Pharmaceutical Impurities

• Impurities are unwanted chemicals that remain with active pharmaceutical ingredients (APIs) or develop during formulation or aging.
• Even trace amounts of unwanted chemicals can influence the efficacy and safety of a pharmaceutical product.

Classification of Impurities (ICH Guidelines)

• Organic impurities (process and drug-related)
• Inorganic impurities
• Residual solvents

Organic Impurities

• Arise during the synthetic process or storage of a drug substance:
  • Starting materials
  • By-products
  • Degradation products
  • Reagents and chiral impurities

Starting Materials or Intermediates

• Impurities from starting materials, intermediates, or by-products can be found in a drug substance if proper care is not taken during multistep synthesis.
• Washing a product removes unreacted starting material; however there is still a chance it will remain in the final product.
• An example is in the synthesis of baclofen from glutamide.

Degradation Product

• Degradation of end products during manufacturing results in the formation of impurities.
• Degradation products arise from the synthetic process, storage, formulation of dosage form, and aging.
• Examples include Penicillins and Cephalosporins.

By-Products

• In synthetic organic chemistry, it is rare to obtain a single end-product with 100% yield.
• By-products can form through a variety of side reactions:
  • Incomplete reaction
  • Over reaction
  • Isomerism
  • Dimerization
• An example is the production of paracetamol from intermediate p-amino phenol.

Inorganic Impurities

• Inorganic impurities are derived from the manufacturing process and excipients.
• Excipients often contain high levels of heavy metals such as arsenic, bismuth, cadmium, chromium, copper, iron, lead, mercury, nickel, and sodium.
• Examples include excipients, hydrogenated oils, and fats.

Residual Solvents

• Residual solvents are potentially undesirable substances that can modify the properties of compounds or be hazardous to human health.
• Solvents used in drug substance manufacturing are classified into four types based on ICH guidelines:
  • Class 1
  • Class 2
  • Class 3
  • Class 4

Class 1 Solvents

• Class 1 solvents and their permissible concentration limits:
  • Benzene: 2 ppm (Carcinogenic)
  • Carbon tetrachloride: 4 ppm (Toxic)
  • 1,1-Dichloroethene: 8 ppm (Toxic)
  • 1,2-Dichloroethene: 5 ppm (Toxic)
  • 1,1,1-Trichloroethane: 1500 ppm (Environmental hazard)

Class 2 Solvents

• Usage of class two solvents should be limited in pharmaceutical products because of their inherent toxicity.
  • Acetonitrile: 4.1 mg/day, 410 ppm
  • Chlorobenzene: 3.6 mg/day, 360 ppm
  • Chloroform: 0.6 mg/day, 60 ppm
  • Cyclohexane: 38.8 mg/day, 3880 ppm
  • 1,2-Dichloroethene: 18.7 mg/day, 1870 ppm
  • Dichloromethane: 6.0 mg/day, 600 ppm
  • 1,1-Dimethoxyethane: 1.0 mg/day, 100 ppm
  • N,N-Dimehtyl acetamide: 10.9 mg/day, 1090 ppm
  • N,N-Dimethyl formamide: 8.8 mg/day, 880 ppm
  • 1,2-Dioxane: 3.8 mg/day, 380 ppm
  • 2-Ethoxyethanol: 1.6 mg/day, 160 ppm
  • Ethylene glycol: 6.2 mg/day, 620 ppm
  • Formamide: 2.2 mg/day, 220 ppm

Class 3 Solvents

• Class 3 solvents are less toxic and pose a lower risk to human health than class 1 and class 2 solvents.
  • Acetic acid
  • Anisole
  • Butanol

Class 4 Solvents

• For class 4 solvents, adequate toxicological data is unavailable.

Qualification of Impurities

• ICH regions have guidelines and evaluation.
• Some examples include but are not limited to:
  • Stability testing
  • Validation of analytical procedures
  • Impurities in new drug substances
  • Guideline for residual solvents
  • Microbiological examination
  • Uniformity of dosage units

Degradation Products (Definition)

• An impurity resulting from a chemical change in the drug substance during manufacture and storage.
• This is caused by light, temperature, pH, H2O, reaction with an excipient, and the container closure system.

Rationale for Reporting and Control

• Drug applicants should summarize degradation products found during manufacture and stability studies.
• This review should include the potential degradation pathways from the drug, interactions with the excipient and container closure system.
• A rationale should be included for impurities that are not degradation products.

Degradation Product Identification and Laboratory Studies

• Any degradation product observed in stability studies at the recommended storage condition should be identified when present at a level greater than the identification threshold.
• If identifying a degradation product is infeasible, a summary of laboratory studies demonstrating the unsuccessful efforts should be included in the registration application.

Analytical Procedure

• The registration application should include evidence that analytical procedures have been validated for detection and quantification of degradation products.
• Analytical procedures should be validated to demonstrate specificity for specified and unspecified degradation products, including samples stored under relevant stress conditions (light, heat, humidity, acid/base hydrolysis, oxidation).
• The quantification limit for the analytical procedure should be no more than the reporting threshold.

Reporting Degradation Product Content of Batches

• Analytical results should be provided in the registration application for relevant batches used for clinical, safety, and stability testing and batches representative of the proposed commercial process.
• Any degradation product at a level greater than the reporting threshold and total degradation products should be reported with analytical procedures indicated.
• Below 1.0%, results should be reported to the number of decimal places (e.g., 0.06%).
• At and above 1.0%, results should be reported to one decimal place (e.g., 1.3%).
• Documentation for each batch of the new drug product should include:
  • Batch identity, strength, and size
  • Date and site of manufacture
  • Manufacturing process
  • Immediate container closure
  • Degradation product content (individual & total)
  • Use of batch (clinical, stability studies)
  • Reference to the analytical procedure used
  • Batch number of the drug substance used
  • Storage conditions for stability studies

Listing of Degradation Products in Specification

• The specification for a new drug product should include a list of degradation products, which should be selected based on those found in batches manufactured by the proposed commercial process.
• Specified degradation products can be identified or unidentified.
• The new drug product specification should include the following:
  • Each specified identified degradation product
  • Each specified unidentified degradation product
  • Any unspecified degradation product - acceptance criterion ≤ the identification threshold Total degradation products

Qualification of Degradation Products

• Qualification involves acquiring and evaluating data to establish the biological safety of a degradation product or profile at specified levels.
• Degradation products can be qualified at higher levels based on a comparison between actual doses in safety studies and the intended dose of the new drug product. Justification for such higher levels should consider:
  • The amount of degradation product administered in previous safety/clinical studies found to be safe
  • The increase in the amount of the degradation product
  • Other safety factors

Residual Solvents Analytical Procedure

• Analytical procedures must be validated and suitable for detecting and qualifying impurities.
• Reference standards for impurity control should be evaluated and characterized for their intended use.
• The drug substance can be used as a standard to estimate impurity levels.
• The quantification limit for the analytical procedure should be no more than the reporting threshold.

Limits of Residual Solvents: Solvents to be Avoided

• Class 1 solvents should not be used in the manufacture of drug substances, excipients, and drug products because of their toxicity or environmental impact.
• Table of Class 1 solvents in pharamaceutical products:
  • Benzene: 2 ppm (Carcinogen)
  • Carbon tetrachloride: 4 ppm (Toxic and envionmental hazard)
  • 1,2-Dichloroethane: 5 ppm (Toxic)
  • 1,1-Dichloroethane: 8 ppm (Toxic)
  • 1,1,1-Trichloroethane: 1500 ppm (Envionmental hazard)

Limits of Residual Solvents: Solvents to be Limited

• Solvents should be limited in pharmaceutical products because of their inherent toxicity.
• PDEs (Permitted Daily Exposures) are given to the nearest 0.1 mg/day, and concentrations are given to the nearest 10 ppm.

Limits of Residual Solvents: Solvents with Low Toxic Potential

• Class 3 solvents are considered less toxic and of lower risk to human health.
• Class 3 includes no solvent known as a human health hazard at levels normally accepted in pharmaceuticals.
• 50 mg per day or less (corresponding to 5000 ppm or 0.5% under Option 1) would be acceptable without justification.
• Higher amounts may also be acceptable if they are realistic in relation to manufacturing capability and good manufacturing practice.
• Examples include:
  • Acetic acid
  • Acetone
  • Isobutyl acetate
  • Anisole
  • Isopropyl acetate 1

Limits of Residual Solvents: Solvents for Which No Adequate Toxicological Data Was Found

• The following is a list of solvents for which no adequate toxicological data was found.
  • 1,1-Diethoxypropane
  • Methyl isopropylketone
  • 1,1-Dimethoxymethane
  • Methyl tetra hydro furan
  • 2,2-Dimethoxypropane
  • Petroleum ether Isooctane
  • Trichloro acetic acid
  • Isopropyl ether
  • Trifluoro acetic acid