Manufacturers of medical devices face some of the most unique challenges of all manufacturing sectors. Being at the intersection of reliability, safety, and precision; medical devices have to meet some of the highest standards of any manufacturing industry.

Regulatory bodies, like the Food and Drug Administration (FDA), help develop medical device standards and provide oversight to ensure every product is safe and dependable. Lives are most certainly at stake if medical devices do not operate without failure, have coatings that aren’t applied according to the needs of healthcare professionals, or simply aren’t consistent from one product to the next. Every medical device needs to be perfectly usable every time, without exception.

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Among all of the challenges particular to medical device manufacturing, one of the most frustrating aspects can be clearing the chasm between product development and production. This is where oversight groups can make progress sluggish but also provide necessary checks on the process that ultimately result in the safest and most reliable products. Manufacturers are always looking for ways to make testing in development as quick, yet accurate, as possible so they can remove obstacles to scaling up to production.

Data from a poll taken by Quality Digest shows that the top problem manufacturers of medical devices face with new production introduction is with quality management. Close behind is validation and also scaling new processes and equipment to production.

Some specific concerns for medical device manufacturers who are trying to overcome these hurdles include:

• Hydrophobicity or hydrophilicity of coated catheters, tubing or balloons’ surfaces
• Adhesively bonding dissimilar materials (such as PTFE to metal or another polymer)
• Managing surface treatment processes that promote adhesion, like plasma treatments
• Verifying the presence and uniformity of coatings
• Ensuring that cleaning steps are removing organic contaminants from material surfaces
• Conformal encapsulation of electronic components of medical devices to protect them from moisture and contamination
• Bonding polymer overmolding on connectors and implantables
• Ensuring uniform coatings on diagnostic plates and equipment
• Verifying treatment of medical tubing prior to connector bonding

All of these characteristics depend on surface properties, and manufacturers need a way to test the surface quality of their materials using a method that not only suits the needs of the research and development laboratory but is also useful in actual production settings. Being able to use the same measurement and test equipment in the laboratory as well as production means manufacturers will be able to decrease the time to get products out of the design phase.

Many manufacturers do most of their high level performance testing before moving to production. The idea is to get the manufacturing process - with all of its operational requirements, cleanliness and sanitation standards, and performance protocols - fully vetted before day one of production. Once the process has been established, it is extremely difficult to make changes, even necessary enhancements, because of the necessary and rigorous path to approval for all aspects of the manufacturing process.

It is very onerous for companies to reiterate their manufacturing process once things have been set in motion since the FDA requirements are so stringent. Attempting to implement even mild changes to a production process mid-production cycle can be extremely burdensome due to protracted approval proceedings and extensive quality assurance obligations. However, it should be noted that the introduction of an unobtrusive quality check into a process in order to support and optimize existing procedures can be easier than trying to alter those procedures with new equipment or cleaning and treatment operations.

There are many reasons why a manufacturer would want to implement a change to their process after initial production is underway.

• Less expensive materials become available
• New or additional cleaning and treatment equipment and procedures can be needed
• Verification of processes previously not verifiable due to the availability of new technologies
• Different handling or storage methods are needed
• More precise and accurate inspection equipment becomes available
• Cost saving measures in adhesives, coatings and deposition equipment become apparent
• New suppliers or component vendors
• Unanticipated changes to materials implemented by suppliers and vendors

Any of these changes can be mandated by new regulations or could be desirable due to cost considerations. Medical devices are extremely costly to produce in part because the materials are highly specialized and sophisticated and the process to get from the design stage to production is time-consuming and cost-intensive.

Because the barriers to altering approved processes are so great, implementation of changes that can reduce cost or improve quality frequently have to wait for introduction of upcoming generations of the products. It’s critically important to make sure that the path from development to manufacturing is as short and efficient as possible.

Anytime that the same techniques used in product development can be directly applied to manufacturing quality control, the path from development to manufacturing is shortened. Such methods are extremely valuable.

Quality testing is nothing new to medical device manufacturers. Process validation is one of the most crucial parts of getting a product out of development and into production. This process validation includes meeting intense prerequisites according to the codes and guidelines like ISO 13485 and the FDA’s Quality System Regulation 820.75. Both of these lay out the necessary evaluative steps, documentation and control procedures companies must go through and provide in order to have the process by which their products will be built approved.

This essential obligation serves a very important role to ensure that these critical products are consistently defect-free. The stipulations in the guidelines are designed to set manufacturers up for success even though they are simultaneously rigid and demanding. The goal is to protect the people who will be using these often life-saving medical devices and, in turn, protect companies from being in the unenviable position of sending faulty medical products out to the market.

These regulations and requirements for process validation are not always easy to understand and, at times, manufacturers can fail to completely implement them. Noncompliance to these stipulations can result in audits leading to starting the entire process over causing major production delays, or worse, sending out products that are not guaranteed to work properly.

In the context of compliance with these standards, process validation means knowing and controlling process input parameters that assure the manufacturing process only releases products that conform to the specifications for a reliable, flawless device. Essentially, a validated process is the one that has been proven to only produce products that will work exactly how they are intended to. These devices are too important to let even one unit make it through the process with the possibility of it not being totally within spec.

Compliance also includes re-qualification of equipment or processes anytime there is major maintenance or any modification done. All of the initial validation procedures, and any subsequent validation, needs to be exhaustively documented in the Validation Master Plan (VMP) which is an instructional record outlining all validation activities as well as a document of compliance with regulatory expectations for proper process control.

Validating processes to ensure this level of performance is possible through strict statistical analysis of the process. The validation should ensure that when the process operates correctly, the process output (i.e. the product) is correct. In other words, when the process input parameters are in the acceptable range, the process produces only conforming products. When all of the operations, equipment, and all other parameters that will be used in the manufacturing process are heavily tested and vetted, manufacturers can have the assurance that the production lines they subsequently build will yield exactly what they desire.

This assurance isn’t possible without quality checks and verification happening during the manufacturing process itself as well. The FDA’s QSR, 820.75(b) even stipulates that you must have procedures for monitoring and controlling process parameters to ensure you meet specified requirements. If manufacturers choose to “fully verify” their products “by subsequent inspection and testing” throughout their manufacturing line (as the QSR states), they can reduce, or even eliminate, costly process validation procedures during product development.

There can be a range of acceptability for all inputs into a manufacturing process, but how can a manufacturer be certain all of the cleaning, coating, bonding and assembly operations are within this range? The QSR 820.75 mandates monitoring at a determined interval and frequency (based on statistical analysis) but continuous monitoring is preferred. You should periodically evaluate the monitoring interval and frequency as well—especially if you change the process or uncover a deviation from the specification.

The class of a medical device will also determine what level of testing and validation is required. The classification of medical devices is based on the nature of contact with a patient. Re-usable examination tools with incidental patient contact might be tested for function and, possibly, bioburden (1). Implantable medical devices with years of intimate, internal patient contact might also be tested for endotoxins (2), cytotoxicity (3), sterility, as well as functionality.

• Bioburden is the amount of viable microbes on the surface of a device and this amount must be lower than the limits outlined for sterilization.
• Endotoxins are bacterial contaminants that are released when a cell disintegrates. Any time a medical device comes into contact with water during a manufacturing process there is a possibility of endotoxin contamination.
• Cytotoxicity refers to leachable components within medical devices that can damage or kill human cells and prove to be toxic to patients.

Each of these threats have assays and tests to assure they are neutralized during production. These are some of the things that make process validation so much more intensive for medical device manufacturers, as several points throughout production microbes, bacterial and chemical contamination can interact with the surfaces of the devices.

The FDA lays out the current good manufacturing practice (CGMP) ordinances in their Code of Federal Regulations. The CGMP principles require that “manufacturing processes be designed and controlled to assure that in-process materials and finished products meet predetermined quality requirements and do so consistently and reliably.” In the FDA QSR 820.75(a) it 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.”

The FDA does not quantify what “fully verified by subsequent inspection and test” specifically is, but, to illustrate their seriousness about this requirement, they have censured a company for not “fully verifying” products on the basis that the company was not doing 100% testing on all products during production. The censured company was using an ultrasonic cleaning step and a passivation treatment on medical devices. The product testing being done was only conducted on a few samples that went through the manufacturing process. In this regard, “fully verified” can be taken to mean every single product that goes through an unvetted process must be inspected and tested to authenticate that they were all completely cleaned and assembled according to the prescribed requirements.

One of the reasons this is difficult for companies to do, even though the idea of not going through the comprehensive and expensive process validation proceeding is very attractive to manufacturers, there are not many testing methods suitable for use in a production setting.

Some of the analytical testing that goes into new product development or even just making improvements to a current product or process include some of the following testing methods:

Anytime a new piece of equipment is introduced, regardless of the function of that equipment, companies will go through vigorous Installation Qualification, Operational Qualification, and Performance Qualification testing. Equipment validation is a critical element of overall process validation. This goes for physical equipment as well as software. Each of the three qualification types are used to determine if the equipment meets requirements for:

• how equipment is configured within the manufacturing process (i.e. the placement of the equipment and its relationship to other equipment in the facility)
• how that equipment works (calibration needs, safety concerns, and other operational parameters)
• how well the equipment outputs products that fall within the performance requirements of the manufacturer.

Chemical contaminants are a real concern in the manufacture of medical devices. Lubricants, plasticizers, and detergents are just some of the undesirable residues that might remain on a device after manufacture, storage and cleaning. Total organic carbon (TOC) tests are indirect methods of evaluating the amount of organic matter present on a surface which can indicate the presence of these sorts of contaminants. It’s typically performed by using a swab or wipe moistened with highly-purified water and flushing that sample in a TOC analyzer with nitrogen or helium to remove all the inorganic carbon and leaving behind just the organic carbon material for measuring.

Testing the frictional qualities of surfaces is extremely important to medical device manufacturers since so many of the products they build are used for bodily insertion. The coatings on these devices need to be highly lubricious and virtually frictionless so they are as comfortable and safe for the patient as possible. Friction can be measured by what is known as a pinch test. In a pinch test, a coated device is pulled between the jaws of a clamp. While clamped, the coated part is pulled at a fixed speed for a fixed distance, and the resistance to the pull is measured in grams of pull force. A similar test, usually for films and flat materials, utilizes a plate that is slid over the surface of the material being tested. The grams of pull force needed to overcome the friction produced by the clamps divided by the clamp force is the calculation for the coefficient of friction (CoF). CoF = Forcepull/ Forceclamp. The higher the pull force needed, the higher the coefficient of friction and the lower the lubricity of the surface. The lower the pull force, the lower the coefficient of friction and the higher the lubricity.

Sterilized surfaces can still be contaminated with endotoxins that could make patients sick. Endotoxin contamination can even be engendered by sterilization techniques like killing bacteria during an autoclave or oven operation during production. Endotoxins are cast off by the dead (often water borne) bacteria’s deteriorated cell walls so when they are killed throughout the manufacturing process, endotoxins can be introduced onto the products. Detection of endotoxins is often tested by the fascinating Limulus Amoebocyte Lysate (LAL) assay. This test mixes the sample water with a test fluid derived from the blood of horseshoe crabs. The presence of endotoxin mixed with LAL causes LAL to clot. When LAL is standardized, quantification is possible.

During process validation, research laboratories will employ a variety of methods of identifying and quantifying chemical residues and contaminants found on the surfaces of materials used in the manufacture of medical devices. Some of these residues are detrimental to operations such as coating, bonding and sealing and some are less so. But, in order to create specifications for what is an acceptable amount of any given substance on a surface, scientists must understand:

• What is present on the surfaces
• What quantities of each contaminant is present
• How they can be prevented from arriving on the surface
• How they can be removed from the surface
• What are the effects of these substances on manufacturing operations

Some of the ways laboratories conduct this analysis is through techniques such as:

• Liquid chromatography
• Gas chromatography
• Mass spectroscopy
• Infrared spectroscopy
• X Ray photoelectron spectroscopy
• Titration
• Direct uv spectroscopy
• Ion chromatography

All of these methods give researchers information about what kinds of substances are on a surface and in what quantities. Paired with other tests to understand the impact of these substances is necessary for fulsome process validation.

Contact angle (CA) techniques are another widely used laboratory method for quantitatively sensing materials surface properties such as cleanliness or treatment level. It’s a simple technique yet extremely sensitive. A drop of liquid (usually water) is placed on a surface and the angle established between the drop perimeter and the surface is measured. The angle is directly related to the surface energy of the material, which is a measure of its chemical reactivity. If the drop is attracted to the surface strongly, it spreads out and establishes a small angle. If the drop is attracted weakly, the liquid remains beaded up and establishes a large angle. A higher angle equates to lower surface energy and a lower angle equates to higher surface energy. Contaminants tend to decrease the surface energy, while cleaning and surface treatments usually increase it. A material with high surface energy is highly reactive and attracts other substances (e.g. adhesives, coatings, paints, inks or contaminants) to it, while a material with low surface energy is non-reactive and inert.

Contact angle measurements are not a test for sanitation or bioburden. While a biofilm would be readily detectable via contact angle methods, the minimum number of microbes necessary to render a surface non-sterile is so small that they would not alter the overall surface energy enough to measurably change the contact angle.

Contact angle measurements are not just used to sense cleaning or surface treatment. These measurements are excellent for ensuring that a hydrophobic coating has been uniformly applied to a wire, catheter, or medical device.

In research and development laboratories, contact angles are typically measured using a bench top goniometer. A planar, smooth sample is placed on a stage, a drop of liquid gently placed on the surface via a syringe, and the contact angle is measured from a side view of the sessile drop. Portable contact angle measurement devices have recently become available to make this validation method possible directly on the factory floor in both handheld and automated solutions. Because results are displayed quantitatively as an exact contact angle, there is no subjectivity and the measurement correlates directly to predictable adhesion and cleanliness.

Contact angle measurements can be key in bridging the gap between the laboratory and the production line. With technology designed to make testing surface energy easy, fast and consistent on real products at any critical point during production, manufacturers can use a proven testing method in a new and effective way for product verification.

A major hurdle for manufacturers has been the difficulty of testing on the unique geometries of their products. With an in-line contact angle measurement system, almost any curved, angled, or grooved surface can be tested on due to the patented ballistic deposition of the probe fluid. When the volume of the fluid is controlled, essentially allowing for extremely tiny drops to be deposited in places that have heretofore never been able to be tested for cleanliness before, then the measurement can be done on any surface.

Medical balloons, populated circuit boards, catheters of nearly all diameters, metal components with recessed channels and even tiny diagnostic wells on microplate assays can be tested to substantiate that process requirements were met throughout production using contact angle measurements.

Contact angle measurements can also be used to determine if a hydrophobic or hydrophilic coating has been uniformly applied to a wire, catheter, or medical device (i.e. the surface needs to repel or attract fluids). Inconsistent contact angles over the entirety of a surface can indicate the coating was not uniformly applied. Using contact angle measurements for coating inspection correlates well to coefficient of friction testing and could enhance or replace common testing methods. Being able to characterize an entire surface is one of the reasons taking measurements in batches to map out the quality of a whole surface is extremely useful. This information can help identify ways coating deposition equipment might be inconsistent or indicate that treatment processes require optimization.

Contact angle measurements can be done with liquids other than water. Even highly-purified water can have unacceptable endotoxin levels. But endotoxin-free water is available for processes where sanitization needs to be maintained. The portable and automated contact angle measurement devices utilize touchless inspection heads so the pure liquid is all that comes into contact with the surface, preserving its pristine condition. Product verification often leads to a tremendous amount of scrap for manufacturers since the tests they currently use are destructive to products that need to maintain very specific levels of cleanliness and sanitation. A nondestructive test like a contact angle measurement is the perfect replacement for methods that increase the cost of manufacturing.

Contact angle measurements are also powerful supply chain control tools. Manufacturers can quantify the quality and cleanliness of incoming components from suppliers to certify that every aspect of production is falling within the designated specifications. Some companies require contact angle measurements as mandatory quality tests from their suppliers and then verify the data their vendors provide with a subsequent check of all incoming materials. Measuring incoming parts also allows manufacturers to detect undisclosed changes in the material, shipping process, or cleaning prior to shipping that could throw off their highly calibrated production process.

Creating a common language through shared quality measurement techniques eliminates barriers to smooth, quick problem solving and stopping issues before they get very far. With inspection equipment that can take contact angle measurements and share the data in real time, this kind of quality assurance can be done remotely and potential issues can be flagged and handled fr om anywhere in the world, saving companies millions of dollars in carting engineers all over the globe.

Being able to fully verify products as opposed to only validating the entire process ahead of time creates an unprecedented level of assurance that isn’t even possible with any amount of testing and planning before production. Even with rigorous analysis and process validation prior to production, the outcomes still rely on the process meeting all of the requirements established at the outset. Without verification, monitoring and in-line inspection, these cleaning, coating, bonding and treatment steps are partially left up to chance.

In a manufacturing field like medical device engineering, failure isn’t an option and assurance that everything will proceed the way it was designed to is paramount. The only way to accurately predict the successful performance of medical devices is to have data-driven inspection and continuous monitoring at every point in production where the material surfaces can be altered, either intentionally or unintentionally, with good or bad outcomes. These places in the manufacturing process are called the Critical Control Points (CCP). When the inspections of these CCPs correlate perfectly with analytics from the research and development lab then there isn’t a regulatory guideline in the world that these measurements wouldn’t fulfill.

Medical device manufacturing CCPs include:

• Supply side inspections
• Quality inspections of all received materials
• Before and after any cleaning step (e.g. aqueous baths, solvent cleaning, etc.)
• Before and after any surface treatment step (e.g. plasma, laser etching, vapor degreasing, etc.)
• Before and after storage
• Before and after coating
• Before and after printing and labeling
• Before adhesive bonding
• Before packaging
• Before sealing

Brighton Science is dedicated to helping medical device manufacturers gain the assurance they need to confidently meet all FDA requirements and build the most reliable products possible. Through process validation and exhaustive product verification - using the proper inspection techniques, equipment and data - predictable performance and product quality are absolutely possible to achieve.

Our approach begins with our Process Experts building a test plan alongside our customers to understand the needs of a proposed or existing production process. We proceed with a Process Walk where our experts examine the manufacturing operations to identify the Critical Control Points and make best practice recommendations about how to properly manage these areas.

Our Material Science Experts have the equipment and experience required to do extensive root cause analysis to determine the sources of variables that could cause a product to fall out of specification. They provide optimization strategies for getting the most out of cleaning and treatment equipment.

We help get new processes online by ensuring validation is occurring throughout the scaling up to production. We can help determine surface quality specifications that need to be put in place at the inception of new processes, streamlining the design to production pipeline. We also help characterize performance of output and offer products that monitor and verify all of these standards at each Critical Control Point.

For more information about how Brighton Science works to give confidence and clarity to manufacturers, download the eBook: Brighton Science's Guide to Adhesion Science for Flawless Manufacturing. Schedule a call to learn how to shorten process validation time and satisfy FDA standards.