1 Applying Cleaning Validation Principles in the Manufacture of Medical Devices and Diagnostics August 20, 2014 IVT San Diego Destin A. LeBlanc Cleaning Validation Technologies 2014 Destin A. LeBlanc
Focus Initial device manufacture Three areas we will cover In vitro diagnostics Implantables Non-implantables 2
3 Won t cover Cleaning of reusable devices Reprocessing of single use devices In vivo diagnostics
In vitro diagnostics Product types Liquids Solids Solid on substrate Production issues are similar to standard pharmaceuticals Liquid doses Tablets/Powder doses Patches 4
Differences? Scale of manufacture may be much smaller Larger number of products on same equipment Limits are not set on dosing and toxicity, but rather on possible interferences with subsequent diagnostic performance 5
How set limits? What effect of carryover on - Performance of next diagnostic Wrong values False positives False negatives Stability of next diagnostic Others? 6
Carryover study? Spiking study in lab Diagnostic A into Diagnostic B at different levels Evaluate Performance of B Stability of B (performance at end of approved shelf life) 7
Acceptable carryover? Highest level with no effect (NOAEL?) Consider additional safety factor (particularly if are able to achieve values significantly below the NOAEL) 0.5 0.2 0.1 8
Every combination? Depends on validation approach Best to use grouping approach Diagnostic most difficult to clean Diagnostic most sensitive to interferences (based on R&D work or scientific judgment) Consider types of interferences and determine whether most critical ones are components of other diagnostics 9
Also consider Effects of residues of cleaning agents Effects of bioburden residues Finally, for small scale consider disposables (such as tank liners) 10
Non-implantable med devices Examples Blood pressure cuffs IV supports Oxygen masks 11
12 Residues Bioburden Cleaning agents Extractables Processing Chemicals
Risk Assessment Bioburden Skin Irritation Functionality Concerns Materials compatibility Lower risk than implantables Some of same issues for analysis and sampling as for implantables 13
Implantable med devices Examples Knees Hips Bone screws Artificial hearts Focus for this talk will be metallic implantables 14
Higher risk Issues Implantables Biocompatibility Functional compatibility Bioburden/endotoxin Systemic toxicity Materials compatibility 15
How different from pharma? Pharma: clean equipment used to manufacture drug Implantable med device: clean the device itself May also clean the equipment used to manufacture device To minimize residue on device To maximize efficiency 16
Possible target residues Manufacturing aids Cutting fluids Coolants Burnishing agents Cleaning agent Bioburden Endotoxin Particles 17
Acceptable level? Based on potential effects of residue on device use Possible effects & issues Biocompatibility Other safety/toxicity issues Functionality May utilize a safety factor 18
19 Possible types of limits Visual Chemical Bioburden Endotoxin Particles
20 Limit for endotoxin Will test devices for endotoxin because of FDA concern Limit based on current standard for medical devices 20 EU per device
Limit for bioburden Will generally test for bioburden to conform to sterilization validation For established device, bioburden limit based on historical data Mean plus 3 standard deviations Default such as 10 CFU per device For new device, base on data for similar device, or on educated estimate With good cleaning, bioburden should be low 21
Limits for process chemicals Option 1 for limits For established product- Assume current production is acceptable Measure residue on current production (3 lots) Set limit at mean plus 3 S.D. 22
Example - Option 1 Measure TOC (μg C/device) on 5 devices each from 3 lots Lot 1: 12, 15, 11, 18, 8 Lot 2: 7, 14, 20, 19, 13 Lot 3: 21, 16, 10, 12, 15 Mean = 14 S.D. = 4 Limit is mean + 3 S.D. = 26 μg C per device 23
24 Option 1 limit For protocol, each device must meet this requirement May also consider a limit for each lot average (e.g., mean + 1 S.D.) Why not more stringent? If changing the cleaning process for better cleaning, may make it more stringent
Process chemicals Option 2 for limits For new product- Determine possible residues Spike clean devices with one or more levels of those residues Test for biocompatibility Lowest level with acceptable results is limit May consider safety factor May consider combination spike (multiple residues) 25
Example - Option 2 Only one process cutting fluid used Spike devices at levels of (for example) 10, 20, 40 and 80 μg of cutting fluid per device Test by appropriate biocompatibility procedure(s) Lowest level with acceptable response is limit 26
Example - Option 2 (cont.) Results 10 μg pass 20 μg pass 40 μg pass 80 μg - fail Limit would be set at 40 μg cutting fluid/device Could add safety factor & use 20 μg 27
28 Example - Option 2 (cont.) Alternative: If know expected levels, test only one level (above expected level) by biocompatibility tests If it passes, it is acceptance limit Example Expect data of 20-40 μg cutting fluid per device Spike only at 50 μg and test for biocompatibility If 50 μg passes, it is set as limit
Issues in limits Effect of residue based on Residue per device? Number of devices implanted or used? One time use or multiple frequency? Is effect based on total residue or residue per surface area? 29
30 Cleaning agent limits Use same principles as for process chemicals with additional option Measure baseline for setting limits Spike with known amount(s) to determine limit based on biocompatibility Determine systemic toxicity of cleaning agent (ADI) ADI estimated based on LD50 Same route of administration (IV for systemic effects)
31 Cleaning agent systemic toxicity Determine from short term LD 50 values Calculate ADI (acceptable daily intake) from short term toxicity by IV route and body weight Base limit on number of devices implanted/used at one time May use additional safety factor
32 Particulates Difficult to establish limits based on spiking and biocompatibility testing Which particles? What sizes? Better approach is to base on baseline data from previous production or for similar product with good track record
Why limits for particulates? It is a good measure of overall cleanliness Like TOC can t tell you what particle is due to, but is good indicator of consistency Need to combine with other measures 33
Target chemical residues Analytical method dependent upon type of residue Select target residues first Processing chemicals Cleaning (or passivation) agent Bioburden Endotoxin Particles 34
35 ASTM method ASTM subcommittee F04.15.17 Extraction of metallic implants Solvent extraction (ultrasonic or reflux) measure dissolved residue gravimetrically Aqueous extraction (ultrasonic) measures dissolved residue gravimetrically Debris (particulate) - insoluble residue by filtration with gravimetric measurement
36 ASTM method (2) What measures Total extractable residues on device by that extraction procedure Is it a good method? Yes, for intended purpose
37 ASTM method (3) Should it be used for cleaning validation? May not be a good measure of cleaning effectiveness Key is before and after results May be a sledgehammer, when a rubber mallet is needed Note: This is my opinion and is definitely not shared by all
Processing chemicals Most are mixture; most are organic Does one use method for a specific component of a possible residue? HPLC FTIR UV Does one use method for a general characteristic of a possible residue? TOC Non-volatile residue (NVR) Conductivity 38
39 Other methods Auger electron spectroscopy ESCA GC-MS or HPLC-MS May be good for investigation of problems to narrow nature and cause but probably should be avoided for validation purposes
40 Cleaning agents Generally will measure cleaner Two limit approaches Limit of cleaner as whole (most common) Limit for each component (less common) Two analytical approaches Measure individual species (representative) within cleaner Measure gross property (e.g., TOC)
41 Bioburden testing Extraction and count Focus on total aerobic count Same method as for bioburden for sterilization validation
42 Endotoxin testing Extraction and measure Gel clot Kinetic USP / AAMI
43 Particulate testing Sample and measure USP <788> Extract or flush sampling Usually extract with water Particle sizes 10-25 μ >25 μ
44 Sampling methods Direct surface (fiber optics) Swab Extraction
45 Direct surface Advantages Immediate results Simplified concept Can focus on worst case locations Avoid recovery issues Issues May requires flat surfaces Calibration Interferences
46 Swabs Advantages Direct surface sampling Can focus on worst case locations Mechanical means of removing substances Issues Swab must release analyte Care in swab handling procedures Interferences from swab Swabbing is a manual procedure
47 Extraction Advantages Samples all surfaces, including hard to reach Can add sonication/shaking Can vary extraction fluid Consistency Issues Must assure conditions/fluid are adequate to dissolve residue Volume of fluid may limit detection limit
Exhaustive extraction Want to make sure extraction is adequate Time Temperature Extracting solvent Sonication/shaking 48
Is extraction adequate? Option 1: Extract different samples for different times and compare Sample A: 10, Sample B: 20, Sample C: 30 Assumes initial samples are the same Option 2: Extract same sample multiple times Sample A: 10 and test; additional 10 and test; additional 10 and test 49
50 Extraction example #1 Results are average of three devices at each time under defined extraction conditions. Time Results for device A Repeat Results 10 minutes 15 μg 13 μg 20 minutes 20 μg 19 μg 30 minutes 20 μg 19 μg
Extraction example #2 Results are average of three devices at each time under defined extraction conditions. Time 1 st 10 minutes 2 nd 10 minutes 3 rd 10 minutes Results for device A Repeat Results 15 μg 13 μg 5 μg 6 μg <1 μg <1 μg 51
52 Recovery studies Procedure Spike clean device with known amount of residue Allow to dry Remove in sampling procedure Analyze Compare to amount spiked Done at acceptance limit on device
Recovery problems Possible causes of low recovery Volatility of spiked material Residue adhesion to surface Interferences Possible cause of high recovery Interferences 53
54 Recovery issues For different sizes In general, recovery may decrease as size increases provided extraction volume constant Worst case = largest device For different geometries In general, recovery may decrease as complexity increases provided extraction volume constant Worst case = more cuts, cannulations, etc.
55 Validation protocols Do not reinvent the wheel Follow your company s practices for other process validation protocols - cleaning is another process!!
Critical regulatory document GHTF SG3/N99-10 (2004): Process Validation Guidance http://www.imdrf.org/docs/ghtf/final/sg3/tech nical-docs/ghtf-sg3-n99-10-2004-qmsprocess-guidance-04010.pdf Global Harmonization Task Force replaced by International Medical Device Regulators Forum (IMDRF), but GHTF document still used Also note that cleaning is just a process and covered by process validation guidance 56
Validation vs. verification Verification Establish by examination and provision of objective evidence that the specified requirements have been fulfilled (verify device) Validation Establishing by objective evidence that process consistently produces product meeting requirements (validate process) 57
58 Fully verifying for cleaning How can fully verify results of cleaning process? Test every device May be possible with nondestructive testing May be more feasible with small number of extremely high value devices
GHTF decision tree Is output verifiable? Yes, and verification is sufficient, then fully verify No, then either validate or redesign process GHTF SG3/N99, section 3.1 59
How apply to cleaning? Cleaning generally viewed as swing process If can test 100% by non-destructive (and non-contaminating) test procedure (such as FTIR), may not need to validate However, for many applications, have to or will want to validate 60
New ASTM guide? Working on new guideline WK33660 Guide for Validating Cleaning Processes Used During the Manufacture of Medical Devices Not yet finalized and approved 61