According to the FDA, “the term qualification refers to activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly. These activities necessarily precede manufacturing products at the commercial scale.”
Qualification can be further broken down into three phases: installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ), or IQ OQ PQ.
IQ OQ PQ is most commonly used in heavily regulated industries and in cases where product quality can affect consumer safety, including pharmaceuticals, medical devices, food, aerospace, and labs involved in R&D or testing inthese areas (note that several of these are FDA-regulated). These are areas where current Good Manufacturing Practices (cGMP) are generally applied, and many of the concepts in IQ OQ PQ will be familiar to those with a knowledge of cGMP.
When done correctly, the three phases of qualification are meticulous and time-consuming. However, they are critical to ensuring repeatable processes and stable product quality, and are important components of an overall validation plan. In addition, they provide rigorous guidelines to bring equipment online systematically and in a compliant manner.
In this article, we provide an overview of how organizations can successfully navigate IQ OQ PQ, and share examples of how they are used as part of a larger overall plan to maintain a robust QA system.
What Does IQ OQ PQ Mean for My Business?
Validation, and the qualification steps involved, are covered by various parts of 21 CFR 211 (pharmaceuticals) and 21 CFR 820 (medical devices), and are enforced by the FDA. In this context, “validation” refers to the use of objective evidence to confirm that a process, and the equipment used in the process, will consistently meet its intended specifications. It is used in cases where verification (confirmation by direct examination) is not feasible.
As an example, consider the startup of a new reactor that is part of a pharmaceutical manufacturing line:
- Before purchase, the specifications of the reactor (e.g., operating temperature, capacity of pumps and motors, materials of construction) would have been determined as part of the overall process design, and possibly as an additional step of design qualification (DQ). In installation qualification (IQ), it is confirmed and recorded that the correct reactor was delivered from the supplier, and was installed and configured according to the supplier’s recommended procedure.
- Next, before bringing the reactor online, operational qualification (OQ) is performed. Operational tests would be performed to verify the reactor can run within its specified limits when under a load simulating process conditions. A second aspect of OQ is setting process boundaries for statistical process control of the equipment later on. For example, the operating temperature window needed to generate the desired product from the reactor would be determined in OQ.
- Finally, in performance qualification (PQ) the reactor is integrated into the full manufacturing line under simulated process conditions. Here, test processes would be run with the reactor operating at the extremes of its established process window (capacity, temperatures, pressures), to test how this affects the final product. This allows the verification of the overall process, and for the process windows that were set in OQ to be further refined.
IQ OQ PQ can be thought of as a set of procedures, but a critical output of all three is a document that provides evidence that qualification standards have been met. As with any procedure done as part of cGMP, complete and accurate record-keeping is essential. Recall the ALCOA standard for data collection: attributable, legible, contemporaneous, original, and accurate.
It is recommended that the team involved in validation, including IQ OQ PQ, should be cross-functional, with a diversity of expertise. Various parts of 21 CFR also state that, “Each manufacturer shall ensure that validated processes are performed by qualified individual(s)”, and that personnel and consultants involved in all aspects of cGMP are required to have the proper “education, training, and experience, or any combination thereof”. Often, the range and depth of required expertise isn’t available in-house, and external consulting is required.
In IQ and OQ, either a single piece of equipment, or entire integrated systems can be qualified. An example of an integrated system is equipment designed to apply antimicrobials to food, which might be made up of individual parts like feed tanks, sprayers, a conveyor system, pumps, motors, and measurement systems.
In some cases, IQ and OQ are grouped together into an “equipment qualification”, and in others PQ is considered part of process validation. Here, we will treat each of the three protocols separately.
Installation Qualification (IQ) for Your Equipment
The main goals of IQ are to verify that:
- The specifications of the delivered equipment match those set by the process design
- The equipment has been properly handled, delivered, and installed
Two sources of information that should be extensively consulted are the equipment manufacturer’s documentation for installation, and the specifications set by the process design.
Specifically, before installation has taken place, issues that should be checked include:
- Confirming that the correct equipment was delivered by using, for example, a purchase order and/or packing list.
- If a nameplate is attached to the equipment, verifying the supplier(s) part number and any configurations given on the nameplate (commonly listed configurations include electrical power requirements and equipment capacity).
- Checking parts for damage.
- When multiple configurations exist, making sure that the correct configuration was selected.
- Taking measurements to confirm that any measurable aspects of the equipment are within tolerance. For example, the dimensions of any parts, of the surface finish.
- Where needed, verifying the materials of construction (MOCs). This is especially important for materials that will be coming directly in contact with the in-process material or final product (so-called “wetted” parts). MOC can be verified through certificates from the manufacturer, certification by a third party, or by direct analysis.
- Confirming that the listed process ranges of the equipment (e.g., temperature and pressure) are compatible with the process.
- Checking that the equipment will be installed in a location that meets the manufacturer’s guidelines (for example, allowing enough air flow around the equipment, or making sure it is away from damaging environmental conditions and vibrations).
- Confirming that any software is properly installed, and that the hardware meets minimum system requirements.
Often, some form of qualification testing is done by the equipment manufacturer prior to shipment. Reviewing and documenting those tests should be part of IQ, but these tests are generally insufficient to represent a full IQ on their own. In this case, it is the responsibility of the customer to validate proper installation and operation of the equipment.
The second part of IQ is confirming proper installation. In most cases, this involves a thorough review of the manufacturer’s installation guidelines for the equipment and any associated sub-systems. Questions that should be covered include:
- Do the supplied utilities conform to the requirements set by the manufacturer? For a complex piece of manufacturing hardware, this could include things like the power requirements (voltage, phase, and total current needed), cooling water specifications (flowrate, purity, temperature), compressed gas requirements, or any other utility connections.
- Are all material and electrical connections made according to the piping and instrumentation diagram (P&ID)? This should involve a thorough checking of all components on the diagram, including flow directions, indicators, and welds.
- Are pipes properly labeled, and insulated where needed? Are filters in place where needed?
- Where needed, are weld log numbers recorded and welds verified?
- Does the required footprint of the equipment fit within the required space?
- Is all ancillary equipment properly installed and communicating with the main piece of equipment?
- Has any required calibration been performed, and proper documentation of calibration evaluated (either internal or vendor calibration)?
- Are SOPs written that cover operation of the equipment? For example, in cases where equipment is cleaned periodically, is there an SOP for cleaning in place before the first use of the equipment?
Examples of the type of problems that can be uncovered during IQ range from minor setbacks (for example, the supplier sending a pump configured for 220 V power, when a 110 V outlet is available for the pump) to major quality issues, like the wrong type of spray nozzles being installed on a food container sanitation unit.
Any important data or previous records related to the equipment is collected and recorded as part of IQ. Recall that the central theme of any cGMP program is a thorough and complete data record. Examples of the additional information that would be collected includes:
- Supplier ID and manufacturing dates
- Serial numbers
- Internal asset numbers tagged onto equipment
- Calibration records or other pre-testing data from the manufacturer
- Documentation and manuals, including for any computer or software control
- Record of calibration and verification dates for any equipment used for the installation
- Records that verify materials of construction or conformance to other specifications, for example certificates of conformance, materials test certifications, or certificates of analysis
- Spare parts list
- Preventive maintenance (PM) schedule
In this process, Commissioning and Qualification (C&Q) engineers are responsible for familiarizing themselves with the manufacturers guidelines to a level where the guidelines can be understood and followed. They also need to have a deep understanding of the process requirements for the equipment, and the utilities available for equipment connection.
In addition to the primary goal of ensuring product quality and protecting consumer safety, good IQ guidelines also provide a framework to bring new equipment into the plant with minimal unnecessary delays. For example, some of the simple checks discussed here, in addition to ensuring product quality, can also prevent the need for costly reconfiguration of improperly installed equipment later.
Operational Qualification (OQ): The Next Step
In OQ, we begin to understand and qualify how the operational parameters of the equipment will affect the in-process material. There are two aspects to OQ. The first is to confirm that the equipment in fact operates according to the specifications verified during IQ. This could include:
- Turning equipment on and running it at various points within its specified operational window, confirming equipment such as pumps, motors, and temperature control systems, perform as expected. Is the equipment running like it should?
- Confirming that utilities are properly connected (cooling water, process gases, electrical power)
- Checking process parameters are set correctly in hardware or software
- Testing that the equipment responds correctly when undesirable operation is encountered (fault, failure, or emergency stop conditions)
- If applicable, confirm that any safety systems on the equipment are working, such as interlocks or emergency stop (EMO) buttons
- Testing that the equipment will operate safely and as expected at the extreme limits of the operational ranges, within a safety factor (“Proven Acceptable Range” testing)
Keep in mind that documenting all of these procedures, in a way that provides objective evidence that the equipment is running properly, is a critical aspect to OQ.
As with IQ, there may be testing done before shipment of the equipment to confirm expected operation (sometimes called a “Factory Acceptance Test”), but additional operational testing is needed for a full OQ.
The second aspect of OQ is to determine how the operational parameters of the equipment (things like temperature, pressure, or process times) will affect the properties of the processed material. This can include:
- Determining whether the specified operating conditions actually do result in the desired outcome, using the process design or the DQ as a guide
- Characterizing the stability of the process, and its capability (note that “capability” has a quantitative technical definition in this context, and is an indicator of the ability of a process to reliably generate a product within spec limits)
- Establishing statistical process control (SPC) parameters for process conditions that can be monitored while the process is running (for example temperature or pressure), or aspects of the generated material that can be analyzed (like color, viscosity, or some other more sophisticated measurement). These parameters will later be used to determine whether the process is running in control, or whether the process is out of control, and what action should be taken in response.
- Define potential failure modes and perform failure mode and effects analysis (FMEA)
- Defining how and when to re-qualify the equipment
OQ should also involve documenting operating procedures, incoming material specifications, and process change control protocols.
Examples of issues that would be identified by OQ include:
- In initial testing, it is found that a machine designed to extrude plastic tubing for medical devices is generating tubing with high roughness. Further investigation reveals that the heater is not delivering sufficient power to the polymer melt, causing it to be too cool and viscous, which leads to melt fracture and high roughness.
- Characterizing the operation of a high volume baking oven indicates that the resulting product meets specifications only when the humidity in the oven is within a narrow window. This window is used to set the process control limits on the oven during full operation.
This part of the qualification process requires skilled engineers who have a thorough understanding of the individual piece of equipment, so they’re able to understand its operational ranges, as well as the role the equipment plays in the overall process. Regarding the latter, consider this recommendation from the FDA: “Focusing exclusively on qualification efforts without also understanding the manufacturing process and associated variations may not lead to adequate assurance of quality.”
Performance Qualification (PQ): The Final Hurdle
The final stage in IQ OQ PQ is where we at last confirm that the equipment functions as intended under actual process conditions, and that running the manufacturing line as a whole using the process parameters set in DQ and verified in OQ results in the final product meeting its intended specs. Specifically, this should include:
- Verifying that the process limits established during OQ result in repeatable, stable production of a final product.
- Challenging the equipment by operating it under a range of conditions, guided by the process limits determined during OQ.
- Determining long term stability and capability of the process.
- If this is the first time the full line has been run, testing the effect of scaling up the process from laboratory or pilot scale.
- Testing the integration of the equipment with the personnel, procedures, and associated systems needed to run the full process. In effect, this means that PQ testing is run under the most “real world” conditions possible, in contrast to OQ which is meant to test only operation of the single piece of equipment.
- Measuring how variations in the process conditions propagate to variation in the final product properties. This is a necessary aspect of knowing whether a process is running in control based on measured process attributes.
- Determining the inherent variability in the process. If this variability is unacceptably high, then measures must be taken to either tighten control limits on the equipment, or to identify and eliminate uncontrolled sources of variability.
Implicit in these items is that the process has been fully documented, including standard operating procedures (SOPs) for all equipment, sampling and test plans for in-process and finished materials, plans for action when the process is found to be out of control (nonconformance contingency plans), as well as pre-defined acceptance criteria for the process.
Examples of some issues that could be revealed at the PQ stage are:
- A process variable in a piece of equipment propagates in a way that was not flagged in OQ. For example, OQ could determine that if a bioprocess reactor maintained a certain temperature window during processing, the material leaving the reactor was within the spec window. However, when integrating the reactor into the full process flow, it was discovered that operating the reactor in the upper half of that temperature window resulted in an out of spec final product, due to a property that could not be measured in the material leaving the reactor.
- The SOP that was established to clean a mixing tank in a food production line is insufficient to prevent allergen cross-contamination, resulting in either a rewrite of the SOP or retraining the operators of the equipment.
Note that in their guidance, the FDA uses the term PQ to mean “process qualification”, which covers the qualification of the equipment (as discussed in this article) and the overall process. Specifically, they break PQ into:
- Design of the facility and qualification of the equipment and utilities
- Process performance qualification (PPQ)
For more information on this please see the FDA guidance for industry on process validation.
IQ OQ PQ is a complicated, detail-oriented set of cGMP protocols designed to validate that individual pieces of equipment are built and configured for their intended purpose, installed correctly, and operate as intended as part of a manufacturing line. Furthermore, these procedures establish statistical process control parameters that will be used continuously to determine that the process is running in control.
While these protocols are time and labor-intensive, they are critical to assuring consumer safety and regulatory compliance in highly regulated industries, particularly where direct verification of the final material is not possible. Furthermore, they represent a set of standardized, systematic steps that can be followed to ensure equipment is specified and operated correctly. Proper OQ and PQ, in particular, can be useful in identifying and fixing problems in the manufacturing process if they arise.
Questions about IQ OQ PQ or other validation needs? Contact Dickson today.
About the author: Before coming to Dickson, Director of Services Antoine Nguyen spent more than 18 years in quality and validation roles in the pharmaceutical and medical device industries.