Dissolution rate stands as a pivotal parameter for assessing oral solid formulations, entailing the assessment of both dissolution and analytical facets. The validation of dissolution analysis methodologies shares commonalities with validations of other analytical methods, while also encompassing its distinctive considerations. Today, I aim to initiate a discussion on the pivotal facets of ‘Dissolution Analysis Method Validation,’ which could potentially offer valuable insights for your consideration.

  1. Preparatory Steps Prior to Method Validation

1.1 Appropriate Personnel and Profound Training (This is a universally critical aspect for all pre-validation stages)
1.2 Blank Solvents, Test Samples, and Blank Excipients

(1) Blank Solvents: Sufficiently prepare blank solvents for each sequence, aiming for a single, adequate preparation.
(2) Blank Excipients: It is recommended to employ blank samples prepared using excipients from the same batch as those used for method validation.
(3) Test Samples: It is advisable to utilize products at pilot scale or higher for validation, considering potential consistency with prescription and processes. Optimal selection involves using a batch of qualified products displaying minimal batch-to-batch variations for analytical method validation.

1.3 Reference Standards

Are the storage conditions appropriate? (Is low-temperature storage necessary, though the actual storage is at room temperature?) Before usage, it is essential to ascertain if the reference standard is meant for quantitative application (with assigned values). For qualitative use, calibration is necessary. For quantitative usage, it’s imperative to distinguish if the intended purpose aligns correctly (whether it’s for HPLC, UV, or other techniques). We must consider weighing conditions for the reference standard, along with the temperature and relative humidity of the weighing environment, to ensure they meet the stipulated requirements.

1.4 Chromatographic Columns, Glassware, and Instruments

Chromatographic Columns: Opt for an appropriate chromatographic column (regarding packing material, inner diameter, specifications, etc.).
Glassware: Calibration of glassware is mandatory, ensuring it’s within its valid calibration period. Dissolution Apparatus, UV, HPLC, etc.: These instruments should be calibrated/verified, and their calibration should be within its effective duration.

2. Summary of Dissolution Analysis Method Validation Content and Key Points:

(1) Specificity: Eliminate interference from excipients and capsule shells on the analyte being measured. (2) Precision: Assess repeatability, intermediate precision (involving different personnel, equipment, and dates; not necessarily different times), or reproducibility. (3) Accuracy: If a dissolution curve is to be constructed, consider concentrations at the first and highest points. (4) Linearity and Range: Include at least 5 concentration levels. (5) Solution Stability: Can be conducted separately or integrated into method robustness studies. Time considerations should encompass multiple sample assessments (e.g., batch validation at multiple points) and investigation timeframes for anomalies/OOS events. (6) Filtration Study: Explore variations in filters from different manufacturers, specifications, materials, initial volume of discarded filtrate, etc. (7) Robustness: Apart from chromatographic system robustness, dissolution analysis must evaluate differences between various dissolution instruments (as outlined in the 2016 CFDA requirements for consistency evaluation submission).

3. Key Points During Each Validation Stage

3.1 Specificity:

3.1.1 Exclusion of Blank Solvent Interference: The interference from blank solvent on the analyte must not exceed 1% (USP 1092).

3.1.2 Exclusion of Blank Excipient Interference: Blank excipient interference should not surpass 2% (USP 1092). If exceeded, method modification might be necessary (such as changing detection wavelength, reducing blank absorption, etc.).

3.1.3 Exclusion of Capsule Shell Interference: In the examination of dissolution for capsule formulations, follow sample testing steps diligently. Conduct tests with 6 empty capsule shells, ensuring complete removal of contents (to exclude human interference). Dissolve empty capsule shells of the same variety, using dissolution medium volume as specified, within the same container. Analyze as per prescribed methods and undertake necessary corrections.

3.1.4 Key Aspects During Experimental Procedure:
(1) 6 capsules correspond to 1 dissolution vessel, not 6 vessels.
(2) Ensure complete removal of contents to avoid human-induced interference (ideally from the same batch of blank capsules).
(3) If there are changes in capsule formulation or a switch of capsule manufacturers, interference testing needs to be repeated.

Additionally, consider the following criteria:

  • (1) If the correction value is ≤ 2% of the labeled amount, it can be disregarded.
  • (2) If the correction value is < 25% of the labeled amount, correction can be applied.
  • (3) If the correction value exceeds 25% of the labeled amount, the test is considered invalid.

3.1.5 Common Issues in Specificity:

  • (1) Personnel forgetting to perform the interference test with empty capsules.
  • (2) Personnel distributing 6 empty capsules into separate dissolution vessels during interference testing.

3.2 Precision: For precision validation in dissolution analysis, it’s crucial to select products with good quality attributes and minimal batch-to-batch variations. Otherwise, the precision results might be influenced by intra-batch variations.

3.2.1 Repeatability:

  • (1) Repeatability of the Method and Sampling Technique: Repeat the sampling from the same dissolution vessel 6 times.
  • (2) Repeatability of Dissolution Method: Samples taken from each of the 6 vessels (n = 6) should either meet the quality standards or have a calculated RSD (which can be influenced by batch-to-batch variations).
  • (3) If an automatic sampling instrument is used: A comparison between manual and automatic sampling is necessary (with a difference within 2%).

3.2.2 Intermediate Precision: Conducted within the same laboratory (analyst 2), using different instruments, chromatographic columns, and separate dates; procedures remain consistent with repeatability.

3.2.3 Reproducibility: Conducted across different laboratories (analyst 2), employing distinct instruments, chromatographic columns, and separate dates; procedures align with repeatability.

3.2.4 Acceptance Criteria for Precision:

  • (1) Calculate the RSD for both repeatability and intermediate precision results separately.
  • (2) Calculate the RSD for a set of 12 results.
  • (3) Calculate the difference between the average dissolution values of analyst 1 and analyst 2.

3.3 Accuracy:

  • (1) Accuracy does not typically apply to the dissolution step due to its involvement with both dissolution and detection methods. Accuracy, as per ICH Q2 (R2), can be assessed through simulation experiments focusing on the accuracy of the detection method. Typically, by simulating the product formulation, preparing three concentrations, and replicating each concentration three times. It’s advisable to begin with the lower limit, considering the lowest point on the dissolution curve or even the quantitation limit, and extend to around 120% or 130% of the labeled amount.
  • (2) USP (1092) suggests a recovery range of 95-105%.
  • (3) The recorded data should include the amount of active ingredient added, the measured amount of active ingredient, the calculated recovery percentage (%), and the relative standard deviation of recovery percentage (RSD %).

3.4 Linearity and Range:

  • (1) Concentration Range: Should encompass concentrations lower than the lowest point and extend higher than the highest point of drug release during the process.
  • (2) Report the correlation coefficient (r) (≥0.999).
  • (3) Include a minimum of 5 concentrations, with distribution as evenly as possible.

3.5 Solution Stability: In the validation of dissolution analysis methods, the stability assessment time for test sample solutions mainly considers the duration of the longest sequence in routine testing, the time during which solutions need to be retained when an Out-of-Specification (OOS) event occurs, and is combined with the duration of each run.

If there’s a plan to prepare control sample solutions, these are typically stored at 2-8°C and brought to room temperature before use (usually around 30 minutes). Fresh control solutions (prepared in parallel) are then formulated at each time point for comparison. The changes at each time point are calculated, with the generally accepted standard often being within the range of 98-102%.

3.6 Filtration Study: In dissolution testing, the dissolution solution is typically clarified by passing it through a filter membrane (Chinese Pharmacopoeia specifies a pore size not exceeding 0.8μm and inert materials for filter manufacturing, to prevent adsorption of active ingredients or interference with analysis). During filtration, adsorption might occur. Therefore, a filtration study can be conducted to select appropriate filter membranes and determine the volume of initial filtrate to discard. It’s generally required that the filter membrane should not significantly adsorb active components from the dissolution solution, nor should it release interfering substances into the dissolution medium.

3.7.1 Dissolution Apparatus:

  • (1) Dissolution medium concentration (±5%).
  • (2) Dissolution medium pH (±0.05).
  • (3) Concentration of buffers or surfactants.
  • (4) Utilization of the sinker.
  • (5) If surfactants are present in the dissolution medium, their concentration should also be examined (±5%).
  • (6) Effects of degassing versus non-degassing.
  • (7) Parameters like dissolution medium volume, stirring rate, and sampling time.
  • (8) If it involves dissolution rate or dissolution curves, the impact of different models or brands of dissolution instruments on dissolution results must be assessed (variations in dissolution instrument models can influence dissolution outcomes).

3.7.2 Analysis Method Aspect (accounting for instrument errors): For UV methods, consider parameters like sampling interval, slit width, etc. For HPLC methods, factors to consider are as follows (expand or reduce durability parameters based on the method’s practical parameters):

  • (1) Flow rate (±0.2ml/min).
  • (2) Column temperature (±3°C).
  • (3) Proportion and pH of the mobile phase.
  • (4) Different brands of chromatographic columns. When selecting a chromatographic column during method development, apart from suitability, factors like availability for long-term purchase and cost-effectiveness should be considered. Ideally, columns from various manufacturers should be screened unless specific criteria dictate otherwise, to facilitate future procurement and selection.
  • (5) Necessary wavelength variations (±2nm, etc.). This varies based on the specific testing items in the method. If not tested, reasonable justifications should be provided, for instance, wavelength durability assessment might not be required for methods utilizing an external standard approach.

3.7.3 Evaluation and Application of Durability Results:

  • (1) Determine if the system’s applicability meets requirements after parameter variations.
  • (2) Assess whether changes in parameters have an impact on dissolution testing results (this is crucial; some assessments focus only on the system’s applicability and overlook the influence of parameter changes on testing results).
  • (3) If analytical conditions significantly affect the testing results, it must be documented in the method (by adding notes or alerts).
  • (4) The comprehensive durability study results must be thoroughly incorporated into the Standard Operating Procedure (SOP) to guide routine testing.

Conclusion: The above are key point summaries for validation in dissolution analysis methods. It might be necessary to align these with the unique characteristics of your product and include specific considerations or elements that require special attention.

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