| HS Code | 972693 |
| Product Name | Vinorelbine Pharma Grade API |
| Pharmacopoeia Grade | Pharmaceutical grade suitable for oral and injectable dosage forms |
| Active Ingredient Salt Forms | Vinorelbine free base and vinorelbine ditartrate |
| Drug Therapeutic Class | Vinca alkaloid antineoplastic agent |
| Mechanism Of Action | Inhibits microtubule polymerization by binding to tubulin, causing mitotic arrest |
| Molecular Formula | C45H54N4O8 (free base); C45H54N4O8·2C4H6O6 (vinorelbine ditartrate) |
| Molecular Weight | 778.93 g/mol (free base); 1079.11 g/mol (vinorelbine ditartrate) |
| Cas Number | 71486-22-1 (vinorelbine); 125317-39-7 (vinorelbine ditartrate) |
| Appearance | White to light yellowish crystalline powder |
| Solubility | Vinorelbine ditartrate is soluble in water; vinorelbine free base is soluble in ethanol and DMSO, practically insoluble in water |
| Storage Conditions | Store at 2–8°C, protected from light and moisture |
| Compatible Dosage Forms | Tablet, capsule, granule, and injection |
| Administration Routes | Oral and intravenous |
| Oral Bioavailability | Approximately 40% |
| Plasma Half Life | Terminal half-life of approximately 27–45 hours |
| Protein Binding | Around 80–90% |
| Metabolism | Primarily hepatic, via CYP3A4 |
| Primary Excretion | Biliary/fecal elimination, with minor urinary excretion |
As an accredited Vinorelbine Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packaged in sealed double polyethylene-lined drums, 1 kg net per drum, with tamper-proof labels for safe pharmaceutical handling. |
| Container Loading (20′ FCL) | One 20′ FCL shipment of Vinorelbine Pharma Grade API, packed securely for tablet, capsule, granule, and injectable production. |
| Shipping | Shipment of Vinorelbine Pharma Grade API requires temperature-controlled, tamper-evident packaging to maintain stability. Handle as hazardous pharmaceutical material. Use secure, labeled containers with absorbents. Comply with IATA/IMDG/ADR regulations and cold-chain protocols. Deliver via validated couriers with chain-of-custody documentation to ensure purity, safety, and regulatory compliance. |
| Storage | Store Vinorelbine Pharma Grade API in a tightly sealed, original container at controlled room temperature (20–25°C, with excursions to 15–30°C), protected from light, heat, and moisture. Keep the area clean, dry, and well-ventilated. Because vinorelbine is a cytotoxic drug, handle using appropriate protective equipment and segregate from incompatible materials. |
| Shelf Life | Shelf life is 24 months from manufacture date when stored unopened in original container, protected from light, moisture, and heat. |
On a cytotoxic injectable manufacturing line, vinorelbine tartrate is dissolved into Water for Injection at a target concentration of 10.0 mg/mL expressed as vinorelbine base, which corresponds to 13.85 mg/mL of vinorelbine tartrate salt. The working solution is adjusted to a pH range of 3.0–3.8; this acidic window preserves the bis-indole alkaloid against oxidative degradation, but it also changes sterilizing-filter membrane wetting, solution viscosity, and the ionized-state solubility of the active species during hold times. Dissolved oxygen is reduced by nitrogen sparging before API addition, with residual oxygen in the vessel headspace maintained below the limit established in the finished-product validation file, and the solution is protected from light below 500 nm throughout compounding, filtration, and filling. Sterilizing filtration is performed through a 0.22 µm hydrophilized PVDF or PES membrane cartridge, with pre-use bubble point or water intrusion testing and post-use integrity testing performed as required by 21 CFR 211.84, 21 CFR 211.113, and EU GMP Annex 1. Aseptic filling takes place under Grade A/ISO 14644-1 Class 5 conditions into Type I borosilicate glass vials, followed by elastomeric stoppering and aluminum oversealing. The terminal finished product types are 1 mL and 5 mL single-dose vials containing 10 mg and 50 mg vinorelbine base, respectively. Release testing includes USP <71>, USP <85>, USP <788>, USP <790>, Ph. Eur. 2.6.1, Ph. Eur. 2.6.14, Ph. Eur. 2.9.19, and Ph. Eur. 2.9.20; the bacterial endotoxin limit is calculated from the maximum intravenous dose per kilogram under USP <85>, not from a fixed concentration. Production-scale failure modes observed on automated cytotoxic fill lines include dose-weight drift caused by peristaltic tubing relaxation, product hold-up in the filter housing when solution viscosity exceeds 2 mPa·s, and visible particulate formation when pH exceeds 4.2 during inadequate pH control.
| Quality Attribute | Reference Method | Acceptance Criterion |
|---|---|---|
| Sterility | USP <71>, Ph. Eur. 2.6.1 | No growth after specified incubation period |
| Bacterial endotoxins | USP <85>, Ph. Eur. 2.6.14 | Calculated per maximum bolus dose and route |
| Sub-visible particulate matter | USP <788>, Ph. Eur. 2.9.19 | For small-volume injectable: ≥10 µm NMT 6000 per container; ≥25 µm NMT 600 per container |
| Visible particulates | USP <790>, Ph. Eur. 2.9.20 | Practically free from visible particles |
| pH | USP <791>, Ph. Eur. 2.2.3 | 3.0–3.8 |
Oral vinorelbine tartrate is filled into soft gelatin capsules at fixed base-equivalent strengths of 20 mg, 30 mg, and 40 mg per capsule; the corresponding tartrate salt masses are 27.7 mg, 41.55 mg, and 55.4 mg per unit. The addition ratio is specified on a per-capsule basis in regulatory dossiers rather than as a universal percent weight of the fill mass, because public SmPC documents do not fix total fill weight for every manufacturer. The fill matrix must be qualified for vinorelbine tartrate solubility, antioxidant capacity, low aldehyde impurity content, and compatibility with the soft gelatin shell; a water-miscible polyethylene glycol-based vehicle is typical, but the exact qualitative formula remains a manufacturer-controlled variable. Downstream processing includes deaerated liquid fill mass preparation, rotary-die encapsulation at 20–25°C, sealing, tumble drying at 25–35°C, solvent washing, leak testing, and visual inspection. The terminal finished product types are immediate-release soft gelatin capsules in 20 mg, 30 mg, and 40 mg strengths. Critical quality failure points include content uniformity drift during long encapsulation campaigns, water migration from the shell into a hygroscopic fill matrix, and shell crosslinking caused by aldehyde impurities in the fill vehicle; these failure mechanisms reduce dissolution recovery under USP <711> and Ph. Eur. 2.9.3. Because vinorelbine tartrate is a cytotoxic agent, powder handling, capsule filling, and washing operations are restricted to contained isolators or equivalent engineering controls per USP <800> and NIOSH hazardous drug guidance, even though the finished oral capsule is non-sterile. Residual solvents are controlled under ICH Q3C, elemental impurities under ICH Q3D, degradation products under ICH Q3B, and stability studies under ICH Q1A.
| Quality Attribute | Reference Method | Acceptance Criterion |
|---|---|---|
| Uniformity of dosage units | USP <905>, Ph. Eur. 2.9.40 | AV ≤ 15 for 10 dosage units |
| Dissolution | USP <711>, Ph. Eur. 2.9.3 | Q value as per approved monograph |
| Residual solvents | ICH Q3C | Class-specific concentration limits |
| Elemental impurities | ICH Q3D | PDE per intended route and daily dose |
| Degradation products | ICH Q3B | Reporting, identification, and qualification thresholds |
When hospital oncology pharmacy operations receive the injectable concentrate as a 10 mg/mL solution, patient-specific infusions are prepared by aseptic transfer into polyolefin, non-DEHP PVC, or glass-compatible infusion containers. The working dilution is commonly targeted to 0.5 mg/mL to 1.0 mg/mL using 9 mg/mL sodium chloride or 50 mg/mL glucose; the maximum concentration is 2.0 mg/mL. Formulation addition is executed by dose-banded volume transfer with closed-system transfer devices and gravimetric confirmation, not by percent-weight adjustment. The downstream process includes body surface area-based dose calculation, independent verification by a second pharmacist, CSTD assembly, diluent transfer, final bag labeling, and beyond-use dating under USP <797> Category 2 compounding. Terminal product types are ready-to-administer intravenous infusion bags in typical diluent volumes of 20–50 mL or polypropylene syringes for short intravenous push. Compatibility with infusion container materials and administration sets must be assessed specifically for leachables, plasticizer migration, and pH-sensitive precipitation; if published data for a specific container configuration are limited, an in-use stability study should be generated. Occupational control is governed by USP <800>, NIOSH Alert, and European Directive 2004/37/EC; closed-system transfer devices must meet the NIOSH definition of a closed system, and containment performance is verified by environmental wipe sampling for vinorelbine tartrate residues. The principal operational failure is incomplete mixing after drug transfer into a standing diluent bag, which can produce local concentration excursions above 2.0 mg/mL and subsequent infusion-site irritation; therefore, aseptic mixing and visual inspection after reconstitution are mandatory.
Commercial tablet and granule presentations of vinorelbine tartrate are not established as primary marketed forms in most jurisdictions; published data for a conventional compressed tablet monograph are limited. Where a development program requires granulation for hard-capsule or single-dose granule dose strengths, the active substance is blended with a pre-mix of microcrystalline cellulose, lactose monohydrate, and crospovidone, then dry-compacted or wet-granulated in a high-shear granulator. The addition ratio is defined by target unit dose; if a hard capsule is formulated to match the 20 mg, 30 mg, or 40 mg oral dose, the API remains a low mass fraction of the final blend, generally below 10% w/w, but public monographs do not fix the ratio because fill mass and excipient grades are specific to each manufacturer. The granulation process includes dry compaction at roll pressures validated to limit excessive fines, milling through a 0.8–1.0 mm screen, blending with lubricant, and encapsulation in hard gelatin or HPMC capsules at controlled relative humidity below 40% RH. Terminal finished product types are hard capsules or single-dose granules for reconstitution in some investigational protocols. Compliance standards for non-sterile oral cytotoxic manufacturing include ICH Q7 for active substance handling, ICH Q3D for elemental impurities, ICH Q3C for residual solvents, USP <905> for content uniformity, and USP <800> for hazardous drug containment. Excipient compatibility studies should be performed by binary isothermal stress testing at 40°C/75% RH for 4 weeks, because vinorelbine tartrate is susceptible to degradation in the presence of reducing sugars and certain formaldehyde-releasing binders. Batch-to-batch variance in granule strength derives mainly from irregular API dispersion during low-drug-load blending; geometric dilution with a pre-screened excipient fraction is used to reduce localized agglomeration.
For clinical trial material production involving vinorelbine tartrate oral capsules and injectable vials, manufacturing is performed under the same GMP controls as commercial product with additional blinding and randomization procedures. Oral capsules are over-encapsulated or matched with placebo capsules containing no active; injectable vials are labeled with kit numbers and stored under ICH stability conditions. The active addition ratio remains identical to the marketed strengths, namely 20 mg, 30 mg, and 40 mg for oral capsules and 10 mg/mL for vials; placebo batches must match color, weight, and fill mass within tolerances of ±5%. Downstream processing includes small-scale batch selection below full commercial scale, electronic batch recording with audit trails, blinding and randomization scheduling, expiry dating, and temperature-logged packaging. Terminal product types include blinded patient kits, open-label vials, and comparator packaging. Compliance standards include 21 CFR 210, 21 CFR 211, ICH E6(R2) for investigational product accountability, EU Clinical Trial Regulation (EU) No 536/2014 for labeling and reporting, and ICH Q1A for stability. The operational challenge lies in maintaining batch-to-batch blinding when active oral capsules have distinct fill mass and shell dimensions; over-encapsulation is therefore used to normalize appearance and prevent unblinding at the dispensing site.
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Vinorelbine Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is supplied as vinorelbine tartrate, the semisynthetic vinca alkaloid salt used in oral capsule and intravenous solution formulations. The free base has a molecular weight of 778.93 g/mol; the tartrate salt form is used in both oral and injectable finished products because it increases aqueous solubility for intravenous dilution. The drug substance is released against the USP Vinorelbine Tartrate monograph, with assay by HPLC and related substances controlled under ICH Q3A. Identity is confirmed by infrared absorption and chromatographic retention. Residual solvents are limited by ICH Q3C(R8) and tested by headspace gas chromatography per USP <467>. Elemental impurities are risk-assessed under ICH Q3D(R2) and tested by USP <232>/<233> when the assessment identifies a control need. Incoming testing at the finished-dose site follows 21 CFR 211.84; any supplier certificate of analysis reduction must be justified by a documented risk assessment. For solid oral dosage forms, the powder is a crystalline material with a particle size distribution that is not defined by the compendial monograph and is therefore set in the supplier–manufacturer quality agreement based on the intended granulation, blending, or direct compression unit operation. For injection, the API is supplied with reduced bioburden, and the finished product is rendered sterile by aseptic filtration because the vinca alkaloid ring system is sensitive to terminal autoclaving. Published data on terminal sterilization of vinorelbine tartrate injection are limited; current pharmacopoeial practice relies on aseptic processing.
Vinorelbine differs from vinblastine and vincristine in the semi-synthetic modification of the catharanthine side of the dimer. The structural change reduces neurotoxic potential relative to vincristine in clinical use, but at the API level the distinction is expressed as a different impurity profile, different extraction solvent systems, and different compendial identification tests. Vinorelbine tartrate is a white to off-white crystalline powder; its salt form allows aqueous dissolution for injection, whereas the free base is a lipophilic substance requiring lipid-based or surfactant-mediated oral delivery. Manufacturers of oral vinorelbine capsules typically use a liquid-filled soft gelatin presentation rather than direct compression of the crystalline tartrate powder, because the dose strength is low and content uniformity targets are easier to meet through solution metering. This does not exclude the tartrate powder from tablets or granules; a wet granulation process with a low-dose active pre-blend can achieve pharmacopoeial content uniformity if the particle size is controlled and segregation is minimized. Unlike vinblastine sulfate, vinorelbine tartrate has a specific optical rotation and related-substance profile that must be independently validated; compendial monographs are product-specific and do not allow interchangeability of vinca alkaloid salts.
Direct compression of vinorelbine tartrate at the low doses used in oncology formulations requires that the API meet a narrow span distribution and that no coarse fraction exceeds the screen aperture of the tableting excipients. A laser diffraction method per USP <429> is used to report D10, D50, and D90. The acceptance limits are product-specific, but a manufacturer may set D90 below 150 µm for direct compression and below 75 µm when the API is pre-blended for wet granulation. Controlled shear testing is performed on a Schulze ring shear cell according to ASTM D6773-16 when the manufacturer must establish whether flow function coefficient values support gravity-fed tableting or require forced feeding and glidant addition. Bulk solids engineering convention classifies flow function coefficient below 2.0 as cohesive; direct compression is therefore not reliable without colloidal silicon dioxide or an equivalent flow aid, and the process should be shifted to wet granulation or capsule filling with tamping or dosator pins. These thresholds are not monographed for vinorelbine tartrate; they are unit-operation decision points derived from bulk solids testing equipment and should be verified on the production batch because particle habit and residual solvent content can vary between recrystallization campaigns. Published production-scale data specific to vinorelbine tartrate direct compression are limited; most licensed oral presentations use liquid-filled capsules.
For parenteral-grade vinorelbine tartrate, the API release specification includes bacterial endotoxins by the lysate method of USP <85>, total aerobic microbial count and total yeast and mold count by membrane filtration, and identification by HPLC with photodiode array. The endotoxin acceptance limit is not fixed in the USP monograph; it is calculated from the maximum total daily dose of vinorelbine and the route of administration, then allocated to the API contribution. The pharmacopoeial calculation uses K = 5 EU/kg/h for intravenous products and the maximum bolus dose in mg/kg/h; the resulting finished-product limit is used to back-calculate an API limit. The conventional intravenous strength is 10 mg/mL, supplied in 1 mL and 5 mL presentations; a finished-dose manufacturer uses this clinical dose to derive an API endotoxin specification that is more stringent than the oral grade. Bioburden of the API is controlled through final recrystallization and drying under ISO 7 classified environments, with terminal API packaging in double low-density polyethylene bags inside high-density polyethylene drums. The injectable grade is not sold as sterile; it is filtered through a 0.22 µm membrane at the point of fill. Because vinorelbine tartrate injection is a solution, subvisible particulate matter is controlled in the finished product by USP <788>, and visible particulates are controlled by USP <790>; the API must fully dissolve in water for injection without visible haze or precipitation at 10 mg/mL. Filter compatibility data for polyethersulfone and polyvinylidene fluoride membranes are generated with the actual batch because trace organic impurities can depress flux.
| Quality attribute | Solid oral grade | Injectable grade | Method/standard |
|---|---|---|---|
| Assay, anhydrous basis | 98.0%–102.0% | 98.0%–102.0% | USP Vinorelbine Tartrate monograph |
| Related substances | Reporting ≥0.05%; identification ≥0.10%; qualification ≥0.15% | Same thresholds | ICH Q3A |
| Residual solvents | Class 1 not detected; Class 2 per ICH Q3C(R8) | Same limits | USP <467> |
| Elemental impurities | Risk assessment-based | Risk assessment-based | ICH Q3D(R2), USP <232>/<233> |
| Water content | Product-specific by Karl Fischer | Product-specific; potency-adjusted | USP <921> |
| Particle size | D10/D50/D90 by laser diffraction; D90 often 150 µm for direct compression | Not applicable; dissolution clarity at 10 mg/mL | USP <429> |
| Microbial limits | Total aerobic count ≤103 CFU/g; yeast/mold ≤102 CFU/g | Bioburden ≤102 CFU/g; endotoxin per dose calculation | USP <61>/<62>/<85> |
| Subvisible particles | Not an API release test | Controlled in finished injection | USP <788> |
| Sterility | Not an API release test | Not sold sterile; aseptic filtration at fill | USP <71> for finished product |
A granulated oral form of vinorelbine tartrate, if required for a pediatric or modified-release presentation, imposes different constraints than a compressed tablet. Wet granulation with aqueous binder can cause partial conversion of the tartrate salt to the free base at the granule surface if the binder solution pH rises above 6.0; therefore, the granulating fluid is typically acidified with tartaric acid or citric acid and the wet mass is dried at a product temperature no higher than 40°C to limit degradation. Drying endpoint is monitored by loss on drying under USP <731>; residual water is set by stability data rather than compendial requirement. The granule particle size is sized through a comil with a 0.8 mm or 1.0 mm screen depending on the intended capsule fill weight. HPLC assay of the granule blend is performed after mixing; acceptance follows USP <905> for dosage unit uniformity on the finished product, but a blend uniformity acceptance criterion of 90.0%–110.0% with an RSD no greater than 5.0% is typically used in process validation. These values are process-specific and not product monograph limits; they must be agreed in the validation protocol. Published scale-up data for vinorelbine tartrate granules are limited.
Analytical transfer for the API release method is governed by USP <621>. The HPLC system suitability criteria are established between the API manufacturer and the finished-dose site; a typical acceptance for replicate injections of the assay standard is an RSD not greater than 2.0% and a tailing factor not greater than 2.0. The related-substances method must separate vinorelbine tartrate from process impurities and degradation products under stressed conditions. Forced degradation studies per ICH Q1A include acid, base, oxidative, thermal, and photolytic conditions; peak purity is verified with a photodiode array detector. The assay procedure is stability-indicating if the main peak purity factor remains above 990 in the presence of degradation products. Method transfer failure is most commonly associated with column temperature control and mobile phase pH; the receiving laboratory should hold the column compartment at the transferred set point and calibrate the pH meter before use.
Vinorelbine tartrate can exhibit multiple crystalline habits depending on crystallization solvent and cooling rate. The USP monograph may include an X-ray powder diffraction identity test; if not, the manufacturer includes XRPD as an internal specification. Polymorphic conversion during micronization is a process conflict: jet milling raises surface energy and can generate amorphous regions that reduce chemical stability and increase hygroscopicity. The milled API is therefore conditioned at 25°C/60% RH until the water activity stabilizes, and the amorphous content is checked by modulated differential scanning calorimetry. Residual solvent control is critical because the semi-synthetic route may use methanol, dichloromethane, or ethyl acetate. Class 1 solvents are controlled to not detected levels by USP <467>; Class 2 solvents are limited by ICH Q3C(R8) with a maximum daily intake-derived limit. The API supplier should provide a full residual solvent profile because the final oral liquid or injection vehicle may interact with trace non-polar solvents to form visible precipitation.
Vinorelbine tartrate is light-sensitive and requires protection from light during storage and processing. The API is packaged in amber glass or double LDPE bags inside opaque drums; storage at 2–8°C is typical for injection-grade material, while oral-grade material is often stored at controlled room temperature 20–25°C with excursions allowed to 15–30°C per USP <659>. Stability-indicating HPLC detects the hydrolytic degradation products that form under high humidity; for this reason the API is not pre-dried unless the process requires dry powder, and if pre-drying is required at RH greater than 60%, a vacuum dryer at not more than 40°C is used. These conditions are not compendial release specifications but stability-derived handling boundaries. The manufacturer’s retest date is based on long-term, intermediate, and accelerated storage conditions per ICH Q1A; published stability data for vinorelbine tartrate API in commercial packaging are available in the drug master file rather than the public domain.
Oral liquid dosage forms of vinorelbine tartrate require a different API specification than tablets. The particle size distribution is irrelevant to dissolution, but the pH of the vehicle and the buffering salt selection govern chemical stability and taste masking. A solution of vinorelbine tartrate in an acidic vehicle at pH 3.0–4.0 is chemically more stable than a neutral solution because the free base precipitates as the pH approaches the basic pKa. The API is dissolved in a vehicle containing a taste-masking buffer and a sweetener; no oil phase is needed because the tartrate salt is water-soluble. Uniformity in oral liquids is controlled by volumetric metering and specific gravity, not by blend segregation. For granules, the API is incorporated as an alcoholic or aqueous suspension in the binder; the granule porosity after drying controls the dissolution rate. If the granule porosity is too low, the dissolution at pH 1.2 and pH 6.8 in USP <711> apparatus II may not match the reference profile. Granule density is measured by helium pycnometry and tapped density by USP <616>; these are in-process controls rather than release tests.
In production-scale manufacture of vinorelbine tartrate oral granules, a high-shear granulator with a 150 L bowl and a three-impeller/chopper configuration is used because low-dose uniform distribution requires high-shear dispersion. The granulation endpoint is controlled by power consumption and impeller torque; endpoint variability is usually accepted only within ±5% of the target torque. After wet massing, granules are discharged through a 0.8 mm screen and dried in a fluid-bed dryer with inlet air temperature not exceeding 45°C. The drying curve is monitored by loss on drying; a stable granule endpoint is typically 2.0%–4.0% residual moisture. These operating parameters are representative for low-dose oncology APIs but must be confirmed for vinorelbine tartrate because of its hygroscopicity. Direct compression of vinorelbine tartrate without granulation is discouraged at production scale unless a force feeder and a pre-blend with flow aid are used; the API has a cohesive nature that can cause sticking to the die wall if the punch tip temperature exceeds 35°C.
