Toxicological evaluation

When different medicinal products are produced in shared facilities, the potential for cross-contamination is a concern. Medicinal products provide a benefit to the intended patient or target animal; however, as a cross contaminant, they provide no benefit to the patient or target animal and may even pose a risk. Hence, the presence of such contaminants should be managed according to the risk posed which in turn are related to levels that can be considered safe for all populations. To this end, health-based limits through the derivation of a safe threshold value should be employed to identify the risks posed. The derivation of such a threshold value (e.g. permitted daily exposure (PDE) or threshold of toxicological concern (TTC) should be the result of a structured scientific evaluation of all available pharmacological and toxicological data including both non-clinical and clinical data.

Limits for residue carryover should be based on the toxicological evaluation of the active materials. These evaluations should be verified by a toxicologist (or equivalent) and performed in accordance with current guidance. (Guidance may be found in EMA/CHMP/ CVMP/ SWP/169430/2012 Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities).

 

We have conducted a toxicological evaluation of the following APIs:

  • Acyclovir (2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6Hpurin-6-one)
  • Activated Dimethicone for oral dosage forms (dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane)
  • Adenosine for injection
  • Agomelatine  (N-[2-(7- methoxy-1-naphthyl)ethyl] acetamide)
  • Albendazole (Carbamic acid, [5-(propylthio)-1H-benzimidazol-2-yl]-, methyl ester)
  • Ambroxol  (Cyclohexanol, 4- (N- (2- amino- 3,5- dibromobenzyl) amino) -, hydrochloride)
  • Ammonium chloride for oral dosage forms
  • Amlodipine besylate  (3-Ethyl-5-methyl (±)-2-[(2-minoethoxy)methyl]- 4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate)
  • Argatroban  (1-[5-[(aminoiminomethyl)amino]-1-oxo-2[[(1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid, monohydrate)
  • Ascorbic acid (2R)-2-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2H-furan-5-one)
  • Azilsartan medoxomil potassium (potassium;(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-3-[[4-[2-(5-oxo-1-oxa-4-aza-2-azanidacyclopent-3-en-3-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylate) for oral dosage forms
  • Azithromycin ((2R,3S,4R,5R,8R, 10R,11R,12S,13S,14R)13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl) oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3(dimethylamino)-β-Dxylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one)
  • Benzerazide hydrochloride (2-amino-3-hydroxy-N’-[(2,3,4-trihydroxyphenyl)methyl]propanehydrazide; hydrochloride)
  • Benzocaine  (Benzoic acid, 4-amino-, ethyl ester)
  • Betahistine Hydrochloride  (2-Pyridineethanamine, N-methyl-, dihydrochloride)
  • Betamethasone sodium phosphate (disodium; [2-[(8S,9R,10S,11S,13S,14S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] phosphate) for injection
  • Bromhexine (Benzenemetanamine, 2-amino-3,5-dibromo-N-cyclohexyl-N-metyl)
  • Caffeine  (1,3,7-trimethylpurine-2,6-dione)
  • Camphor (1,7,7-Trimethylbicyclo [2.2.1] heptan-2-one) orodisperse route of administration
  • Cefalexin ((6R,7R)-7-[[(2R)-2-amino-2-phenylacetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid) for oral dosage forms
  • Ceftriaxone Na (disodium;(6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-6-oxido-5-oxo-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate) for injection
  • Cefuroxime ((6R,7R)-3-(carbamoyloxymethyl)-7-[[(2Z)-2-(furan-2-yl)-2-methoxyiminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid) for oral dosage forms
  • Chlorhexidine  (2,4,11,13- Tetraazatetradecanediimidamide, N, N”- bis (4-chlorophenyl) -3, 12- diimino)
  • Chlorpheniramine maleate for oral dosage forms  ((Z)-but-2-enedioic acid;3-(4-chlorophenyl)-N,N-dimethyl-3-pyridin-2-ylpropan-1-amine)
  • Cholecalciferol ((1S,3Z)-3-[(2E)-2-[(1R,3aS,7aR)-7a-methyl-1-[(2R)-6-methylheptan-2-yl]-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidenecyclohexan-1-ol)
  • Cinnarizinum
  • Ciprofloxacin  (1-cyclopropyl- 6-fluoro- 1, 4-dihydro- 4-oxo- 7- (1-piperazinyl)-
    3quinolinecarboxylic acid)
  • Cisatracurium besylate  ([1R-[1α,2α(1’R*,2’R*)]]-2,2′-[1,5pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinolinium] dibenzenesulfonate)
  • Clarithromycin  (6-0-methyl erythromycin)
  • Clopidogrel Bisulfate  (Мethyl (+)-(S)-α(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate)
  • Clotrimazole  (1H-Imidazole, 1-[(2-chlorophenyl)diphenylmethyl])
  • Dalteparin Sodium  (strongly acidic sulphated polysaccharide chains (oligosaccharide, containing 2,5-anhydro-D-mannitol residues as end groups)
  • Dantrolene sodium  (hydrated 1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione sodium salt)
  • Desloratadine  (8-chloro- 6,11-dihydro- 11- (4- piperdinylidene) -5H- benzo [5,6] cyclohepta [1,2-b] pyridine)
  • Dexamethazone Metasulfobenzoate Sodium  (sodium 3-[2-[(8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethoxy]carbonylbenzenesulfonate)
  • Dexpanthenol for topical dosage forms   ((2R)-2,4-dihydroxy-N-(3-hydroxypropyl)-3,3-dimethylbutanamide)
  • Dexketoprofen Tromethamine  (Benzeneacetic acid, 3-benzoyl-α-methyl-, (+)-, with 2-amino-2-(hydroxymethyl)-1,3-propanediol(1:1))
  • Dexrazoxane  ((S)-4,4′-(1-methyl-1,2-ethanediyl)bis-2,6-piperazinedione)
  • Dicyclomine HCl for oral dosage forms  (2-(diethylamino) ethyl 1-cyclohexylcyclohexane-1-carboxylate; hydrochloride)
  • Diethanolamine (2-(2-hydroxyethylamino) ethanol) for injection
  • Disulfiram
  • Diphenhydramine HCl for oral dosage forms  (2-benzhydryloxy-N,N-dimethylethanamine; hydrochloride)
  • Divalproex Sodium
  • Dydrogesterone ((8S,9R,10S,13S,14S,17S)-17-acetyl-10,13-dimethyl-1,2,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-one) for oral dosage forms
  • Domperidone
  • Donepezil Hydrochloride
  • Dry Aluminum Hydroxide Gel for oral dosage forms
  • Duloxetine hydrochloride ((3S)-N-methyl-3-naphthalen-1-yloxy-3-thiophen-2-ylpropan-1-amine;hydrochloride) for oral dosage forms
  • Enalapril Maleate
  • Enoxolone
  • Eptifibatide Injection
  • Esomeprazole (6-methoxy-2-[(S)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-benzimidazole) for oral dosage forms
  • Esomeprazole sodium (sodium;5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide) for injection
  • Estradiol ((8R,9S,13S,14S,17S)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol) for oral dosage forms
  • Estradiol Valerate ([(8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] pentanoate) for oral dosage forms
  • Ethacrynate sodium
  • Etizolam
  • Famotidine
  • Febuxostat
  • Finasteride ((1S,3aS,3bS,5aR,9aR,9bS,11aS)-N-tert-butyl-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroindeno[5,4-f]quinoline-1-carboxamide) for oral dosage forms
  • Fluconazole
  • Fluoxetine hydrochloride
  • Flupirtine Maleate
  • Flurbiprofen
  • Fluvoxamine Maleate
  • Foscarnet Sodium for Injection
  • Fosphenytoin Sodium for Injection
  • Framycetin Sulfate for injection
  • Ganciclovir
  • Glimepiride
  • Glycopyrrolate for Injection (3[(cyclopentyl hydroxyphenylacetyl) oxy]-1,1-dimethyl pyrrolidinium bromide)
  • Gramicidin for injection
  • Guaifenesin
  • Hydrochlorothiazide
  • Ibutilide Fumarate for injection
  • Ibuprofen for oral dosage forms  (2-[4-(2-methyl propyl) phenyl] propanoic acid)
  • Ilaprazole
  • Imipenem ((5R,6S)-3-[[2-(formimidoylamino)ethyl]thio]-6-[(R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid) for injection
  • Isradipine (3-O-methyl 5-O-propan-2-yl 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) for oral and inhalation dosage forms
  • Iron dextran for injection
  • Itraconazole
  • Lamivudine
  • Lansoprazole
  • Levofloxacin ((2S)-7-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)-10-oxo-4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5(13),6,8,11-tetraene-11-carboxylic acid) for oral dosage forms
  • Levothyroxine Sodium for injection
  • Levonorgestrel ((8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one) for oral dosage forms
  • Loratadine for oral dosage forms
  • Magnesium acetate tetrahydrate (magnesium; diacetate; tetrahydrate) for injection
  • Magnesium hydroxide for oral dosage forms
  • Medroxyprogesterone Acetate ([(6S,8R,9S,10R,13S,14S,17R)-17-acetyl-6,10,13-trimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl] acetate) for oral dosage forms
  • Melperone hydrochloride (1-(4-fluorophenyl)-4-(4-methylpiperidin-1-yl)butan-1-one;hydrochloride) for oral and inhalation dosage forms
  • Menthol for oral dosage forms
  • Mesalamine
  • Metaraminol for injection
  • Methampyrone (sodium;[(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)-methylamino] methanesulfonate) for injection
  • Metronidazole for injection
  • Metronidazole benzoate for oral dosage forms
  • Micafungin Sodium for injection
  • Milrinone Lactate for injection
  • Montelukast Sodium
  • Moxifloxacin Hydrochloride
  • Moxonidine
  • Mycophenolate mofetil  for injection
  • Naphazoline HCl (2-(naphthalen-1-ylmethyl)-4,5-dihydro-1H-imidazole; hydrochloride) for ocular dosage forms
  • Nimesulide
  • Nitroglycerin
  • Netilmicin ((2R,3R,4R,5R)-2-[(1S,2S,3R,4S,6R)-4-amino-3-[[(2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-6-(ethylamino)-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol) for injection
  • Nicardipine Hydrochloride (5-O-[2-[benzyl(methyl)amino]ethyl] 3-O-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate; Hydrochloride) for injection
  • Nystatine
  • Omeprazole
  • Orlistat
  • Ornidazole
  • Pantoprazole for injection
  • Pantoprazole Sodium for oral dosage forms
  • Paracetamol for oral dosage forms
  • Passiflora extract
  • Pheniramine Maleate
  • Phenylephrine for oral dosage forms
  • Phenylpropanolamine HCl for oral dosage forms  ((1S,2R)-2-amino-1-phenylpropan-1-ol;hydrochloride)
  • Piracetam (2-(2-oxopyrrolidin-1-yl)acetamide) for oral dosage forms
  • Plerixafor for injection
  • Prochlorperazine Edisylate for injection
  • Progesterone ((8S,9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one) for vaginal dosage forms
  • Prothionamide
  • Rabeprazole for oral dosage forms
  • Regadenoson for injection
  • Ritonavir for oral dosage forms
  • Rocuronium bromide for injection
  • Roxithromycin for oral dosage forms
  • Salbutamol Sulphate for oral dosage forms
  • Sertraline hydrochloride for oral dosage forms
  • Sildenafil Citrate for oral dosage forms
  • Simvastatin for oral dosage forms
  • Sodium citrate for oral dosage forms
  • Succinylcholine for injection (trimethyl-[2-[4-oxo-4-[2-(trimethyl azaniumyl) ethoxy] butanoyl] oxyethyl] azanium; dichloride)
  • Sugammadex for injection (octasodium;3-[[(1S,3S,5S,6S,8S,10S,11S, 13S,15S,16S,18S,20S,21S, 23S,25S,26S,28S,30S,31S,33S, 35S,36S,38S,40S,41R,42R,43R,44R,45R,46R,47R,48R,49R,50R,51R,52R,53R,55R,56R)-10,15,20,25,30,35,40-heptakis (2-carboxyl atoethyl sulfanylmethyl) -41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56-hexadecahydroxy-2,4,7,9,12,14,17,19, 22,24,27,29,32,34,37,39 -hexadecaoxanonacyclo [36.2.2.23,6.28,11.213,16.218,21.223,26.228,31.233,36] hexapentacontan-5-yl] methylsulfanyl] propanoate)
  • Tacrolimus for injection
  • Tadalafil ((6R,12aR)-6-(1,3-Benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione) for oral dosage forms
  • Tamsulosin for oral dosage forms
  • Teneligliptin for oral dosage forms
  • Terbinafine hydrochloride for oral dosage forms
  • Tobramycin ((2S,3R,4S,5S,6R)-4-amino-2-[(1S,2S,3R,4S,6R)-4,6-diamino-3-[(2R,3R,5S,6R)-3-amino-6-(aminomethyl)-5-hydroxyoxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-6-(hydroxymethyl)oxane-3,5-diol) for ocular use
  • Tropicamide (N-ethyl-3-hydroxy-2-phenyl-N-(pyridin-4-ylmethyl) propanamide) for ocular use
  • Vecuronium bromide for injection
  • Venlafaxine for oral dosage forms
  • Vitamin A – palmitate for Injection  ([(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenyl] hexadecanoat)
  • Vitamin B2 for injection (Riboflavin 5′-phosphate sodium)
  • Vitamin B3 for injection (Niacinamide)
  • Vitamin B5 for injection (Dexpanthenol)
  • Vitamin B7 for injection (Biotin)
  • Vitamin B9 for injection (Folic acid)
  • Vitamin C for injection (Ascorbic acid)  (2R)-2-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2H-furan-5-one)
  • Vitamin C for oral dosage forms (Ascorbic acid) (2R)-2-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2H-furan-5-one)
  • Vitamin E for injection (DL Alpha tocopheryl acetate)
  • Vitamin K1 for injection (Phytonadione)
  • Warfarin sodium (sodium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate) for oral and inhalation dosage forms