Examples of Modelling, Characterization & Problem Solving

Cetry helps medical device manufacturers and their suppliers by means of problem solving, process modelling, characterization of product properties, device and materials qualification, process and manufacturing validation, related regulatory issues, quality assurance, as well as design and build of specialized equipment. Here follow some examples of modelling, characterization and problem solving by Cetry.

List of Examples:

GPC Modelling

Coating model for UV-curable hydrogel

UV hydrogel coating consistency problems

Leakage through hub-catheter connection

In-vivo catheter friction problem

Coating adhesion problem

Residual solvent problem in biodegradable polymer

Improvement on competitor - hydrogel coating

Quality Control of coating solutions

Heparin leaching test

• Client:	Manufacturer of excipient materials
• Subject:	Variation in GPC outcomes due to polynome fitting

Gel Permeation Chromatography (GPC) is used to determine molecular sizes of mostly organic molecules, that in turn often relate to their molecular weights. For instance: Polyethylene glycol (PEG) is a linear polymer that comes in quite a variety of lengths and the mass varies linearly with the length. The GPC system uses a column filled with gel beads. A flow of solvent (e.g. water, THF, etc.) is established, going from one end of the column to the other. When molecules are injected at the start of the column, it will take some time for them to arrive at the end. Here, a detector (e.g. UV or IR) will measure the concentration of molecules arriving. The larger molecules will arrive first (assuming no adhesion occurs to the gel material) since they cannot travel through the pores of the gel. They thus experience a smaller column volume and will therefore travel faster from injection point (start) to detection point (finish). The detector will thus register arrival of certain molecular sizes as function of the travel time after injection.

Computer software, that normally comes with the GPC equipment, is able to compare the time-of-flight data with that of a calibration time-curve. This curve can be made by injecting known molecular sizes, ideally from molecules that are family of the ones under investigation. The match between the measured values and the calibration curve is usually done by simple general mathematical algorithms such as polynomes, logarithms, etc. These algorithms, however, have nothing to do with the actual physical properties of the GPC system.
A client, specialized in polymer synthesis and modification, experienced large fluctuations in outcome especially at the higher end of the scale, even though the column specification claimed this to be well within its limits. The data was processed by polynome fitting, as supplied with the software. Although the client was convinced that some of the materials that had been tested by means of GPC should have passed the criteria regarding molecular weight determination, the GPC software told otherwise. The products were kept in quarantine pending investigation.
Inspection of the data, by Cetry, quickly revealed that most of the fluctuation in this region of operation was caused by the fit-algorithm. Unfortunatelly for the user, no better algorithm was available. A physical model of the system, drawn by Cetry, proved to address the affected region with great stability, as was extensively tested/validated by means of repeated calibration runs and the like. The company was proved to be right about their material, and quarantine was lifted. Added advantage of the physical model was found at the low-molecular end of the scale, which now could be analyzed with extreme precision, even revealing the monomer weight of polyethylene glycol. The model extended the operation window of the column, thus also opening up new possibilities.

• Client:	Major European manufacturer of PTA and PTCA balloon catheters
• Subject:	Modelling of the entire coating process

The client requested full characterization and modelling of a UV-curable hydrogel coating. This was to be used for engineering purposes as well as registration support. The modelling and characterization included that of (1) the coating compounds, (2) the coating solutions, (3) the application mechanism (in this case: dip-coating), (4) UV exposure, (5) actual curing (both short-term and long-term effects), (6) friction properties, (7) in-vivo and in-vitro performance, (8) gel-particle generation upon use (USP/EP conform testing). The modelling involved a combination of a descriptive and a mathematical approach. This project was not only interesting from a technical point of view, but also from the point of co-operation between parties (well organized). The model directly generated spin-off and device upgrading.

• Client:	Major manufacturer of diagnostic catheters
• Subject:	Adhesion problem with UV-curable hydrogel coating

Testing had shown that coating adhesion was sub-standard for a fraction of certain types of hydrogel-coated catheters. Investigation addressed: coating integrity, condition of coating chemicals, preparation of coating solutions, storage of coating solutions, catheter materials comparison, surface cleanliness assessment, UV lighting, catheter shapes, heating during curing, handling and storage of the catheters, etc. Affected catheters were scrutinized and experiments were conducted to test some theories. It was found that certain catheter-tip shapes, in combination with the total catheter length, gave rise to UV-underexposure of certain parts. This explained the catheter-type correlation with coating quality. The UV exposure could be fixed with minor equipment adjustment, and the problem disappeared.

• Client:	Manufacturer of PTA and PTCA balloon catheters
• Subject:	Leakage between catheter and glued-on hub

There are a couple of well-established manners for connecting a hub to a piece of catheter tubing. Think of glueing, melting, screwing, or dissolving and mixing the materials. The client experienced difficulties with their glued-on hubs. It was found that small leaks had been formed between the hub material and the catheter. The client had also found out that this appeared after a couple of weeks. Cetry was asked to look into the matter. It was found the the glue, after UV curing, showed huge stress forces, which inevitably led to stress cracking between the glue and the bonding surfaces. We were able to demonstrate this by putting some glue on the bottom of a polycarbonate petri-dish, and wait for a couple of weeks (after UV curing) to find out whether the stress impact would become visible. Indeed it did! The hardened glue had cracked the polycarbonate beneath it and almost (literally) fell through. Possible solutions to the problem involved a.o. (1) use of less glue - requiring tighter tolerances between hub and catheter -, (2) use of a more compliant (rubbery) glue, (3) less UV exposure, so that less cross-linking will occur in the glue substance, (4) more homogenic UV lighting for more homogenic stress-force distribution. The client picked their own choice and the problem was solved.

• Client:	Major European manufacturer of diagnostic catheters
• Subject:	In-vivo friction from diagnostic catheters

Complaint rates had sky-rocketed for one of our client's diagnostic catheters. The physicians remarked that they experienced increased friction, compared to older products of the same type. The client immediately took action. With a medical coating involved, Cetry was asked to also look into the matter. Physicians were interviewed, production lines were inspected, complaint files were studied and the product itself was investigated. Scanning electron microscopy (SEM) revealed morphological changes of the surface in comparison to older catheters and a relationship was established between customer-complaint and certain surface roughness features - this is not an everyday result! The suspected coating had nothing to do with the problems. The cause of the increased surface roughness was quickly identified and corrected, so that the complaint rate dropped to its normal noise level. It was an interesting experience, because a clear effect on microscopic scale (surface morphology) resulted in such a massive effect on macroscopic scale.

• Client:	Manufacturer of diagnostic catheters
• Subject:	Coating adhesion problem - research phase

The client had problems with the development of a hydrogel coating for cardiology catheters. The project had come to a stop. Looking into the matter, Cetry was able to modify the coating solution, so that adhesion was improved to a level that allowed the project to move on again. Explanation was provided about adhesion mechanisms, stress-induced detachment, aging, layer-thickness control, etc.

• Client:	Manufacturer of biodegradable coating materials
• Subject:	Risidual solvent after polymer synthesis

The client had problems removing all solvent from a certain coating material, after its synthesis. Air drying, vacuum drying, etc. took away most of the solvent, but too high trace amounts were left behind. One of their customers complained about this high level of residual solvent, in the light of regulatory compliance. Looking into the matter, Cetry postulated that adhesion of the solvent to the coating material occurs at several energy levels. Think of weak adhesion versus incorporation into a crystalline structure. The latter requires more than vacuum or elevated temperatures to get rid of the solvent. A two-stage method was devised in order to bring residual levels down: (1) interchange of molecules, (2) break-down of crystalline structures without damaging the polymer (no scission, no oxidation). The method worked as intended, as was confirmed by extensive analyses.

• Client:	Major manufacturer of PTCA balloon catheters
• Subject:	Beating the industry's bench-mark coating

The request was to use the client's own coatings and coating materials in order to decrease in-vivo friction to levels of the (then) competitor bench-mark coating. Boundary conditions involved regulatory requirements (can the coating be modified within the current regulatory approvement?), manufacturing scale, patents and contracts, cost, and time. It was found that one of the ugly duck UV-curable hydrogel coatings could be turned into a swan by means of a combination of upgraded processing parameters and application mechanisms. In-vivo results proved that the bench-mark coating was beaten.

• Client:	Manufacturer of diagnostic catheters
• Subject:	QC difficulties regarding in-house mixed coating solutions

It was requested to provide quality control methods for various coating solutions that were made by the client's chemistry lab. Each solution consisted of various sorts of polymers and salts. The main question was: How can we detect whether a coating solution was prepared correctly or not? The lab was well equipped with all sorts of analyzers, which made it easy to start. Most chemical compounds showed unique fingerprints under infra-red or ultraviolet. One of the salts proved to be tricky - only trace amounts were used. None of the available analytical techniques were able to detect these small amounts, so that a new method was developed by Cetry. This new technique proved to be very capable of detecting the salt. The whole set of quality control tests was successively validated, with protocols provided by Cetry and implemented by the people who would have to work with the new Quality Control methods. Protocols and results were inspected and approved by the client's quality assurance unit. The tests then became standard (within the company) for this matrix of coating solutions.

• Client:	Start-up manufacturer of diagnostic catheters
• Subject:	Heparin leaching test - detection limit difficulties

The client was testing the possibilities of developing their own type of heparinized cardiology catheter. This required extensive characterization, ranging from biocompatibility testing to heparin leaching assessment. One of the problems was to actually quantify the very low amount of heparin that could leach out of the coating. Cetry was asked to solve this problem and applied its own in-house developed heparin leaching test. Its resolution goes down to less than 0.02 IU per square centimeter, typical accuracy is about 10%, and it involves an extensive in-test validation in order to substantiate the results. The heparin-leaching assessment was done for sterilized and non-sterilized samples. The test results were complemented by an extensive rationale in order to put the detected leaching quantities into (clinical/biological) perspective.