| HS Code | 595534 |
| Product Name | Clostridial Enteritis Vaccine for Newborn Piglets, Inactivated Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions |
| Product Type | Inactivated veterinary vaccine active pharmaceutical ingredient |
| Target Species | Newborn piglets |
| Disease Indication | Clostridial enteritis caused by Clostridium perfringens |
| Active Component | Inactivated Clostridium perfringens toxoid or whole-cell antigens |
| Adjuvant | May contain aluminium hydroxide or approved veterinary adjuvant |
| Mechanism Of Action | Induces active immunity by stimulating antibody production against clostridial toxins |
| Route Of Administration | Oral or parenteral depending on final formulation |
| Dosage Forms | Tablets, injections, capsules, powders, granules, premix, solutions |
| Veterinary Grade | Produced under GMP for veterinary use |
| Storage Conditions | Store refrigerated at 2-8°C; protect from light and freezing |
| Shelf Life | Typically 12-24 months from manufacture date depending on final formulation |
| Withdrawal Period | No withdrawal period generally required for newborn piglets when used per label |
| Regulatory Status | Subject to veterinary biological licensing in the country of use |
| Immunogen | Clostridium perfringens type-specific toxoids (e.g., types A, B, C) |
| Excipients | May include stabilisers, preservatives, buffers, and carriers for solid or liquid forms |
| Primary Target Pathogen Binding | Neutralises clostridial alpha, beta, or epsilon toxins depending on serotype coverage |
| Administration Timing | Intended for administration to newborn piglets in early life, typically within the first days after birth |
| Packaging Consideration | API must be formulated into final veterinary medicinal products before administration |
As an accredited Clostridial Enteritis Vaccine for Newborn Piglets,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 100 mL sterile glass vials with rubber stoppers and aluminum crimp seals, stored refrigerated at 2–8°C. |
| Container Loading (20′ FCL) | 20′ FCL: temperature-controlled, palletized vaccine API drums/cartons loaded securely, sealed, documented for safe transport. |
| Shipping | This inactivated veterinary vaccine API is shipped under strict cold-chain conditions at 2–8°C to preserve potency and stability. Sealed in sterile, moisture-resistant containers with cooling packs and tamper-proof labelling, it includes full documentation—Certificate of Analysis, MSDS, and handling protocols—for compliant, expedited worldwide pharmaceutical transport. |
| Storage | Store under refrigeration at 2–8 °C in the original airtight, light-protected container. Do not freeze or expose to excessive heat or sunlight. Keep container tightly sealed to prevent moisture absorption, especially for powders, granules, premixes, and capsules. Avoid repeated temperature fluctuations. Use only before expiry date. Keep out of reach of children; dispose of unused vaccine appropriately. |
| Shelf Life | Shelf life is typically 24 months when stored refrigerated at 2–8°C, protected from light, and not frozen. |
In pre-farrowing sow and gilt vaccination programmes, the inactivated Clostridium perfringens type C toxoid API is formulated into a 2 mL intramuscular suspension to raise colostral neutralizing antitoxin above the protective threshold during the first 24–48 h of lactation, when newborn piglets absorb maternal immunoglobulin across the gut. Production-scale batch records from contract vaccine manufacturers commonly show bulk API incorporation at 0.25–0.75 mL per dose before sterile dilution and aluminium hydroxide adsorption. The downstream process starts with inactivation confirmation in thioglycollate medium, followed by adsorption onto sterile aluminium hydroxide gel at 2.5% w/v final matrix concentration under 150 rpm stirring for 60 min at 20–25 °C. The final aluminium content is standardized to 1.0–2.0 mg Al³⁺/mL; below 0.8 mg Al³⁺/mL, antigen desorption at 2–8 °C reaches 15–20% by month 6, while above 2.5 mg Al³⁺/mL, formulation viscosity rises to 35–50 cP and 23G needle syringability fails. After adsorption, the bulk is passed through a 0.45 µm prefilter and 0.22 µm sterilizing-grade membrane into a 50 L stainless steel surge vessel, then filled by peristaltic pump into multi-dose vials or prefilled syringes. Release testing is governed by USDA 9 CFR Subchapter E Part 113 killed-bacterial serial requirements, Regulation (EU) 2019/6, sterility by Ph. Eur. 2.6.1, pH by Ph. Eur. 2.2.3, aluminium content by ICP-OES, and bacterial endotoxins by Ph. Eur. 2.6.14. Terminal product types include 10-dose, 25-dose, and 50-dose multi-dose vials and 2 mL single-dose prefilled syringes. Terminal heat sterilization is incompatible with the final adsorbed suspension because autoclaving collapses the adjuvant gel matrix and releases toxoid from the aluminium surface; therefore filling is performed aseptically within an ISO 14644-1:2015 Class 8 cleanroom.
| Test | Method / standard | Typical release limit |
|---|---|---|
| Sterility | Ph. Eur. 2.6.1 / USDA 9 CFR Subchapter E Part 113 | No growth after 14 days |
| Aluminium content | ICP-OES | 1.0–2.0 mg Al³⁺/mL |
| pH | Ph. Eur. 2.2.3 | 6.2–6.8 |
| Bacterial endotoxins | Ph. Eur. 2.6.14 | Licensed product-specific limit |
Aqueous oral drench formulations for day-old piglets require a stabiliser system distinct from injectable suspensions because the antigen is exposed to salivary amylase, gastric pH 3.0–4.5, and bile salts before contact with jejunal Peyer’s patches. The drench is compounded as a single 1.0 mL oral dose containing 0.05–0.10 mL of API concentrate dispersed in 0.3% w/v sodium alginate and 0.1% w/v chitosan at pH 6.8; published data for this specific oral configuration remain limited, and mouse antitoxin titre is used as the release potency marker. Production uses a 100 L jacketed vessel with bottom-sweep agitation at 120 rpm; the API is added by peristaltic pump under nitrogen overlay, deaerated at -0.6 bar for 10 min, and filtered through a 0.22 µm membrane before filling into 1 mL single-dose oral syringes or 10 mL oral dose pump bottles. Target animal safety evaluation follows VICH GL44, and the filling line operates under EU GMP Annex 2 biological active substance provisions for inactivated immunological veterinary medicinal products under Regulation (EU) 2019/6. Terminal product types include 1 mL single-dose oral syringes for farrowing-cart use, 10 mL pump bottles for litter treatment, and 50 mL polypropylene bottles for automated drenching stations. High-shear mixing above 500 rpm must be avoided because foam generated at the air-water interface denatures toxoid protein.
Lyophilization embeds the inactivated toxoid API in a glassy mannitol-gelatin matrix that slows moisture-induced aggregation and permits oral disintegration in the piglet oral cavity within 30 s. The API is added at 2.5–7.5% w/w of dry matrix solids, with gelatin at 1.5% w/w, mannitol at 85% w/w, and 0.05 M citrate buffer. Freezing proceeds from 4 °C to -45 °C at 0.5 °C/min; primary drying is held at -30 °C shelf temperature and 80–150 µbar chamber pressure for 18–24 h, followed by secondary drying at 25 °C for 6 h until Karl Fischer moisture is <1.0%. Compression on a rotary tablet press is limited to 8–15 kN compaction force; higher force collapses the porous matrix and raises disintegration time above 30 s. The collapse temperature of the API-containing matrix is approximately -28 °C; if shelf temperature exceeds -25 °C during primary drying, collapse occurs in 30–40% of vials. Compliance for the lyophilized intermediate follows EU GMP Annex 2 for biological active substances, and tablet uniformity is tested using Ph. Eur. 2.9.5 or USP <905>. Terminal product types include 250 mg orally disintegrating tablets sealed in 10-unit aluminium/aluminium blisters. Because residual lipid content shifts collapse temperature by 1–3 °C, differential scanning calorimetry is required on each API lot before cycle validation.
| Phase | Shelf temperature / chamber pressure | Duration / endpoint |
|---|---|---|
| Freezing | 4 °C to -45 °C at 0.5 °C/min | End of ramp |
| Primary drying | -30 °C, 80–150 µbar | 18–24 h, Pirani vs capacitance pressure convergence |
| Secondary drying | 25 °C, 80–100 µbar | 6 h, Karl Fischer moisture <1.0% |
| Collapse control | Below -25 °C | No collapsed cake |
Dry powder and granulated intermediates for colostrum replacer or milk replacer addition are prepared only in facilities with controlled humidity below 40% RH, because the lyophilized toxoid API sorbs moisture above 0.8% w/w and loses antigenicity within 24 h at 30 °C/75% RH. The addition ratio is 1.0–5.0 g of API premix per 10 L of reconstituted milk replacer, corresponding to 0.01–0.05% w/v dry powder in the final liquid. Production begins with low-shear ribbon blending of the API with a lactose-free carrier, 2% w/w colloidal silicon dioxide, and 0.5% w/w sodium carboxymethylcellulose; the blend is passed through an 0.5 mm oscillating granulator and fluid-bed dried at inlet air temperature 30–35 °C to prevent thermal inactivation. Compliance falls under EU GMP Part II for APIs used in veterinary medicinal products and Regulation (EU) 2019/6 labelling provisions; microbial quality is tested by Ph. Eur. 5.1.4. Terminal product types include 100 g printed foil sachets, 1 kg HDPE jars with induction-seal liner, and 25 kg drums with desiccant canisters. Heat input above 40 °C is the process boundary because residual toxoid protein aggregates; fluid-bed top-spray granulation with water is therefore preferred over melt granulation.
When the API is shipped to a remote liquid-drench compounding plant, the preferred intermediate is a 10–25% w/w premix dispersed on maltodextrin and fumed silica rather than sterile bulk solution. This format reduces cold-chain volume while providing calibrated dosing for downstream aseptic reconstitution. The premix is manufactured in a 500 L bin blender at 12 rpm for 20 min, with the intensifier bar disabled because shear heat and metal friction can denature the toxoid; the mixture is then passed through a 0.25 mm conical mill and filled into 20 kg PE-lined drums or 200 kg bulk totes. Compliance is controlled under EU GMP Part II Chapter 4 documentation and process validation, with homogeneity sampling at 10 points using near-infrared spectroscopy against a validated standard curve. Residual moisture is maintained below 5.0% w/w and water activity below 0.4. Terminal product types include 20 kg drums for liquid-drench plants and 200 kg bulk totes for centralized aseptic compounding. This premix is not suitable for direct oral administration; it requires reconstitution and final sterile filtration or aseptic dilution before use. In-feed application is not supported because unprotected antigen in creep feed is inactivated by gastric acid and intestinal proteases without the enteric matrix used in oral drench formulations.
Powder-filled hard capsules are produced only for opened-dose application in farrowing rooms, not for intact swallowing by neonatal piglets. The capsule shell functions as an oxygen and moisture barrier during storage, and the content is dispersed into 2 mL of potable water or milk replacer immediately before dosing. The fill material is a granulated blend containing 5–20 mg of lyophilized API per size 3 capsule, with 0.5% w/w magnesium stearate and 1.0% w/w croscarmellose sodium to ensure complete dispersion in 2 mL of water within 15 s. Filling is performed on a dosator capsule machine at 25 °C and <40% RH; filled capsules are sealed in cold-form aluminium blister strips. Compliance includes USP <905> uniformity of dosage units and Ph. Eur. 2.9.5 mass uniformity; bioburden is controlled to Ph. Eur. 5.1.4. Terminal product types include 30-capsule cold-form blisters and 100-capsule HDPE bottles with desiccant. Chlorinated water above 1.0 ppm free chlorine is incompatible because it oxidizes toxoid epitopes; dechlorinated water or sterile saline is required for dispersion.
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Clostridial Enteritis Vaccine for Newborn Piglets, Inactivated Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions is supplied as a formalin-inactivated antigen concentrate derived from a Clostridium perfringens type C piglet enteritis isolate. The master seed is cultivated under anaerobic conditions in tryptose–sulfite–cycloserine broth containing 0.1% w/v sodium thioglycollate and 0.5% w/v yeast extract. After 18 h at 37°C, the culture is clarified by continuous disk-stack centrifugation at 12,000 × g and inactivated with 0.4% v/v formaldehyde at 37°C for 7 days with intermittent agitation. The inactivated broth is ultrafiltered through a 10 kDa nominal molecular weight cutoff membrane and concentrated to a beta toxoid activity of not less than 8.0 AU/mL in the aqueous concentrate. The two released model designations are CVE-NP-LQ for the aqueous concentrate and CVE-NP-LYO for the lyophilized antigen complex. The API is an unadjuvanted intermediate, not a final dosage form, and is intended for further compounding into injectable solutions, oral solid dosage forms, feed premixes, granules, or reconstituted solutions.
In final form, the product is intended for the prevention of clostridial enteritis caused by C. perfringens type C in piglets less than 7 days of age. The API must not be used as the sole intervention; farrowing-room hygiene, colostrum intake, and sow vaccination status contribute to the control of beta toxin-induced necrotic enteritis. The product does not treat active cases and is not a substitute for antimicrobial therapy when secondary bacterial translocation is present.
The immunodominant fraction of Clostridium perfringens type C enteritis vaccine comprises beta toxoid, alpha toxoid, and variable amounts of theta toxin and hyaluronidase. Beta toxoid is the primary protective antigen because beta toxin is the key virulence factor in necrotizing enterocolitis of neonatal piglets. The API is standardized by in vitro neutralization against a reference beta antitoxin in Vero cell monolayers; the assay readout is the highest dilution that neutralizes 50% of cell rounding after 48 h at 37°C in 5% CO2. Potency results are expressed in antitoxin units per milliliter, with a target of ≥8.0 AU/mL for the aqueous concentrate. The alpha toxoid content is not quantified for routine release but is monitored by SDS-PAGE fingerprinting to ensure batch consistency. This antigenic profile distinguishes the API from single-component beta toxoid vaccines because the retained alpha toxoid may contribute to protection against co-infection with Clostridium perfringens type A enterotoxigenic strains.
Release of this API follows 9 CFR 113.111 for Clostridium perfringens type C toxoid potency and 9 CFR 113.26 for sterility. The target beta toxoid activity for the liquid concentrate is ≥8.0 AU/mL, with a phase I/phase II limit of ≥6.0 AU/mL for final formulated lot release. Lyophilized complex antigen recovery after reconstitution must exceed 80% of the pre-lyophilization value, measured by capture ELISA using a monoclonal ligand directed against the beta toxoid C-terminal domain. Sterility is evaluated by membrane filtration in tryptic soy broth and fluid thioglycollate medium incubated at 20–25°C and 30–35°C for 14 days. Residual formaldehyde is controlled at ≤0.5 g/L in the aqueous concentrate and ≤0.05% w/w in the lyophilized cake. Bacterial endotoxins are monitored by the Limulus amebocyte lysate method, with a target below 1,000 EU/mL in the aqueous concentrate. Heavy metal content is checked by inductively coupled plasma-mass spectrometry with lead, cadmium, and mercury limits per regional veterinary pharmacopoeial monographs. The receiving facility must hold appropriate manufacturing authorization; in the United States, this intermediate falls under USDA APHIS veterinary biologics requirements under 9 CFR Part 113; in the European Union, final formulations require an authorisation under Regulation (EU) 2019/6. The API is not intended for human use and must be segregated from human pharmaceutical manufacturing streams.
| Parameter | Aqueous concentrate | Lyophilized complex | Reference method |
|---|---|---|---|
| Appearance | off-white homogeneous suspension | white to off-white cake | visual inspection |
| Beta toxoid potency | ≥8.0 AU/mL | ≥80% recovery after reconstitution | 9 CFR 113.111 |
| Sterility | no growth after 14 days | no growth after 14 days | 9 CFR 113.26 |
| Residual formaldehyde | ≤0.5 g/L | ≤0.05% w/w | colorimetric acetylacetone |
| Residual moisture | not applicable | ≤3.0% w/w | Karl Fischer coulometry |
| pH | 6.8–7.4 | 6.5–7.5 after reconstitution | potentiometric |
Production of the lyophilized complex uses a top-spray fluid-bed granulation step at an inlet air temperature of 50°C to 55°C and outlet relative humidity below 30%. A 200 L working volume of aqueous concentrate was sprayed onto a mannitol-trehalose glass matrix at 8.0% w/w solids. When outlet RH exceeded 40% during the final 20 minutes of drying, visible cake collapse occurred and beta toxoid activity declined by 0.4 log10 AU/mL relative to the pre-dry reference. The process therefore requires in-line near-infrared moisture measurement and automatic feed shutdown at the indicated endpoint. For tableting, the dried complex must be compressed in an environment below 25% RH; powder flow measurements show a tapped density of 0.42–0.55 g/mL and Carr index of 28–34, indicating fair to poor flow. A rotary tablet press with gravity feed at 25 rpm and 10 kN compression force produced tablets with hardness of 60–80 N and friability below 1.0% when a glidant was included. Batch-to-batch variance in granule moisture was controlled within ±0.5% w/w by closed-loop inlet air temperature adjustment.
Oral administration of the inactivated toxoid fraction to newborn piglets is constrained by gastric acid and pepsin exposure. The beta toxoid fraction loses binding activity after 30 minutes at pH 3.0 at 37°C; in simulated gastric fluid at pH 2.0 with pepsin, antigenicity is reduced by more than 90% within 1 hour. Therefore, tablets, capsules, and granules intended for intestinal release require enteric coating. A methacrylic acid–ethyl acrylate dispersion applied until 8% w/w weight gain provided disintegration in phosphate buffer at pH 6.8 within 15 minutes and retained 85% of beta toxoid activity in the dissolution medium. The coat is not effective below 6% w/w weight gain; in testing, capsules coated at 5% w/w showed pinholes after 15 minutes in acid and 30% loss of antigen. Published data for this specific API in newborn piglets is limited; mucosal immune activation may be incomplete before 10 days of age, and colostral anti-beta toxin antibodies remain the primary protective pathway in the first week. Because the vaccine is inactivated, it does not replicate in the gut; protection is dependent on local toxin neutralization and systemic immunologic processing after antigen sampling by Peyer’s patches.
For granules and premixes, the lyophilized complex is adsorbed onto a calcium carbonate or microcrystalline cellulose carrier at 1:9 w/w. Mixing is carried out in a ribbon blender at 25 rpm for 10 minutes; shorter mixing produces segregative loss of the antigen fraction, while longer mixing increases dust formation and can reduce beta toxoid recognition by 15% after 30 minutes due to shear and localized heating. Thermal differential scanning calorimetry of the lyophilized complex shows an onset of unfolding at 64–68°C, so pelletizing above 70°C is prohibited. In field-scale creep feed production, post-pelleting spray application is preferred because conventional conditioning temperatures of 75–85°C are above the inactivation threshold.
For injectable formulations, the aqueous concentrate is compounded aseptically with phosphate-buffered saline and mixed with 10% v/v aluminum hydroxide gel. The final injection volume is 2 mL per piglet, administered subcutaneously in the inguinal fold or intramuscularly in the neck using a 22G × 25 mm needle and a compression-type syringe calibrated to ±0.05 mL. Formulated injections are held at 2–8°C and must be used within 8 h after compounding. One freeze-thaw cycle at −20°C reduced beta toxoid activity from 8.4 AU/mL to 6.1 AU/mL in a controlled stability study, and the liquid presentation must not be stored in frost-free freezers because temperature cycling causes particle growth. Injection-site reactivity is minimized by phasing the aluminum gel addition at a stirring rate of 200 rpm for 30 minutes; rapid high-shear addition produces gel aggregates larger than 20 µm that clog 22G needles during field vaccination.
For oral solution or drench presentations, the aqueous concentrate is diluted with phosphate buffer to pH 6.8–7.4 and used within 8 h at 2–8°C. No aluminum hydroxide is added to oral solutions because the gel is not required for local gut exposure and may produce sedimentation. The oral solution must not be mixed with acidified replacers or citric acid buffers because beta toxoid aggregation occurs below pH 5.5. Published data for this specific API in newborn piglets is limited; direct oral dosing does not bypass the neutralizing effect of colostral immunoglobulin unless the piglet is fasted for 1 hour before and after administration.
Long-term stability of the aqueous concentrate is established at 2–8°C for 24 months in butyl rubber-stoppered Type I glass vials. Intermediate stability at 25°C shows a loss of 0.2 log10 AU/mL at 6 months, and exposure to 40°C for 14 days reduces potency below the release limit. The lyophilized complex maintains potency for 24 months at 2–8°C; at 25°C, the loss is 0.1 log10 AU/mL over 6 months when residual moisture remains below 3.0%. Containers are stoppered under nitrogen headspace with oxygen below 2% to limit oxidative modification of methionine residues in beta toxoid. Reconstitution of the lyophilized cake is performed with sterile water at 2–8°C; the cake is swirled, not vortexed, to avoid foaming and shear stress. After reconstitution, the solution is held for no more than 2 h before final formulation. Glass transition of the dried matrix is observed at 48–52°C; exposure above 60°C results in irreversible collapse and loss of antigenicity.
Compared with autogenous bacterins prepared from a single farm isolate, the API is derived from a characterized master seed under defined inactivation and concentration steps. It differs from subunit beta toxoid products by retaining alpha toxoid and other extracellular immunoreactive components, which may extend neutralizing activity but requires stricter residual formaldehyde and sterility control. Compared with alum-adjuvanted final products, the unadjuvanted API can be partitioned into multiple dosage forms; however, it cannot be directly administered without final formulation and does not provide ready-to-use convenience. Unlike live avirulent vaccines, the inactivated antigen has no risk of reversion to toxigenic phenotype; unlike DNA- or antigen-surface vaccine platforms, it is a complex toxoid-rich fraction and may show lot-to-lot variation in minor exoproduct bands.
| Dosage form | Key process boundary | Stability or recovery | Use limitation |
|---|---|---|---|
| Injection | alum 10% v/v; fill volume 2 mL | 8 h at 2–8°C after compounding | no preservative; single-use; no freeze-thaw |
| Oral solution/drench | pH 6.8–7.4; no alum | 8 h at 2–8°C | do not mix below pH 5.5; fast piglet 1 h before and after |
| Lyophilized powder | residual moisture ≤3.0% w/w; compression RH ≤25% | ≥80% antigen recovery | hygroscopic; requires desiccant and sealed closure |
| Tablet/capsule | enteric coat 8% w/w; disintegration at pH 6.8 within 15 min | 85% beta toxoid retention in vitro | enteric protection mandatory; piglet age constraint |
| Granules/premix | inlet air 50–55°C; outlet RH ≤30% | loss 0.4 log10 AU/mL if outlet RH > 40% | avoid pelletizing above 70°C; use in creep feed within 24 h |
The API is incompatible with cationic surfactants, strong oxidizing disinfectants, and amine-based buffers because these can precipitate the toxoid or disrupt the aluminum hydroxide gel. Mixing with glucose-containing rehydration fluids above 5% w/v should be avoided because nonenzymatic glycation can reduce beta toxoid recognition by monoclonal capture ligands. The lyophilized complex should be stored at 2–8°C in original sealed containers protected from light; if a cake appears shrunken or discolored from white to tan, the lot must be rejected. The product contains no antimicrobial preservative. Aseptic opening and single-use handling are compulsory, and residual contents must be inactivated by autoclaving at 121°C for 30 minutes before disposal.
