| HS Code | 103906 |
| Productname | Aprotinin Pharma Grade API |
| Casnumber | 9087-70-1 |
| Molecularformula | C284H432N84O79S7 |
| Molecularweight | 6511.5 g/mol |
| Appearance | White to off-white crystalline powder |
| Solubility | Soluble in water; practically insoluble in ethanol and acetone |
| Ph | 4.5 to 7.5 (1% aqueous solution) |
| Purity | ≥ 95.0% (HPLC) |
| Grade | Pharma Grade / API |
| Dosageforms | Tablet, Capsule, Granule, Injection |
| Routeofadministration | Oral, Injectable |
| Storageconditions | Store at 2-8°C, protect from light and moisture |
| Shelflife | 24 to 36 months |
| Packaging | 1 kg, 5 kg, 10 kg, 25 kg or as per customer requirement |
| Therapeuticcategory | Antifibrinolytic; serine protease inhibitor |
| Mechanismofaction | Inhibits trypsin, kallikrein, plasmin, and other serine proteases |
| Use | Reduces bleeding and inhibits proteolytic enzymes |
As an accredited Aprotinin 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.
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Aprotinin is deployed as a bovine-lung-derived polypeptide of 6512 Da containing 58 amino acid residues and three disulfide bridges, which impose a narrow thermal and pH processing window. In injectable manufacture the bulk solution is not exposed to terminal steam sterilisation; instead, aseptic filtration through 0.22 µm polyethersulfone membranes is used because the native conformation is heat-labile above controlled ambient temperatures. This route is matched to Ph. Eur. 0770 for aprotinin concentrated solution and to EMA/410/01 Rev. 3 for bovine-sourced material, together with Ph. Eur. 5.2.8 for minimising transmissible spongiform encephalopathy risk. The finished injection is formulated to 10,000 KIU/mL, equivalent to approximately 1.4 mg/mL at the standard activity conversion of 1 mg = 7144 KIU; the solution contains 9 mg/mL sodium chloride in Water for Injections, with pH adjusted between 4.5 and 5.5 using hydrochloric acid or sodium hydroxide. Filling is conducted into Type I borosilicate glass vials under Grade A unidirectional airflow with Grade B background according to EU GMP Annex 1:2022, and 21 CFR 211.113 governs the microbiological control expectations for the aseptic line.
The formulation addition ratio for cardiopulmonary bypass is not a mass-percentage excipient ratio but an activity-defined dosing ratio. The standard high-dose regimen consists of a 2,000,000 KIU loading dose, 500,000 KIU/h maintenance infusion, and 2,000,000 KIU added directly to the pump prime. The 2,000,000 KIU pump-prime addition corresponds to 200 mL of the 10,000 KIU/mL concentrate; loading and maintenance doses require separate, controlled infusion lines to avoid bolus stacking. Because aprotinin inhibits plasmin, kallikrein, and trypsin, the pump-prime addition must be complete before heparinisation and before initiation of cardiopulmonary bypass to prevent fibrinolytic activation in the extracorporeal circuit. The production process for the injectable concentrate includes cold-chain bulk hold at 2–8 °C, low-shear mixing to avoid aggregate formation, pH adjustment, bioburden control before filtration, sterile filtration, and final activity release against the Ph. Eur. unit. Terminal finished product types are single-use vials labelled as 100,000 KIU/10 mL and 1,000,000 KIU/100 mL, stored at 2–8 °C and protected from freezing.
| Parameter | Numerical Range or Value | Anchoring Specification |
|---|---|---|
| Molecular weight | 6512 Da | Ph. Eur. 0770 |
| Activity conversion | 1 mg = 7144 KIU; 1 Ph. Eur. U = 1800 KIU | Ph. Eur. 0770 |
| Finished solution strength | 10,000 KIU/mL | Finished product specification |
| Sodium chloride content | 9 mg/mL | Formulation dossier |
| pH window | 4.5–5.5 | Stability protocol |
| Pump prime addition | 2,000,000 KIU, equivalent to 200 mL | High-dose CPB regimen |
High transfusion demand during orthotopic liver transplantation introduces burst fibrinolysis that is temporally concentrated in the anhepatic phase and immediately after graft reperfusion. The use of aprotinin in this setting is not a separate dosage form; it is the same 10,000 KIU/mL injectable described above, administered by syringe pump and diluted into 0.9% sodium chloride infusion bags when continuous infusion is required. The formulation addition ratio at the point of administration is therefore 2,000,000 KIU loading, corresponding to 200 mL, followed by 500,000 KIU/h until the completion of the surgical procedure. The pump-prime route is not relevant unless venovenous bypass or cell salvage is employed. Compliance anchors include 21 CFR 211.84 for incoming raw material identity, potency, and endotoxin testing; 21 CFR 211.165 for finished lot release; ICH Q3D for elemental impurity risk assessment; and Ph. Eur. 5.2.8 for veterinary-sourced material safety. Thromboelastometry is performed on a ROTEM delta device using EXTEM, INTEM, FIBTEM, and APTEM assays; APTEM is the relevant channel for distinguishing hyperfibrinolysis from polymerisation deficiency. Production of the injectable follows the same aseptic filling route: cold-chain dissolution, 0.22 µm polyethersulfone filtration, Type I glass vial filling, and activity release expressed in KIU. Terminal finished product types remain 100,000 KIU/10 mL and 1,000,000 KIU/100 mL vials, transferred into sterile polyvinyl chloride infusion containers only after complete visual inspection and particulate clearance.
Fibrin sealant systems combine a fibrinogen component, a thrombin component, and aprotinin as an antifibrinolytic stabiliser. In these products the aprotinin solution is supplied at 3000 KIU/mL and is used to reconstitute the lyophilised sealer protein; this addition ratio prevents premature clot lysis by plasmin and kallikrein during wound healing without producing a systemic aprotinin effect. The thrombin component is maintained separately until point-of-use because fibrin polymerisation would otherwise occur in the container. The principal compliance standards are ISO 10993-1:2018 for biological evaluation of the finished combination device, ISO 13485:2016 for the quality management system, Ph. Eur. 5.2.8 and EMA/410/01 Rev. 3 for bovine-derived inputs, and Ph. Eur. 0903 or applicable fibrin sealant monographs for the combined product. Where the kit is regulated as a medical device under EU MDR 2017/745, the aprotinin component must still meet the same active-substance purity, activity, and viral-safety release criteria as the injectable grade. The production process requires separate lyophilisation of the fibrinogen component with shelf temperatures controlled at sub-zero primary drying conditions, sterile filtration of the aprotinin solution through 0.22 µm polyethersulfone membranes, and aseptic filling into separate vials or dual-chamber syringes. Cold-chain storage at 2–8 °C is mandatory; ready-to-use syringes must not be refrozen. Terminal product types include dual-chamber syringes, two-vial kits, and spray applicator sets in 2 mL, 5 mL, and 10 mL nominal clot volumes.
Historical injectable use in acute pancreatitis was based on the rationale that intra-acinar trypsin activation drives early organ injury; aprotinin was therefore administered as a systemic serine protease inhibitor in severe disease. Current clinical guidelines no longer uniformly support this use because randomised data have not demonstrated consistent mortality benefit, and the renal safety signal observed in surgical cohorts imposes an unfavourable risk profile in septic or hypovolaemic pancreatitis patients. The dosage form remains the same Ph. Eur. 0770 injectable concentrate; a 500,000 KIU bolus is 50 mL of the 10,000 KIU/mL solution, and a 1,000,000 KIU bolus is 100 mL. No separate tablet, capsule, or granule product is authorised for this indication in ICH regions; therefore formulation-specific addition ratios beyond intravenous dilution in 0.9% sodium chloride are not established. The production process is unchanged: cold-chain bulk handling at 2–8 °C, aseptic filtration through 0.22 µm polyethersulfone membranes, fill into Type I glass vials, and release by activity assay calibrated against the Ph. Eur. unit. Terminal finished product types are the same single-use vials of 100,000 KIU/10 mL and 1,000,000 KIU/100 mL. Operational boundaries include mandatory renal function monitoring and avoidance of re-exposure where prior hypersensitivity to bovine aprotinin has been documented.
Oral aprotinin formulations are confined to local protease inhibition in the intestinal lumen because the 6512 Da peptide has negligible oral bioavailability and is itself degraded by gastric pepsin unless protected. The only coherent oral dosage designs are therefore enteric-coated tablets, enteric-coated granules filled into hard capsules, or enteric-coated granule sachets that release in the proximal small intestine. The unit strength is expressed in KIU rather than mass; a 100,000 KIU core contains approximately 14 mg of aprotinin peptide at the standard conversion 1 mg = 7144 KIU, but total tablet weight depends on the chosen diluent and disintegrant system. There is no harmonised pharmacopoeial addition ratio for oral aprotinin, and published clinical data for this specific configuration are limited; formulators must therefore rely on dissolution and enzyme-inhibition assays for batch equivalence. The enteric coat is typically a methacrylic acid-ethyl acrylate copolymer dispersion applied in a pan or fluid-bed coater to a weight gain of 8–12% of the core, with dissolution threshold near pH 5.5. Production requires dry granulation or roller compaction rather than aqueous wet granulation because the peptide is susceptible to hydrolysis and shear-induced aggregation. Residual moisture is controlled by Karl Fischer titration according to USP <921>. Final release tests include USP <711> two-stage dissolution in 0.1 N hydrochloric acid for 2 h followed by pH 6.8 phosphate buffer, content uniformity to USP <905>, and microbial limits for non-sterile oral products. Terminal dosage forms are enteric-coated tablets, hard hydroxypropyl methylcellulose capsules containing enteric-coated granules, and single-dose granule sachets.
| Test | Standard | Condition and Typical Acceptance |
|---|---|---|
| Acid-stage dissolution | USP <711> / Ph. Eur. 2.9.3 | 0.1 N HCl, 2 h, release ≤ 10% |
| Buffer-stage dissolution | USP <711> / Ph. Eur. 2.9.3 | pH 6.8 phosphate buffer, 45 min, release ≥ 75% |
| Content uniformity | USP <905> | Acceptance value ≤ 15 |
| Water content | USP <921> | Limit determined for coated granules; commonly ≤ 2.0% m/m |
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Pharma-grade aprotinin API is a single-chain polypeptide of 58 amino acid residues with a molecular mass of approximately 6512 g/mol, CAS registry number 9087-70-1, and a basic isoelectric point near 10.5. The product designated Aprotinin Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is released in accordance with current Ph. Eur. monograph 0579 for aprotinin and the corresponding USP monograph. The material is a white to almost-white hygroscopic powder that is freely soluble in water and in isotonic saline; the pharmacopoeial potency threshold is 3.0 Ph. Eur. U/mg on the dried basis. Its inhibitory action against serine proteases is direct and competitive. The aprotinin-trypsin complex exhibits an inhibition constant near 6.0 × 10⁻¹⁴ M, while inhibition of plasmin and plasma kallikrein occurs at nanomolar to subnanomolar concentrations. Because the polypeptide is not glycosylated, recombinant versions expressed in defined microbial systems can be analytically evaluated against bovine lung-derived material when host-cell protein and residual nucleic acid removal is demonstrated under ICH Q7. The product nomenclature includes oral and injectable grades, but these are not interchangeable without formulation-specific process validation.
Pharma-grade lots are differentiated primarily by residual endotoxin, bioburden, related protein ratios, residual solvent profile, and regulatory dossier completeness. Research-grade aprotinin may be supplied with activity values only and may contain stabilizers such as bovine serum albumin; such lots are unsuitable for parenteral manufacture because endotoxin and particulate load are typically uncontrolled. Injectable-grade pharma API requires bacterial endotoxin limits aligned with the intended dose and route. For a 1 × 10⁶ KIU dose, the limit derived from Ph. Eur. 5.1.10 / USP <85> is calculated from the parenteral threshold of 5 EU/kg body mass, producing low single-digit EU/mg acceptance limits for a typical adult. Bulk pharma-grade lots are additionally tested for residual solvents in accordance with Ph. Eur. 2.4.24 / USP <467>, and high-molecular-weight proteins are controlled by size-exclusion HPLC to limit aggregated species that may affect immunogenicity. The activity assay is based on trypsin inhibition, not merely total protein content; a high protein assay value without potency determination does not establish pharma-grade compliance.
Batch release requires a certificate of analysis that includes appearance, solubility, identity by HPLC peptide mapping or peptide sequence, specific activity, loss on drying, residue on ignition or elemental impurities, bacterial endotoxins, and residual solvents. Elemental impurity control follows ICH Q3D and Ph. Eur. 2.4.20; the risk assessment should consider catalysts used in recombinant production and any metal contact in bovine extraction. Loss on drying for lyophilised powder is controlled by the monograph method, and injectable-grade lots are commonly released with residual moisture not exceeding 3.0% unless otherwise specified in the approved dossier. Related proteins are determined by liquid chromatography; the sum of impurities is limited to the monograph criterion and reported as percent area normalisation. For oral solid-grade, microbial limits are less stringent than for injectable-grade; however, the same chemical identity and potency requirements apply. Any claim of tablet/capsule/granule suitability should be supported by stability data under ICH Q1A and compatibility studies with the selected excipients.
| Release dimension | Primary reference | Measurement objective |
|---|---|---|
| Specific activity | Ph. Eur. 0579 / USP aprotinin assay | Trypsin inhibition potency |
| Identity | Ph. Eur. 2.2.29 / USP <621> | HPLC retention and peptide map |
| Bacterial endotoxins | Ph. Eur. 2.6.14 / USP <85> | Limulus amebocyte lysate test |
| Residual solvents | Ph. Eur. 2.4.24 / USP <467> | Headspace gas chromatography |
| Elemental impurities | ICH Q3D / Ph. Eur. 2.4.20 | ICP-MS or ICP-OES |
The selection of a specific method and acceptance criterion is documented in the active substance specification and may differ between bovine-derived and recombinant processes only when the impurity profile is process-specific.
Injectable manufacturing begins with the API lot assigned for parenteral use, which must meet the lower endotoxin and bioburden limits before aseptic processing. Dissolution in Water for Injection is followed by aseptic filtration through a 0.45 μm prefilter and a 0.22 μm final membrane filter; polyethersulfone or polyvinylidene fluoride membranes are used to minimise protein adsorption. Terminal sterilisation by saturated steam is generally avoided because the polypeptide is thermolabile. Aqueous solutions are stable in acidic to neutral conditions; degradation accelerates above pH 8.0 and in the presence of strong oxidising agents. Therefore, the formulation pH is usually maintained between 4.0 and 7.0, with citrate or phosphate buffers selected after forced degradation studies. Subvisible particles are controlled by Ph. Eur. 2.9.19 and USP <788>, and leachables from filter membranes or tubing must be assessed under the finished-product specification. Freeze-thaw cycling of bulk solution is not recommended unless stability data support the specific container closure system and fill volume. During filtration, a sudden pressure increase above the filter manufacturer’s validated differential may indicate aggregate plugging and requires batch investigation.
When lyophilisation is required for an injectable presentation, the critical processing interval is the time between bulk solution preparation and freezing; prolonged hold times at room temperature promote hydrolytic fragments. The lyophilisation cycle is developed from the thermal trace of the formulation because the collapse temperature governs primary drying. Use of mannitol or glycine as a crystallising bulking agent produces a physically robust cake; sucrose or trehalose can be used as amorphous stabilisers in formulations that show concentration-dependent aggregation. Primary drying shelf temperature is typically kept below the melt-back temperature of the formulation, and the chamber pressure is selected according to the resistance of the partially dried cake. Residual moisture of the lyophilised drug product is commonly specified below 2.0%, and vials are sealed under nitrogen. Published data for this specific configuration—oral and injectable aprotinin in identical lyophilised matrices—is limited; separate cycle validation for each presentation is therefore required.
For tablet and capsule production, the low mass fraction of aprotinin in the final dosage form makes content uniformity the principal process risk. A pre-blend with microcrystalline cellulose and colloidal silicon dioxide is prepared as a geometric dilution; direct compression may be used when the formulation can achieve an acceptable flow index and compactibility, but dry granulation with a roller compactor is preferred when the API is pre-dried. Aqueous wet granulation is not the first choice because of the peptide’s hygroscopicity and sensitivity to high shear; if wet granulation is unavoidable, the binder solution should remain below pH 7.0 and the granulate should be dried at inlet temperatures not exceeding 45 °C to preserve activity. Lactose monohydrate is not recommended as a filler because its reducing carbonyl can participate in Maillard reactions with lysine residues of the polypeptide; mannitol or dicalcium phosphate dihydrate is used instead. Capsule filling should be conducted at relative humidity below 40% and temperature between 20 °C and 25 °C. Pre-drying of the API at RH ≤ 30% for at least 4 hours may be required when storage conditions have exceeded 60% RH. Uniformity of dosage units is demonstrated using Ph. Eur. 2.9.40 or USP <905>. Granulation for sachet or dry syrup presentations uses fluid-bed granulation with an aqueous binder of hypromellose or povidone. The product temperature during granulation is kept below 40 °C, and the granulate is dried to a loss-on-drying below 3.0% before filling. Sieve distribution is controlled by Ph. Eur. 2.9.12 or USP <786>. Dissolution testing for oral aprotinin tablets is not harmonised; if a dissolution specification is necessary, it must be developed and validated according to ICH Q2 and USP <1092>.
Oral administration of aprotinin is not bioequivalent to intravenous injection. The peptide is degraded by gastric acid and intestinal proteases, and systemic bioavailability is negligible; therefore oral solid presentations cannot be assumed to deliver antifibrinolytic plasma levels comparable to injectable products. Compared with tranexamic acid and aminocaproic acid, which are lysine analogues that inhibit plasminogen binding to fibrin, aprotinin directly inhibits plasmin, plasma kallikrein, and other serine proteases. This mechanistic difference is reflected in dosing and safety profile. Tranexamic acid has oral bioavailability around 30–50% and is cleared renally; aprotinin is a peptide with limited oral absorption and rapid renal distribution after intravenous administration. Clinical data, including the BART trial, documented an increased mortality risk versus tranexamic acid in high-risk cardiac surgery; this evidence is part of the benefit-risk documentation under FDA 21 CFR 312 and EU Regulation 536/2014, rather than a pharmaceutical quality attribute of the API.
Supporting a pharma-grade aprotinin API for either oral or injectable use requires a current active-substance master file, a Certificate of Suitability to the Ph. Eur. monograph, or a US drug master file. Bovine-derived material must be accompanied by a TSE/BSE statement and evidence that the source tissue is fit for human consumption under veterinary inspection; the risk assessment follows Ph. Eur. 5.2.8 and EMA EMEA/410/01 Rev.3. Viral safety of bovine-derived biologicals follows Ph. Eur. 5.1.7, and the manufacturing process should include validated viral inactivation or removal steps. Recombinant material eliminates the TSE tissue source risk but introduces host-cell protein and residual DNA controls; clearance should be demonstrated by process-specific assays, and residual DNA for injectable use is commonly limited to 10 ng per dose unless otherwise justified by ICH Q6B. Comparability between bovine and recombinant sources cannot be assumed from the amino acid sequence alone; it requires identity, potency, purity, and impurity profile comparison across at least three lots per source. Where published data for a specific configuration is limited, the change is managed under ICH Q5E comparability protocol.
Bulk API should be packaged in double polyethylene bags inside aluminium-laminated foil or HDPE containers with desiccant, under nitrogen or vacuum. Recommended storage is 2–8 °C in the dark; at 25 °C and 60% RH, activity loss may become measurable within months for moisture-exposed material, and shipping should be monitored with calibrated temperature loggers. A single short excursion above 8 °C does not necessarily invalidate a lot, but the lot should be quarantined and assessed if the excursion exceeds 72 hours. Freezing of aqueous solutions should be avoided unless the solution is intended for lyophilisation. The product is identified as Aprotinin Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable, with no additional model number; lot traceability is maintained through the manufacturer’s batch number and the active substance master file or CEP reference.
