thinking at 

that time. 
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Slide 4 

First, I want to provide some background history on Process Validation. Process Validation is 

codified in the regulation under 21 CFR 820.75. It was not new to the 1996 Quality System 

Regulation. Parts of it came from the original 1978 medical device Good Manufacturing 

Practice regulation or GMP. Lots of work was done regarding process validation during the 

1970s, 80s, 90s. After this presentation please feel free to click on the hyperlink. 

Slide 5

Process Validation, like many other quality practices, has consistently evolved. The Global 

Harmonization Task Force, or GHTF, 2004 Guidance is the most current resource that addresses 

medical device process validation. As a reminder, guidances are voluntary and not mandatory. 

However, guidances often provide good suggestions, ideas, and recommendations on how to 

meet Agency requirements. The GHTF Guidance may be found at the International Medical 

Device Regulators Forum webpage in the GHTF archives, under Study Group Three. Here's a 

link to the Study Group Three webpage. 

Slide 6

Next I want to mention that the quality system works together and is intertwined. It is not in 

separate silos. Design and design transfer will feed into production and process controls as well 

as process validation. Let's consider the example of Risk Analysis. You will want to know the 

impact of risk on the manufacturing processes and specifications, especially for essential design 

outputs. Risk Analysis can help you to determine priorities and focus resources even in regards 

to processes and process validation. ISO 14971, a voluntary risk management standard can help 

and I have seen it used in industry for analyzing process risk.

Also what is purchased - products and equipment - and their specifications will affect your 

processes. For example, if there is a component and it is deemed an essential design output, you 

may request your supplier to perform process validation as part of your purchasing controls 

agreement.

Who you hire and how they are qualified or trained will impact your processes and process 

validation. And of course production and process controls in general will impact process 

validation. For example the regulation requires under 820.70(i) that automated processes be 

validated. 

Slide 7

Now let us review several definitions as they relate to process validation as I want to be clear on 

these terms. This is important when conversing in your own internal cross functional teams or 

when speaking with an investigator. Verification means confirmation by examination and 

provision of objective evidence that specified requirements have been fulfilled. By objective 
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evidence, I mean supporting the existence or truthfulness of it. Objective evidence may be an 

observation, a measurement or a test; for example I can measure an item on a scale to verify how 

much it weighs. 

Slide 8

Next let us define validation. Validation means confirmation by examination and provision of 

objective evidence that the particular requirements for a specific intended use can be consistently 

fulfilled. Again objective evidence that confirms requirements for first specific intended use, 

design validation and second can be consistently fulfilled, process validation; for design 

validation an example may be a clinical trial and the results and for process validation an 

example may be a process validation protocol and its results.

Slide 9

Last we will look at Process Validation – it means establishing (define, document, implement –

do it) by objective evidence that a process consistently produces a result or product meeting it 

predetermined specifications. It is reproducible and predictable and gives me a known 

predetermined output. This is the end goal for process validation as we know that manufacturers 

should not rely solely on inspection and testing to ensure that product is adequate. 

Slide 10

Now that we know what process validation means, when do we have to do it? Process validation 

is required when a process cannot be “fully verified” by subsequent inspection and test. “Fully 

Verified” means being able to confirm with high confidence all of the key quality attributes.

For example, if I am performing an injection molding process, I need to look at all the molded 

pieces as well as all of their key quality attributes. These may be dimensional measurements 

which may be fully verifiable and also strength specifications which may require impact 

resistance testing which I cannot fully verify since it is destructive. Therefore the process must 

be validated. Also all injection molding processes I am aware of are automated, another reason 

to validate, and injection molding is specifically noted in the preamble as a process that requires 

validation. However you will need to make these determinations for your own processes.

Slide 11

To further expand upon this, here are three other process examples and the thoughts behind why 

I believe they would or would not require validation. Please note these are examples and not 

absolutes, so you will need to characterize your own specific processes and their results.

Is validation required for a sterile package sealing process? The answer is yes - sterility requires 

process validation and the packaging process requires destructive “burst” testing. 
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What about Dimensional Manual Cutting Process? In this case, likely not, if I can measure all 

dimensions from the cutting if doing so allows me to fully verify this process. Also the key word 

“manual." We validate processes, whereas we qualify people. So if a person is manually 

performing the whole process, then likely will be handled through training and qualification

And finally, let's consider the example of a Filling Process. This will depend. Is the filling 

process automated or manual? Is it Aseptic? The preamble and the GHTF guidance provide 

some good examples as to when certain processes should be validated. Also even if not required 

to validate I may want to do so for other reasons such as cost. I recommend reviewing the GHTF 

Guidance Decision Tree Figure One, as it is a good tool to use. For example, you may have a 

process that can be fully verified but the test is cost prohibitive, which is not an FDA concern but 

still is your concern and therefore you may want to validate. According to 21 CFR 820.75, if the 

process cannot be fully verified then you must validate.

Slide 12

A natural question is when should you start your process validation? The answer is: the earlier 

the better. There are no requirements in design controls but there are requirements under 

finished device acceptance activities that all activities must be completed prior to release, 

including the device master record requirements such as process validation. Therefore, no 

finished device can be released into distribution until process validation activities are completed. 

As for when to begin, I recommend determining what processes need process validation during 

design; that is one reason why it is good to have cross functional teams. During design transfer I 

recommend beginning process validation so that you will have actual manufacturing units for 

design validation. Otherwise, you will need to prove why the units are equivalent to 

manufacturing units. Pragmatically, you can also start to address any issues that may arise from 

manufacturing scale up, production facilities, capital equipment, identified process risk and 

potential changes.

Slide 13

Master validation plans are not required in the quality system regulation. However I highly 

recommend using a master validation plan as it helps you develop a road map for what needs to 

be done, how it will be done and who will do it. It is recommended in the GHTF guidance and is 

considered a quality plan. It becomes extremely important when you have multiple process and 

multiple process validations going on all at the same time. For example, I once set up a 

manufacturing process in a clean room that needed to look at contamination controls, HVAC and 

air flow, water systems, gowning and multiple manufacturing processes. The only way I could 

keep track of everything was by using a master validation plan.

Slide 14
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The requirement in the regulation is that you must have those approving the validation both date 

and sign it and include “where appropriate” all the major equipment used. “Where appropriate” 

means it is appropriate unless you document a justified rationale for why it is not. For example 

if I have a heat sealing process and I have multiple heat sealers, it is appropriate to identify each 

of them specifically. 

Slide 15

Those personnel performing validation work must be qualified to do so, which means they must 

be trained and qualified in the process, using the equipment and process validation. Personnel 

who perform verification and validation activities also need to know about defects that may be 

encountered. Again using the heater sealing example – personnel performing the validation must 

be trained in the heat sealing process, including use of heat sealer, and be aware of defects that 

may occur such as not having a proper seal or any other defect.

Slide 16

Please note we validate processes and qualify all equipment used in the manufacturing processes. 

21 CFR 820.70(g) states that you must ensure all the equipment used meets its specified 

requirements and is designed, constructed, placed and installed correctly for its use.

Slide 17

The GHTF guidance discusses this further and simply puts it as everything being installed 

correctly. It provides items to consider such as equipment design features, installation and 

environmental conditions including ancillary systems such as electrical requirements. For 

example with a heat sealer, is there a 110V or 220V electrical outlet requirement? Is there 

enough space in room if it requires cooling? Also safety features and supplier documents such as 

equipment manuals and more are noted for consideration. In the end, for installation 

qualification you want to be sure that your equipment is installed correctly and is capable of

doing what you need it to do.

Slide 18

To continue on with the guidance, next I want to discuss operational qualification or OQ. Here 

you want to challenge your process and its parameters in order to understand and characterize it. 

You want to know its capabilities, its capacity and ranges. You want to determine your process 

control limits, material specifications and process change control and training needs. It is an 

experimental phase and you can see worst case scenarios including running to device failure. 

Just make sure the resulting product is quarantined and you do not damage your equipment. You 

want to see how far you can push your processes. If you had previously done process risk 

analysis, such as Failure Mode Event Analysis then test that analysis and see if the results match 

up to the initial analysis and update it accordingly. Perform verification and validation for any 

software used in the process.
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Slide 19

Operational Qualification is a time to understand your manufacturing processes, including how 

process inputs impact process outputs and how they relate to specified criteria and limits. The 

time investment upfront understanding these parameter and their impacts will pay off later on.

For example in the heat sealing process what interactions among different parameter settings 

affect the seals output. If I change the temperature, pressure and time what does it do to the seal 

thickness and strength. If these are set to high they may damage the materials and equipment, if 

to low there is not a proper seal. What happens when these are changed? How does it affect 

process outputs? I want to know this in order to set the most appropriate process parameters 

settings. 

Slide 20

Once you verify output, that your product meets specification when manufacturing within 

established operating limits set in your operational qualification, you will move on to 

performance qualification or PQ. In PQ we do not expect failure. It builds off the work done in 

OQ and continues to look at measureable attributes for continuous monitoring. Use the approved 

documented procedures that will be used by all the trained and qualified manufacturing staff. 

Perform it under anticipated normal manufacturing operations. It's a good idea to cover multiple 

operators, lines and shifts, if you have more than one. I have noticed for overnight shifts it is 

always interesting to see what happens differently compared to the day shift. You do not want 

differences in performance; instead, you want things to operate the same on all shifts, night or 

day, and regardless of operator. Also you should consider possible factors that result in longerterm variation, such as seasonal changes in humidity, which is an issue in certain regions like the 

southern United States. The goal is to ensure the process is repeatable and stable long term. 

Slide 21

How many runs and samples and are needed and at what frequency? You determine it. What I 

can say is three is no longer the magic number. I understand it once was and was even debated 

in the regulation. I remember using three back in the mid-1990s but today you should determine 

the number of runs using a rationale such as a statistical significance. You determine it and 

support your rationale. For example, if you use a percent confidence then you must understand 

what that means for the process and why that statistical tool was utilized. Run Length, Sample 

size, Frequency and Duration need to be defined and understood when used. The GHTF 

guidance says it should be repeated enough to assure that the results are meaningful and 

consistent. 
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Slide 22

If things go well and you have a controlled process, you will build upon each aspect of the 

validation and zero in as it moves forward. The IQ will provide your equipment capabilities, the 

OQ your operational limits, as identified from the challenge conditions, and then PQ, in the 

center, with your nominal operating settings. This is what you want and this leads to a stable and 

capable process. Stable means you get the same results over and over. Capable means those 

reproducible results fit with its remaining variation into your specifications. This is what gives 

you confidence that the process with known inputs will give you predictable and predetermined 

outputs, these maybe materials, components or finished devices. Unfortunately not all processes 

work out this easily. Sometimes you may have to redesign the process and other times you may 

even have a known rate of failure, when this is the case be able to control and explain it. Also 

know how you monitoring, inspecting and testing, relates back to your device risk and the risk 

benefit determinations identified.

Slide 23

Does this mean we are now done, to never to look at the process again? No. You still have to 

monitor it over time. Now if you have done OQ correctly then you already know the important 

measurements to monitor and if you have done PQ correctly you know their frequency with 

regards to every day operations. The regulation state you must establish procedures for 

monitoring and control to ensure that specified requirement continue to be met. The proper 

monitoring is important as it will identify and detect changes over time. 

Slide 24

The process validation monitoring will take into consideration how robust the process is. If the 

process is influenced by some variation, thereby making it not fully capable, then it will likely 

require more monitoring. You may also want to use statistical process controls to look at 

deviation and percent confidence. Also controls charts and action limits can be established and 

used. For example, action limits for seal temperature can be set prior to device specification 

failure, as the results are monitored you can adjust temperature and monitor the process before 

specification failure occurs. As time goes on and your process shows to be stable, always at 

target, you may decrease frequency of monitoring. But you determine it.

Slide 25

Production and process changes: One thing I can tell you, it is not a matter of if but when you 

will have process changes. When you make changes to specifications, methods or process, 

equipment and materials, you have to see if those changes now require verification or validation, 

where appropriate. The verification or validation must be done prior to implementation of the 

change. This may prompt a new validation or if previously validated, require revalidation.
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Slide 26

Revalidation, when changes to a process or deviation occurs the manufacturer must review and 

evaluate the process and perform revalidation where appropriate. Changes to processes as we 

just discussed or process deviations such as an increase towards action limits or failures, for 

example a decrease in seal strength or open seals from the heat sealing, then the process must be 

evaluated and revalidated unless there is a documented justification as to why it is not needed.

Slide 27

Here is a list of additional examples of revalidation:

Changes to the actual process, such as a new heat sealer or piece of equipment.

Negative trends, for example, monitoring shows that the sealer is running hot and trending 

higher.

Product design changes, like a new pouch packaging material that could have an effect on the 

sealing process and finished device.

Even moving the equipment from one part of facility to another may require revalidation.

Also for revalidation maybe just part or the entire original validation needs to be completed 

again. That is for you to determine, just make sure to document and justify why. 

Slide 28

Historical data, information and data from device history records such as batch records, control 

charts and inspection can be used. I will let you know quantitative data is generally more useful 

than qualitative. Also, the historical data does not usually give you a complete picture. So while 

useful, by itself it will likely not be enough. However historical data can be used for any 

validation.

Slide 29

Thank you for your time and in summary I ask that you take on the following call to actions:

Understand your legal obligations for process validation. Use the GHTS guidance as a voluntary

tool to meet those obligations. Perform process validation to ensure that predictable and 

predetermined outputs are always the case and specifications are always met. 

Slide 30

This presentation and other helpful videos and educational resources can be found at CDRH 

Learn. For text based information on premarket and post market topics including how to bring a 
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medical device to market please visit device advice. For additional information on these or any 

other medical device regulatory topics feel free to call us at the Division of Industry and 

Consumer Education by phone or email - our contact information is listed on this slide. Thanks 

for watching.