Evaluation of Quality and Interchangeability of Medicinal Products
Evaluation of quality and interchangeability of medicinal products Training workshop for evaluators...
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Transcript of Evaluation of quality and interchangeability of medicinal products Training workshop for evaluators...
Evaluation of quality and interchangeability of medicinal productsTraining workshop for evaluators from National Medicines
Regulatory Authorities in East Africa Community
10-14 September 2007, Dar Es Salaam, Tanzania
Presented by
Rutendo Kuwana
Dissolution Testing
Dissolution Testing2 |
Dissolution testing: conventional tablets and capsules
Dissolution testing: conventional tablets and capsules
It measures the portion (%) of the API that (1) has been released from tablets/capsules and (2) has dissolved in the dissolution medium during controlled testing conditions within a defined period– The tablet thus first disintegrates– Then the API will be able to dissolve– Slow disintegration ➜ slow dissolution– The % API dissolved is determined with an appropriate
validated method: UV/VIS, HPLC, AA, GC, etc
Dissolution testing is also applicable to suspensions and suppositories
Dissolution Testing3 |
Solid oral dosage formsSolid oral dosage forms
Immediate release typically means that 75% of the API is dissolved within 45 minutes
– Rapidly dissolving: ≥ 85% in ≤ 30 minutes– Very rapidly dissolving: ≥ 85% in ≤ 15 minutes
Dissolution Testing4 |
Challenges in Dissolution TestingChallenges in Dissolution Testing
Dissolution testing in immediate-release (IR) solid dosage forms poses many challenges
developing and validating the test method
ensuring that the method is discriminatory
addressing the potential for an in vivo–in vitro relationship (IVIVR) or correlation (IVIVC).
Dissolution Testing5 |
Why in-vitro dissolution testing? Why in-vitro dissolution testing?
Dissolution Testing6 |
ApplicationsApplications
1. For selection of the formulation in the development phase– By comparison of the dissolution profiles of innovator
product with those of formulations– Hint: start with comparator product to see:
• Immediate release?• Rapidly dissolving?• Very rapidly dissolving?• Disintegration testing can aid in the early phases
– This should be a basic strategy in R&D to maximize the chances of bioequivalence
Dissolution Testing7 |
Applications (cont.)Applications (cont.)
2. It is a requirement for comparative dissolution data for the bio-batch and innovator batch– Same batches as used in bioequivalence study
– Submit report with data, profile comparison & discussion (see report requirements)
– This report forms part of pharmaceutical development report• Inclusion of the same report in the bioequivalence study report is
recommended
Dissolution Testing8 |
Applications (cont.)Applications (cont.)
3. Demonstration of in vivo bioequivalence of one or more of the lower strength(s) of an FPP may be waived based on1. an acceptable in vivo BE study of the highest strength
against the comparator product
2. demonstration of similarity of dissolution profiles,
3. if the lower strength is proportionally similar in formula to the higher strength (bio-batch) and
4. if all pharmacokinetic requirements are met
Dissolution Testing9 |
Applications (cont.)Applications (cont.)
4. Comparison of the release properties of pivotal batches– To demonstrate in vitro similarity of such batches
• This is considered essential for retention of efficacy and safety• Note that bioequivalence studies are done normally only once on a
bio-batch during development• It must be demonstrated that the product retains the dissolution
characteristics up to production scale– The studies should be submitted in dossier as part of the
FPP development report
Dissolution Testing10 |
Applications (cont.)Applications (cont.)
5. Selection of the dissolution specifications for product release & stability purposes Conditions and acceptance criteria to be set The dissolution profiles of the bio-batch should be used for
this purpose A dissolution specification should be able to detect
inadequate release properties of the commercial batches• A “generous” dissolution limit has no quality selectivity
Dissolution Testing11 |
Applications (cont.)Applications (cont.)
6. Post-approval amendment application– Assessment of formulation changes to demonstrate that the
profiles of the amendment batch and the current batch are similar
Dissolution Testing12 |
Variables affecting dissolution Variables affecting dissolution
characteristics of the API e.g., particle size, crystal form, bulk density
product composition e.g., drug loading, and the identity, type, and levels of excipients
manufacturing process e.g., compression forces, equipment
effects of stability storage conditions e.g., temperature, humidity
Dissolution Testing13 |
Mechanism of dissolution Mechanism of dissolution
Dissolution test determines the cumulative amount of drug that goes into solution as a function of time
Steps involved
liberation of the solute or drug from the formulation matrix (disintegration)
dissolution of the drug (solubilization of the drug particles) in the liquid medium
The overall rate of dissolution depends on the slower of these two steps
Dissolution Testing14 |
Mechanism of dissolutionMechanism of dissolution
First Step
Cohesive properties of the formulated solid dosage form drug play a key role disintegration and erosion
semi- solid or liquid formulations, the dispersion of lipids or partitioning of the drug from the lipid phase is the key factor
If the first step of dissolution is rate-limiting, then the rate of dissolution is considered to be disintegration controlled
Dissolution Testing15 |
Mechanism of dissolutionMechanism of dissolution
Second Step
Solubilization of the drug particles depends on the physicochemical properties of the drug such as its chemical form (e.g., salt, free acid, free base) and physical attributes
Dissolution Testing16 |
Dosage form type and design affect dissolution testing (1)Dosage form type and design affect dissolution testing (1)
For intrinsic dissolution-limited absorption (i.e., the disintegration of the dosage form is rapid, but dissolution is slow) reduce the particle size of the API
Small particle size creates challenges as they can pass through filters and subsequently dissolve
Dissolution Testing17 |
Dosage form type and design affect dissolution testing (2)Dosage form type and design affect dissolution testing (2)
For solubility-limited absorption (intrinsic- solubility controlled) enhance the transient solubility of the API
different salt forms of the API
surfactants in the formulation
solubilized liquid formulations in hard or soft gelatin capsules
non-crystalline materials
Dissolution Testing18 |
Media selectionMedia selection
For batch-to-batch quality testing medium selection may be based on the solubility data and the dose range of the drug product to ensure that sink conditions are met
The term sink conditions is defined as the volume of medium at least greater than three times that required to form a saturated solution of a drug substance.
Dissolution Testing19 |
Media selection (2)Media selection (2)
When the dissolution test is used to indicate the biopharmaceutical properties - closely simulate the environment in the GIT than sink conditions
First evaluate using test media within the physiologic pH range of 1.2–6.8 (1.2–7.5 for modified-release formulations)
Dissolution Testing20 |
Apparatus selectionApparatus selection
Described in the United States Pharmacopoeia (USP) under the General Chapters of Dissolution and Drug Release
Dissolution Testing21 |
Discriminatory power Discriminatory power
The discriminatory power of the dissolution method is the method’s ability to detect changes in the drug product.
Once a discriminating method is developed, the same method should be used to release product batches for future clinical trials, if possible.
Dissolution Testing22 |
Alternative methods to dissolution testing Alternative methods to dissolution testing
In ICH Q6A permits use of disintegration testing as a surrogate for conventional Compendial dissolution tests, provided
highly soluble drug substances
intrinsic rate of solubilization is rapid
overall drug release rate is dominated by cohesive properties of the formulation
Dissolution Testing23 |
Alternative methods to dissolution testing (2)Alternative methods to dissolution testing (2)
APIs with good solubility at gastric pH levels may be granted BCS Class I and III classification i.e. may be characterized by disintegration testing alone
In liquid filled capsule drug dissolved in solubilization aids offering a true mechanism for drug release is likely to be the rupture of the capsule use disintegration as a surrogate for the QC dissolution test
Dissolution Testing24 |
Multi-point dissolution?Multi-point dissolution?
In multipoint dissolution– multiple (≥ 3) samples are withdrawn from the dissolution
medium during dissolution testing– at pre-determined time points and– each sample is analysed for the % API dissolved– A graph of % API dissolved against time:
• The dissolution profile
Dissolution Testing25 |
Multi-point dissolutionExample of dissolution profile
Multi-point dissolutionExample of dissolution profile
0
20
40
60
80
100
120
0 10 20 30 40 50
WITHDRAWAL TIME IN MINUTES
Dis
solu
tio
n (
%)
Clarithromycin 250 mg tablets
Dissolution Testing26 |
Comparative dissolution testingThe principle
Comparative dissolution testingThe principle
Two or more products or batches containing the same API are compared
The strength of products / batches may or may not be the same (depending on purpose of test)
The dissolution conditions are similar, e.g.• Apparatus, medium, volume, rotation speed & temp.• Minimize possible experimental differences in conditions
Samples are taken at the same time points and the data (dissolution profiles) compared
Calculations: correct for volume change of dissolution medium
Dissolution Testing27 |
Comparative dissolution testingProfile similarity determination
Comparative dissolution testingProfile similarity determination
Two conditions to determine if the dissolution profiles of two products/batches in a particular dissolution medium are similar: 1. If both the test and reference product show more than 85%
dissolution within 15 minutes, the profiles are considered to be similar• No calculations are required
If this is not the case, apply point 2
2. Calculate the f2 value (similarity factor):
• If f2 ≥ 50, the profiles are normally regarded similar
Dissolution Testing28 |
Comparative dissolution testingSimilarity factor f2
Comparative dissolution testingSimilarity factor f2
n = number of time points
R(t) = mean % API dissolved of reference product at time point x
T(t) = mean % API dissolved of test product at time point x
Minimum of 3 time points (zero excluded)
12 units (each in own dissolution vessel) for each product (for “official” purposes)
Only one measurement should be considered after both products have reached 85 % dissolution
RSD at higher time points ≤ 10%
Dissolution Testing29 |
Comparative dissolution testingDissolution conditions (study design)
Comparative dissolution testingDissolution conditions (study design)
Apparatus
(choice)
• Paddle, 50 (75) rpm or
• Basket, 100 rpm
Dissolution media
All three media for full comparison
1. Buffer pH 6.8 or simulated intestinal fluid without enzymes
2. Buffer pH 4.5
3. 0.1 M HCl or buffer pH 1.2 or simulated gastric fluid without enzymes
Volume of media 900 ml or less
Temperature 37°C ± 0.5°C
Sampling points 10, 15, 20, 30, 45, (60, 120) min. (typical)
Units (individual) 12 for “official” studies
Dissolution Testing30 |
Typical time pointsImmediate release tablets (capsules)
Typical time pointsImmediate release tablets (capsules)
Rationale:
1. Condition 1– ≥ 85% dissolution of both products within 15
minutes
– 15 minute time point thus essential
2. Condition 2, for calculation of f2– a minimum of 3 points are required
– Only one measurement should be considered after 85 % dissolution (both tablets)
– 20 minute time point thus first possible one (if 15 minute fails 1st condition)
Point Time
1 10
2 15
3 20
4 30
5 45
Dissolution Testing31 |
Comparative dissolution testingComparison of products
Comparative dissolution testingComparison of products
Dissolution properties of two products (batches) regarded as similar when
– The profiles are similar– in all three media
• Statements of instability or insolubility are not acceptable, but should be demonstrated / justified
Dissolution Testing32 |
Example Determination of similarity of profiles
Example Determination of similarity of profiles
Example 1-B
% API dissolved
Time(min)
Tablet D (Ref)
Tablet E (Test)
10 55 57
15 72 78
20 85 91
30 97 100
45 102 100
60 103 101
f2 required? Yes
f2 (n = 3 ?) 64 (similar)
Example 1-A
% API dissolved
Time(min)
Tablet A (Ref)
Tablet B (Test)
10 87 94
15 96 99
20 99 99
30 100 99
45 101 99
60 101 99
f2 required? No, ≥ 85% in 15 min
f2 (n = N/A ?) profiles similar
Dissolution Testing33 |
ExampleDetermination of similarity of profiles (cont.)
ExampleDetermination of similarity of profiles (cont.)
Example 1-D
% API dissolved
Time(min)
Tablet A(Ref)
Tablet Y (Test)
10 87 55
15 96 72
20 99 85
30 100 97
45 101 102
60 101 103
f2 required? Yes
f2 (n = 3 ?) 31 (not similar)
Example 1-C
% API dissolved
Time(min)
Tablet X(Ref)
Tablet Y(Test)
10 29 34
15 38 41
20 47 50
30 63 64
45 80 79
60 95 91
f2 required? Yes
f2 (n = 6 ?) 74 (similar)
Dissolution Testing34 |
Reporting Comparative dissolution data
Reporting Comparative dissolution data
Full report, including Purpose of study Products / batches information
Batch number, manufacturing/expiry date, packaging, etc. CoA & size for “own” batches (and BMR for bio-studies report)
Dissolution conditions and method Analytical method or reference to part of dossier Results (% API dissolved)
Tabulated Graphically Similarity determination / calculation
Conclusion
Dissolution Testing35 |
GuidelinesGuidelines
WHO Prequalification
1. Supplement 1 [for use from July 2005 (CPH25)] to:
Guideline on Submission of Documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of
HIV/AIDS, Malaria and Tuberculosis
Dissolution testing
Others
Guidance for Industry. Waiver of In-Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), August 2000.
CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence. The European Agency for the Evaluation of Medicinal Products CPMP/EWP/QWP/1401/98, July 2001
SADC Guidelines (Draft)
Dissolution Testing36 |
Some conclusionsSome conclusions
Comparative dissolution– should form an essential part of R&D of solid oral dosage forms
(including suspensions),– supports bio-studies,– is required for comparison of pharmaceutical release properties of
pivotal batches,– is used to set dissolution specifications, and– assists in post-approval changes
It is thus important– to conduct the studies under controlled conditions in the 3 media,
all as required by the guidelines,– to take samples for analysis at meaningful intervals and– to be able to determine similarity of profiles