3-1_Dissolution WHO - Copy.ppt

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.

Artemisinin based combined medicines
February 23-27, 2009, Kampala, Uganda
2 |
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

3 |
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).

4 |
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.”

5 |
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?

6 |
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

7 |
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

8 |
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).

9 |
PhInt Monographs
Monographs under development and future monographs:
Monographs in progress:
Amodiaquine tablets
Sulfadoxine/Pyrimethamine tablets.
Proposed for work:
Mefloquine tablets

10 |
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”

11 |
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.

12 |
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)

13 |
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.

14 |
USP Apparatus 1: Basket

15 |
PhInt Basket Apparatus

16 |
PhInt Paddle Apparatus

17 |
Disintegration (DT) Testing
 For immediate release tablets and capsules, dissolution
rate is determined by:
1) Rate of release of the API from the matrix, and
2) 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.

18 |
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”.

19 |
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)).

20 |
ICH Q6 Decision Tree 7/1

21 |
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.

22 |
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.

23 |
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.

24 |
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.

25 |
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.

26 |
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;

27 |
 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.

28 |
 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.

29 |
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.

30 |
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

31 |
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).

32 |
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.

33 |
Factors to consider:
 Qualitative and quantitative excipient changes
 Manufacturing parameters:
– Lubrication
– Blend time
– Compression force
– Drying parameters

34 |
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.

35 |
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)

36 |
Physicochemical characteristics
 Solubility
 pH
 API quantitation

37 |
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)).

38 |
 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

39 |
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.

40 |
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)

41 |
 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).

42 |
 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.

43 |
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

44 |
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.

45 |
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.

46 |
Appropriateness of Method
Check:
1) Whether BCS Class 1 or 3
2) Results (BE batch characteristics, COA’s, stability data)
3) Has data been provided to demonstrate the method is
discriminatory?
4) Published methods

47 |
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

48 |
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)).

49 |
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.

50 |
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.

51 |
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

52 |
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.

53 |
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

54 |
ICH Q6 Decision Tree 7/2.

55 |
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.

56 |
Validation
Compendial dissolution methods should be revalidated
(verified) for:
– Specificity
– Accuracy
– Precision (repeatability).

57 |
Validation
House dissolution methods (HPLC, UV) should be fully validated:
Specificity
Linearity
Accuracy
Repeatability
Intermediate precision
Robustness (performed but not provided)

58 |
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.

59 |
Validation
Precision:
 System precision
 Repeatability (method precision)
 Intermediate precision (precision with variations, eg days,
analysts, equipment)
 Reproducibility (inter-laboratory trial)

60 |
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

61 |
Validation
Intermediate Precision:
Variations: days, analysts, equipment (matrixing allowed)
Precision Results: RSD ≤ 2.5%

62 |
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.)

63 |
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.

64 |
Questions?

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