Legacy Evaluations - WuXi · PDF filelegacy evaluations: the process 2 Gap Evaluation Testing...

LegacyEvaluations

Ensuring your

commercialized

products meet

the current

regulations

legacy evaluations:the process

2

Gap Evaluation

Testing

Risk Assessment

Scalable Programs • Proven Performance

TRAININGTeam training and cross-training to maximize �exibility and meet project timing.

OPERATIONS Performance metrics to ensure best practices and consistency.

CAPACITYProactive planning to achieve program goals.

3

METHOD• Available data/reports review

• Current standards compared to work performed

DELIVERABLE: Final Report

• Summary table of work performed

• Gap analysis by section

• Summary table of gaps found

• Recommendation for remediation

gap evaluation

Test Test

Article Name

Final Report

Number

ISO 10993 Standard

References

Current ISO 10993

Version

ISO L929 MEM Elution

Cytotoxicity Test 10993-5:1999

10993-12:2002 10993-5:2009

10993-12:2012

ASTM Hemolysis Assay Direct

Contact Method

10993-4:2002 ASTM F-756-00 10993-12:2002

10993-4:2002 10993-12:2012

ISO Intracutaneous Reactivity Test 10993-10:2002

10993-12: 2002 10993-10:2010 10993-12:2012

ISO Guinea Pig Maximization

Sensitization Test 10993-10:2002

10993-12: 2002 10993-10:2010 10993-12:2012

I. Gap Analysis of ISO 10993-5

ISO 10993-5:2009, Tests for in vitro cytotoxicity is the current version of the standard. The requirements of ISO 10993-5: 2009 place emphasis on quantitative evaluation of cytotoxicity, the normative section of the standard references the MEM Elution Cytotoxicity test. According to ISO 10993-5, extractions are to be conducted per ISO 10993-12. A new version of ISO 10993-12 was released in 2012. There are many editorial changes implemented in the newer version that have no impact on testing. There were a few changes that were substantive. In reference to cytotoxicity testing, Section 10.3.1 now states “For medical devices which are in short-term contact with intact skin or mucosa and which are not implanted, extraction times of less than 24 h, but not less than 4 h are acceptable (see ISO 10993-5)”. This now allows for shorter extraction periods for cytotoxicity testing of certain devices. None of the recommendations for extract ratios or conditions have changed. In project reports, the extract ratio and conditions meet the requirements of ISO 10993-12:2012. No gaps were identified in cytotoxicity testing.

II. Gap Analysis of ISO 10993-4

No changes have been made to ISO 10993-4:2002 since testing was completed. However, this standard does expect use of the most current version of ASTM Hemolysis standard. The ASTM standard F-756-08 was updated in 2008. Many of the changes to the method were editorial in nature and did not specifically impact assay performance. The revised document did suggest the use of a cyanmethemoglobin reagent versus the use of Drabkin’s for measuring hemoglobin. Both are still considered acceptable, though Drabkin’s could have a slightly lower sensitivity to binding hemoglobin. Further, the 2008 version is stronger in its recommendation to test materials in both direct and indirect hemolysis assays. The project was performed as a direct contact assays using Drabkin’s reagent. From a technical perspective, the direct contact assay was performed in a manner consistent with the 2008 revision. However, an extract (indirect) version was not performed. The results from the direct contact assay were clearly negative. Based on intended clinical use, the direct method is an appropriate evaluation methodology.

Test Test

Article Name

Final Report

Number

ISO 10993 Standard

References

Current ISO 10993

Version

ISO L929 MEM Elution Cytotoxicity

Test 10993-5:1999

10993-12:2002 10993-5:2009

10993-12:2012

ASTM Hemolysis Assay Direct

Contact Method

ISO10993-4:2002 ASTM F-756-00 10993-12:2007

ISO10993-4:2002 10993-12:2007

ISO Intracutaneous Reactivity Test 10993-10:2002

10993-12: 2002 10993-10:2010 10993-12:2012

ISO Guinea Pig Maximization

Sensitization Test 10993-10:2002

10993-12: 2002 10993-10:2010 10993-12:2012

I. Gap Analysis of ISO 10993-5

ISO 10993-5:2009, Tests for in vitro cytotoxicity is the current version of the standard. The requirements of ISO 10993-5: 2009 place emphasis on quantitative evaluation of cytotoxicity, the normative section of the standard references the MEM Elution Cytotoxicity test. According to ISO 10993-5, extractions are to be conducted per ISO 10993-12. A new version of ISO 10993-12 was released in 2012. There are many editorial changes implemented in the newer version that have no impact on testing. There were a few changes that were substantive. In reference to cytotoxicity testing, Section 10.3.1 now states “For medical devices which are in short-term contact with intact skin or mucosa and which are not implanted, extraction times of less than 24 h, but not less than 4 h are acceptable (see ISO 10993-5)”. This now allows for shorter extraction periods for cytotoxicity testing of certain devices. None of the recommendations for extract ratios or conditions have changed. In project reports, the extract ratio and conditions meet the requirements of ISO 10993-12:2012. No gaps were identified in cytotoxicity testing.

II. Gap Analysis of ISO 10993-4

No changes have been made to ISO 10993-4:2002 since testing was completed. However, this standard does expect use of the most current version of ASTM Hemolysis standard. The ASTM standard F-756-08 was updated in 2008. Many of the changes to the method were editorial in nature and did not specifically impact assay performance. The revised document did suggest the use of a cyanmethemoglobin reagent versus the use of Drabkin’s for measuring hemoglobin. Both are still considered acceptable, though Drabkin’s could have a slightly lower sensitivity to binding hemoglobin. Further, the 2008 version is stronger in its recommendation to test materials in both direct and indirect hemolysis assays. The project was performed as a direct contact assays using Drabkin’s reagent. From a technical perspective, the direct contact assay was performed in a manner consistent with the 2008 revision. However, an extract (indirect) version was not performed. The results from the direct contact assay were clearly negative. Based on intended clinical use, the direct method is an appropriate evaluation methodology.

example

4

METHOD• Based on gap evaluation, select appropriate tests

testing – biocompatibility

biocompatibility test matrix

DEVICE CATEGORIES BIOLOGICAL EFFECT

Initial Other

Body Contact

Contact Duration

A – Limited

[ 24 hrs]

B – Prolonged [>24 hrs to 30 days]

C – Permanent

[>30 days]

Cyt

otox

icity

Sen

sitiz

atio

n

Irrita

tion

Sys

tem

ic T

oxic

ity (A

cute

)

Sub

chro

nic

Toxi

city

(Sub

acut

e)

Gen

otox

icity

Impl

anta

tion

Hem

ocom

patib

ility

Chr

onic

Tox

icity

Car

cino

geni

city

SURFACE DEVICES

Skin A B C

Mucosal Membranes

A B C

Breached or Compromised Surfaces

A B C

EXTERNAL COMMUNICATING

DEVICES

Blood Path, Indirect

A B C

Tissue /Bone/ Dentin Communicating

A B C

Circulating Blood

A B C

IMPLANT DEVICES

Tissue / Bone A B

C

Blood A

B

C

“TESTS FORCONSIDERATION”

Per ISO10993and FDA Guidances

● = ISO Evaluation Tests for Consideration

◊ = Additional tests that the FDA considers may be applicable

DELIVERABLE: Individual Final Reports

• Methods summary

• Results

• Evaluation

5

METHOD

• Design extractables study based on product risk

• Utilize multiple extracts

• Choose analytical methods based on expected chemicals


• Methods summary

• Results – chromatograms, spectra, calculated data

• Evaluation

testing –materials characterization

2540 Executive Drive • St. Paul, MN 55120 • 888.794.0077 • 651.675.2000 • Fax: 651.675.2005

CAS Name Formula RT Mass Score

(MFG) ug/

device 112-27-6 Triethylene glycol C6H14O4 2.39 150.0892 87.17 2 4918-95-0 2,6-Diisopropyl-4-((dimethylamino)methyl)phenol C15H25NO 9.25 235.1928 97.14 2

95656-85-2 Carbamic acid, [3-(methylthio)propyl]-, 1,1-dimethylethyl ester C9H19NO2S 10.02 205.1137 93.72 5

82349-74-4 Phosphorous acid, 2-(2-butoxyethoxy)ethyl 2-(2-ethoxyethoxy)ethyl2-ethoxyethyl ester C18H39O8P 10.69 414.2384 98.74 8

112-73-2 Bis(2-butoxyethyl)ether C12H26O3 11.07 218.1870 92.38 10

14960-11-3 Ethanol, 2-[2-[2-(dodecyloxy)ethoxy]ethoxy]-, hydrogen sulfate C18H38O7S 11.65 398.2319 81.60 103

194425-46-2 17-Sulfanyl-3,6,9,12,15-pentaoxaheptadecan-1-ol C12H26O6S 11.72 298.1458 87.79 7

258884-33-2

Pentacyclo[19.3.1.13,7.19,13.1,15,19]octacosa-1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-25,26-diol, 5,11,17,23-tetrakis(1,1-dimethylethyl)-27,28-bis[(dimethylphosphino)methoxy]-

C50H70O4P2 11.82 796.4741 89.91 19

78-51-3 tri(2-butoxyethyl) phosphate C18H39O7P 12.81 398.2421 95.27 41 na

Polyethylene glycol (PEG) related fragments (0 DBE)1

C2 H54O7 13.21 478.3861 88.39

11 C28H58O8 13.47 522.4123 88.51 C30H62O9 13.55 566.4382 86.63 C32H66O10 13.60 610.4655 80.49

124-26-5 Octadecanamide C18H3NO 14.22 283.2866 96.28 18


4 . 0 0 5 . 0 0 6 . 0 0 7 . 0 0 8 . 0 0 9 . 0 0 1 0 . 0 0 1 1 . 0 0 1 2 . 0 00

1 0 0 0 0 0

2 0 0 0 0 0

3 0 0 0 0 0

4 0 0 0 0 0

5 0 0 0 0 0

6 0 0 0 0 0

7 0 0 0 0 0

8 0 0 0 0 0

9 0 0 0 0 0

1 0 0 0 0 0 0

1 1 0 0 0 0 0

1 2 0 0 0 0 0

1 3 0 0 0 0 0

1 4 0 0 0 0 0

1 5 0 0 0 0 0

1 6 0 0 0 0 0

T im e - ->

A b u n d a n c e

T I C : 0 9 1 0 1 3 _ R e s e a r c h _ 0 0 4 . D \ d a t a . m sT I C : 0 9 1 0 1 3 _ R e s e a r c h _ 0 0 5 . D \ d a t a . m s ( * )

Test Number: R & D Project No. Internal

Page 2 of 21


data examples

6

METHOD

• Review available data/reports

• Review literature and databases

• Calculate risk factors

risk assessment

example of report contentWuXi AppTec Report No. 194366 Page 2 of 66 _________________________________________________________________________________________

! Proprietary Information!


Table of Contents

Approvals: ............................................................................................................................................. 1!

1.0! Executive Summary ................................................................................................................... 3!

2.0 ! Background and Purpose .......................................................................................................... 3!

3.0 ! Test Article / Device Identification ............................................................................................ 3!

4.0 ! Test Article / Device Classification ........................................................................................... 3!

5.0! Test Article / Device Description ............................................................................................... 4!

6.0 ! Chemical Characterization ......................................................................................................... 4!

Table 1: Chemical Characterization Analysis Summary ................................................................. 4!

7.0 ! General Toxicological Risk Assessment Approach ................................................................ 4!

7.1! Determination of Tolerable Intake (Hazard Identification and Dose Response Assessment) (General Approach) ............................................................................................ 5!

Table 2: Use of Modifying Factors (ISO 10993-17) ........................................................................... 6!

7.2 ! Exposure Assessment ............................................................................................................... 6!

7.3 ! Risk Characterization ................................................................................................................. 6!

8.0 ! Databases .................................................................................................................................... 7!

9.0 ! Risk Assessment of Extractable Chemicals ............................................................................ 7!

9.1 ! Extractables Chemicals by GC-MS (Hexane Extract) .............................................................. 8!

Table 3: Risk Assessment of Extractable Chemicals by GC-MS (Hexane Extract) ..................... 25!

9.2 ! Extractable Chemicals by LC-MS (IPA/Water Extract) .......................................................... 29!

Table 4: Risk Assessment of Extractables by LC-MS (IPA/Water Extract) .................................. 43!

9.3! Extractable Metals by ICP-MS (5% Nitric Acid (HNO3) Extract) ........................................... 49!

Table 5: Risk Assessment of Extractable Metals by ICP-MS (5% Nitric Acid (HNO3) Extract) .. 52!

9.4 ! Extractable Chemicals by HS/GC/MS (Water Extract) ........................................................... 53!

Table 6: Risk Assessment of Extractable Chemical by HS/GC/MS (Water Extract) ..................... 54!

10.0 !Biocompatibility Testing .......................................................................................................... 55!

Table 7: Summary of Biocompatibility Testing .............................................................................. 55!

11.0 ! Discussion and Conclusion ..................................................................................................... 56!

12.0 ! References ................................................................................................................................ 57!

13.0 ! Acronyms and Abbreviations .................................................................................................. 66!


• Summary opinion

• Extractable/leachable data

• Potential breakdown products, and mechanism by which they are formed

• Complete chemical formulations

• Final toxicological evaluation ofall available data

7

Typical Program for Long-Term Implant in Bone

BIOCOMPATIBILITYCytotoxicity

Genotoxicity• Ames • Mouse Lymphoma• Mouse Micronucleus

Irritation – Intracutaneous

Sensitization – Guinea Pig Maximization

Acute Toxicity

Subacute/Subchronic – 14-day/14-dose

Implantation – 2-week, 13-week, 26-week

MATERIALS CHARACTERIZATIONExtractables

• Non-Polar • Mid-Polar • Polar

LeachablesDependent on extractables results

RISK ASSESSMENTEvaluation of Biocompatibility

Toxicological Evaluation of Chemistry

Typical Program for Instruments

BIOCOMPATIBILITYCytotoxicity

Irritation – Intracutaneous

Sensitization – Guinea Pig Maximization

Acute Toxicity

MATERIALS CHARACTERIZATIONExtractables

• Non-Polar • Mid-Polar • Polar

RISK ASSESSMENTEvaluation of Biocompatibility

Toxicological Evaluation of Chemistry

examples of typicalprograms

ST. PAUL2540 Executive Drive

St. Paul, MN 55120

651.675.2000

ATLANTA1265 Kennestone Circle

Marietta, GA 30066

770.514.0262

PHILADELPHIA4751 League Island Blvd.

Philadelphia, PA 19112

215.218.5500

www.wuxiapptec.com • [email protected]

and above all...exceptional client service

PROJECT MANAGEMENT

Dedicated resources

Single point of contact

Program planning

Program scheduling and timeline management

Internal monitoring and troubleshooting

Status reporting

Quote, budget and invoice management

555-14-05.07.14

Legacy Evaluations - WuXi · PDF filelegacy evaluations: the process 2 Gap Evaluation Testing...

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