Over the past decade, the medical device and biomaterials industries have undergone tremendous amounts of innovation and change, with a corresponding increase in regulatory involvement to ensure the safety and efficacy of all products. These trends have resulted in a growing requirement for the full mechanical evaluation of biomedical products from the research and development stage through the quality control testing of finished goods.
In the biomedical industry, quality control testing presents a significant challenge for manufacturers. These companies must know what to test and how to test it while also ensuring the quality of their results and achieving regulatory compliance. Failure to successfully achieve these goals can be extremely costly to the organization, and significant laboratory resources are often committed toward mitigating these risks. This article discusses how a robust, optimized mechanical testing program is key to successful quality control testing.
Knowing How and What to Test
Although a number of ASTM and ISO standards do exist for biomedical products, no single test is usually enough to fully evaluate all the different components of a product throughout its entire life cycle. From development to prototype evaluation, manufacturing, and packaging, products require many different types of testing in order to ensure proper functioning. It is crucial for manufacturers to perform thorough research into which properties they need to evaluate, and then discuss these needs with their testing equipment provider.
Testing of a product can be broken down into testing of the raw materials used, components of the final product, and the fully assembled, finished device. As an example, let’s look at the different ways in which vascular stents can be evaluated.
Stents are mesh tubes commonly used to increase the internal diameter of arteries and veins. The preferred material for stents is nitinol wire because nitinol exhibits shape memory, a unique biomechanical characteristic which allows it to self-expand. Before the stent itself is manufactured, the elongation and tensile strength of the wire must be determined, as well as its shape memory, which is evaluated by loading and unloading in a cyclic test per ASTM F2516 (see Figure 1).
After the material is tested and the stent is produced, the stent must be evaluated to ensure that it meets the required expectations. Stents must pass through curvatures in the vascular system in order to reach their intended destination. Therefore, their flexibility must be evaluated per ASTM F2606, which subjects them to a three-point bend test to generate a force-displacement curve for both unload and unloading. Manufacturers are also interested in quantifying the frictional forces of the stent to simulate the action of the product being pushed through a patient’s body. This type of test is often referred to as tortuosity testing.
Another critical property is the radial force that a stent or graft imparts onto the arterial wall. Evaluating the radial strength of a stent graft, e.g., radial stiffness, chronic outward forces during expansion and compression, and reactive force helps to ensure the efficacy and reliability of the medical device when implanted in vivo.
Finally, the stent is subjected to millions of fatigue loading cycles as part of the product durability and validation testing. ASTM F2477 involves placing complete devices into mock arteries and subjecting them to 400 million cycles of internal pressure pulsation (10 years of human heartbeats), forcing them to radially expand and contract in each cycle. This test can reproduce the minimum and maximum diameters that a stent would see in vivo under worst-case conditions.
Other medical devices such as syringes, pacemakers, and implants also require their own unique testing profile depending on the materials being used and the device’s end-use application. Manufacturers must have a thorough understanding of the different testing requirements in order to ensure that their products meet expectations, and a well-optimized lab will invest in testing equipment that allows them to efficiently perform all relevant tests.
Ensuring the Quality of Your Results
After the initial challenge of understanding the various testing requirements for each of their products, the most critical concern in global medical device QC laboratories is resolving inconsistencies in their test results. Mechanical testing results must be repeatable and reliable between individual testing systems, whether those systems are located in the same lab or in different labs, or when a comparison is being made between multiple suppliers or customers. Quality assurance depends on the ability of testing systems to provide accurate results.
Furthermore, as many industries expand R&D and manufacturing operations into different parts of the world, data comparisons have become increasingly more important and complex. Sources of test errors can be categorized into six distinct categories: method, measurement, operator, material, machine, and environment. Within these major categories are subcategory sources of error that must be specifically addressed (see Figure 2).
The consequence and magnitude of a test error depends on what the error is. Testing at body temperature vs. room temperature can drastically affect results. A ±1 percent measurement error of a specimen’s dimensions will result in a ±2 percent error in the stress result. An incorrect machine calibration means that all test measurements and results are invalid — resulting in product being recalled or scrapped.
To resolve these inconsistences, the first course of action is to perform an audit of the lab, equipment, and operating procedures to see which of these variables could be causing the inconsistency in test results. Modern testing equipment provides many opportunities to reduce the likelihood of erroneous results, ranging from system setup optimization to requiring admin-level permissions to edit test methods and calculations. The quality of audit results can also be evaluated using a Gage Repeatability and Reliability (GR&R) study, which is used to qualify and/or validate equipment and “quantify” total system error.
Regulatory compliance is possibly the biggest challenge facing any manufacturer in the biomedical device industry and testing equipment and software validation are critical for achieving this compliance (see Figure 3). Although there are several different regulatory standards that testing laboratories often need to meet, the two most common are 21 CFR Part 11 (Electronic Records and Electronic Signatures) and 21 CFR part 820 (Quality System Regulation/ Medical Device Good Manufacturing Practices). Although these standards have broad-ranging requirements, materials testing suppliers offer products and services designed for companies testing in highly regulated environments.
21 CFR Part 820
All laboratory product development and manufacturing processes are subject to 21 CFR Part 820 validation. Materials testing suppliers typically assist companies in the required creation of a qualification plan. This plan typically includes several phases: performance specifications, risk analysis (RA), design qualifications (DQ), installation qualifications (IQ), operational qualifications (OQ), and performance qualifications (PQ). Most materials testing suppliers provide independent assessments and documentation for the IQ and OQ, which typically includes system checks, transducer and system verifications, functional checks of test software, and validation of calculations. Laboratories working collaboratively with testing suppliers in the development of robust RA and DQ documentation as well as fulfillment of the PQ can save valuable time as well as internal costs associated with the validation process.
ISO 13485 supports medical device manufacturers in designing quality management systems that establish and maintain the effectiveness of their processes for consistent design, development, production, installation, and delivery of medical devices. The differences between 21 CFR Part 820 and ISO 13485 are subtle, but recent revisions (2016 for ISO and 2018 for Part 820) now have them wellaligned. Conformance to ISO 13485 is an internal decision while 21 CFR Part 820 is an FDA-mandated system of product design quality. Due to their similarities, organizations can use the implementation of ISO 13485 to establish compliance to 21 CFR Part 820. Some requirements of 820 might not be fully covered by 13485, but a simple gap analysis and proposed actions to fill those gaps can ensure compliance to 820. Similar to 21 CFR Part 11, noncompliance is not an option.
21 CFR Part 11 Compliance
The 21 CFR Part 11 standard initially created a great deal of tension within the medical device and pharmaceutical industries, with the most common concern being the potential cost of achieving compliance. There was also considerable confusion regarding implementation processes and procedures. Several guidance documents were written by the FDA to clarify the situation.
Along with other companies, materials testing suppliers were challenged to supply testing systems and software that could comply with the broad scope of the regulation. One common fallacy is the notion that materials testing systems manufacturers can provide “21 CFR Part 11 compliant software.” In reality, it is up to the user to establish processes and procedures that lead to compliant actions and activities. A supplier must provide the appropriate software structure and features that allow the user to create those processes and procedures that meet the requirements of the standards. This may seem like a subtle distinction, but a software package that can create a hard copy test method and hard copy results reports that can be printed, signed, and stored according to company operating procedures could be called “21 CFR Part 11” compliant, though not particularly “audit-friendly.” The real intent of the regulation is to move to a more efficient, effective, and secure electronic process.
The technical requirements of FDA 21 CFR Part 11 provide guidelines for integrity and traceability in three key areas: security, audit trail, and signatures. Many laboratories have transitioned, or are transitioning in some manner, to electronic records and signatures as outlined in Part 11. Several features are now typically included with systems and software that help facilitate compliance with the standard.
Inspectors from the FDA now audit laboratories to ensure compliance. If processes and procedures are found to be out of compliance, a warning letter could be issued. FDA data shows that over 5,000 of these warning letters were issued in 2018 alone. Poor audit results can mean delays in product delivery, time lost in preparation for audit follow-up, fines (sometimes into the millions of dollars), and time lost chasing paper records errors. In this environment, non-compliance is not an option.
In all cases, a strong working relationship between biomedical manufacturers and their mechanical testing suppliers is critical to a successful quality control program. By working closely with testing experts, quality control labs can optimize their equipment and software to efficiently perform all the types of testing necessary for their product while ensuring consistency in their results and achieving regulatory compliance. A well-optimized lab is poised to meet growing demands for throughput while mitigating risk for both the manufacturer and the product consumer.
This article was written by Frank Lio, Global Product Support Lead, Instron, Norwood, MA. For more information, visit here .