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The objective of this article is to provide clarity on manufacturing process validation requirements associated with orthopedic products. The focus will be on process validation of manufacturing processes common to orthopedic implants and surgical instruments. Not covered are terminal sterilization validation and sterile packing validation, which are well described in industry standards. Also not covered are manufacturing cleaning validation and software validation, as they each have some unique aspects. However, many of the principles described herein can be applied to these types of validations. FDA regulations and guidance are covered in depth, and EU Medical Device Regulations are referenced when helpful in understanding requirements.
What is Process Validation?
According to 21 CFR 820.3(z)(1)1 the definition of process validation is as follows:
Process validation means establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications.
EU Guidelines for Good Manufacturing Practice, Volume 4, Annex 152 defines process validation as:
The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.
Although the definitions seem somewhat ambiguous, there are two key phrases: “objective evidence/documented evidence” and “predetermined specifications.” Objective evidence is documented evaluation of a requirement, including the result of the observation. The result of each validation task is typically reported as pass/fail, yes/no, as expected, etc. When the acceptance criteria for a requirement is based in variable data, it should be clearly stated what the value should be to be considered pass or fail. It is inadequate to state on the result only. If a requirement is to be evaluated, there must be clear predetermined specifications. We use written and approved protocols for process validations to specify validation requirements with defined acceptance criteria. A report of the validation outcome, with appropriate approval, provides objective evidence.
When is Process Validation Required?
21 CFR 820.75(a)1 Process Validation states:
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.
Historically, manufacturing processes where the result cannot be verified by subsequent inspection and testing have been referred to as special processes. In 1996, FDA discontinued the use of the term special process3; however, the term “special process” continues to be used in the orthopedic industry. Regardless, FDA is clear: if the outcome of a process cannot be verified, the process must be validated. This requirement aligns with ISO 13485 Section 7.5.6.
The organization shall validate any processes for production and service provision where the resulting output cannot be or is not verified by subsequent monitoring or measurement and, as a consequence, deficiencies become apparent only after the product is in use or the service has been delivered.
Therefore, it would seem logical that the converse — a process that can be fully verified by subsequent test and inspection — does not require validation. But this does not seem to be the case based on the 1996 Federal Register3:
One of the principles on which the quality systems regulation is based is that all processes require some degree of qualification, verification, or validation, and manufacturers should not rely solely on inspection and testing to ensure processes are adequate for their intended uses.
So, what may have seemed clear is now not so clear, as this statement indicates that all processes must be qualified, verified or validated to some degree. According to 21 CFR 820.3(a)1:
Verification means confirmation by examination and provision of objective evidence that specified requirements have been fulfilled.
Most would consider verification to be some form or type of inspection. What else could it be? But the guidance states that “manufacturers should not rely solely on inspection and testing.” So, since we “should not” rely solely on inspection/verification, we probably should choose to validate or qualify.
21 CFR 820.3 does not include a definition of the term “qualified.” There is a definition of “process qualification” in Current Good Manufacturing Practices Process Validation: General Principles and Practices, Revision 1, 20114:
Process Qualification: Confirming that the manufacturing process as designed is capable of reproducible commercial manufacturing.
This definition seems to be the same as the 21 CFR 820 definition of process validation. So, we are faced with a bit of ambiguity.
Exemptions
Are any products exempt from process validation requirements? Some FDA Class I and Class II devices may be exempt from Current Good Manufacturing Practices (cGMP). One might assume because requirements for process validation fall under Subpart G – Production and Process Controls, that there are products that could be exempt. However, upon investigation into using the online resource, FDA Class I and Class II Device Exemptions5, it seems unlikely that any orthopedic implants and surgical instruments are exempt from cGMP2.
Are any processes exempt from validation? In the FDA Guide to Inspections of Medical Device Manufacturers, December 1997, under Section 7 Process Validation6, it states:
The QS/GMP does not require the validation of all manufacturing processes.
If all manufacturing processes do not require validation, which processes do require validation and which processes do not require validation? Lists of processes that require validation can be found in various FDA documents. The 1997 FDA Guide to Inspections6 states:
Validation should be performed (as applicable) for processes such as sterilization operations (steam, dry heat, ETO, radiation, filtration, aseptic fill), manufacturing operations (lyophilization, molding, soldering, machining, blending/mixing, water purification systems), environmental control systems (clean rooms and laminar air flow units), test methodology, and packaging/labeling operations.
The Global Harmonization Task Force Process Validation Guidance from 20047 also lists “Processes which should be validated.” In addition to those listed above, it adds heat treating, plating and plastic injection molding. The 2004 Guidance also lists some processes under the heading “Processes which may be satisfactorily covered by verification,” which includes manual cutting processes, visual inspection of printed circuit boards and some others.
It’s interesting to note the use of the words “should” and “may” in the requirements. In a legal sense, the words should and may are not words of obligation; therefore, these requirements are optional. Also interesting is that molding should be validated per the 1997 Guide6, but the 2004 GHTF Guidance7 narrows molding to plastic injection molding. The 2004 Guidance also indicates that manual cutting processes may be satisfactorily covered by verification. It seems it would be illogical to validate any manual process where the outcome is totally dependent on the skill and artistry of the operator (e.g., sewing or gas tungsten arc welding). These processes do require well developed procedures, qualified/certified operators and robust inspection to insure capability and stability of the process. The key takeaway is that these guidance documents are, as the name implies, guides and other factors often require consideration. Manufacturers need to understand the processes they use and should apply the regulations and guidance documents in a logical and reasonable manner.
What needs to be validated?
Orthopedic devices are complex. A single implant can easily have hundreds of dimensions. For years, the industry and FDA have taken a risk-based approach to ensure that appropriate levels of quality are achieved. Features that are determined to be of significant risk have been classified as Critical To Quality (CTQ), Critical Quality Attribute (CQA), Control Features (CF) or other descriptors. These design output features are required according to 21 CFR 820.30(d)1 which states:
Design output procedures shall contain or make reference to acceptance criteria and shall ensure that those design outputs that are essential for the proper functioning of the device are identified.
An appropriate risk evaluation such as a design or process failure mode and effects analysis (dFMEA or pFMEA) should be used to determine when a design output should be a critical feature. Features deemed critical require “some degree of qualification, verification, or validation.”
The Basics of Manufacturing Process Validation: IQ, OQ, PQ
Installation Qualification (IQ). The requirement for conducting an installation qualification is clear and straightforward. 21 CFR 820.70(g)1 states:
Each manufacturer shall ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use.
An IQ provides objective evidence that equipment is installed correctly. It’s a reasonable requirement. It would be illogical to validate a process on a piece of equipment that may not be installed correctly. Utility provisions, such as electricity, air, water and sewer, must be verified. For example, if a rinse following a cleaning operation requires a continuous flow of deionized water, the IQ protocol should require that the water supply to the equipment is evaluated to meet the flow requirements. Similarly, if a solution is required to be heated, the IQ should confirm the equipment can maintain the temperature within the expected operating range. The equipment installation should verify the full range of expected operating parameters.
Some have argued that an IQ must verify the full capabilities of the equipment, but this approach is not reasonable. Imagine a large CNC milling machine with multiple axes. It would be extremely difficult to test all possible tools in all the axes to determine if the machine meets the manufacturer’s claim of precision, accuracy and repeatability. The level of difficulty is not the reason that this is not necessary. It is not required because the capability of the machine should be evaluated during performance qualification (e.g., part process capability). If it is demonstrated that the machining process is capable, it also confirms that the operation of the equipment is also capable. So, in an IQ, if the equipment is capable of a temperature range of 80 – 140˚F but the expected temperature operating range is 115 – 135˚F, it is reasonable that the IQ verifies the range that will be used. If temperature displays are critical to the process, they should be calibrated or verified. An IQ should also verify machine operation, preventative maintenance schedules and safety.
What equipment requires an IQ? Certainly, any piece of equipment that creates or may influence a part feature or part performance needs an IQ. An IQ would not be required for non-production-related equipment which has no direct or indirect effect on product quality, such as material handling equipment (e.g., forklifts, chain hosts) or certain facility equipment (e.g., garage door openers).
It is common for equipment used to manufacture orthopedic products to be computer controlled. That raises the question of what is required for Software Validation (SV) for manufacturing equipment. Medical devices that function on software such as implantable pacemakers and defibrillators must undergo rigorous software validation. For standard manufacturing equipment, it is not reasonable to validate the software that operates CNC machines. The machine operating system, application software and part programs should be validated by part-specific process capability evaluation (PQ). However, it is reasonable to ensure that appropriate software controls are in place and functioning on the equipment. These should include operating system and application software version control, and part program revision control.
A protocol covering all of the installation qualification activities should be written and approved prior to performing the IQ. Commissioning reports for machinery typically are not executed from a protocol conforming to the manufacturing site’s quality management system. It is for this reason that commissioning reports are not a substitute for an IQ. The results of the IQ should be written in a report and approved. An approved protocol and report are good practice and should be used for all validations.
Operational Qualification (OQ). The purpose of an OQ is to challenge a process to produce acceptable product at the extremes of allowable process parameters. OQs are clearly applicable to special processes.
A critical requirement for any process validation is to have clearly defined acceptance criteria. For example, passivation is a process that often does not have clearly defined acceptance criteria. Part drawings often specify only that the part is to be passivated. It may be specified that passivation is to use nitric acid or citric acid. The part drawing may reference ASTM A967/A967M8. The ASTM standard, however, offers six different verification tests ranging from a simple water immersion test to a copper sulfate test. Obviously, it’s critical to define what it is that the process is to accomplish. How can a process be validated if it’s not clear what the acceptance criteria are? In other words, you must define the acceptance criteria before executing the validation.
EU Guidelines for Good Manufacturing Practice Qualification and Validation, Section 3.22 makes reference to a User Requirements Specification (URS): “The specification for equipment, facilities, utilities or systems should be defined in a URS and/or a functional specification.” Recall too that “Process validation means establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications.” Somewhere in a URS, a process specification, a standard reference or on the engineering drawing, the requirement needs to be clearly defined.
Many special processes used in the manufacture of medical devices have been used for years, and process parameters are well understood. However, when process parameters are not well understood, there is risk of failure of the OQ. To reduce the risk of failure, it is recommended that a characterization study and/or design of experiment (DOE) be used prior to OQ protocol execution. Process characterization focuses on identifying process variables and parameters that affect process outcomes. A DOE can provide insight into the interactions between process variables and parameters and the effect on process output. It should also be noted that an OQ is not required to optimize process parameters but to demonstrate that the process consistently produces the expected result in the full range of process parameters.
It’s appropriate at this point to discuss process parameters where a dead band exists. The most common example of a dead band parameter is temperature. Let’s say we have a fluid, and the temperature is set at 125˚F. In most cases, temperature is controlled by turning a heating element on and off. The temperature will rise to a point where the heating element will turn off. The temperature will decrease to a point where the heating element will be turned on. The temperature where the heating element turns on and where it turns off cannot be the same as this would result in constant on/off, off/on cycling. In our example, depending on the temperature controller and its settings, the heating element may turn on when the fluid is at or below 125 ˚F. The heating element will turn off when the fluid rises to 128˚F. Depending on the retained heat of the heating element, the fluid temperature may continue to increase even though the power has been turned off, resulting in reaching a higher temperature than the high set point before subsiding. This range is commonly referred to as a dead band. A similar effect can occur at the low set point. Let’s say the fluid is at 125.2˚F and a large load of parts, which are at 75˚F, are put into the fluid. The fluid temperature may drop considerably below 125˚F before the heating element can raise the temperature. Although the temperature was set at 125 ˚F, the actual temperature range may vary by a few degrees, or it could be considerably more. The key takeaway is that it is important to understand the real operating range of temperature, and other dead band-controlled parameters, and consider the actual parameter range when developing OQ parameters.
It certainly makes sense to perform OQs for special processes. Challenging the outcome of the process using extremes of parameters such as temperature, time, chemical concentration, solution age, etc., will test that the process will provide the expected results at the extents of operating parameters. Some in the industry refer to this type of OQ as a Process Operational Qualification (POQ).
Is an OQ always required? If features of the new product are fully covered under an existing validation, the existing OQ and PQ may be leveraged. It is not difficult to determine whether the new product falls under an existing validation in some circumstances. An example would be if the new parts being validated were a line extension adding additional sizes that fall within the range of sizes that were previously validated. In some cases, however, it can be quite difficult to determine objectively if the new product would be a new “worst case” and would fall outside of the existing validation. It may be prudent to re-validate either fully or partially.
For verifiable processes such as CNC machining, does an OQ make sense? It depends on a few factors. Following the flow chart in Figure 1, when the process does not have an effect on any Critical To Quality features, an OQ may not be required. An example may be electro-polishing to remove machining burrs on a surgical instrument, especially when such features are influenced by subsequent operations such as manual deburring and metal finishing.
Figure 1. Manufacturing Process Validation Flow Chart.
Click the image for a full Manufacturing Process Validation Flow Chart.
When CTQs features are affected by process parameters, and the process is special in that the part would be destroyed by inspection (e.g., cannot be verified), there is no choice but to perform an OQ. Remember, “Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated. . . .”1
Continuing down the flow chart, if process parameters are not adjusted during normal operation and the parameters are not affected by dead-band control, an OQ may not make sense. This may be the case because there isn’t a reasonable approach to challenge the process. This would apply to most CNC machining operations. Typically, parameters such as speeds and feeds are not changed during normal operations. Offsets may be adjusted under normal operating conditions, but offsets, when used correctly, are adjustments for tool setup and tool wear. Tool/part movement and other parameters should be evaluated during performance qualification. Therefore, there really are no meaningful parameters to challenge. When it is deemed unnecessary to conduct an OQ, a rationale should be documented that justifies this action.
Note that this applies to most CNC machining processes, but there are exceptions, such as gun drilling. When the inside diameter surface finished is noted as a CTQ and process parameters are adjusted based on material mechanical properties and other factors, it would be reasonable to perform an OQ to ensure the required surface finish conforms to requirements throughout the full range of parameters. Conversely, if studies have proven that the surface finish is statistically consistent throughout the entire part length, gun drilling does not need to be treated as a special process.
If inspection is impractical or uneconomical, one may choose to conduct an OQ. An example might be heat treatment. It’s certainly possible to verify hardness, but in most cases, it’s impractical (e.g., aesthetic issue with hardness test indentations) and/or uneconomical (e.g., testing every piece).
The last factor that should be considered is production volume. When production quantity is low, it is often unreasonable to perform a traditional process validation. Under ideal conditions, all process validation activities are completed prior to commercial production. For typical process validation with two OQ runs, and three PQ runs with 95/95 confidence reliability and variable features, it would require almost 300 parts to perform the validation. In some cases, this could represent years of production volume. In circumstances where the initial production release quantity is significantly below the quantity required considering risk and statistical relevance, 100% inspection is the logical option to choose. As previously stated, the 1996 Federal Register Guidance states, “manufacturers should not rely solely on inspection…” Recall that “should” is not a word of obligation. When the initial production release is greater than the quantity required for validation, the validation (including OQ) should be performed with a concurrent release. The 2011 cGMP process validation guidance4 details concurrent release of PQ lots for drugs which seems relative to concurrent release of device OQ and PQ runs.
Performance Qualification (PQ). The objective of a performance qualification is to demonstrate the process will consistently produce acceptable product under normal operating conditions. For special processes, the PQ uses the same parameters that were used in the OQ. However, in an OQ, the parameters are forced to the extents of the allowable range to create worst-case challenges to the process. In a PQ, the process is performed essentially under normal production conditions. Parameters can be adjusted within the operating range. Typically, the PQ consists of three production runs. However, the number of runs must capture all of the expected conditions that could have an effect on product quality. To simulate variation in normal operating conditions, different operators may be required on different shifts. The acceptance criteria used for the PQ should be the same as used in the OQ.
For most verifiable processes where the process creates a CTQ features that are variable dimensions, the PQ takes the form of a process capability study resulting in a measure of capability, which is typically Ppk. Attribute feature process capability analysis is complex and will not be covered here. The process capability study should be conducted with a protocol that simulates normal conditions. In traditional pre-commercial process validation, a minimum of three production runs are used to determine initial process capability. Remember, the goal of the PQ is to evaluate the process under normal production conditions. Equipment setup is often a source of variability. To capture this variability, a setup should be performed between PQ runs, preferably with different operators.
How Every Thing Fits Together
Process validation activities are influenced by three main factors: regulatory requirements, business risks and customer/corporate requirements. We’ll consider regulatory and business risks as we put the pieces together. We will not consider customer or corporate requirements which may not align completely with regulations.
It would be illogical to perform any process validation activities on equipment that may not be installed correctly. An IQ should be performed on any piece of equipment that influences part features prior to other validation activities.
For processes where the outcome cannot be verified, 21 CFR 820.75(a)1 is quite clear: “Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated.” So, in addition to IQs for equipment, an OQ and PQ are required for all special processes.
Next, we’ll find an indirect but clear requirement for process validation. 21 CFR 820.250(b)1 states:
Sampling plans, when used, shall be written and based on a valid statistical rationale.
Process capability analysis combined with risk severity is certainly a valid rationale for sampling inspection. It would be prudent to consider the capability of a process when determining Acceptable Quality Level (AQL) or Lot Tolerance Percent Defective (LTPD). It seems logical that a process with low capability should have a higher level of inspection. When a process is highly capable, it would make sense that the level of inspection would be lower. Without considering process capability when setting AQL/LTPD, one would need to assume that the process has low capability, but how low? Some will set AQL/LTPD based on risk severity alone, leading to over inspection. Process capability is the PQ for verifiable processes. Therefore, if inspection sampling is going to be used, it certainly makes sense to perform an IQ and PQ/process capability analysis. Additionally, an OQ may be required in some circumstances, as discussed previously.
Additionally, performing process capability also demonstrates that the equipment is installed correctly and the mechanical and software aspects of the equipment are functioning properly. A PQ provides objective evidence that “a process consistently produces a result or product meeting its predetermined specifications.” It makes sense that a machine that can consistently make parts with a high level of capability has been installed correctly.
Are there other requirements in the regulations that require an OQ or PQ for verifiable processes? Recall that CFR820.75(a)1 states, “Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated…” Notice that it states “fully” validated. Some interpret this literally. For example, if there is a CTQ diameter that is being machined, the diameter can be verified with a micrometer. However, the micrometer measures only one point on the surface of the diameter, it is not fully verifying the diameter, and therefore, process validation is required. One could take a position that a go and no-go ring gauge could be used to fully verify the diameter. This is true but only if the full OD surface is accessible to the ring gauge. There are likely other CTQ features that cannot be fully checked with go/no-go gauges or other methods of surface measurement. Additionally, qualification of attribute gauges is expensive and complex. Conducting process capability analysis provides valuable insight into the process and meets regulatory requirements.
At this point, we know that regulations require all special processes must be validated and require an IQ, OQ and PQ. We also know that verifiable process validation (process capability) is an unquestionable approach to providing a valid statistical rationale for sampling inspection and objective evidence of equipment installation qualification. We also know that in most cases, validation is the solution to the “fully validated” requirement. Therefore, for a verifiable process, IQ and PQ/process capability should be performed and sometimes an OQ is also required.
We also know that when inspection of a verifiable process is impractical or uneconomical, the business may choose to perform process validation to reduce or eliminate inspection.
However, when production volumes are low, concurrent OQ/PQ or 100% inspection is the rational choice for verifiable processes.
In summary, most of the requirements for process validation activities can be derived from regulations either directly or indirectly. Other reasons for validation are driven by the logical application of sound business practices. In either case, it is important to understand and document all facets of manufacturing process validation and to justify the approach taken.
References
1 Code of Federal Regulations, Title 21, Volume 8, Part 820
https://www.ecfr.gov/current/title-21/chapter-I/subchapter-H/part-820?toc=1
2 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 15: Qualification and Validation, 2015
https://ec.europa.eu/health/system/files/2016-11/2015-10_annex15_0.pdf
3 Federal Register: October 7, 1996, Volume 61, Number 195, Rules and Regulations, Page 52631
https://www.govinfo.gov/content/pkg/FR-1996-10-07/pdf/96-25720.pdf
4 Current Good Manufacturing Practices Process Validation: General Principles and Practices; Revision 1; 2011
https://www.fda.gov/files/drugs/published/Process-Validation–General-Principles-and-Practices.pdf
5 FDA Class I and Class II Device Exemptions
https://www.fda.gov/medical-devices/classify-your-medical-device/class-i-and-class-ii-device-exemptions
6 Guide to Inspections of Medical Device Manufacturers December 1997
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/page-9
7 The Global Harmonization Task Force; Quality Management Systems; Process Validation Guidance; Edition 2 – January 2004
https://www.imdrf.org/sites/default/files/docs/ghtf/final/sg3/technical-docs/ghtf-sg3-n99-10-2004-qms-process-guidance-04010.pdf
8 ASTM A967/A967M Standard Specification for Chemical Passivation Treatments for Stainless Steel Parts
I would like to express my appreciation to the following individuals that contributed to this article: Garth Conrad, Vice President, Quality, Flex Health Solutions; Joseph M. Farinella, Quality Director, Orchid Orthopedic Solutions; Melissa Fowler, Senior Manager, Program Management & Innovation Orchid Orthopedic Solutions; Rob Pierson, President, Grover Precision; Tom Slagle, Senior Quality Systems Director(retired) Medtronic; Nathan Tempco, Senior Design Quality Engineer, ZimVie.
Dale Tempco is a medical device consultant specializing in product development, operations, quality, design for manufacturability, supply chain, M&A and finance. He has expertise in low-cost sourcing, design transfer, special process validation, cleaning validation, QMS, additive manufacturing, failure analysis and cost accounting, and has extensive global experience in China, Costa Rica, Europe and the Middle East.
