Dissolution Sink Conditions TA 1035 David Darling
Dissolution Sink Conditions TA 1035 David Darling
Dissolution Sink Conditions TA 1035 David Darling
Regulatory Expectations
of Presentation of
Dissolution Data
David Darling
Pharmaceutical Assessor
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Content
Slide 2
September 2012
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Why Use Dissolution Testing?
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Dissolution Method Development & Validation
Slide 4
September 2012
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Dissolution Method Development & Validation
(continued)
• Choice of Apparatus
- Depends on physicochemical characteristics of dosage form
- Apparatus 1: basket – capsules, tablets
- Apparatus 2: paddle - tablets, capsules
- Apparatus 3: reciprocating cylinder - bead-type MR dosage forms, soft capsules,
suppositories, poorly-soluble drugs
- Apparatus 4: flow-through cell – if change of pH needed; also as Apparatus 3
Slide 5
September 2012
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Dissolution Method Development & Validation
(continued)
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Dissolution Method Development & Validation
(continued)
• Demonstrating Discrimination
- Above work may already demonstrate this
- Formulation and/or manufacturing process development work
– Tablet hardness trials
– Varying quantity of lubricant and/or lubricant mixing time
Dissolution conditions:
PhEur apparatus 1 (basket),
100 rpm, 1000 ml 0.1 M HCl
Slide 7
September 2012
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Dissolution Method Development & Validation
(continued)
• Potential Pitfalls
- For generics, US FDA Dissolution Database helpful, but…
– Check if applicable to formulation and justify suitability
– Example 1: Escitalopram oxalate tablets
· FDA database: Paddle, 75 rpm, 0.1 N HCl, 900ml
· Applicant’s data: > 90% dissolution after 5 minutes
· No discussion of why 50 rpm not investigated
· Escitalopram Tablets USP monograph method: 50 rpm
– Example 2: Lamivudine tablets
· FDA database: 100 & 150 mg – Paddle, 50 rpm, H2O (deaerated), 900 ml
· FDA database: 300 mg – Paddle, 75 rpm, 0.1 N HCl, 900 ml
Slide 8
September 2012
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Dissolution Method Development & Validation
(continued)
Slide 9
September 2012
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Dissolution Data for Marketing Authorisation
Applications (MAAs)
• Generics
- Comparison to reference medicinal product
- Biowaivers for multiple strengths
- BCS biowaivers [covered by next presentation]
Slide 10
September 2012
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Dissolution Data for Generic MAAs -
Comparison to reference medicinal product
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Dissolution Data for Generic MAAs -
Comparison to reference medicinal product
(continued)
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Similarity Factor (f2)
Defined as:
f2 = 50.log{[1+(1/n)∑t=1n(Rt-Tt)2]-0.5.100}
n is the number of time points
Rt is the mean % drug dissolved for the current formulation
Tt is the mean % drug dissolved for the changed formulation
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Similarity Factor (f2) – Prolonged Release
Preparations
Slide 14
September 2012
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Dissolution Data for Generic MAAs –
Comparison to reference medicinal product:
Gastro-resistant preparations
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Dissolution Data for Generic MAAs -
Biowaivers for multiple strengths: Prerequisites
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Dissolution Data for Generic MAAs -
Biowaivers for multiple strengths: Investigations
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Dissolution Data for Generic MAAs -
BCS biowaivers
Slide 18
September 2012
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Dissolution Data for Generic MAAs –
Post authorisation requirements (if not in submission)
- Comparative dissolution profile testing on first three
production batches
– batch cannot be marketed until comparative dissolution profile
testing completed.
- Results to be provided at Competent Authority’s request,
or if dissolution profiles not similar, together with
proposed action to be taken
100
% Drug Released
80
60
40
20
0
5 10 15 30 45
Time (minutes)
Slide 19
September 2012
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Dissolution Data for MAAs
– Potential Pitfalls
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Dissolution Data for MAAs
– Potential Pitfalls (continued)
Slide 21
September 2012
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Dissolution Data for MAAs
– Potential Pitfalls (continued)
Slide 22
September 2012
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Dissolution Data to Support Post-Approval
Changes / Variation Applications
• What type of changes?
- Any change which could impact dissolution!
- Good starting point: EU Commission classification guidance on
variations
· Which changes need comparative dissolution profiles
· Number and size (pilot or production scale) of batches required
· Type IA and IB changes (not Type II)
• Examples of changes
- Formulation
· Quantitative changes including coating weight
· Qualitative: Change of functional excipient (i.e. other than flavour or colour)
· Shape or dimensions of dosage form changed
- Manufacturing process
- Active or excipient specifications (e.g. particle size parameters)
- In-process controls or product specifications (e.g. tablet hardness)
- Source of active substance (case-by-case basis)
Slide 23
September 2012
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Dissolution Data for Post-Approval Changes
– Potential Pitfalls
• Example: Orodispersible tablet
- Bitter tasting active
- Formulation not acceptable to patients
- Solution:
– Reformulate to minimise drug release in the mouth
– Claim (supported by data): Rapidly dissolves at gastric pH (1.2) releasing drug, but
does not dissolve at higher pHs, such as that of saliva (pH 6.8), preventing release
of the bitter drug in mouth
120
% Drug Released
100
80 Old Formulation
60
40 New Formulation
20
0
5 10 15 30 60
Time (minutes)
Slide 24
September 2012
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Dissolution Data for Post-Approval Changes
– Potential Pitfalls (continued)
120
% Drug Released
100
80 Old Formulation
60
40 New Formulation
20
0
5 10 15 30 60
Time (minutes)
120
% Drug Released
100
80 Old Formulation
60
40 New Formulation
20
0
5 10 15 30 60
Time (minutes)
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Dissolution Data for Post-Approval Changes
– Potential Pitfalls (continued)
• Taste masked, but now absorption issue?
• Dosing instructions – with or without food
– Based on old formulation
– Inadequate bioequivalence and bioavailability data to support non-
applicability of dissolution findings in vivo
• Product status: not yet marketed in EU
• Solution: revise dosing instructions – take without food
Slide 26
September 2012
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Setting Release and Shelf Life Specification
Limits for Dissolution
PhEur limits for oral dosage forms
• Conventional-release
– usually 1 time point
– ≤ 45 min, ≥ 80% (Q ≥ 75%)
• Prolonged-release dosage forms
– ≥ 3 time points:
• 20 - 30% (to exclude ‘dose dumping’)
• 50% (defines dissolution pattern)
• > 80% (ensures almost complete release)
- Guideline allows ± 10% limits at each time point
Slide 27
September 2012
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Setting Release and Shelf Life Specification
Limits for Dissolution (continued)
PhEur limits for oral dosage forms (continued)
Slide 28
September 2012
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Setting Release and Shelf Life Specification
Limits for Dissolution (continued)
Slide 29
September 2012
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Thank you
for your attention
Slide 30
September 2012