| HS Code | 832283 |
| Product Name | Rabbit Viral Haemorrhagic Disease Vaccine, Inactivated Veterinary Grade API |
| Product Type | Inactivated veterinary vaccine |
| Target Pathogen | Rabbit Viral Haemorrhagic Disease Virus (RHDV) |
| Disease Prevented | Rabbit Viral Haemorrhagic Disease (RVHD) |
| Target Species | Rabbits |
| Vaccine Category | Inactivated (killed) antigen |
| Api Form | Veterinary grade active pharmaceutical ingredient |
| Available Dosage Forms | Tablets, Injections, Capsules, Powders, Granules, Premix, Solutions |
| Administration Route | Dependent on final dosage form; injectable, oral, or other applicable route |
| Mechanism Of Action | Induces active immunity by presenting inactivated RHDV antigens to the rabbit immune system |
| Storage Conditions | Store refrigerated at 2–8°C, protected from light |
| Shelf Life | Typically 18–24 months from date of manufacture |
As an accredited Rabbit Viral Haemorrhagic Disease Vaccine,Inactivated 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 | Packaged in sterile, sealed multidose vials, supplied as 100 mL veterinary-grade inactivated vaccine for injection, tablet, powder, or solution formulations. |
| Container Loading (20′ FCL) | One 20′ FCL container loaded with palletized, temperature-controlled inactivated vaccine API, secured, sealed, and documented for safe transport. |
| Shipping | Shipment requires temperature-controlled cold chain transport at 2–8°C, using insulated containers with validated cool packs. Protect from light, moisture, and freezing. Use leak-proof, sealed primary packaging with absorbent material, clearly labelled as veterinary biological product. Include Certificate of Analysis and maintain continuous temperature monitoring during transit. |
| Storage | Store at 2–8°C in a clean, dry, well-ventilated area, protected from light and moisture. Do not freeze. Keep container tightly sealed when not in use. Avoid exposure to excessive heat or direct sunlight. Follow manufacturer’s label instructions and local veterinary regulations for safe handling and disposal. |
| Shelf Life | Shelf life typically 2 years when stored at 2–8°C, protected from light, and not frozen. |
In high-output rabbit meat and breeding farms, the inactivated Rabbit Viral Haemorrhagic Disease Virus (RHDV) antigen concentrate is formulated into a sterile aqueous suspension for subcutaneous or intramuscular injection. The batch dossier must satisfy European Pharmacopoeia monograph 2325 Rabbit haemorrhagic disease vaccine (inactivated), and the antigen production chain is audited against EudraLex Volume 4 Annex 2 for biological active substances and WOAH Terrestrial Manual Chapter 3.6.2. Sterility is evaluated under Ph. Eur. 2.6.1, and absence of extraneous agents uses Ph. Eur. 2.6.16. The formulation addition ratio is determined by the antigenic mass per 0.5 mL dose; after standardisation of the incoming concentrate in a haemagglutination inhibition test against the homologous reference serum, the aqueous blending step typically combines 1.0–2.5 parts of standardised antigen concentrate with 97.5–99.0 parts sterile diluent plus aluminium hydroxide gel, followed by gentle stirring at 4–8°C. The downstream production process for the injectable suspension includes aseptic mixing of the non-adjuvanted aqueous phase, sterile filtration through a 0.22 µm PVDF cartridge, addition of sterile Al(OH)3 gel under low-shear agitation, and filling into Type I glass vials or blow-fill-seal polymer containers in a Grade A environment. Terminal product types are 0.5 mL and 1.0 mL single-dose or multidose injectable suspensions for fattening rabbits, breeding does, and exhibition animals; multidose presentations typically avoid thiomersal if rubber closure extractable profiles indicate incompatibility with mercury preservatives. Production-scale filling behaviour shows that long hold times of the adjuvanted bulk beyond 24 hours at 2–8°C may result in slow sedimentation, so continuous gentle recirculation with a peristaltic pump and single-use silicone tubing is applied before the filling needle manifold.
Oil-adjuvanted bivalent RHDV1/RHDV2 emulsions are formulated when a single injection must provide homologous and heterologous protection against both VP60 lineage groups. Compliance for this presentation is governed by Ph. Eur. monograph 2325, Regulation (EU) 2019/6 for veterinary medicinal products, and the extraneous agent chapters Ph. Eur. 2.6.7 and 2.6.16, with batch release sterility under Ph. Eur. 2.6.1. The formulation addition ratio is not a fixed antigen-diluent proportion but is derived from separate haemagglutination standardisation of each antigen pool; after each pool is adjusted to the same haemagglutinating unit content, the combined aqueous antigen phase typically represents 30–40% by weight of the final water-in-oil emulsion, while the mineral oil-mannide monooleate continuous phase represents 60–70% by weight. The downstream production process uses a rotor-stator homogeniser with tip speed between 12 and 18 m/s, producing a target droplet size Dv90 ≤5 µm and a viscosity at 20°C of 20–80 mPa·s; overshearing above 22 m/s raises bulk temperature and degrades emulsion stability, while undershearing below 8 m/s leaves an unstable coarse dispersion that can separate during storage. Terminal product types are 0.5 mL injectable emulsions in Type I glass vials or pre-filled polymer syringes for breeding does, show rabbits, and long-lived companion rabbits; the intramuscular or subcutaneous route is used. Tablets, capsules, granules, and oral premix presentations are not suitable for inactivated RHDV antigen because gastric acid and intestinal proteases degrade the intact viral capsid before immune presentation, and no regulatory pathway has been validated for oral administration of inactivated RHDV.
When a vaccinated rabbit colony presents confirmed RHDV2 losses despite homologous commercial vaccine coverage, the next downstream intervention is an autogenous inactivated vaccine produced from the field isolate. Field isolate identity is confirmed by RT-PCR and VP60 sequencing before the antigen producer performs liver-tissue propagation in specific-pathogen-free rabbits; the clarified homogenate is inactivated with β-propiolactone or binary ethylenimine and then transferred as an inactivated antigen concentrate to the downstream formulator under national autogenous vaccine provisions aligned with Regulation (EU) 2019/6 and GMP Annex 2. The formulation addition ratio is shifted upward compared with routine monovalent vaccine because field isolates often show variable haemagglutination titre between 1:1024 and 1:4096; the inactivated concentrate is blended at 10–20 parts per 100 parts final aqueous suspension with sterile diluent and an approved adjuvant, and the potency target is set using challenge-serum correlation data from the index farm. Production process includes tangential flow filtration concentration, sterile filtration of the dilution buffer, adjuvanted adsorption, and filling; because autogenous batches are small, disposable bag mixing and single-use filling manifolds reduce cross-contamination risk. Terminal product types are prescription-only injectable suspensions, usually 5 mL or 20 mL multidose vials, for restricted use in affected rabbit colonies; expiry is typically short, often 6 months at 2–8°C, due to limited stability data on emergency batches. Published data for commercial autogenous RHDV formulation ratios is limited because each batch is matched to a single outbreak isolate, but the production route is well established in veterinary biologics emergency authorisations.
Lyophilised inactivated RHDV antigen powder is used where cold-chain-free stockpiling is required or where downstream formulators need an intermediate powder for later aseptic reconstitution into injectable solution. The lyophilised intermediate must meet Ph. Eur. monograph 2325 for the active component and is produced under EudraLex Volume 4 Annex 2 biological manufacturing conditions; the reconstituted product is tested for sterility under Ph. Eur. 2.6.1, bacterial endotoxins under Ph. Eur. 2.6.14, and mycoplasma under Ph. Eur. 2.6.7. The formulation addition ratio for this presentation includes a cryoprotectant load of 4–8% w/v mannitol or sucrose in the pre-lyophilisation liquid bulk, followed by reconstitution with sterile water for injection at a 1:1 volume replacement to return the original antigen concentration before final dilution. The downstream production process uses aseptic filling into partially stoppered Type I glass vials, freezing at -40 to -50°C, primary drying at shelf temperature -40 to -30°C under 50–150 µbar chamber pressure, and secondary drying at 20–25°C to residual moisture ≤3.0% w/w. Terminal product types are lyophilised powder vials that are reconstituted immediately before use into 0.5 mL or 1.0 mL injectable suspensions; this presentation is used for emergency antigen banks and for long-term stability studies in veterinary vaccine development. Failure modes observed on production freeze-dryers include collapsed cake when shelf temperature rises too early during primary drying and slow reconstitution exceeding 120 seconds when residual moisture is controlled too tightly below 1.0% w/w.
| Lyophilisation parameter | Observed range | Control method |
|---|---|---|
| Shelf temperature primary drying | -40 to -30 °C | In-process thermocouple array |
| Chamber pressure | 50–150 µbar | Capacitance manometer |
| Residual moisture | ≤3.0% w/w | Karl Fischer titration |
| Reconstitution time | ≤120 seconds with 20–25°C sterile water | Visual inspection after swirling |
| Cryoprotectant load | 4–8% w/v mannitol or sucrose | Formulation record |
If a downstream filling site requires a sterile liquid concentrate for final volume adjustment into prefilled syringes or multidose injectable packs, the inactivated RHDV antigen is supplied as a filtered solution concentrate rather than an adjuvanted suspension. This presentation is governed by Ph. Eur. monograph 2325, Regulation (EU) 2019/6, and EudraLex Volume 4 Annex 2; release testing includes sterility under Ph. Eur. 2.6.1, bacterial endotoxins under Ph. Eur. 2.6.14, and extraneous virus detection under Ph. Eur. 2.6.16. The formulation addition ratio for the final injectable is set by dilution of the concentrate between 1:5 and 1:20 with sterile isotonic buffer, then further adjustment according to the potency test result from the homologous reference serum; final antigen load is expressed as the dose needed to pass the batch potency threshold, not as a fixed volumetric percentage. The downstream production process includes aseptic cascade filtration through 0.45 µm and 0.22 µm PES capsules, pH adjustment to 7.0–7.6, osmolality adjustment to 280–320 mOsm/kg, and filling under high-speed aseptic filling lines with in-line particle counting. Terminal product types are 0.5 mL or 1.0 mL liquid solution presentations in prefilled syringes, single-dose vials, or preservative-containing multidose vials for use in rabbit vaccination programmes; the solution is intended for intramuscular or subcutaneous injection after optional mixing with a compatible adjuvant immediately before administration. This liquid concentrate route avoids the higher shear stress of emulsion manufacture and is preferred when downstream formulators must combine RHDV antigen with separate bacterial toxoid or viral antigen components in regionally approved vaccination schedules, provided compatibility testing has been completed for each mixture.
| Release test | Standard | Typical acceptance criterion |
|---|---|---|
| Sterility | Ph. Eur. 2.6.1 | No growth |
| Mycoplasma | Ph. Eur. 2.6.7 | Negative |
| Extraneous viruses | Ph. Eur. 2.6.16 | No cytopathic effect |
| Bacterial endotoxin | Ph. Eur. 2.6.14 | ≤ 2.0 EU/dose |
| Potency | Ph. Eur. 2325 | Meets reference serum threshold |
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Rabbit Viral Haemorrhagic Disease Vaccine, Inactivated Veterinary Grade API is a purified whole-virus antigen intermediate derived from rabbit haemorrhagic disease virus (RHDV), intended for further manufacture into finished veterinary immunological dosage forms. The API is produced from characterised seed lots of the GI.1 classical RHDV lineage, the GI.2 RHDV2 lineage, or a bivalent blend of both lineages. Manufacturer-specific model identifiers typically encode the antigenic configuration as RHDV-API-GI.1, RHDV-API-GI.2, or RHDV-API-GI.1/GI.2. The designation “Inactivated Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions” identifies the substance as an antigen concentrate that can be incorporated into multiple presentations after dilution, adsorption, lyophilisation, granulation, or coating. It is not a finished vaccine; it contains no adjuvant, no preservative, and no final buffer system unless agreed as part of a custom blend.
Manufacture of the API begins with propagation of the virus in specific-pathogen-free rabbits because routine cell-culture amplification of RHDV remains unreliable for many production strains. Harvested liver homogenate is clarified by depth filtration and tangential-flow filtration, concentrated by ultrafiltration, and chemically inactivated with binary ethylenimine or formaldehyde. Inactivation is conducted under defined temperature, pH, and time conditions and is confirmed by at least two blind passages in susceptible rabbits, as cell-culture-based exclusion of residual live virus is not considered sufficient for this virus. The inactivated antigen is then filtered through 0.45 µm and 0.22 µm membrane capsules in an ISO 14644-1:2015 classified cleanroom. Liquid API is stored at 2–8 °C, while lyophilised cake is typically held at −15 °C or below for long-term storage. Repeated freeze-thaw cycles are avoided because loss of haemagglutination titre has been observed after multiple thaw episodes in validation studies. The API is supplied as a sterile-filtered liquid concentrate or as a lyophilised powder with cryoprotectant, depending on the intended downstream dosage form.
Release acceptance of the API is built around haemagglutination titre, VP60 antigen content, sterility, endotoxin, residual inactivator, and confirmation of absence of live virus. Haemagglutination titre is used because RHDV agglutinates human type O erythrocytes, and the assay provides a reproducible in-process measure of intact capsid function. VP60 antigen content is determined by species-specific or in-house ELISA calibrated against a release reference. Residual moisture in the lyophilised powder is controlled by loss-on-drying. If formaldehyde is used as the inactivator, residual formaldehyde is limited because excess residual aldehyde can reduce antigen stability and may create local reactogenicity in injectable products. The API manufacturer also controls rabbit tissue-derived host protein and lipid content because these impurities influence downstream adjuvant adsorption and emulsion stability.
| Release parameter | Representative acceptance criterion | Test basis |
|---|---|---|
| Haemagglutination titre, GI.1 monovalent antigen | ≥1:512 per dose equivalent | WOAH Chapter 3.6.2 haemagglutination assay |
| VP60 antigen content | Lot-specific target range | ELISA calibrated to in-house reference |
| Sterility | No growth | Ph. Eur. 2.6.1 |
| Bacterial endotoxin | ≤5 EU/mL | Ph. Eur. 2.6.14 |
| Residual formaldehyde, if used | ≤0.02% | Ph. Eur. 2.4.18 |
| Residual moisture, lyophilised powder | ≤2.0% | Ph. Eur. 2.2.32 |
| Inactivation confirmation | No clinical signs or seroconversion in sentinel rabbits after two passages | Ph. Eur. 0454, WOAH Chapter 3.6.2 |
Where a finished product is licensed in the United States, the relevant USDA 9 CFR 113.308 pathway for killed rabbit haemorrhagic disease vaccine may apply. The API itself is normally controlled through the manufacturer’s veterinary active substance master file rather than as a standalone licensed product. The release profile therefore functions as a drug-substance specification, while finished-product potency, safety, and efficacy remain the responsibility of the downstream marketing-authorisation holder.
The central operational distinction is that the inactivated whole-virus API does not replicate in the vaccinated animal. Live attenuated RHDV preparations may induce strong local and systemic immune responses, but they carry risks of reversion, silent shedding, and accidental introduction of virus into naïve breeding colonies. The inactivated API presents native VP60 capsid antigen without replication-competent nucleic acid. Compared with recombinant VP60 subunit or virus-like particle intermediates produced in baculovirus or yeast expression systems, the inactivated whole-virus API retains the complete particulate structure of the native virion, including haemagglutinating domains that are used for in-process potency estimation. Recombinant products can be manufactured without large-scale rabbit tissue harvest and may exhibit lower host-protein burden, but they may require additional adjuvant optimisation to match the immunogenicity of inactivated whole-virus antigen in some field programmes. The API also differs from raw infected liver homogenate because clarification, filtration, standardisation, and residual testing reduce batch-to-batch variance in antigen mass, host-cell protein, endotoxin, and residual inactivator that would otherwise be unacceptable in a veterinary drug substance.
A further difference is the route of administration supported by the product. Injectable finished vaccines produced from the inactivated API are the reference presentation for systemic immunity. Oral presentations such as tablets, capsules, granules, and premixes are technically possible from the lyophilised powder, but published data for this exact API in oral solid dosage forms are limited. Therefore, any oral or feed-based presentation requires finished-product challenge studies because antigen uptake across the intestinal mucosa is formulation-dependent and cannot be inferred from haemagglutination titre alone.
Injectable formulations are prepared from the liquid antigen concentrate by dilution into buffered solution and adsorption onto aluminium hydroxide or incorporation into an oil-in-water emulsion. If aluminium-based adjuvants are used, the adsorption step should be performed in a low-phosphate buffer because phosphate ions can compete with antigen for binding sites on the adjuvant surface. Adsorption efficiency is measured by residual antigen in the supernatant after centrifugation; a target of ≥70% adsorption is commonly applied during formulation development, though the acceptable value depends on the final potency specification. Emulsion-based injectables require high-shear dispersion. Bench-scale optimisation frequently uses a rotor-stator homogeniser at 3,000–6,000 rpm for 5–10 min, followed by droplet-size verification by laser diffraction. Excessive shear or prolonged recirculation may disrupt the antigen capsid and should be avoided unless stability data support the selected energy input.
For tablets, capsules, and granules, the lyophilised API powder is hygroscopic and requires pre-drying or controlled handling when relative humidity exceeds 60%. Direct compression and capsule filling are preferred over wet granulation because aqueous granulation can destabilise haemagglutinating activity and redistribute antigen unevenly within the granule. Where granulation is unavoidable, fluid-bed granulation with inlet air temperature not exceeding 40 °C and product temperature maintained below 30 °C is used to limit thermal stress. Particle-size reduction of the lyophilised cake is preferably performed by jet milling under refrigerated air; hammer milling can generate local temperature excursions that reduce titre. A target particle-size distribution of D90 ≤150 µm is typical for uniformity of blending in direct-compression formulations.
Tablets and capsules intended for oral vaccination require a gastroresistant or enteric coating to deliver antigen beyond the acidic stomach environment. A pH-dependent polymer such as Eudragit L 100-55, which releases at approximately pH 5.5, is one available option, but the finished dosage form must be tested by compendial dissolution or disintegration methods such as Ph. Eur. 2.9.3. Premixes and feed granules are produced by blending the antigen powder with carriers and binders, followed by extrusion or coating. Homogeneity of antigen distribution in a premix should meet a coefficient of variation of ≤5.0% for the active antigen component. Solutions for oral administration are simpler to prepare from the liquid concentrate but require stabilised buffer at pH 6.0–7.5 and protection from microbial growth through preservative selection that does not denature the antigen.
On production-scale lyophilisation lines, edge-vial failures such as collapsed cake and elevated residual moisture have been observed when ramp rates exceed 0.5 °C/min during primary drying. Conservative cycles therefore use shelf temperatures between −25 °C and −15 °C for primary drying and a secondary drying step at 25 °C until the pressure-rise test meets the acceptance limit. Published cycle data for this specific API are limited, so the lyophilisation recipe is normally developed for each model variant and cryoprotectant system. Batch-to-batch variation in tissue-derived antigen is controlled by pooling liver homogenates from multiple rabbits and by normalising antigen mass to the release reference. Finished dosage form manufacturers must verify that each batch of API performs equivalently in their adjuvant and drying process because minor shifts in host-cell protein or lipid content can alter emulsion stability, adsorption kinetics, and powder flow.
Storage and transport conditions impose additional operational boundaries. Liquid concentrates must not be frozen unless the manufacturer’s stability data demonstrate retention of haemagglutination titre after thawing. Lyophilised powders should be protected from moisture and oxygen; containers are flushed with nitrogen where authorised. The API is incompatible with strong oxidising agents and with high concentrations of organic solvents that may denature VP60. In downstream formulation, combination with cationic polymers or high-molarity salts may precipitate the antigen and reduce uniformity. The product is intended for use by veterinary pharmaceutical manufacturers operating under good manufacturing practice; it is not supplied as a ready-to-administer vaccine.
