Documentos de Académico
Documentos de Profesional
Documentos de Cultura
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
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
2|
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 invitro correlation study (IVIVC).
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
3|
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.
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
4|
5|
https://www.who.int/medicines/publications/pharmacopoeia/mo
6|
8|
PhInt Monographs
Monographs under development and future monographs: Monographs in progress: Amodiaquine tablets Sulfadoxine/Pyrimethamine tablets. Proposed for work: Mefloquine tablets
9|
11 |
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.
12 |
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
13 |
14 |
15 |
16 |
For highly soluble APIs, the rate is largely determined by the disintegration of the dosage form.
17 |
18 |
Disintegration vs Dissolution
ICH Q6: Disintegration may be substituted for dissolution when: -rapidly dissolving FPPs (dissolution >80% in 15 minutes at pH 1.2, 4.0 and 6.8) and FPPs containing APIs 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)).
19 |
20 |
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 APIs, for example chloroquine sulfate tablets and isoniazid tablets. the disintegration test is considered to be generally satisfactory for such products. Note that APIs in ACTs are generally low solubility, and dissolution testing is required.
21 |
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 shelflife specifications). Release limits = Shelf-life limits. Multipoint dissolution profiles of both the test and the reference FPPs should be compared.
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
22 |
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.
23 |
24 |
25 |
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;
26 |
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
27 |
Note that the batches tested must be the batches of test and comparator product used in the BE study. Artemisinin based combined medicines
28 |
February 23-27, 2009, Kampala, Uganda
29 |
6) Conclusion/recommendation
30 |
31 |
32 |
33 |
34 |
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)
35 |
Physicochemical characteristics
Solubility pH API quantitation
36 |
Physicochemical characteristics
Solubility: Solubility of the API in 37C 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)).
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
37 |
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 ACTs are unstable in acidic medium
38 |
Physicochemical characteristics
API quantitation: UV is often used; for UV the applicant should have demonstrated: a) non-interference with formulation components (spectra of API in the formula and in standard solutions should be identical in shape/magnitude); b) 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.
39 |
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
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)
40 |
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
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).
41 |
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.
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
42 |
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
43 |
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
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.
44 |
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.
45 |
Appropriateness of Method
Check: 1) Whether BCS Class 1 or 3 2) Results (BE batch characteristics, COAs, stability data) 3) Has data been provided to demonstrate the method is discriminatory? 4) Published methods
46 |
BCS Classification
PhInt monographs for class 1 or 3 APIs 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
47 |
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
48 |
49 |
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
51 |
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
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.
52 |
Published Methods
For the 7 APIs in the ACTs, the only hit on the FDA site is for mefloquine HCl tablets: Apparatus: Speed: Medium: Sampling: Basket 100 rpm 900 mL SGF without enzyme 10, 20, 30, 45, and 60 minutes
53 |
54 |
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.
55 |
Validation
Compendial dissolution methods should be revalidated (verified) for: Specificity Accuracy Precision (repeatability).
56 |
Validation
House dissolution methods (HPLC, UV) should be fully validated: Specificity Linearity Accuracy Repeatability Intermediate precision Robustness (performed but not provided)
57 |
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.
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
58 |
Validation
Precision: System precision Repeatability (method precision) Intermediate precision (precision with variations, eg days, analysts, equipment) Reproducibility (inter-laboratory trial)
59 |
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 OR 6 determinations at 100% of the concentration
60 |
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
Validation
Intermediate Precision: Variations: days, analysts, equipment (matrixing allowed) Precision Results: RSD 2.5%
61 |
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.)
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
62 |
Example Issues
Example 2 For some FDCs, 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.
63 |
Questions?
64 |