Octreotide API CAS 79517-01-4

Octreotide API CAS 79517-01-4 | Octreotide acetate cGMP production | Acromegaly/neuroendocrine tumor API | Science-Peptide

Octreotide API CAS 79517-01-4 - Peptide API for acromegaly, neuroendocrine tumors.Science-Peptide provides Octreotide Acetate which meets cGMP standard, with mature process, clear impurity profiles, support for China, USA and Europe declarations, and can be authorized for DMF.Welcome to contact us.

Octreotide is one of the best known of the growth inhibitor analogs. Acromegaly, neuroendocrine tumors (NETs), esophageal variceal hemorrhage, pancreatitis - it works, and it's available in a variety of dosage forms: regular injections, long-acting microspheres (every 4 weeks), and for indications spanning endocrinology, gastrointestinal, and oncology.

Its mechanism of action is similar to that of growth inhibitors, but the half-life is longer (about 1.5-2 hours vs. 1-3 minutes for natural growth inhibitors), so it is more convenient for clinical use. In patients with acromegaly, octreotide can control the levels of growth hormone and IGF-1; in gastroenteropancreatic neuroendocrine tumors, it can inhibit the release of hormones and control tumor-related symptoms.

Science-Peptide has been working on peptide API for more than 20 years, and octreotide is one of the species that we entered into early. Octreotide is an 8-peptide with a pair of disulfide bonds, which is moderately difficult to synthesize, but it requires specialized experience to achieve a stable impurity profile, good batch consistency, and good control of special indicators (e.g., particle size and solvent residue) for APIs used in long-lasting microspheres. Our Octreotide Acetate API can be stably supplied from grams to kilograms, has completed the FDA DMF filing, and supports China, the United States and Europe to declare. Especially for the raw materials used in long-acting microsphere formulations, we have optimized the purification process and strictly controlled the residual solvents and moisture.

Octreotide is an octapeptide that forms a cyclization by a disulfide bond between the 2- and 7-position cysteines, with threoninol at the C-terminus. It has two D-type amino acids (D-Phe, D-Trp) in its structure, which increases its stability to proteases and therefore has a much longer half-life than natural growth inhibitors.

Main clinical applications:

• Acromegaly: inhibit growth hormone secretion, control symptoms, reduce IGF-1 level. Regular injections are used for initial treatment or dose adjustment, and long-acting microspheres are used for long-term maintenance.
• Neuroendocrine tumors (NETs): controls diarrhea and flushing in carcinoid syndrome, inhibits hormone secretion in functional NETs, and also has some antiproliferative effects.
• Acute esophageal variceal bleeding: adjunct to endoscopic ligation to reduce portal pressure, similar to growth inhibitors.
• Pancreatitis, pancreatic fistula: inhibit pancreatic enzyme secretion, promote healing of fistula.

From the API point of view, the market for octreotide is much larger than that of growth inhibitors - because its long-acting microsphere dosage form (Xanlong) is a heavyweight variety, and there is a great demand for generic drugs. The requirements for APIs are also higher: in addition to the usual purity and impurities, microsphere formulations also need to focus on the particle size distribution of the API, residual solvents, moisture and other indicators.

We have worked with customers who make long-lasting microspheres, and we know what they are concerned about: high batch-to-batch consistency, stable impurity profiles, residual solvents compliant with ICH Q3C, and moisture control, otherwise the curing process of the microspheres will be problematic.

1. Mature technology, optimized especially for microsphere dosage forms
The synthesis route of octreotide is not complicated - solid-phase synthesis of linear precursors, liquid-phase cyclization to form disulfide bonds. However, in order to achieve high purity, low impurity and suitable for microsphere formulation, we have made efforts in several aspects:

• Linear precursor: Fmoc solid-phase synthesis, because there are D-type amino acids and C-terminal threoninol (not standard amino acids) in the sequence, the coupling conditions need to be optimized. We have been doing this for many years and the yield of crude peptide is stable.
• Cyclization: Mild oxidation in liquid phase, precise formation of 2-7 disulfide bond. We strictly control the amount of oxidizing agent and pH, and the cyclization efficiency is stable at more than 95%, with a very low content of mismatched isomers.
• Purification: Multi-step HPLC preparation: For the microsphere formulation, we added a residual solvent removal step at the end of the purification to ensure that the residues of acetonitrile, TFA, etc. complied with ICH Q3C (≤410ppm acetonitrile).
• Freeze-drying and pulverization: After freeze-drying, the particle size distribution of the powder is controlled according to the needs. Microsphere customers usually require a certain particle size range, we can adjust the pulverization process according to the needs.

The process validation data showed that the purity was stabilized at over 99.0% with highly overlapping impurity profiles in successive batches.

2. Quality control, covering specific targets for microsphere formulations
Each batch of Octreotide API is released in accordance with cGMP requirements, and the test items include general indexes and indexes of interest to microsphere preparations:

• Content:95.0%-105.0% based on anhydrous and solvent free, in accordance with USP/EP.
• Purity: HPLC ≥99.0%, actual batch is usually 99.2%-99.5%.
• Related substances: single impurity≤0.15%, total impurity≤1.0%.
• Key impurities: disulfide bond mismatch isomers, oxidized impurities (tryptophan, methionine?), missing peptides, dimers, D-Trp differential isomers. Octreotide has no Met, but Trp is easily oxidized), missing peptides, dimers, D-Trp differential isomers, all with controls and quantification methods.
• Residual solvents: acetonitrile, TFA, methanol, etc. in accordance with ICH Q3C.
• Moisture: ≤5.0%, can be controlled at a lower level (e.g. ≤2.0%) at the request of customers.
• Particle size distribution (on demand): D90, D50, etc. are available.
• Safety indicators: endotoxin <0.25 EU/mg, microbial limit in accordance with the Pharmacopoeia.

Stability is long-term and accelerated, supporting a 24-36 month retest period. The analytical methods are validated and comply with ICH Q2 and USP/EP.

3. Fully documented and DMF filed
Octreotide has a mature filing pathway, and the information we provide can be used directly for ANDA or domestic generic filing:

• Process development report (with key parameters, especially cyclization conditions, residual solvent control)
• Process validation programs and reports (multi-batch data) analytical method validation reports
• Stability data (long-term, accelerated, impact factors)
• Heterogeneous mass spectrometry report (with structural confirmation)
• Structural corroboration information (NMR, MS, IR) batch production records
• In conjunction with on-site audits

Our Octreotide API has completed the FDA DMF filing, and can be authorized to be used in China, the United States and Europe declaration. If you need European CEP, we can also cooperate with you.

4. Stable supply chain with backup of critical materials
Among the amino acids used for octreotide, there are several special materials (Fmoc-D-Phe-OH, Fmoc-D-Trp(Boc)-OH, threoninol derivatives), which have a long procurement cycle. We have done several things:

• At least two qualified suppliers for key materials, regular factory audits.
• Establish safety stocks for materials with long procurement lead times.
• Multiple production lines with parallel scheduling.
• Cooperation Mode: API sales, DMF authorization, technology transfer, customized packaging.

General injection production: direct feeding, good solubility, aseptic filling no problem.
Long-lasting microsphere formulation development/production: We optimize the residual solvent and moisture control for our microsphere customers, and provide particle size data. A customer has done microsphere pilot test with our raw material and the release profile is smooth.
Generic filing: Preparing for ANDA or domestic generic filing, need a full API package. We provide DMF authorization and validation data.
Consistency assessment: the listed varieties to do consistency assessment, we provide with the original research quality consistent with the API and impurity profile comparison data.
R&D and Pilot: Provide small quantities, a few grams to tens of grams.

• Manufacturing facility 10 acres, cGMP standard, FDA, EMA, NMPA compliant, ISO 9001:2015 certified.
• Synthesis plant: automated solid-phase synthesis, 100 kg capacity
• Purification plant: Multiple sets of preparative HPLC with enhanced elution for residual solvents
• Freeze-drying workshop: 30 square meters +, industrial freeze-drying machine, can control the particle size
• Clean area: ISO class 7/8
• QC Lab: HPLC, UPLC, LC-MS, GC, Moisture meter
• Quality System: Change Control, Deviation Management, CAPA, Supplier Audit, Annual Quality Review, FDA, EMA, NMPA Site Audit.

Customer A, a domestic pharmaceutical company, long-lasting microsphere project: they are developing octreotide microspheres, and the residual solvent fluctuation of the raw material used before was large, which led to the inconsistency of microsphere curing batch to batch. According to their requirements, we controlled the acetonitrile residue below 200ppm (far below the ICH standard) and the moisture below 2%. They ran three batches of pilot tests with our raw materials, and the release curves were highly consistent, and the project has now entered clinical batch production.

Octreotide is the mainstay of growth inhibitor analogs, which is in great demand in the market, especially the long-acting microsphere dosage form has high requirements for APIs. We have accumulated more than 10 years of experience in this product, with mature technology, fine impurity control, and optimized residual solvent and moisture control especially for microsphere customers. If you are developing octreotide formulations, whether it is a general injection or long-acting microspheres, and need a stable and compliant API supplier, welcome to talk to us.