Description

Description

(USP 44)

1. Drug Substance General Information (ICH 3.2.S.1)

1.1. Nomenclature (ICH 3.2.S.1.1)

International non-proprietary name: Docetaxel (Brand Name: Taxotere, Sanofi Oncology (Sanofi), USA

Compendial name: Docetaxel

Chemical name: 1,7β,10β-trihydroxy-9-oxo-5β,20-epoxytax-11-ene-2α,4,13α-triyl 4-acetate 2-benzoate 13-{(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate}

Arasto’s code: DOC

CAS Registry Number: [114977-28-5]

1. Drug Substance General Information (ICH 3.2.S.1)

1.2 Structure (ICH 3.2.S.1.2)

3H₂O

Empirical formula: C₄₃H₅₃NO_14. 3H₂O

Molecular Weight: 861.90 g/mol

1. Drug Substance General Information (ICH 3.2.S.1)

1.3. General Properties (ICH 3.2.S.1.3)

Docetaxel is a white crystalline substance. It is practically insoluble in water and soluble in polar organic.  Docetaxel is used in the form of injection concentrate for the treatment of breast cancer, advanced non-small cell lung cancer, metastatic androgen-independent prostate cancer, advanced gastric/GE junction cancer, locally advanced head and neck cancer (.http://www.taxotere.com/). Its log P is 4.26 (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR-Public _assessment_report /human/001107/WC500073418.pdf).  Docetaxel is not stable in acid or base (see Stability Studies and EP 1978953A1). LD₅₀ of docetaxel has been reported ( > 2000 mg/kg oral  rat; 138 mg/kg IV mouse, http://www.pfizer.com/files/products/material safety data/ PZ00906 .pdf).

The determination of purity and assay of APIs require comparison of the product with their respective Reference Standards (RS) and Related Compounds (RC or known impurities).  Accordingly, ICH regulations on the purity and assay of reference standard and related compounds are clearly defined and must be followed by drug substance and drug product manufacturers.

According to ICH Q7, 11.1 there are 3 types of standards.  This is summarized in the following chart and discussed in detail below.

The impurities provided in the following table represent Secondary Reference Standards (SRS) that are prepared in-house by synthesis or by isolation. Each SRS has undergone extensive characterization ( IR, UV, 1HNMR, 13CNMR. Mass Spec) and determination of its purity and assay (HPLC). For specification of the SRS of those products that have a monograph, the SRS is compared with a pharmacopoeia Primary Reference Standard (UV, HPLC retention time). For specification of those products that do not have a monograph (known as House Primary Standard), we compare their UV ε or ג /_max , IR major absorptions, ¹HNMR d (ppm) , ¹³ CNMR d (ppm) or HPLC retention time with values reported in the chemical literature for these compounds.

1. Primary and Secondary Reference Standard (ICH 3.2.S.5)

  5.1. Active Pharmaceutical Ingredient

Primary Reference Standard for docetaxel is available from United States Pharmacopoeia. We will use a Secondary Reference Standard (previously referred to as Working Standard) for direct control of all batches of docetaxel.

As per ICH (Q7, 11.1) and ICH (Q6, 2.11, 3.2, 3.3)the Secondary Reference Standards, which include the API and its Related Compounds, must be examined for their proof of structure (characterization), assay and purity and specification (identification by comparison). Furthermore, ICH Guideline on the Preparation of Common Technical Document (Q4M) requires that the data obtained from characterization, assay and purity and specification must be included in section 3.2.S.3.2 for Related Compounds (already discussed in that section) and section 3.2.S.5 of the DMF for the API. To this end, the Secondary Reference Standards of the API docetaxel has undergone extensive characterization (UV, IR, ¹ H NMR, ¹³C NMR, and Mass Spec) to assure its structure, assay and purity (HPLC and/or titration) and specification (comparison of its HPLC retention time and UV ג /_max with USP Primary Reference Standard.

The Secondary Reference Standard for docetaxel was produced from a released batch of docetaxel by subjecting it to an additional crystallization from the final solvent system used in the production of the API to avoid the possibility of other polymorph formation.

SPECIFICATION OF ANALYSIS