Analytical Quality by Design (AQbD) Approach to the Development of In Vitro Release Test for Topical Hydrogel
Abstract
:1. Introduction
1.1. Product Quality Tests for Topical and Transdermal Drug Product
1.2. Quality by Design Usage in the Development of Topical Semi-Solid Dosages
2. Materials and Methods
2.1. Materials
2.2. Methods
2.2.1. USP Apparatus IV: Flow-Through Cell with a Semi-Solid Adapter
2.2.2. Ultra-High-Performance Liquid Chromatography Analysis
2.2.3. Analytical Quality by Design
2.2.4. Definition of the Analytical Target Profile
2.2.5. Definition of the Critical Method Attributes and Critical Method Parameters
2.2.6. Establishing Failure Mode Effects Analysis (FMEA)
- Low (acceptable) 1 ≤ RPN ≤ 29;
- Medium (to be considered) 30 ≤ RPN ≤ 59;
- High (not acceptable) 60 ≤ RPN ≤ 125.
2.2.7. Design of Experiments (DoE) for IVRT Method
2.2.8. Determination of the Osmolality of Different Media
2.2.9. Performing Membrane Inertness Test
2.2.10. Discriminatory Power of the In Vitro Release Test Method
3. Results
3.1. Definition of ATP and Determination of CMAs
3.2. Identification of the MP using the Ishikawa Diagram
3.3. Initial Risk Assessment using FMEA (Effects of MPs on CMAs)
3.4. Carrying out Preliminary Experiments
3.4.1. In Vitro Release Test Study Design with USP Apparatus IV
3.4.2. Investigation of the Rate of Flow and Sample Weight with the One-Factor-at-a-Time (OFAT) Method
3.4.3. Effect of pH and Osmolality on Drug Release from Topical Hydrogel
3.5. The 23 Full Factorial Design for the IVRT Method
3.6. Updating the FMEA Table
3.7. Investigating Discriminatory Power
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Category | Ranking | ||||
---|---|---|---|---|---|
1 | 2 | 3 | 4 | 5 | |
Occurrence (O) | nearly impossible | randomly occurring | 50% chance of occurring | likely to occur | certain to occur |
Severity (S) | no effects | insignificant effect | moderate effect | strong effect | severe effect |
Detectability (D) | excellent | good | moderate | poor | undetectable |
ATP Element | Target |
---|---|
Target sample (product name) | Diclofenac sodium 1% topical gel |
API name | Diclofenac sodium |
Dosage strength | 1% (10 mg/g) |
Dosage forms | Hydrogel |
Route of administration | Topical |
Matrix | Propylene glycol (50%), HPMC (1.5%), purified water (47.5%) |
Packaging | Plastic tube |
Regulatory specification | ICH, EMA (European Medicines Agency), FDA (Food and Drug Administration) |
Release/in vitro release test | The release tests should be sensitive to relevant changes in the ingredients and process parameters. They should have adequate release efficiency, release profiles, and reproducibility. They should meet regulatory requirements [1]. Precision RSD ≤ 10% (6 parallel). |
Analytical measurements | Analytical measurements: the procedure must be able to accurately quantify diclofenac sodium in IVRT samples over the range of 25–200% of the nominal concentration with an accuracy of 2.0% |
CMA Parameters | Target | Justification |
---|---|---|
Release efficiency in 6 h | Q (6 h) ≥ 70% | IVRT is a fundamental tool used to identifyformulation factors that influence the release of the API, an effective method to monitor lot-to-lot changes and stability during development. A draft guideline on the quality and equivalence of topical products described this criterion [1]. |
Characterize the release profile | 6 time points should be obtained in the linear portion of the drug release profile | |
RSD% of the released API amount of the 6 parallel samples at given sampling points | RSD ≤ 10% (6 parallel) | RSD values below 10% are considered to be an indication of the good reproducibility of the IVRT method. |
Accuracy | Between 98 and 102% | In the case of UHPLC measurements, the weak point of the true value determination is accuracy. |
System suitability test of the chromatography system | USP plate count: N ≥ 3000 | There is a need for a chromatography system in which the API can properly separate from the matrix components. The plate count has a fundamental impact on the extent of measurement error through the peak’s capability of being integrated. Therefore, the chromatography method should be suitable within the purpose to detect the API in IVRT samples at 25% of the nominal concentration. |
Method Parameter | Critical Method Attributes | Cause of the Deviation | Effect of the Deviation | F (Occurrence) | S (Severity) | D (Perceptibility) | RPN | Action/Strategy of Risk Decrease |
---|---|---|---|---|---|---|---|---|
Release test | ||||||||
Ionic strength of the medium | min. 70% (Q)—6 h | The gelling agent is HPMC | Release might change | 4 | 5 | 4 | 80 | We need to investigate the effect of the ionic strength of the medium (pH 7.4 PBS ± NaCl). |
Ionic strength of the medium | 6 time points should be obtained in the linear portion of the drug release profile | The gelling agent is HPMC | Release might change | 4 | 5 | 4 | 80 | We need to investigate the effect of the ionic strength of the medium (pH 7.4 PBS ± NaCl). |
pH of the medium | min. 70% (Q)—6 h | Changing the pH of the medium | RSD might be increasing; outliers below 70% | 3 | 5 | 4 | 60 | Controlled parameter: prescription is needed to make the medium pH 7.4 ± 0.5. Investigation of the effect of pH change is needed. |
Membrane type | min. 70% (Q)—6 h | Different membrane and manufacturer | The membrane should be inert and not be rate-limiting to active substance release | 4 | 5 | 3 | 60 | We need to investigate the inertness of the membrane in pH 7.4 PBS medium. |
Rate of flow | min. 70% (Q)—6 h | The increase in the rate of flow, maintaining the concentration gradient, results in faster drug release | Release kinetic might change; increase or decrease in RSD | 5 | 5 | 3 | 75 | We need to investigate the effect of the flow rate changing (4 mL/min to 8 mL/min). |
Rate of flow | 6 time points should be obtained in the linear portion of the drug release profile | Quicker flowing causes quicker release | Release kinetic might change | 5 | 5 | 3 | 75 | We need to investigate the effect of the flow rate changing (4 mL/min to 8 mL/ min). |
Sample weight (0.4 mL or 1.2 mL SSA) | min. 70% (Q)—6 h | Different size of SSA | Sample weight increasing, leading to release kinetic change/release rate change | 5 | 5 | 3 | 75 | We need to investigate the effect of the sample weight (0.4 mL or 1.2 mL SSA). |
Sample weight (0.4 mL or 1.2 mL SSA) | 6 time points should be obtained in the linear portion of the drug release profile | Different size of SSA | Sample weight increasingleading to release kinetic change/release rate change | 5 | 5 | 3 | 75 | We need to investigate the effect of the sample weight (0.4 mL or 1.2 mL SSA). |
Individual flow rate of cells | min. 70% (Q)—6 h | The release of API might be changing cell by cell | RSD might be increasing; outliers above 70% | 3 | 5 | 5 | 75 | Measuring the flow rate cell by cell of the release and calculating the release with the measured flow rate. Conducting training about how to assemble the cells. Annual maintenance. |
Individual flow rate of cells | 6 time points should be obtained in the linear portion of the drug release profile | The release of API might be changing cell by cell | RSD might be increasing; fluctuating release curve is caused by RSD% | 3 | 5 | 5 | 75 | Measuring the flow rate cell by cell of the dissolution and calculating the dissolution with the measured flow rate. |
Individual flow rate of cells | RSDConc ≤ 10% (6 vessels) | The release of API might be changing cell by cell | Fluctuating release curve is caused by RSD% | 3 | 5 | 5 | 75 | Conducting training about how to assemble the cells. Annual maintenance. |
API% | min. 70% (Q)—6 h | Sink conditions must be ensured in the receptor medium | Limited drug solubility effects can play a major role in the control of API release | 5 | 5 | 3 | 75 | What is the hydrogel diclofenac sodium’s maximum dosage that we are going to use? |
API% | 6 time points should be obtained in the linear portion of the drug release profile | The method’s requirement is to detect different IVRRs according to the strength of the formulations | The IVRT method might not be sensitive | 4 | 5 | 3 | 60 | We need to investigate the discriminatory ability of the IVRT method (different formulation strengths: 0.5, 1, and 2%). |
Composition of the product | min. 70% (Q)—6 h | Gelling agent type | Release might change | 4 | 5 | 3 | 60 | We need to prescribe that the matrix is fixed. |
Media | Osmolality | Flow Rate | Semi-Solid Adapter | Computed Released Amount at the End of the Experiment at 6 h | IVRR | Lag Time | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Mean | SD | RSD | Mean | SD | RSD | Mean | SD | RSD | ||||
mOsmol/kg | mL/min | mL | % | % | % | µg × cm−2 × min0.5 | µg × cm−2 × min0.5 | % | min | min | % | |
pH 7.4 PBS | 279.5 | 4 | 1.2 | 75.5 | 3.5 | 4.6 | 420.2 | 21.6 | 5.2 | 22.9 | 1.3 | 5.5 |
pH 7.4 PBS | 279.5 | 8 | 0.4 | 100.6 | 3.6 | 3.6 | 273.8 | 10.2 | 3.7 | 8.6 | 1.2 | 14.0 |
pH 7.4 PBS | 279.5 | 4 | 0.4 | 99.5 | 4.6 | 4.7 | 278.5 | 10.5 | 3.8 | 11.7 | 0.7 | 6.0 |
pH 7.4 PBS | 279.5 | 8 | 1.2 | 81.2 | 3.5 | 4.3 | 446.7 | 18.2 | 4.1 | 20.1 | 1.5 | 7.3 |
pH 7.4 PBS + NaCl | 769.3 | 8 | 0.4 | 94.4 | 2.2 | 2.3 | 274.6 | 9.5 | 3.5 | 9.7 | 0.6 | 6.3 |
pH 7.4 PBS–NaCl | 99.3 | 8 | 0.4 | 91.3 | 1.8 | 1.9 | 275.6 | 4.5 | 1.6 | 8.3 | 0.5 | 5.7 |
pH 6.9 PBS | 274.5 | 8 | 0.4 | 86.5 | 2.5 | 2.9 | 262.1 | 8.6 | 3.3 | 9.4 | 0.8 | 8.2 |
pH 7.9 PBS | 277.0 | 8 | 0.4 | 99.5 | 3.0 | 3.0 | 299.1 | 8.9 | 3.0 | 9.7 | 0.7 | 7.0 |
Experiment | Flow Rate (mL/min) | Volume of SSA (mL) | pH |
---|---|---|---|
1 | 4.00 | 0.40 | 7.40 |
2 | 8.00 | 0.40 | 7.40 |
3 | 4.00 | 1.20 | 7.40 |
4 | 8.00 | 1.20 | 7.40 |
5 | 4.00 | 0.40 | 7.90 |
6 | 8.00 | 0.40 | 7.90 |
7 | 4.00 | 1.20 | 7.90 |
8 | 8.00 | 1.20 | 7.90 |
Factor | Effect | t(32) | p | Coefficient | Standard Error Coefficient |
---|---|---|---|---|---|
Mean/intercept | 365.9818 | 137.8254 | 0.0000 | 365.9818 | 2.6554 |
(1) A: Flow rate (mL/min) | 4.2335 | 0.7971 | 0.4312 | 2.1168 | 2.6554 |
(2) B: Volume of SSA (mL) | 158.0885 | 29.7673 | 0.0000 | 79.0443 | 2.6554 |
(3) C: pH | 23.9005 | 4.5004 | 0.0001 | 11.9503 | 2.6554 |
1 by 2 | 6.8665 | 1.2929 | 0.2053 | 3.4333 | 2.6554 |
1 by 3 | −3.5875 | −0.6755 | 0.5042 | −1.7938 | 2.6554 |
2 by 3 | 0.5395 | 0.1016 | 0.9197 | 0.2698 | 2.6554 |
1 × 2 × 3 | −7.2765 | −1.3701 | 0.1802 | −3.6383 | 2.6554 |
Factor | Effect | t(32) | p | Coefficient | Standard Error Coefficient |
---|---|---|---|---|---|
Mean/intercept | 88.2920 | 150.1317 | 0.0000 | 88.2920 | 0.5881 |
(1) A: Flow rate (mL/min) | 1.8480 | 1.5712 | 0.1260 | 0.9240 | 0.5881 |
(2) B: Volume of SSA (mL) | −22.4020 | −19.0462 | 0.0000 | −11.2010 | 0.5881 |
(3) C: pH | −1.5510 | −1.3187 | 0.1966 | −0.7755 | 0.5881 |
1 by 2 | 0.9680 | 0.8230 | 0.4166 | 0.4840 | 0.5881 |
1 by 3 | −1.3130 | −1.1163 | 0.2726 | −0.6565 | 0.5881 |
2 by 3 | −0.9070 | −0.7711 | 0.4463 | −0.4535 | 0.5881 |
1 × 2 × 3 | −1.1150 | −0.9480 | 0.3502 | −0.5575 | 0.5881 |
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Szoleczky, R.; Budai-Szűcs, M.; Csányi, E.; Berkó, S.; Tonka-Nagy, P.; Csóka, I.; Kovács, A. Analytical Quality by Design (AQbD) Approach to the Development of In Vitro Release Test for Topical Hydrogel. Pharmaceutics 2022, 14, 707. https://doi.org/10.3390/pharmaceutics14040707
Szoleczky R, Budai-Szűcs M, Csányi E, Berkó S, Tonka-Nagy P, Csóka I, Kovács A. Analytical Quality by Design (AQbD) Approach to the Development of In Vitro Release Test for Topical Hydrogel. Pharmaceutics. 2022; 14(4):707. https://doi.org/10.3390/pharmaceutics14040707
Chicago/Turabian StyleSzoleczky, Réka, Mária Budai-Szűcs, Erzsébet Csányi, Szilvia Berkó, Péter Tonka-Nagy, Ildikó Csóka, and Anita Kovács. 2022. "Analytical Quality by Design (AQbD) Approach to the Development of In Vitro Release Test for Topical Hydrogel" Pharmaceutics 14, no. 4: 707. https://doi.org/10.3390/pharmaceutics14040707