| HS Code | 208438 |
| Product Name | Fibrauretine Injection Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions |
| Grade | Veterinary Grade |
| Api Type | Active Pharmaceutical Ingredient |
| Physical Form | Fine crystalline powder |
| Color | Yellow to yellowish-brown |
| Odor | Slight or characteristic odor |
| Solubility | Soluble in water and ethanol depending on salt form |
| Compatible Dosage Forms | Tablets, Injections, Capsules, Powders, Granules, Premix, Solutions |
| Storage Conditions | Protected from light, kept in a dry and well-ventilated place |
| Shelf Life | 24 months if stored properly |
| Packaging | Sealed, light-resistant, moisture-proof veterinary-grade container |
As an accredited Fibrauretine Injection Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Fibrauretine veterinary grade API for formulations is packed in sealed, moisture-proof, light-resistant drums, 1 kg per drum, with tamper-evident closures. |
| Container Loading (20′ FCL) | 20′ FCL: Fibrauretine veterinary API loaded on palletized drums/cartons, secured, sealed, with proper documentation and temperature-safe handling. |
| Shipping | Ship Fibrauretine Veterinary Grade API in sealed, moisture-proof containers, clearly labeled for veterinary use. Protect from light and extreme temperatures. Comply with all applicable transport regulations for pharmaceutical raw materials. Include documentation of purity, batch number, and safety data sheet. Ensure secure packaging to prevent leakage or contamination during transit. |
| Storage | Store Fibrauretine Veterinary Grade API in a tightly sealed, light-resistant container in a cool, dry, well-ventilated area. Protect from moisture, excessive heat, and direct sunlight. Recommended storage temperature: 20–25°C. Keep away from incompatible substances and out of reach of children. Do not use if container shows damage or contamination. |
| Shelf Life | Shelf life is typically 24 months from manufacture when stored sealed, dry, protected from light, at controlled room temperature. |
In parenteral veterinary manufacturing, the API is first screened for aqueous solubility at 20–25 °C across a pH range of 3.0–6.5 using 0.1 M citrate-phosphate buffers. Because published forced degradation data for fibrauretine in alkaline and oxidative media are limited, terminal heat sterilisation is not assigned without kinetic justification. The bulk solution is compounded in a 316L stainless steel vessel with silicon carbide mechanical seal and bottom-mounted rotor-stator mixing at 150–300 rpm. If pH drift exceeds 0.15 units during hold time, re-adjustment with 0.1 M hydrochloric acid or 0.1 M sodium hydroxide is performed before sterile filtration. The solution is passed through a 0.22 μm polyvinylidene fluoride or polyethersulfone membrane under nitrogen pressure at 0.8–1.2 bar. Aseptic filling is conducted in an ISO 14644-1 Class A/Grade A unidirectional airflow workstation. Multi-dose vials receiving a preservative system are tested per Ph. Eur. 5.1.3; single-dose vials are released on sterility per Ph. Eur. 2.6.1, bacterial endotoxins per Ph. Eur. 2.6.14, and sub-visible particles per Ph. Eur. 2.9.19. The target final sub-visible particulate counts are ≤600 particles per vial at ≥10 μm and ≤60 particles per vial at ≥25 μm. Toned glass vials of Type I amber borosilicate are filled to 10 mL, 20 mL, or 50 mL nominal volumes. The injection is designed for intra-muscular or subcutaneous administration in cattle and swine when such route is authorised in the target market; packaging is completed with sterilised rubber stoppers and aluminium flip-off seals.
Low-dose veterinary tablets containing the API at 5–20 mg per unit are produced by wet granulation when direct compression trials show ejection force exceeding 800 N due to high fine-particle cohesion. The granulation vehicle is a 5% w/w povidone K30 aqueous solution applied at 45–55 °C to a blend of lactose monohydrate 45–70%, microcrystalline cellulose 20–40%, and crospovidone 2–5%. High-shear granulation in a 10 L bowl at impeller speed 300–500 rpm and chopper speed 1,500–2,500 rpm produces granules with loss on drying 1.5–2.5%. After fluid-bed drying at inlet air temperature 55–65 °C, granules are sieved through a 0.8 mm screen and lubricated with magnesium stearate 0.25–0.75% in a 20 rpm bin blender for 3–5 min. Excessive lubrication beyond 5 min reduces tablet hardness by 10–25% and should be avoided. A rotary tablet press with 8 mm round concave B-tooling runs at 25–45 rpm and compression force 8–14 kN. In-process checks measure hardness 60–120 N, friability ≤1.0%, and mass variation ±5%. Content uniformity is evaluated under Ph. Eur. 2.9.40 and USP <905>; disintegration is tested per Ph. Eur. 2.9.1 with a limit of ≤15 min in water at 37 °C. Dissolution is assessed by Ph. Eur. 2.9.3 or USP <711> using 0.1 M hydrochloric acid at 37 °C and 50 rpm paddle speed, with provisional acceptance of Q≥75% at 45 min. Finished tablets are film-coated with hydroxypropyl methylcellulose to 2.5–3.5% weight gain, then packed into polyvinyl chloride/aluminium blisters.
On a dosator-type capsule filling machine, low bulk density feedstock in the range 0.35–0.50 g/mL generates short-fill excursions when the powder blend has poor flow function coefficient. The capsule blend is prepared with sieved lactose monohydrate 10–45%, pregelatinized starch 5–15%, and fumed silica 0.5–1.0% through a 600 L IBC blender at 10 rpm for 20 min. Magnesium stearate is added at 0.5% and blended for an additional 3 min. Hard gelatin capsules size 1 or 2 are filled to a target weight of 180–280 mg; acceptable fill weight variation is controlled within ±5% for individual capsules. The filling operation is maintained at 40–50% relative humidity and 18–22 °C to reduce triboelectric charging. Metal detection sensitivity is set to 0.3 mm ferrous, 0.4 mm non-ferrous, and 0.5 mm stainless steel depending on aperture size. Uniformity of dosage units is tested per Ph. Eur. 2.9.40 and USP <905>; capsule disintegration follows Ph. Eur. 2.9.1 with a limit of ≤10 min in 0.1 M hydrochloric acid at 37 °C. Final capsules are dedusted and packed into high-density polyethylene bottles with a silica gel sachet. The primary application is oral administration in companion animals and horses, where capsule dosage allows lower handling frequency than oral solutions.
For drinking-water administration in poultry, the API is dry-blended with water-soluble excipients in a 1,000 L double-cone tumble blender to produce a soluble powder with target reconstitution concentration of 0.5–2.0 g/L in final drinking water. Carriers include dextrose monohydrate 60–90% and sodium citrate 2–5%; a small quantity of sucralose 0.05–0.15% is added for palatability only when required by the market authorisation holder. Because hard water cations can reduce dissolution clarity, formulations are screened against synthetic hard water at 350 mg/L calcium carbonate equivalent at 15 °C and 25 °C. Clarity is assessed by nephelometry at 2 h and 8 h; a turbidity increase above 10 NTU across 8 h triggers addition of 0.1–0.3% disodium EDTA as a chelator. Blending is run at 6–12 rpm for 15–25 min; fill weight variation of sachets is controlled to ±2%. Final pack formats are metallized polyethylene terephthalate/low-density polyethylene sachets at 50 g, 100 g, and 1 kg. Microbiological quality of the dry powder is tested per Ph. Eur. 5.1.4 and total aerobic count is maintained below 10³ CFU/g. The powder must be completely dissolved before chlorinated water is introduced; simultaneous addition with hypochlorite solution at concentrations above 1 ppm free chlorine should be avoided until compatibility is confirmed by assay recovery. Published data for this specific combination with fibrauretine and chlorinated drinking water are limited, so a head-to-head dissolution and potency retention study is required before field use.
Granulation is used when the API must be dispersed evenly into larger feed matrices and when dust exposure during feed mill handling must be reduced. A fluid-bed granulator with 18 L product bowl and top spray is charged with a dry mix of lactose monohydrate 30–60%, microcrystalline cellulose 10–20%, and povidone K30 3–5%. The binder solution is sprayed at 8–12 g/min with inlet air temperature 50–60 °C; product temperature is maintained at 38–42 °C to avoid granular agglomeration. Drying continues until loss on drying by Ph. Eur. 2.2.32 is ≤2.5%. The dried granules are screened through 0.5 mm and 0.2 mm sieves meeting ASTM E11; the target particle-size distribution is D10 ≥75 μm, D50 180–300 μm, and D90 ≤600 μm. Bulk density is controlled between 0.45–0.65 g/mL and tapped density between 0.55–0.80 g/mL to maintain consistent fill weight in sachet and jar packaging. Blend uniformity after granulation is verified by sampling 10 points across a 50 kg lot; acceptance is relative standard deviation ≤5.0% for API content. The finished granules are packed in moisture-barrier bags under ≤40% relative humidity. Intended use is top dressing on feed for swine or oral drench after reconstitution in water; final in-feed concentration is calculated from the approved product dossier and the prescribing veterinarian’s dose determination.
High-concentration medicated premixes are manufactured by stepwise dilution of the API into a carrier system of calcium carbonate 30–60%, rice hulls 5–10%, and soybean meal 20–40%. A horizontal ribbon mixer with working capacity 500 kg is loaded at 70–80% volume; mixing time is set by tracer validation using 0.5% w/w sodium chloride or ferric oxide, with sampling at 10 points and a target coefficient of variation ≤5%. After each batch, residual API in the mixer is removed only partially by standard vacuum flushing; therefore a structured cleanout sequence is required. Ground corn cob is passed through the mixer for 5 min, followed by a 2 min vacuum purge, and the subsequent batch is assayed for fibrauretine carryover at the first 50 kg of discharge. Carryover acceptance is ≤1% of the labelled dose in the following non-medicated feed batch. This is verified by high-performance liquid chromatography calibrated over the range 0.1–120% of the label claim, with LOQ not higher than 0.05% of the target premix concentration. The premix is discharged through a rotary valve into multi-wall paper bags with a polyethylene inner liner; fill weight is 25 kg per bag. Medicated feed mills then blend the premix into complete feed under EU Regulation 2019/4 and, for export to the United States, 21 CFR 225 current good manufacturing practice for medicated feed. Sampling of the final feed follows ISO 6497; a minimum of 20 incremental samples is taken per lot, and assay variability across sampling points is expected to remain below 10% relative standard deviation. The premix is not used for direct administration; dilution factor is calculated from the approved premix inclusion rate and the feeding rate of the target species.
| Dosage form | Critical processing parameter | In-process limit | Release method |
|---|---|---|---|
| Injection | Sterile filtration pressure | 0.8–1.2 bar | Ph. Eur. 2.9.19 |
| Tablet | Compression force | 8–14 kN | Ph. Eur. 2.9.40 |
| Tablet | Disintegration time | ≤15 min | Ph. Eur. 2.9.1 |
| Capsule | Fill weight variation | ±5% | Ph. Eur. 2.9.40 |
| Soluble powder | Hard water screening | 350 mg/L CaCO₃ | Nephelometry ≤10 NTU |
| Granule | Loss on drying | ≤2.5% | Ph. Eur. 2.2.32 |
| Premix | Tracer mixing CV | ≤5% | Tracer assay |
| Premix | Carryover | ≤1% of label dose | HPLC assay |
| Oral solution | pH range | 3.8–4.5 | Ph. Eur. 2.2.3 |
| Oral solution | Headspace oxygen | ≤2.0% v/v | Gas chromatography |
Aqueous oral solutions are prepared in purified water with a citrate buffer system maintaining pH 3.8–4.5. Where solubility at this pH is less than 20 mg/mL, propylene glycol 5–15% v/v or glycerol 5–10% v/v is used as a co-solvent. Preservative efficacy is confirmed by Ph. Eur. 5.1.3; typical preservative loads are methyl parahydroxybenzoate 0.1–0.2% and propyl parahydroxybenzoate 0.02–0.05%, but the acceptance criterion is not chemical load alone. The solution is filled into amber polyethylene terephthalate bottles with child-resistant polypropylene closures; nitrogen flushing on the filling line keeps headspace oxygen below 2.0% v/v. Clarity is checked by visual inspection against a black-and-white background at 2,000–3,000 lux; sub-visible particles are controlled per Ph. Eur. 2.9.19 when the preparation is used for oral administration in neonates. pH, assay, and related substances are tested at release and through accelerated storage at 40 °C/75% RH for 6 months and long-term storage at 25 °C/60% RH. Photostability challenges per VICH GL3/ICH Q1B are performed before the market batch release; if solution photo-degradation is confirmed, overwrapping with aluminium foil is added. The product is intended for oral administration to calves, foals, and small ruminants; administration volumes are derived from calibrated oral dosing syringes with an in-use stability window of 28 days after first opening. No data are presented here to extend that window beyond 28 days without preservative efficacy and in-use assay verification.
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Fibrauretine Injection Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions is a high-purity active pharmaceutical ingredient for veterinary pharmaceutical manufacturing. The injection-grade designation is the specific product model within the Fibrauretine API series. It is released under tighter microbiological, endotoxin, particulate, and moisture controls than oral-grade or premix-grade material. The bulk product is not a finished veterinary medicinal product, and direct administration to animals in the bulk state is not intended.
A specification for this grade generally includes identification by infrared spectrophotometry and reversed-phase high-performance liquid chromatography, assay on the anhydrous and solvent-free basis, chromatographic purity, residual solvents under VICH GL18 and ICH Q3C, elemental impurities under ICH Q3D, water content by Karl Fischer titration, loss on drying, bulk density, tapped density, and particle-size distribution. For parenteral applications, bacterial endotoxin content is calculated using the K/M approach of USP <85> and Ph. Eur. 2.6.14. Subvisible particulate matter is controlled by light obscuration according to USP <788> or Ph. Eur. 2.9.19 after reconstitution. Exact numerical limits are supplied in the current certificate of analysis and the approved veterinary master file; pharmacopoeial monograph requirements for Fibrauretine, where published, take precedence over general injection-grade defaults.
Production-scale handling of the injection-grade material is performed in polished stainless-steel 316L equipment with polytetrafluoroethylene gaskets. For non-sterile bulk, final drying and packaging are conducted in an ISO 14644-1 Class 8 area. For sterile injection-grade API, micronisation, sieving, and packaging occur under ISO 14644-1 Class 5 conditions. A typical batch train includes a 500 L glass-lined reactor for crystallisation, a 0.22 µm polyvinylidene fluoride membrane filter for bioburden reduction or sterilising filtration, and a lyophiliser with at least 20 m² shelf area when freeze-drying is specified. Exact equipment is described in the site master file and may differ across contract manufacturing lines.
The decisive difference is not chromatographic identity but the limit placed on pyrogenic and particulate contamination. Using the K/M calculation in USP <85>, an injection-grade API is released against an endotoxin limit derived from the maximum intended dose. If the threshold pyrogenic dose is 5 EU/kg and the maximum dose is 1 mg/kg, the API limit is 5 EU/mg; if the maximum dose is 10 mg/kg, the limit becomes 0.5 EU/mg. Non-parenteral grades are usually released on total aerobic microbial count and specified absence of enterobacteria rather than on endotoxin. Parenteral material is also subject to subvisible particle testing by light obscuration after reconstitution, according to USP <788> or Ph. Eur. 2.9.19.
When the injection-grade bulk is claimed sterile, the lot must satisfy sterility testing according to USP <71> or Ph. Eur. 2.6.1. For heat-sensitive APIs, sterilising filtration through a 0.22 µm membrane is preferred over terminal steam sterilisation. In aseptic processing, pre-filtration bioburden is controlled at not more than 10 CFU/100 mL as recommended by EU GMP Annex 1. Oral-grade and premix-grade Fibrauretine are not released with this requirement, and their packaging is not configured for aseptic transfer into a sterile manufacturing suite.
For tablets and capsules, the injection-grade API can be used when a single high-purity source is required across multiple dosage forms, but the additional endotoxin and particulate controls do not replace oral solid-dose uniformity obligations. Blend uniformity is demonstrated under USP <905> or Ph. Eur. 2.9.40; content uniformity for single-dose preparations follows USP <905> or Ph. Eur. 2.9.5. Hard gelatin capsule filling uses powder dosing discs or dosator nozzles on an automatic capsule machine. Filled capsules and compressed tablets are evaluated for dissolution according to USP <711> or Ph. Eur. 2.9.3 where the veterinary dossier requires proof of release.
| Dosage form | Bioburden/endotoxin interface | Sterility | Particulate or identity requirement |
|---|---|---|---|
| Sterile injection | Endotoxin per USP <85>/Ph. Eur. 2.6.14; pre-filtration bioburden ≤ 10 CFU/100 mL per EU GMP Annex 1 | USP <71>/Ph. Eur. 2.6.1 | USP <788>/Ph. Eur. 2.9.19 |
| Non-sterile oral solution | Total aerobic microbial count per Ph. Eur. 5.1.4; endotoxin not normally required | Not required | Clarity and pH; no parenteral particle test |
| Tablets/capsules | Bioburden per Ph. Eur. 5.1.4; endotoxin not normally required | Not required | Assay and uniformity per USP <905> |
| Powders/granules/premix | Total aerobic microbial count, moulds/yeasts, Salmonella absence; endotoxin not normally required | Not required | Assay and homogeneity with RSD ≤ 5.0% |
Finished injectable solutions are compounded in a closed stainless-steel system under aseptic conditions. Water for injection is used as the solvent; the API is dissolved below the degradation threshold established by forced-degradation studies. pH adjustment is made with dilute hydrochloric acid or sodium hydroxide, tonicity is adjusted with sodium chloride or mannitol, and the solution is pre-filtered through a 0.45 µm clarification membrane before sterilising filtration through 0.22 µm filter. Filling is performed in an isolator or restricted access barrier system under ISO 14644-1 Class 5 conditions. Process simulation with sterile media follows EU GMP Annex 1 and ISO 13408-1; filter integrity is tested by bubble point or diffusive flow before and after filling.
If terminal steam sterilisation is considered, a cycle at 121 °C for 15 min may be used only after thermal stability data show not more than 0.5% total degradation. Published thermal stability data specific to Fibrauretine under terminal steam sterilisation are limited; therefore, aseptic filtration is the default route unless the dossier contains direct heat-stress data.
Non-sterile oral solutions prepared from the injection-grade powder are preserved with an antimicrobial system and filled into amber type III glass or high-density polyethylene bottles. Preservative efficacy testing follows Ph. Eur. 5.1.3 or USP <51>; bioburden is controlled within the limits of Ph. Eur. 5.1.4. The prepared solution is not sterile, and the injection-grade endotoxin controls do not exempt it from microbial quality requirements for oral liquids.
Residual solvent control is aligned with VICH GL18 and ICH Q3C. Class 1 solvents are excluded from the crystallisation solvent system. Class 2 solvents such as dichloromethane and acetone are controlled at their permitted daily exposure limits, and Class 3 solvents are limited by the general 50 mg/day threshold unless the approved dossier specifies a tighter allowance. Elemental impurities are evaluated under ICH Q3D with reference to the maximum daily dose. For parenteral use, parenteral permitted daily exposure values apply to arsenic, cadmium, lead, and mercury; oral and premix uses may adopt the corresponding oral values when the dose is exclusively non-parenteral.
Residual solvent quantification is performed by headspace gas chromatography with flame ionisation detection. The analytical procedure is validated for specificity, linearity, accuracy, precision, and limit of quantification according to VICH GL1. Elemental impurity determination is performed by inductively coupled plasma mass spectrometry after microwave-assisted acid digestion. Published forced-degradation data for Fibrauretine are limited; therefore, the impurity profile must be established on the actual batch by forced degradation under heat, humidity, acid, base, and oxidation, with peak purity confirmed by photodiode array detection.
Micronisation may be required for injectable suspensions or low-dose solid formulations. Air-jet milling with cooled nitrogen is preferred when the compound is heat-sensitive. Feed rate, grinding nozzle pressure, and classifier speed are adjusted to reach the target particle-size distribution. For injectable suspensions, a volume-median diameter of 1–10 µm is commonly required to prevent needle blockage and to maintain resuspendability. Laser diffraction according to USP <429> or Ph. Eur. 2.9.31 is used for measurement. Crystalline form is confirmed by X-ray powder diffraction. If polymorphic conversion occurs during micronisation, re-equilibration or an alternative milling strategy is required.
Hygroscopicity screening at 60% relative humidity and 25 °C determines whether the API must be packaged with desiccant or handled under dry nitrogen. A moisture uptake above 0.5% by mass at this condition is generally considered significant for stability and flow; exact action limits are container-specific. Published data for the specific hygroscopicity of Fibrauretine are limited, so the sorption isotherm should be measured on each new polymorph or particle-size grade.
Powders and granules for oral administration are prepared by geometric dilution in a V-blender or bin blender. Blend uniformity is demonstrated by sampling at least 10 locations and accepting an assay relative standard deviation not greater than 5.0%. For low-dose products containing less than 1 mg of Fibrauretine per unit, ordered mixing with a pre-blended lactose-cellulose carrier reduces segregation and improves content uniformity.
Wet granulation in a high-shear granulator with a 10 L bowl or dry granulation by roller compaction is used for tablet manufacture. In wet granulation, binder addition is controlled by power draw or torque; the granulate is dried in a fluid-bed dryer at an inlet air temperature below the degradation threshold. Because published degradation threshold data specific to Fibrauretine are limited, a thermogravimetric scan and a forced-degradation study under VICH GL3 should precede scale-up.
Feed premixes are produced by stepwise dilution with ground limestone or wheat middlings in a twin-shaft paddle mixer or ribbon blender. Mixing time is established by tracer studies; a coefficient of variation below 5.0% is commonly required for active marker distribution. In ribbon blenders, active ingredient segregation has been observed when fill volume exceeds 70%; validation batches should sample the discharge chute and the regions near the end plates. If the premix is intended for medicated feed, cross-contamination control follows the applicable requirements of EU Regulation (EU) 2019/4 and national veterinary drug regulations.
| Unit operation | Equipment type | Typical control range | Reference method |
|---|---|---|---|
| Micronisation | Spiral jet mill with cooled nitrogen | D90 1–10 µm for injectable suspension | USP <429> |
| Blending | V-blender or bin blender | RSD ≤ 5.0% | USP <905> |
| Wet granulation | High-shear granulator, 10 L bowl | Endpoint by power draw or torque; moisture by loss on drying | Site validation protocol |
| Lyophilisation | Shelf freeze dryer | Chamber pressure 0.1–0.3 mbar; shelf ramp from -40 °C to 25 °C | Thermal mapping and mass balance |
| Sterile filtration | 0.22 µm PVDF membrane | Pre-filtration bioburden ≤ 10 CFU/100 mL | EU GMP Annex 1 |
The injection-grade powder is dissolved or suspended in drinking-water medication systems only after compatibility with local water quality is confirmed. pH-dependent solubility and precipitation at the anticipated dilution ratio are measured in benchtop trials with a nephelometer or turbidity meter. Hard water cations can form insoluble salts; a chelator such as disodium edetate may be required if physical incompatibility is observed. The solution is prepared no earlier than the same day of use unless chemical stability data support a longer hold time. Because the injection grade carries a low endotoxin burden, it can be selected for drinking-water administration to highly sensitive animals, but oral use does not require sterile material. The decision to use the injection grade in place of an oral grade for drinking-water solutions is a supply-chain and regulatory control choice rather than a technical requirement for oral efficacy.
Primary packaging for the injection grade consists of double low-density polyethylene bags inside a high-density polyethylene drum. The inner bag is sealed under nitrogen when the product is oxygen-sensitive; desiccant is added when the hygroscopicity screen indicates moisture uptake above 0.5% by mass at 60% relative humidity. The label includes grade designation, batch number, date of manufacture, retest date, and the statement “For veterinary pharmaceutical manufacture only.” Retest dating is assigned from stability data generated under VICH GL2.
