Residual Solvents: Classification, analytical procedures and reporting limits MCQs With Answer

Introduction

This quiz collection on Residual Solvents: Classification, analytical procedures and reporting limits is designed for M.Pharm students preparing for advanced pharmaceutical analysis. It covers ICH Q3C and USP principles, solvent classification (Class 1, 2, 3), common examples, analytical strategies including headspace-GC, GC-MS, purge-and-trap and SPME, sample preparation and validation requirements. Emphasis is on practical decision-making: selection of methods, interpretation of chromatograms, calibration, and how reporting limits are derived from toxicological PDE concepts and regulatory guidance. These 20 MCQs with answers will strengthen your conceptual understanding and exam readiness for residual solvent assessment in drug substances and products.

Q1. Which regulatory guidance specifically addresses residual solvents and their classification in pharmaceutical products?

• ICH Q2(R1)
• ICH Q3C
• ICH Q1A
• ICH Q9

Correct Answer: ICH Q3C

Q2. According to ICH Q3C, solvents placed in Class 1 are characterized as which of the following?

• Solvents with low toxic potential acceptable at high ppm
• Solvents to be avoided because of known human carcinogenicity or environmental hazards
• Solvents with no evidence of toxicity and exempt from control
• Solvents preferred for routine manufacture

Correct Answer: Solvents to be avoided because of known human carcinogenicity or environmental hazards

Q3. Which solvent is a classic example of a Class 1 residual solvent that should be avoided where possible?

• Ethanol
• Benzene
• Methanol
• Toluene

Correct Answer: Benzene

Q4. Which class of residual solvents is described as having “low toxic potential” and often permitted at higher limits?

• Class 1
• Class 2
• Class 3
• Unclassified

Correct Answer: Class 3

Q5. Which analytical technique is most commonly used for routine quantitation of volatile residual solvents in pharmaceutical dosage forms?

• High-performance liquid chromatography (HPLC)
• Headspace gas chromatography with flame ionization detection (HS-GC-FID)
• Nuclear magnetic resonance (NMR)
• Infrared spectroscopy (IR)

Correct Answer: Headspace gas chromatography with flame ionization detection (HS-GC-FID)

Q6. What is the main advantage of headspace sampling for residual solvent analysis compared to direct injection of sample solution?

• It always provides higher recovery for nonvolatile excipients
• It isolates volatile analytes from nonvolatile matrix components, reducing interferences and contamination of the GC column
• It eliminates the need for calibration standards
• It is the only method suitable for solids

Correct Answer: It isolates volatile analytes from nonvolatile matrix components, reducing interferences and contamination of the GC column

Q7. Which of the following sample preparation techniques enhances sensitivity for trace residual volatile organics by concentrating analytes onto a sorbent before GC analysis?

• Direct aqueous dilution
• Purge-and-trap or thermal desorption
• Simple filtration
• Gel permeation chromatography

Correct Answer: Purge-and-trap or thermal desorption

Q8. Which detection technique combined with GC provides the greatest confidence for both quantitation and structural identification of residual solvents at low levels?

• GC-FID
• GC with thermal conductivity detector (GC-TCD)
• GC-mass spectrometry (GC-MS)
• GC with refractive index detector

Correct Answer: GC-mass spectrometry (GC-MS)

Q9. In validation of a residual solvent method, which parameter defines the lowest concentration that can be measured with acceptable accuracy and precision?

• Limit of Detection (LOD)
• Limit of Quantitation (LOQ)
• Specificity
• Linearity range

Correct Answer: Limit of Quantitation (LOQ)

Q10. The term “PDE” used in relation to residual solvents stands for which of the following?

• Permitted Daily Exposure
• Pharmacopoeial Detection Estimate
• Permissible Dilution Equivalence
• Primary Detection Endpoint

Correct Answer: Permitted Daily Exposure

Q11. How are concentration limits for residual solvents in ppm generally derived in regulatory practice?

• From solubility of the solvent in water
• From the solvent’s boiling point alone
• From toxicological PDE values and the maximum daily dose of the drug product
• By averaging concentrations found in market samples

Correct Answer: From toxicological PDE values and the maximum daily dose of the drug product

Q12. USP <467> is a regulatory reference describing procedures for residual solvent testing. Which statement about USP <467> is correct?

• It mandates HPLC as the only acceptable method
• It provides guidance on GC methods including headspace and direct injection, and establishes limits
• It exempts all Class 1 solvents from testing
• It only applies to parenteral products

Correct Answer: It provides guidance on GC methods including headspace and direct injection, and establishes limits

Q13. When performing headspace GC analysis, which parameter is critical to ensure reproducible partitioning of solvent between sample matrix and headspace?

• Column length only
• Equilibration temperature and time
• Injector split ratio alone
• Detector temperature alone

Correct Answer: Equilibration temperature and time

Q14. Solid-phase microextraction (SPME) used for sampling residual solvents is best described as which of the following?

• A liquid–liquid extraction technique requiring large solvent volumes
• A sorptive extraction technique that concentrates volatiles onto a coated fiber for thermal desorption into GC
• A method that chemically derivatizes solvents to nonvolatile products
• A filtration-based cleanup method for particulates

Correct Answer: A sorptive extraction technique that concentrates volatiles onto a coated fiber for thermal desorption into GC

Q15. In method validation, which characteristic ensures that the residual solvent method can separate the solvent peak from other formulation components?

• Linearity
• Specificity/selectivity
• Accuracy
• Repeatability

Correct Answer: Specificity/selectivity

Q16. For quantitation of residual solvents, why is use of an internal standard commonly recommended?

• To eliminate the need for calibration curves
• To compensate for variable sample introduction, headspace extraction efficiency and instrument response
• To increase solvent toxicity limits
• To change the solvent classification

Correct Answer: To compensate for variable sample introduction, headspace extraction efficiency and instrument response

Q17. Which of the following is true about reporting limits for residual solvents that are not listed in the regulatory tables?

• They are automatically considered safe at any concentration
• Analytical assessment and risk-based justification or toxicological evaluation may be required to set appropriate limits
• The manufacturer must always report them as Class 1 solvents
• They must be reported as 0 ppm

Correct Answer: Analytical assessment and risk-based justification or toxicological evaluation may be required to set appropriate limits

Q18. Which approach is most appropriate when a drug product has a maximum daily dose much lower or higher than the default value used to translate PDE into ppm?

• Always use the default concentration value regardless of dose
• Recalculate concentration limits using the actual maximum daily dose to derive appropriate ppm limits
• Classify all solvents as Class 3
• Ignore PDE and rely on impurity profiling only

Correct Answer: Recalculate concentration limits using the actual maximum daily dose to derive appropriate ppm limits

Q19. Which of the following statements about GC-FID vs GC-MS for routine residual solvent testing is most accurate?

• GC-FID provides both superior identification and quantification compared with GC-MS
• GC-MS offers better identification power (mass spectra) while GC-FID often provides robust and sensitive quantitation when identity is confirmed
• GC-MS cannot be used for quantitation of volatile solvents
• GC-FID is obsolete and not permitted by pharmacopeias

Correct Answer: GC-MS offers better identification power (mass spectra) while GC-FID often provides robust and sensitive quantitation when identity is confirmed

Q20. During a stability study, a residual solvent is detected slightly above its limit in one timepoint. The best immediate action is which of the following?

• Ignore the result because it occurred only once
• Investigate analytically (re-run test, check system suitability and sample handling), evaluate trend and perform risk assessment before reporting or recalling
• Automatically recall all batches worldwide
• Change the limit in the specification without justification

Correct Answer: Investigate analytically (re-run test, check system suitability and sample handling), evaluate trend and perform risk assessment before reporting or recalling

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