You‘ve completed the Installation Qualification (IQ) – now it’s time for the next critical step in the validation process: Operational Qualification (OQ).
Right at the beginning, we want to point out that this blog is about the process of operational qualification in the medical device industry, which is different from the pharmaceutical industry.
In the medical device industry, OQ is where things get interesting.
It’s not just about checking boxes; it’s about demonstrating that your equipment and processes perform reliably within defined operating ranges. This phase is essential for compliance with ISO 13485, FDA 21 CFR Part 820, and your internal Validation Master Plan.
The Operational Qualification (OQ) is the exciting part of Medical Device Process Validation – we finally get to produce some parts and see the process performance.
"establishing by objective evidence process control limits and action levels which result in product that meets all predetermined requirements."
GHTF (Global Harmonization Task Force)
An Operational Qualification is the worst-case challenge of the process at the limit of the process parameters.
That means we set the process parameters to their limits and run the process.
The limits might be set on process equipment and/or ancillary systems, but could also refer to personnel, i.e., for gluing processes or other highly manual processes.
However, you might not even have process parameters at this stage, nor do you know their limits.
Number of Worst Cases
It is important to point out that there are not always two worst cases. The number of worst cases depends on the process and the number of factors influencing the process.
While a heat sealing process might have only two worst cases (minimum and maximum energy), an injection molding process might have more worst cases to really test all worst-case conditions.
It should also be mentioned that an OQ is a "formal" act, meaning you should not develop the process during this phase, but test it at its limits.
Most companies we see perform steps within the OQ phase that should have been done prior to starting the OQ. Determining the critical factors that influence the process and identifying the process window that yields a product meeting all predetermined requirements (acceptance criteria) are tasks to be carried out during the process development phase. Unfortunately, this phase often does not occur.
Process OQ vs. Equipment OQ
While we only looked at process OQ, many companies also utilize something like an equipment OQ. The difference is straightforward. While a process OQ challenges the process by setting the process parameters to their extremes, an equipment OQ challenges the equipment by setting it to the equipment limits.
The equipment OQ is more part of something that can be performed within an Installation Qualification (IQ); IQ is also sometimes referred to as equipment qualification, where it is not only verified that the equipment was installed correctly, but also that it works as specified by the manufacturer.
Why Should You Perform an Operational Qualification (OQ)?
The Operational Qualification has two objectives:
- Identify critical parameters, characterize the process, and establish an operating window (also referred to as a process window).
- Run the process under worst-case conditions to demonstrate that these conditions result in an acceptable product; this further demonstrates that the process is robust against variation of process parameters [1].
Risk assessments are essential in developing OQ protocols to identify potential hazards and guide the design of testing procedures, ensuring that critical points are thoroughly evaluated for compliance and quality assurance.
Unfortunately, most often, an Operational Qualification (OQ) is performed due to regulatory requirements. ISO 13485 requires a process to be validated if its “resulting output cannot be or is not fully verified by subsequent monitoring or measurement". This is the requirement for when to perform process validation. User requirement specifications serve as the basis for defining OQ acceptance criteria, ensuring that equipment or systems meet the performance needs of end-users and regulatory standards.
Now, you might ask, “Well, who says that a process validation needs to have an operational qualification?”.
It is good to bring up these questions – always doubt everything.
However, there are guidance documents and FDA material out there that explain what a process validation includes.
A popular example of such guidance is the GHTF (Global Harmonization Task Force) process validation guidance from 2004 (!).
Another resource is the FDA’s presentation by Joseph Tartal from 2015. A couple of warning letters from the agency go to show how serious this really is [FDA Warning Letter #598171] or [FDA Warning Letter #681977].
The overall validation process typically includes Installation Qualification (IQ, including Software installation), Operational Qualification (OQ), and Performance Qualification (PQ) – collectively referred to as IQ, OQ, and PQ.
Performance qualification is the final stage, verifying that manufacturing processes consistently produce quality products in accordance with regulatory expectations. It is worth mentioning that many companies also have PPQ (Product Performance Qualification).
Operational Qualification Protocol
An Operational Qualification (OQ) protocol is a comprehensive document that serves as the blueprint for verifying that the process consistently operates within its defined operating parameters.
Developed from the User Requirements Specification (URS), the OQ protocol details every step of the validation process, ensuring that all critical aspects are addressed. It specifies the process under evaluation, outlines the precise testing methods to be used, and clearly defines the acceptance criteria that must be met. The protocol also assigns responsibilities to the validation team and operating personnel, ensuring accountability throughout the process.
By following a well-structured OQ protocol, organizations can demonstrate that their equipment operates as intended, supporting both quality assurance and regulatory compliance in manufacturing processes.
A typical Table of Contents of an OQ protocol might look as follows:
1) Protocol Signature Page
2) Objective
3) Scope
3.1) Equipment
3.2) Product/Material
4) Responsibilities
5) General Procedure for OQ
6) OQ Test Cases
6.1) Pre-Requisite Verification
6.2) Operator Training Verification
6.3) Process Procedure Verification
6.4) Worst-Case Qualification Runs
6.5)...
7) Appendices
8)...
Why Test Method Validation Must Come Before Operational Qualification
In a medical device manufacturing process, quality control is essential. During an operational qualification, we need reliable measurement data to determine whether validation tests confirm that a production process performs as intended.
Since OQ involves documented verification of performance testing, any test methods (e.g., analytical methods, physical test methods, etc.) and ancillary equipment used must already be validated and qualified.
Without validated test methods, the tests conducted during OQ cannot be trusted.
Therefore, test method validation must always be completed before operational qualification to ensure that results are accurate, reproducible, and provide the necessary confidence in the performance of the manufacturing process.
How to Establish a Process Window for Operational Qualification
We already know that the first objective is to characterize the process and establish an operating window. The keyword here is another three-letter acronym, DoE – Design of Experiment.
Design of experiment is a vast topic, but we will try to break it down into a couple of simple steps by using it on a process most of us are familiar with – a heat sealing process of a sterile barrier system.
The first step of a DoE is to choose the input factors and the output responses.
In the case of the heat sealing process, the input factors might be temperature (T), time (t), and pressure (p).
In some cases, the time (t) is given as speed (v) and the pressure (p) in force (F), but for the sake of this example, we will stay with T, t, and p as our input factors.
Let’s assume our output response is seal strength (Fs).
Based on this information, we can already say there are 2³ = 8 cases we have to produce and analyze to get a better picture of the process.
You might ask where the 2³ cases are coming from.
The 3 input parameters are the exponent and the basis 2, which are used for each end of a specific parameter, i.e., temperature high/low, time high/low, and pressure high/low.
In the next step, we combine these extremes and assign “1” to high values and “0” to low values.
Table 1 – Full Factorial Design for 3 Inputs
Table 1 shows the different combinations of the input factors. Each combination will be produced and measured for its output response seal strength (Fs).
NOTE: TBD stands for “to be determined”.
The output response is then fed into a statistical software like Minitab to analyze the factorial design.
A complete and more comprehensive guide to designing an experiment can be found here.
While a heat sealing process is manageable in terms of the number of cases to test, a more complicated process like injection molding, where the number of input factors can easily go into hundreds, is far more difficult to characterize.
Even though Minitab helps you analyze the design, you might still be asking, “What values do I choose for all those 0s and 1s?”
Well, that is a good question.
The material datasheet can be a good and valuable source of information to answer this question. Some material suppliers provide information on where their products work best.
The above process parameters are the apparent considerations when one thinks about Operational Qualification and worst-case testing.
However, other aspects need to be considered too; examples are:
- Software parameters
- Raw material specification
- Process operating procedure
- Material handling requirements
- Process change control
- Training
- Environmental conditions
Operational Qualification (OQ): Running at Worst-Case Settings and Acceptance Criteria
Assuming we found the following set of process parameters:
- Temperature (T): 150,0 ± 10,0 °C
- Time (t): 2,0 ± 0,5 sec
- Pressure (p): 3,0 ± 0,5 bar
The process parameters set on the machine for the two worst cases (upper and lower) are shown in Table 2.
Table 2 – Worst-Case Parameter Settings
Now you know what parameters you must set to run the Operational Qualification studies.
To answer the question of how many samples you must produce, read our blog posts about "Process Validation Sample Size“ and “Statistical Tolerance Interval".
A tip related to sample size and Operational Qualification is that you can use reduced reliability levels (with a confidence level of at least 95%) for OQ runs.
These lower requirements for OQ are because these tests are performed under worst-case conditions, which makes them stress tests [1].
While the above sealing process example might be easy, we can briefly touch on something more difficult, like a cleaning process.
In a cleaning validation, a worst-case scenario could involve selecting the most difficult-to-clean product residue (e.g., highly viscous or sticky substances) from the most difficult-to-clean product. The most difficult-to-clean product might have various product features, like threads or intentionally rough surfaces with undercuts.
Testing under real-world conditions ensures the reliable operation of equipment and consistently operating systems, supporting high-quality products throughout manufacturing and production processes.
You see that an operational qualification can very quickly become very big (and powerful).
What Do We Mean by "Worst-Case"?
In the context of Operational Qualification, “worst-case” refers to the process conditions that put the greatest challenge on your system while still being within the defined operating range.
Worst-case conditions are the settings for the input factors that cause the worst-case performance of the output responses. Identifying and testing these conditions is critical to demonstrating that the process is robust and consistently delivers products meeting specifications. A simple heat sealing process may have two worst cases – minimum and maximum sealing energy – whereas more complex processes like injection molding may involve multiple worst-case scenarios.
By defining and testing these extremes, manufacturers can build confidence that their process validation truly covers the full range of potential variability
Acceptance Criteria for Operational Qualification
Acceptance criteria are the cornerstone of any Operational Qualification (OQ), providing clear, measurable standards that the process and the product must meet during testing.
These criteria are established based on the User Requirements Specification (URS) and are tailored to the specific operating parameters of the process. Process acceptance criteria typically define upper and lower limits for critical parameters such as temperature, pressure, or flow rate, ensuring that the process operates within a safe and effective range.
By setting these predefined acceptance criteria, organizations can objectively assess whether the process's performance meets the necessary standards for quality and safety. Including these criteria in the OQ protocol ensures that the operational qualification OQ process is both rigorous and transparent.
Analyzing Operational Qualification Results
Once Operational Qualification (OQ) testing is complete, the next step is a thorough analysis of the results. The validation team reviews all test data collected during the OQ to determine if the equipment or system has met the specified acceptance criteria.
This involves checking that all measured values fall within the established limits and identifying any deviations or trends that could indicate potential issues. If any results fall outside the specified limits, the team investigates the root cause and assesses the impact on the manufacturing process.
This analysis not only confirms whether the process is qualified for use but also highlights areas for improvement or further testing, ensuring that only processes operating correctly and consistently are integrated into production.
Best Practices for Operational Qualification
To ensure a successful Operational Qualification (OQ), it’s essential to follow industry best practices. Start by developing a detailed OQ protocol that outlines all testing methods and acceptance criteria. Involve experienced personnel who understand the equipment and the manufacturing process, and make sure the equipment is installed and calibrated correctly before testing begins. Use a risk-based approach to focus on the most critical aspects and potential failure modes that could impact product quality or patient safety.
Thorough documentation of every step, from test execution to results analysis, is vital for data integrity and regulatory compliance. Regularly review and update OQ protocols and procedures to address new risks and maintain high-quality standards throughout the validation lifecycle.
Common Challenges in Operational Qualification
Operational Qualification (OQ) can present several challenges, especially in regulated industries.
One common issue is ensuring that the testing process is both comprehensive and well-documented, which is crucial for regulatory compliance. Identifying and addressing potential failure modes requires careful planning and a deep understanding of the equipment and its role in the manufacturing process. Establishing clear acceptance criteria can be complex, particularly for systems with multiple critical parameters.
Other challenges include ensuring proper equipment installation and calibration, managing deviations or unexpected results during testing, and maintaining the integrity of the validation process.
Additionally, OQ can be resource-intensive, requiring significant time and coordination among the validation team.
Overcoming these challenges is essential to ensure that equipment operates reliably and safely within its specified limits.
Further helpful links & resources:
SIFo Medical YouTube Channel: Short, valuable videos on Quality Management.
Free Resources: Get free access to checklists & templates.
TMV Guide: Your practical guide to perform test method validation (incl. templates & videos).
SIFo Medical Newsletter: Join our mailing list to receive updates and exclusive content delivered straight to your inbox as soon as it's released.
Are you unsure how to perform an Operational Qualification (OQ)? Contact us today at office@sifo-medical.com, and we'll support you perform an OQ correctly.
References
[1] W. Taylor, Statistical Procedures for the Medical Device Industry. Taylor Enterprises, Inc., 2017. [Online]. Available: www.variation.com
[2] Global Harmonization Task Force, "Quality Management System - Process Validation Guidance," GHTF/SG3/N99-10:2004, 2004. [Online]. Available: http://www.imdrf.org/docs/ghtf/final/sg3/technical-docs/ghtf-sg3-n99-10-2004-qms-process-guidance-04010.pdf
[3] Quality-on-site.com, "GMP Documentation: Process Validation," [Online]. Available: http://www.quality-on-site.com/get.php?fileid=139
[4] ISO 11607-2:2019, Packaging for terminally sterilized medical devices — Part 2: Validation requirements for forming, sealing and assembly processes. International Organization for Standardization, Geneva, Switzerland, 2019.
[5] ISO 13485:2016, Medical devices – Quality management systems – Requirements for regulatory purposes. International Organization for Standardization, Geneva, Switzerland, 2016.
[6] U.S. Food and Drug Administration, "21 CFR Part 820 - Quality System Regulation," [Online]. Available: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=820&showFR=1
