U.S. Food and Drug Administration

Catalog of Regulatory Science Tools to Help Assess New Medical Devices 

 

The CLAP tool is chemical dataset intended to help analytical laboratories demonstrate their ability to detect the broad range of chemicals that may be encountered in a non-targeted analysis as part of a comprehensive extractables leachables program.

 

Technical Description

CLAP is a collection of over 100 example chemicals that have been characterized in CDRH laboratories and are provided with the following information:

• Trivial/ common name or acronym
• Full name and CAS#
• Empirical formulae
• Double bond equivalent (DBE), range -2 to 25
• Molecular Weight (g mol^-1), range 102 to 1178
• Boiling point (°C @760 mmHg), range 148 to 922
• pKa, range -9.1 to 18.25
• LogP, range -0.7 to 23
• Refractive Index, range 1.289 to 1.757
• Relative Response Factor (RRF) for GCMS and LCMS (both positive and negative ion detection modes), determined against the internal standard (code RM5) 2,4-Di-t-butyl phenol at concentrations of 5µg ml^-1 , 10µg ml^-1 , and 20µg ml^-1 .

 In addition, the specific gas chromatography mass spectrometry (GC/MS) and Liquid Chromatography mass spectrometry (LC/MS) parameters used to determine the RRF for each chemical are provided. 

 

Intended Purpose 

The information is intended to be used by analytical chemistry labs to determine their ability to detect chemicals of sufficiently broad physicochemical properties.  The chemicals have been specifically chosen to represent broad physicochemical properties and are readily available.

Using the GC/MS or LC/MS parameters provided or variations that have already been developed by individual laboratories, detectability of the chemicals is assessed by the chromatographic relative response factor. Demonstration that the techniques used can detect chemicals across a broad set of all physicochemical properties of chromatographic importance is an important surrogate measure for the completeness of non-targeted analysis during chemicals characterization of medical device extractables. 

The set of RRFs measured can then be used to populate a coverage map comparing the RRFs obtained across the breadth of physicochemical properties. Such data may be useful in chemical characterization as described in the International consensus standard ISO10993-18 “Biological Evaluation of Medical Devices. Part 18: Chemical characterization of medical device materials within a risk management process.”

As a part of premarket biocompatibility evaluation for medical devices, appropriate chemical characterization is an essential step to inform the toxicological risk assessment (TRA) process and determine the benefit risk profile for a medical device.

Use of the coverage map approach outlined in this tool increases the confidence that all relevant chemicals have been detected, allowing for identification and TRA to be conducted.

GCMS Testing

• All testing was undertaken in the OSEL labs using an Agilent Technologies 6890N gas chromatograph coupled with an Agilent Technologies 5975B mass spectrometer.
• The columns used were an Agilent HP-5MS (30m X 0.25mm i.d., 0.25µm) and an Agilent DB-5HT ((30m X 0.25mm i.d., 0.1µm). Helium (99.999% purity) was used as the carrier gas at a flow rate of 1mL min^-1.
• Injection volumes were 1µL or 2µL.  Other parameters were:

 

LCMS Testing

• All testing was undertaken in the OSEL labs using a Thermo Scientific^TM Vanquish^TM LC system coupled with a Thermo Scientific^TM Q Exactive^TM HF hybrid quadrupole-Orbitrap spectrometer.
• The LC column used was an Agilent Zorbax Eclipse Plus C18 (2.1 X 100mm, 1.8µm) and the Guard Column used was an Agilent Zorbax Eclipse Plus C18 (2.1 X 100mm, 1.8µm). 

• Injection volumes were 1µL.  Other parameters were:

   

Parameter	Value
Mobile Phase A	H2O with 0.1% formic acid
Mobile Phase B	Acetonitrile with 0.1% formic acid
Ionization Source	Heated ESI
Flow Rate	0.4ml min-1
Capillary Temperature	320OC
Spray Voltage, (Positive)	3.8kV
Spray Voltage, (Negative)	-3.5kV
LC Gradient 1	2%(0min)-2%(5min)-35%(20min)- 100%(40min)-100%(50min)-2%(55min)-2%(60min)
LC Gradient 1	0%(0min)-0%(5min)-10%(15min)-100%(25min)-100%(30min)-2%(35min)-2%(40min)
AGC Target (Full MS)	1,000,000
Max Injection Time	50 msec
Resolution	45,000
Scan Range (m/z)	100-1500

 

Limitations

• Use of the chemical data set does not guarantee that an appropriate range of detectability has been necessarily achieved.
• RRFs are highly dependent on the specific protocols used for GCMS and LCMS and should always be specified when using the chemical dataset to generate a coverage map. 
• The chemical data set has been designed to cover a specific range for each physicochemical property. The specific ranges should not be interpreted as a limit on the breadth of physicochemical properties of extractables that may be relevant for TRA.

Supporting Documentation

• Specific detailed reports on the materials investigated can be found on the FDA website here. 

Contact

• RST_CDRH@fda.hhs.gov

Tool Reference

• In addition to citing relevant publications please reference the use of this tool using RST24MC05.01