Residual Solvents for Drug Substance

ANALYTICAL RESEARCH AND 

DEVELOPMENT 

FOR GENERIC DRUG 

仿制药分析研发 

Anna Shen Ph.D. 

Anbison Analytical Research and development Lab 

2009-03-11 

ANBISON LAB. 安必生

Information search and DMF evaluation: 

(Literature, Internet-online, Merck index, CPS/PDR, 

USP/EP/JP, analytical profiles, patents, etc.) 

Physicochemical properties (chemical structure, isomers, 

chirality, solubility, stability, pKa, hygroscopicity, mp, 

partition coefficient) 

List all polymorphic forms reported in literature (which 

one is the most stable form) 

List all possible impurities based on API synthetic routes 

List all organic solvents used in API synthetic process 

Predict potential degradants based on the chemical 

structure 


Set-up API Specification: 

ICH Q6A– SPECIFICATIONS: TEST PROCEDURES AND 

ACCEPTANCE CRITERIA FOR NEW DRUG 

SUBSTANCES AND NEW DRUG PRODUCTS: 

CHEMICAL SUBSTANCES 

A List of Tests 

Reference to Analytical Procedures 

Appropriate Acceptance Criteria 


API Specification: 

Description (solid/liquid, color) 

Identification (IR, UV, Chloride, Sulfate, etc.) 

USP General Method 

Note: NMR, MS, etc. for primary identification standard 

Physicochemical properties (mp, pH, RI, acidity/alkalinity, 

optical rotation, etc.) 


Water content/L.O.D. 


Inorganic impurities (Residue on Ignition, Heavy Metals) 




Assay 

In-house method to be developed by HPLC, titration, etc. 

Organic impurities/degradants 

In-house method to be developed by HPLC 

Residual solvents 

In-house method to be developed by GC 

Particle size 

USP General method for sieve analysis 

In-house method to be developed by Laser Diffraction 

Polymorphic forms 

In-house method to be developed by IR, DSC or X-Ray 



Tests Acceptance Criteria 

Analytical 

Procedure 

Appearance (表观) White or almost white powder Visual 

Identification (鉴别) 

A: IR (红外) 

B: HPLC-RT 

(高效液相保留时间) 

C: Chloride (氯离子) 

Acidity or alkalinity 

(酸度或碱度) 

Heavy metals 

(重金属) 

Loss on drying 

(干燥失重) 

Residue on ignition 

(灼烧残渣) 

A. The infrared absorption spectrum must be concordant with the IR spectrum obtained 

from Venlafaxine HCl standard. If the spectra obtained in the solid state show 

differences, dissolve the substance to be examined and the reference standard 

separately in 2-propanol, evaporate to dryness and record new spectra using the 

residues. 

B. The retention time of the major peak in the chromatogram of the assay preparation 

corresponds to that in the chromatogram of the standard preparation 

C. It gives positive reaction for chlorides 

Dissolve 0.20 g in carbon dioxide-free water and dilute to 10 ml with the same 

solvent. Add 0.05 ml of methyl red solution and 0.1 ml of 0.01 M hydrochloric acid. 

The solution is pink. NMT 0.2 ml of 0.01 M sodium hydroxide is required to change 

the color of the indicator to yellow. 

NMT 20 ppm (10ppm in Carelife COA) 

Dissolve 1.0 g in 20 ml of water. 12 ml of the solution complies with the test A 

Prepare the reference solution using lead standard solution (1 ppm Pb). 

Dry it in vacuo at 80 o C for 3 hours: 

It loses NMT 0.5% of its weight 

NMT 0.1% 

USP 

In-house Method 

ABS_T002A_1.0 

USP< 191> 

USP 

USP 

Method? 

USP 

USP 

Assay (含量) by HPLC 99.0% to 101.0% of C 17 H 28 ClNO 2 on the dried basis In-house Method 


(残留溶剂) 

by GC 

Related compounds 

(相关物质) 

by HPLC 

Particle size (粒径) 

Polymorphism (晶形) 

Ether: NMT 5000 ppm 

Tetrahydrofuran: NMT 720 ppm 

Methanol: NMT 3000 ppm 

2-Propanol: NMT 5000 ppm 

Ethyl acetate: NMT 5000 ppm (not in Carelife COA) 

Toluene: NMT 890 ppm 

Specified impurities: 

Ven-imp-1*: NMT 0.15% 

EP-impurity C**: NMT 0.15% 

EP-impurity F***: NMT 0.15% 

Each unknown impurity: NMT 0.10% 

Total impurities: NMT 0.5% 


ABS_T002A_1.0 


ABS_T002A_1.0 

Test Results 

Lot# 

ANBISON LAB. 安必生 


In-house Method

Acceptance Criteria 

USP monograph or other compendia monograph 

(EP, BP, JP etc.) 

DMF holder’s specification (DMF) 

ICH guidelines: 

Impurities in Drug Substance: ICH Q3A(R2) 

Impurities in Drug Products: ICH Q3B(R2) 

Impurities: for Residual Solvents: ICH Q3C(R3) 

Use MDD to calculate the ICH Thresholds: 

Reporting Threshold (RT) 

Identification Threshold (IT) 

Qualification Threshold (QT) 


Acceptance Criteria: 

Maximum 

Daily Dose 1 

Reporting 

Threshold 2,3 

Identification 

Threshold 

≤ 2g/day 0.05% 0.10% or 

1.0 mg per day intake 

(whichever is lower) 

> 2g/day 0.03% 0.05% 0.05% 

1 The amount of drug substance administered per day 

Qualification 

Threshold 3 

0.15% or 

1.0 mg per day intake 

(whichever is lower) 

2 Higher reporting thresholds should be scientifically justified 

3 Lower thresholds can be appropriate if the impurity is unusually toxic 


Acceptance Criteria: 

Justification for the acceptance criterion for each test 

should be provided. 

Justify limits above Qualification Threshold (QT) with: 

USP monograph 

Literature or other compendial monographs (EP, BP, JP, etc.) 

Metabolite of the drug substance 

Compare RLD product 

Pharm/Toxicity Study 


Analytical Methods Need to be Developed for API: 

Assay for Drug Substance 

Related Compounds for Drug Substance 

Residual Solvents for Drug Substance 

Particle size for Drug Substance 

Polymorphic forms for Drug Substance 


All Methods Need to be Validated for API: 







Method Validation Reports Need to be Summited: 







Compendial Method Validation/Verification: 

For Methods adapted from USP: 

USP assay method is specific (e.g., main peak can be 

separated from all process impurities arising from your 

manufacturing process and from degradation products); 

USP related substance method is specific (e.g., all your 

process impurities and degradants can be separated each 

other and also separated from main peak). 

For method adapted from DMF/BP/EP: 

Reproduce the method validations/verifications 

Full validation reports or 

Full validation reports from DMF holder and method 

transfer report 


Reference Standard: 

If a USP RS is available: 

Using USP RS as primary RS 

Provide USP RS Lot number 

Qualification for an “In-house working standard”: 

Source and Lot# 

Certificate of analysis (including potency 

assessment against USP RS and USP RS Lot 

number ) 


Reference Standard: 

If a USP RS is not available: 

Identify Primary RS source and Lot number 

All related characterization information for the drug 

substance (IR, Mass, 1 H and 13 C NMR spectroscopy, 

elemental analysis etc.) should be provided: 

Full test results including purity test for this primary RS 

lot should be provided. 

Qualification for an “In-house working standard”: 

Source and Lot# 

Certificate of analysis (including potency test against 

primary RS) 


Impurities in Drug Substance 

Summarize all potential and actual impurities 

arising from the synthesis/degradation 

Identify impurities by names, impurity ID, chemical 

structures, or RRT/HPLC 

Specify impurities as process impurities and/or 

degradant (impurities origin) 


Solubility Determination and BCS Classification: 

The aqueous solubility as a function of pH at 37º C 

0.1 N HCl 

0.01 N HCl 

Solvent Media pH of 

Media 

Final 

pH* 

pH Solubility** 

1 1.0 

(mg/ml) 

47.2 

0.15 M acetate buffer 4 3.7 56.8 

0.15 M phosphate buffer 

6 5.8 60.8 

0.15 M phosphate buffer 

2 1.7 49.2 

8 7.8 56.0 

* Refers to the pH of aqueous media following addition of Drug Substance 

** Solubility measures were carried out on polymorphic Form I, the form used in the DP. 

Note: The relative solubility (at one pH) should be provided for any other more stable forms. 

Calculated dose solubility volume: 32 mg (highest strength)÷(47.2 mg/ml) = 0.68 ml. 

Since the dose solubility volume is less than 250 ml, based on BCS System: the drug 

substance is high solubility 


Information to be Referenced to the DMF: 

Drug substance structure elucidation 

Drug substance manufacturing process and 

controls 

Container/closure system used for packaging 

and storage of the drug substance 

Drug substance stability 


Information Required from ANDA Holder for API: 

Physicochemical properties (pKa, Polymorphism, solubility, 

hygroscopicity, mp, Log P) 

Manufacture and performance-NEW 

Adequate drug substance specification 

Test methods (Full details of test procedure, 

chromatograms) 

Impurity profile in drug substance (process impurities and 

degradants) 

Limits for impurities/residual solvents 

Method validation/verification reports for all methods 

Reference standard 

Stress study/Chromatograms 


Set-up DP Specification: 

ICH Q6A– SPECIFICATIONS: TEST PROCEDURES AND 

ACCEPTANCE CRITERIA FOR NEW DRUG 

SUBSTANCES AND NEW DRUG PRODUCTS: 

CHEMICAL SUBSTANCES 

A List of Tests 

Reference to Analytical Procedures 

Appropriate Acceptance Criteria 


Drug Product Specification: 

Appearance (外观) 

Visual 



USP General method, but the sample preparation 

procedure needs to be developed 

B: HPLC-RT (高效液相保留时间) 

Same as Assay method 

Dissolution (溶出度) 

In-house method to be developed by UV or HPLC 

Content Uniformity(均匀度) 


Assay (含量) 


Degradation Products (降解产物) 


Residual solvents (残留溶剂) if used in formulation 

In-house method to be developed by GC 


Drug Product Specification: 

Tests Acceptance Criteria 

Analytical 

Procedure 

Appearance (外观) Visual 



B: HPLC-RT 

(高效液相保留时间) 

Dissolution 

(溶出度) 

Content Uniformity 

(均匀度) 

A: The IR spectrum matches that of Venlafaxine 

HCl RS between 4000-650 cm-1 . 

B: The retention time of the major peak in the 

chromatogram of the assay preparation 

corresponds to that of the standard preparation as 

obtained in the assay. 

USP 

Not less than 80% (Q) of the labeled claim is dissolved 

in 30 minutes 

USP 


ABS_T002A_1.0 


ABS_T002D_1.0 

Meet requirements of USP In-house Method 

ABS_T002C_1.0 

Assay (含量) 95.0% to 105.0% of the labeled claim of C 17 H 27 NO 2 In-house Method 

Degradation Products 

(降解产物) 


(残留溶剂) 

Specified impurities: 

EP-impurity F*: NMT 0.2% 

Each unspecified impurity: NMT 0.20% 

Total impurities: NMT 0.5% 

Method 

ABS_T002I_1.0 

Test Results 

Lot # 

Based on the Statements from API/Excipients and the calculation as per USP Option 2, 

the product meets the USP residual solvent limits criteria. No testing is needed. 


Acceptance Criteria 

USP monograph or other compendia monograph 

(EP, BP, JP etc.) 

DMF holder’s specification (DMF) 

ICH guidelines: 

Impurities in Drug Substance: ICH Q3A(R2) 

Impurities in Drug Products: ICH Q3B(R2) 

Impurities: for Residual Solvents: ICH Q3C(R3) 

Use MDD to calculate the ICH Thresholds: 

Reporting Threshold (RT) 

Identification Threshold (IT) 

Qualification Threshold (QT) 


Analytical Methods Need to be Developed for DP: 

Assay/CU for Drug Product 

Degradation Products for Drug Product 

Dissolution for Drug Product 

Residual Solvents for Drug Product 


All Methods Need to be Validated for DP: 






Method Validation Reports Need to be Summited:

Residual Solvents for Drug Substance

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