Dissolution Lynda Paleshnuik Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.

Overview Starting Point: Establishing Dissolution Criteria ACT Monograph Availability in the International Pharmacopeia Availability of other Pharmacopeial Monographs Disintegration vs Dissolution Prequalification Dissolution Requirements Development Strategy for Dissolution Methods Validation of Dissolution Methods

Dissolution - Introduction The pharmaceutical scientist would like to find a relationship between an in vitro characteristic of a dosage form, and its in vivo performance. Disintegration was originally thought to be this characteristic. The USP introduced its disintegration test in 1950. With advances in methodology, the disintegration test was found to be too insensitive, and dissolution test methods were introduced in the USP in 1968. Dissolution is principally useful as a QC test. It can be predictive of in vivo behaviour, but this must be demonstrated by an in-vivo in- vitro correlation study (IVIVC).

Dissolution - Introduction USP <1088>: “No product, including suspensions and chewable tablets, should be developed without dissolution or drug release characterization where a solid phase exists.” and “Dissolution testing is required for all solid oral Pharmacopeial dosage forms in which absorption of the drug is necessary for the product to exert the desired therapeutic effect. Exceptions are for tablets meeting a requirement for completeness of solution or for rapid (10 to 15 minutes) disintegration for soluble or radiolabeled drugs.”

Establishing Dissolution Criteria Starting point: What monographs are available? What are the dissolution requirements in the available monographs? What other sources of information are available?

Finding Current PhInt Monographs The International Pharmacopeia Supplement 1 to the 4th Edition (2008) is available at: http://www.who.int/phint/en/p/docf/ For the latest monographs, including a list of those under development: https://www.who.int/medicines/publications/pharmacopoei a/mono_dev/en/index.html

PhInt Monographs and Requirements: ACT’s ACT’s include 7 API’s present in 4 possible combinations. PhInt monographs are available for all API’s and for the following FPP’s: Single-API FPP’s Artemether capsules Artemether tablets Artesunate tablets

PhInt Monographs and Requirements ACT’s (multiple API FPPs): Artemether/lumefantrine tablets (new) Artemether/lumefantrine oral suspension (new) Note that the above are available under monograph development (second link on previous slide), not in the online PhInt (first link on previous slide).

PhInt Monographs Monographs under development and future monographs: Monographs in progress: Amodiaquine tablets Sulfadoxine/Pyrimethamine tablets. Proposed for work: Mefloquine tablets

PhInt Dissolution Requirements Artemether capsules - Dissolution. Carry out the test as described under 5.5 Dissolution test for solid oral dosage forms. Artemether tablets – as above Artesunate tablets – as above Artemether/lumefantrine tablets – no reference to dissolution Artemether/lumefantrine oral suspension – no reference to dissolution, including in the referenced general monograph: “Liquid preparations for oral use” under the section, “Powders for oral solutions/suspensions/drops”

Availability in Other Pharmacopeia BP 2008: no monographs. USP 2009: API’s: amodiaquine, amodiaquine HCl, mefloquine Dosage Forms: Amodiaquine HCl Tablets Sulfadoxine/Pyrimethamine Tablets For both of the above, dissolution limits are included.

USP Monograph Dissolution Methods/Limits Amodiaquine HCl Tablets Medium: water; 900 mL. Apparatus 2: 50 rpm. NLT 75% (Q) in 30 minutes Sulfadoxine/Pyrimethamine Tablets Medium: pH 6.8 phosphate buffer, prepared as directed under Buffer Solutions in the section Reagents, Indicators, and Solutions; 1000 mL. Apparatus 2: 75 rpm. NLT 60% (Q) each API in 30 minutes. (The above are in USP 2009 and USP 2009 S1)

USP vs PhInt Dissolution for Solid Orals The apparatus 1 (basket) and apparatus 2 (paddle) are essentially the same in USP, BP and PhInt pharmacopeia. (See next slides.) The acceptance criteria in the PhInt dissolution chapter for solid orals is the same as USP Acceptance Table 1, ie S1/S2/S3 stages and reference to Q.

USP Apparatus 1: Basket

PhInt Basket Apparatus

PhInt Paddle Apparatus

Disintegration (DT) Testing For immediate release tablets and capsules, dissolution rate is determined by: Rate of release of the API from the matrix, and The rate at which the API dissolves in the medium. For highly soluble API’s, the rate is largely determined by the disintegration of the dosage form.

Disintegration (DT) Testing Note that disintegration is generally an in-process test when the API is not highly soluble. Disintegration is indicated in the PhInt General Chapter on tablets for various tablet types (uncoated, soluble tablets, effervescent tablets, coated tablets). However: a statement is included regarding all tablets: “Where a requirement for the “Dissolution test” is specified in the individual monograph, the 5.3 Disintegration test for tablets and capsules is not required”.

Disintegration vs Dissolution ICH Q6: Disintegration may be substituted for dissolution when: -rapidly dissolving FPP’s (dissolution >80% in 15 minutes at pH 1.2, 4.0 and 6.8) and FPP’s containing API’s which are highly soluble throughout the physiological range (dose/solubility volume < 250 mL from pH 1.2 to 6.8) Most appropriate when: - relationship between DT and dissolution is established, or - DT shown to be more discriminating than dissolution. In these cases development information should be provided to support the robustness of the formulation and manufacturing process with respect to the selection of dissolution vs. disintegration testing (see Decision Tree #7(1)).

ICH Q6 Decision Tree 7/1

Disintegration vs Dissolution In the introduction to the current PhInt, it states that disintegration testing has been added to monographs for tablets and capsules containing highly soluble API’s, for example chloroquine sulfate tablets and isoniazid tablets. “…the disintegration test is considered to be generally satisfactory for such products”. Note that API’s in ACT’s are generally low solubility, and dissolution testing is required.

Prequalification Requirements A discriminating dissolution method should be developed for the final composition of the FPP, when applicable. This is a general requirement for solid orals. Limits should be set for each API in fixed-dose FPPs. The dissolution method should be incorporated into the stability and quality control programs (release and shelf- life specifications). Release limits = Shelf-life limits. Multipoint dissolution profiles of both the test and the reference FPPs should be compared.

Prequalification Requirements A tabulated summary of the compositions of the FPP batches (batch number, batch size, manufacturing date and certificate of analysis at batch release) used in clinical trials and in bioequivalence studies and a presentation of dissolution profiles must be provided. A discussion of the documented information and data should be presented. Results from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) should be discussed when appropriate.

Supplement 1 to the Main Generics Guide: Dissolution Testing Suggested media for comparative dissolution studies: pH 6.8 buffer pH 4.5 buffer pH 1.2 buffer or 0.1N HCl Water may be used as an additional medium, especially when the API is unstable in buffered media to the extent that data is unusable.

Supplement 1 – Comparative Dissolution Calculation of similarity: If both test and reference products show >85% dissolution in 15 minutes, profiles are considered similar and f2 calculation is unnecessary. Otherwise, calculate f2 (calculation next page). If f2>50, the profiles are considered similar.

Supplement 1 – Comparative Dissolution f2 is the similarity factor, n is the number of time points, R(t) is the mean %drug dissolved (reference product), and T(t) is the mean %drug dissolved (test product). The evaluation of similarity is based on the conditions of: A minimum of three time points (zero excluded); time points for comparator and test products should be the same. 12 dosage units of each formulation;

Supplement 1 – Comparative Dissolution A maximum of one time point after 85% of the comparator product has been reached. If 85% is not reached due to poor solubility, dissolution should be conducted until an asymptote (plateau) is reached. The RSD (relative standard deviation) of the mean of any product should be <20% for the early time point and <10% for subsequent time points.

Supplement 1 – Comparative Dissolution Reporting data: the report should include at least: 1) Purpose of study 2) Products / batches information Batch numbers, manufacturing/expiry date, and packaging of the two batches used in the study Batch manufacturing record(s), batch size(s), manufacturing sites and CoAs for the batch(es) of the test product(s). Note that the batches tested must be the batches of test and comparator product used in the BE study.

Supplement 1 – Comparative Dissolution 3) Full dissolution conditions and method, as well as the number of units (tablets, capsules, etc) per study. It should be indicated how and when the samples were filtered. Any problems with pH related stability of samples should be indicated and discussed in terms of preventative handling measures, analysis and interpretation of data.

Supplement 1 – Comparative Dissolution 4) Analytical method (validated) or reference to part of dossier 5) Results (% API dissolved) Tabulated (individual results, mean and %CV) Graphically Similarity determination / f2 calculation if necessary 6) Conclusion/recommendation

Development of a Discriminating Method A method must be developed which is both a) discriminating, and b) rugged and reproducible enough for day-to-day operation, and capable of transfer between labs. The acceptance criteria should be representative of multiple batches with the same formulation/manufacturing process, including key batches (eg BE).

Development of a Discriminating Method The method should be discriminating enough: The procedure should be capable of distinguishing significant changes in composition or manufacturing process that might be expected to affect in vivo performance. The method should not be overly sensitive: Assessing the results from multiple batches that represent typical variability in composition and manufacturing parameters may assist this evaluation.

Development of a Discriminating Method Factors to consider: Qualitative and quantitative excipient changes Manufacturing parameters: Lubrication Blend time Compression force Drying parameters

Development Strategy for Dissolution Methods Adopt the compendial method if one exists - exception: unsuitable (example interference) When no compendial method exists: - develop a method using compendial methodology (general chapters) and a study of three factors.

Development Strategy Documented dissolution study focuses on three factors: 1: -the physicochemical characteristics of the product (solubility, pH and quantitation of API released) 2: -the extent and rate of release of API from the FPP 3: - QC of the system (performance checks)

Physicochemical characteristics Solubility pH API quantitation

Physicochemical characteristics Solubility: Solubility of the API in 37◦C in water, other media (ie HCl) or buffers of different pH should meet “sink condition” (volume of medium at least three times that required in order to form a saturated solution of API). In the absence of sink conditions, investigate methods to enhance solubility, eg use of a surfactant. If a surfactant is used, its concentration should be properly justified (e.g. typically <2% Sodium Lauryl Sulfate (SLS)).

Physicochemical characteristics pH: water may be used as medium, however the effect of the formulation on the pH of water must be investigated and if it changes, the use of buffers or HCl should be considered. pH should have in-vivo relevance if possible; Stability and solubility of API should be considered, for example some ACT’s are unstable in acidic medium

Physicochemical characteristics API quantitation: UV is often used; for UV the applicant should have demonstrated: non-interference with formulation components (spectra of API in the formula and in standard solutions should be identical in shape/magnitude); linearity (absorbance vs concentration) up to the highest expected concentration. Note that these will be determined as part of routine validation. Chromatography is often necessary instead of UV when there is excipient interference, it is low dose or it is a FDC-FPP that requires more sensitivity and/or selectivity.

Performance Checks Performance checks include calibration of the system “with suitable calibrators” (PhInt). The USP calibrator tablets are considered acceptable for dissolution method calibration. System suitability testing (SST) is required to be included in methodology. For a dissolution method, limits should be established for: - Precision (≤ 2%) plus either: - Peak asymmetry/tailing factor (preferable) (≤ 2) or - Theoretical plates (≥ 2000) or - Resolution (>2)

Development Strategy Establish dissolution profiles in at least two media within the physiological pH range. One should be a compendial medium, if a monograph exists. Investigation of more than one medium, or a single buffer with different pH values or ionic strength, can aid in determining the optimum medium for use in quality control (eg to evaluate lot-to-lot changes).

Development Strategy If no compendial monograph exists, a suitable procedure should be developed based on the physicochemical properties of both the API and the FPP. Choosing a medium in which dissolution is relatively slower, for eg pH close to the pKa value of the drug, may be advantageous as it may be more discriminating. Once a satisfactory system is achieved, the factors in its development should be summarized so the assessor can follow the evolution and determine whether the system is appropriate.

Method Description The written procedure should include: Apparatus Standard and sample preparation Method of analysis (eg UV, HPLC) Sampling procedure (intervals, filtration*, handling of samples, dilutions) Calculations Acceptance Criteria

Method Description Filtration: It should be indicated how and when samples are filtered. An inert filter is required with a suitable pore size. The intent is to avoid a) adsorption of active from solution or b) interference due to substances extractable by the dissolution medium.

Sample Stability Stability of samples: Any problems with pH related stability of samples should be indicated and discussed in terms of preventative handling measures, analysis and interpretation of data. Note that some of the ACT molecules are unstable in acidic medium.

Appropriateness of Method Check: Whether BCS Class 1 or 3 Results (BE batch characteristics, COA’s, stability data) Has data been provided to demonstrate the method is discriminatory? Published methods

BCS Classification PhInt monographs for class 1 or 3 API’s have (or will have) a standard dissolution method: Paddle, 75 rpm 500 mL pH 6.8 phosphate buffer Criteria: NLT 80% l.c. in 30 minutes or DT NMT 10 min

Justification Based on Results ICHQ6 states that actual results obtained (batch analysis, stability studies) should form the primary basis of all justification. Do results indicate the method is discriminating? (Results of studies on different formulations (qualitative/quantitative excipient differences), API particle size distribution (PSD), process parameters or In-Process Controls (eg hardness, coating thickness)).

Justification Based on Results Example 1: FDC product with fairly rapid release of both API’s; > 80% dissolution is reached at 20 minutes (for both APIs in product) The next time point can be chosen, ie NLT 80% in 30 minutes. This would be considered an acceptable limit.

Justification Based on Results Example 2: for slow dissolution of immediate release tablets, it is recommended that two points be used. The following behaviour is observed for a product: Time (min): 10 20 30 45 60 90 120 % released: 15 33 49 68 83 98 102 Applicant proposed: ≥ 75 % (Q) in 120 minutes Limits requested: (1) Limit should be tightened to Q = 75% in 90 minutes. (2) A limit should also be established at 45 minutes and implemented immediately during stability studies.

Published Methods Compendial general chapters - PhInt: Methods of Analysis: 5.5 Dissolution test for solid oral dosage forms. - USP <711> Dissolution and <724> Drug Release - USP <1088> In-Vitro and In-Vivo Evaluation of Dosage Forms - USP <1092> The Dissolution Procedure: Development and Evaluation

Published Methods 2) FDA dissolution site http://www.accessdata.fda.gov/scripts/cder/dissolution/ - Gives reference to USP monograph if one exists - Gives approved method parameters where no monograph exists.

Published Methods For the 7 API’s in the ACT’s, the only hit on the FDA site is for mefloquine HCl tablets: Apparatus: Basket Speed: 100 rpm Medium: 900 mL SGF without enzyme Sampling: 10, 20, 30, 45, and 60 minutes

ICH Q6 Decision Tree 7/2.

Validation Validation: Testing a method to demonstrate it is suitable for its intended purpose and the results obtained are meaningful. Provides confidence that the method will perform properly under intended conditions.

Validation Compendial dissolution methods should be revalidated (verified) for: Specificity Accuracy Precision (repeatability).

Validation House dissolution methods (HPLC, UV) should be fully validated: Specificity Linearity Accuracy Repeatability Intermediate precision Robustness (performed but not provided)

Validation Specificity: Chromatograms: sample containing placebo excipients vs sample without these components. Linearity: range to be validated: ±20% of limits; eg if limits cover from 20% to 90% l.c. (controlled release), linearity should cover 0-110% of l.c. Coefficient of Determination (r2) ≥ 0.997 Accuracy: assay samples/placeboes spiked with API; analysis in triplicate. A bias of 2% or less is acceptable.

Validation Precision: System precision Repeatability (method precision) Intermediate precision (precision with variations, eg days, analysts, equipment) Reproducibility (inter-laboratory trial)

Validation Repeatability determination: 9 determinations covering the range, eg 3 concentrations in triplicate (n=3) OR 2 or 3 determinations on each of 3 days 6 determinations at 100% of the concentration

Validation Intermediate Precision: Variations: days, analysts, equipment (matrixing allowed) Precision Results: RSD ≤ 2.5%

Example Issues Example 1: Granules are formulated to be dispersed in water prior to administration. The API is very bitter and granules are coated to mask the taste. The dissolution studies provided should include a demonstration that the coating serves its purpose, ie it can withstand the dispersion process. (Failure would result in a product which cannot be taken due to bitterness.)

Example Issues Example 2 For some FDC’s, the comparator is in the form of more than one tablet. When running comparative dissolution, only one tablet should be placed in any one vessel. Therefore the evaluation may have to be performed one API at a time. If the study uses more than one tablet per vessel, solubility issues arise.

Questions?