VDR SMPR - Public Comment

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Version 7; June 20, 2018

Method Name:

Screening and identification method for regulated veterinary drug residues in

food

Intended Use : 6 7 1. Purpose: AOAC SMPRs describe the minimum recommended performance characteristics to be 8 used during the evaluation of a method. The evaluation may be an on-site verification, a single- 9 laboratory validation, or a multi-site collaborative study. SMPRs are written and adopted by AOAC 10 Stakeholder Panels composed of representatives from the industry, regulatory organizations, 11 contract laboratories, test kit manufacturers, and academic institutions. AOAC SMPRs are used by 12 AOAC Expert Review Panels in their evaluation of validation study data for method being considered 13 for Performance Tested Methods or AOAC Official Methods of Analysis , and can be used as 14 acceptance criteria for verification at user laboratories. Routine surveillance for GMP compliance. A method or a suite of methods that can screen for and identify regulated veterinary drug residues with established Maximum Residue Limits (MRLs) in bovine milk, muscle, and fat; chicken muscle, skin with adhering fat, and eggs; and fish. See Table 2 for information on veterinary drug residue / matrix combinations and associated MRLs. Additional matrices may be added as appendices to this SMPR in the future. A single method is not required to cover all drug/matrix combinations, but method developers should strive to include as many relevant drug residues as possible for each matrix claimed. Method developers may choose to claim one or more matrices. Applicability :

15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

2. Analytical Technique :

Liquid chromatography-tandem mass spectrometry (LC-MS/MS).

3. Definitions :

Probability of detection (POD) .—The proportion of positive analytical outcomes for a qualitative method for a given matrix at a given analyte level or concentration. [Appendix H: Probability of Detection (POD) as a Statistical Model for the Validation of Qualitative Methods, Official Methods of Analysis of AOAC INTERNATIONAL (2016) 20th Ed., AOAC INTERNATIONAL, Gaithersburg, MD, USA Maximum Residue Limit (MRL) .—The maximum allowable concentration of a drug residue in a particular matrix. Also known as Tolerance in the US. MRL varies by matrix and by country or regulatory agency. For the purposes of this SMPR, the lowest MRL currently in effect amongst EU, Codex, Canada, China, and United States regulations will be used as “the MRL”. In cases in which an MRL applies to the sum of metabolites or sum of drugs, that MRL was chosen over MRLs for a single metabolite or marker residue. If no MRL is provided in Table 2 (shaded cells), then the drug is either prohibited in that matrix by one or more regulatory agencies or an MRL is not required. ( http://www.eoma.aoac.org/app_h.pdf )]

4. Method Performance Requirements :

Table 1. Method Performance Requirements

Residue Concentration in Matrix

Acceptance Criterion

0 (blank) 0.5x MRL

≤10% POD with 95% confidence ≤10% POD with 95% confidence

30 per drug a

1.0x MRL

30 per drug a

≥90% POD with 95% confidence b

49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92

a Tested as drug cocktail(s).

b All incorrect results must be investigated for the determination of the concentration at which POD 90

with 95% confidence

is achieved.

5. System suitability tests and/or analytical quality control:

Suitable methods will include blank check samples and check standards at 0.5x and 1.0x MRL. Method developers will provide information on how cutoffs are determined.

6. Reference Material(s):

Refer to Annex F: Development and Use of In-House Reference Materials in Appendix F: Guidelines for Standard Method Performance Requirements , 19 th Edition of the AOAC INTERNATIONAL Official Methods of Analysis (2012). Available at: http://www.eoma.aoac.org/app_f.pdf

7. Validation Guidance :

Appendix D : Guidelines for Collaborative Study Procedures To Validate Characteristics of a Method of Analysis; 19 th Edition of the AOAC INTERNATIONAL Official Methods of Analysis (2012). Available

at: http://www.eoma.aoac.org/app_d.pdf

Appendix F : Guidelines for Standard Method Performance Requirements; 19 th Edition of the AOAC

INTERNATIONAL Official Methods of Analysis (2012). Available at:

http://www.eoma.aoac.org/app_f.pdf

Method developers may prepare cocktails of multiple drug residues. Method developers are cautioned that some drug residues may have additive or masking effects when combined and should be prepared to demonstrate that these concerns have been addressed with their submitted materials/data. Method developers should consider the stability of drug residues in cocktails and be prepared to demonstrate that these concerns have been addressed in their data submission

package.

The performance criteria in Table 1 are for single laboratory validation. Method developers should

contact AOAC for developing a collaborative study design.

Method developers must provide the precursor ion and at least two SRM transitions with ion ratios

and retention parameters for each veterinary drug.

8. Maximum Time-To-Result: None

Table 2: Veterinary Drugs Residues in Bovine Milk, Bovine Muscle, Bovine Fat, Chicken Muscle, Chicken Skin/fat, Fish, and Eggs 93 94

Lowest Global MRL, µg/kg

Liquid Bovine Milk

Raw Bovine Muscle

Raw Bovine Fat

Raw Chicken Muscle

Raw Chicken Skin/Fat

Compound

Regulated Marker

Raw Fish

Raw Egg

Abamectin (B1a)

Acetylisovaleryltylosin

Albendazole Albendazole Albendazole

Albendazole sulfone Albendazole sulfoxide

Albendazole 2-aminosulfone

100

Albendazole Oxide Albendazole Oxide Albendazole Oxide

Albendazole oxide Albendazole sulfone

Albendazole 2-aminosulfone sum of metabolites containing 2,4-DMA moiety

Amitraz

200

Amoxicillin Ampicillin Amprolium Apramycin Avilamycin

4 4

10 10

50 50

500

2000

500

4000

50 50

Dichloroisoeverninic acid

Bacitracin (A, B, C)

100

500

Baquiloprim

Betamethasone

0.3

0.75 200

0.75

Bicozamycin Buquinolate Cabergoline

100

200

0.1

Carazolol Carprofen Carprofen

Carprofen

500

1000

Carprofen glucuronide

Lowest Global MRL, µg/kg

Liquid Bovine Milk

Raw Bovine Muscle

Raw Bovine Fat

Raw Chicken Muscle

Raw Chicken Skin/Fat

Compound

Regulated Marker

Raw Fish

Raw Egg

Cefacetril Cefalexin Cefalonium

125 100

200

Cefapirin Cefapirin Cefazolin

Cefapirin

Deacetylcefapirin

50 50 20

Cefoperazone Cefquinome

Ceftiofur Ceftiofur

Ceftiofur

100

1000

2000

Desfuroylceftiofur

Cefuroxime Chloramine-T Chlormadinone Chlortetracycline Chlortetracycline Clavulanic acid

Para-toluenesulfonamide

900

2.5

Chlortetracycline a

100

200

400

4-epi-chlrotetracycline a

200 0.05

100 0.1 200

100 0.2 200

Clenbuterol Clopidol Clorsulon Closantel Cloxacillin Cyfluthrin Cyhalothrin Cypermethrin Cypermethrin Colistin

20 16 45 10 50 20 30

5000

1000

3000

300 150

150

300

10 20

400

Cypermethrin

200

Alpha-Cypermethrin

Lowest Global MRL, µg/kg

Liquid Bovine Milk

Raw Bovine Muscle

Raw Bovine Fat

Raw Chicken Muscle

Raw Chicken Skin/Fat

Compound

Regulated Marker

Raw Fish

Raw Egg

Cyromazine Danofloxacin Decoquinate Deltamethrin

100 200

300

100

1000

2000

1000

2000

500

Dexamethasone

0.3

0.75

Diaveridine

Diazinon

20 50

700

Dichlorvos Diclazuril Diclofenac Dicloxacillin Difloxacin

500

1000

0.1

300 400 600 500

300 100 600

300 300 600

300 400 600

300 300

Sum of dihydrostreptomycin + streptomycin

Dihydrostreptomycin b

200 150

Diminazene

500

Doramectin (B1a)

150 300

Doxycycline

100

300

Emamectin (B1a)

100

Enramycin Enrofloxacin Enrofloxacin Eprinomectin Erythromycin Ethopabate

Ciprofloxacin Enrofloxacin

100

Eprinomectin (B1a)

150 100

100

100 500

100

200

Eugenol Famphur

100

Lowest Global MRL, µg/kg

Liquid Bovine Milk

Raw Bovine Muscle

Raw Bovine Fat

Raw Chicken Muscle

Raw Chicken Skin/Fat

Compound

Regulated Marker

Raw Fish

Raw Egg

Febantel

Oxfendazole sulphone Oxfendazole sulphone

Fenbendazole/Oxfend azole Fenbendazole/Oxfend azole

Fenbendazole

Fenbendazole Fenvalerate

Fenbendazole Sulfoxide

250

Flavophospholipol

Florfenicol Florfenicol Fluazuron

Florfenicol

200

100

200

Florfenicol-amine

200

1000

200

7000

Flubendazole

2-amino 1H-benzimidazol-5- yl-(4- fluorophenyl)methanone

400

Flubendazole

Flugestone acetate

Flumequine Flumethrin

50 30

200

300 150

400

250

500

10 20

Flunixin Flunixin

Flunixin

5-hydroxyflunixin

Fluralaner Fluvalinate

1300

Gamithromycin Gentamicin(s) Halofuginone

20 50 10

20 50 20

Sum of C1, C1a, C2, C2a

100

20 40

Haloxon

100

Hexaflumuron

500

Lowest Global MRL, µg/kg

Liquid Bovine Milk

Raw Bovine Muscle

Raw Bovine Fat

Raw Chicken Muscle

Raw Chicken Skin/Fat

Compound

Regulated Marker

Raw Fish

Raw Egg

Hydrocortisone

10 50

Imidocarb Isoeugenol

300

6000

Isometamidium

100

Ivermectin Josamycin

Ivermectin B1a

Kanamycin A Ketoprofen Kitasamycin Lasalocid A Levamisole Lincomycin Lufénurone Maduramicin Marbofloxacin Mebendazole

150

100 250

100

200

200 100

200

50 10

100

20 10

10 50

150

100

1350

100

150

50 20

Melengestrol acetate

Meloxicam Metamizol

15 50

4-Methylaminoantipyrin

100

Methylprednisolone

Metoserpate Monensin Morentel Moxidectin

20 10

20 50

N-methyl-1,3- propanediamine

50 40 30

100

100 500 300

Nafcillin

300

Lowest Global MRL, µg/kg

Liquid Bovine Milk

Raw Bovine Muscle

Raw Bovine Fat

Raw Chicken Muscle

Raw Chicken Skin/Fat

Compound

Regulated Marker

Raw Fish

Raw Egg

Narasin

Neomycin Nequinate Netobimin Netobimin Netobimin Nicarbazin Nitroxinil

Neomycin B

150

500

500 100

500

Albendazole oxide Albendazole sulfone

100

Albendazole 2-aminosulfone

200

400 0.2

200 0.2

Norgestomet Nosiheptide Novobiocin Oleandomycin Orbifloxacin Ormetoprim Oxibendazole Oxolinic acid Oxyclozanide Oxytetracycline Oxytetracycline Paromomycin Penethamate Penicillin G (Benzylpenicillin) Oxacillin

0.12

50 50 20

1000

150

100 300

30 50

300 100 100

300 100

50 20

100

Oxytetracycline a

100

200

400

4-epi-oxytetracycline a

500

Penicillin G Penicillin G

50 50

Penicillin V (Phenoxymethylpenicil lin)

Lowest Global MRL, µg/kg

Liquid Bovine Milk

Raw Bovine Muscle

Raw Bovine Fat

Raw Chicken Muscle

Raw Chicken Skin/Fat

Compound

Regulated Marker

Raw Fish

Raw Egg

Permethrin

50 50 50

500 400

Phoxim

550 100

Piperazine

50 50

100 500

2000 1000

Piperonyl butoxide

100 100

Pirlimicyn

100

Prednisolone

0.7

Pyrantel Pyrantel

Pyrantel

500

N-methyl-1,3- propanediamine

Pyrimethamine Ractopamine

10 30

Rafoxanide

10 60

Rifaximin

Robenidine

100 500 100

200

100 500

Roxarsone (Arsanilic acid)

Arsenic

Salinomycin Sarafloxacin Semduramicin Spectinomycin

100

10 50

500 100

200

250

500

100

300

Spiramycin Spiramycin

Spiramycin

200

300

200

300

200

Neo-Spiramycin

Sum of dihydrostreptomycin + streptomycin

Streptomycin b

200

600

Sum of all substances belonging to the sulfonamide group

SULFONAMIDE

100

Lowest Global MRL, µg/kg

Liquid Bovine Milk

Raw Bovine Muscle

Raw Bovine Fat

Raw Chicken Muscle

Raw Chicken Skin/Fat

Compound

Regulated Marker

Raw Fish

Raw Egg

Teflubenzuron

300

Tetracycline Tetracycline

Tetracycline a

100

200

400

4-epi-tetracycline a

Thiabendazole Thiabendazole Thiamphenicol

Thiabendazole

100

5-hydroxy-thiabendazole

Tiamulin Tiamulin

Tiamulin

100

1000

8-alpha-hydroxymutilin

Tildipirosine

400

1000

Tilmicosin

50 50

Tolfenamic acid

Toltrazuril Trenbolone

Toltrazuril sulfone Beta-trenbolone

100

150

100

200

Tricaine methanesulfonate

10 10

Trichlorfon

50 10 50 20

Triclabendazole Trimethoprim Tripelennamine Tulathromycin A

Ketotriclabendazole

200

100

200 100 100

Tylosin

100

200 200

Tylvalosin Tylvalosin

Tylvalosin

3-O-acetyltylosin

Virginiamycin (M1)

100

400

Zeranol

2 2

Zilpaterol

Lowest Global MRL, µg/kg

Liquid Bovine Milk

Raw Bovine Muscle

Raw Bovine Fat

Raw Chicken Muscle

Raw Chicken Skin/Fat

Compound

Regulated Marker

Raw Fish

Raw Egg

Zoalene (Dinitolmide) Zoalene (Dinitolmide)

Zoalene

3000

2000

3-amino-5-nitro-o- toluamide a MRL applies to the sum of chlortetracycline, oxytetracyclin, tetracycline, and their epimers. 95 b MRL applies to the sum of dihydrostreptomycin and streptomycin.

96 97 98

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