Pharmaceutical Research and Development ConsiderationsMultisource Tuberculosis Medicines
Kuala Lumpur – Malaysia
21-25 February 2005
Research Institute for Industrial Pharmacy
North-West University, Potchefstroom, South Africa
iiftgd@puk.ac.za
EOI Expression of interest
FDC Fixed dose combination
FPP Finished pharmaceutical product
Int.Ph. International Pharmacopoeia
TB Tuberculosis
Feb 2005
The perspective
Pharmaceutical R & D provides the foundation of the activities aimed at ensuring that the patient receives an FPP (product) that consistently meets established standards & specifications of
Safety
Efficacy
Quality
The FPP should be stable - and thus retain these standards – throughout the shelf-life,
if kept in the original packaging
when correctly distributed, stored & handled
*
Collect & analyse available information on e.g.: APIs, formulas, excipients, compatibility, stability, dosage form, strength, packaging & analysis
Compile a Product Profile Report
Development according to plan, including:
Preformulation studies
Accelerated stability
The FDCs anti-tuberculosis tablets – a problem mix
API-API interactions of particular importance
Solid state properties of APIs
Rifampicin as example
Formulation development & comparison of pivotal batches
Setting product dissolution specifications
To compile a comprehensive summary, with conclusions, of all available information that may be important for the development of the product
To have a standard (pro-forma) style for the report, facilitating compilation/application
Assign experts in preparation of relevant parts
To use this report as base for development pharmaceutics (though considered part thereof)
Example
PRODUCT UNDER CONSIDERATION
Reference product(s) information
WHO model list of essential drugs (current)
Rifampicin 150 mg, Isoniazid 75 mg, Pyrazin-amide 400 mg & Ethambutol 2HCl 275 mg
Prequalification EOI requirement (current)
*
Prequalified products according to current list
Wyeth Pakistan - tablet (blister)
Sandoz – tablet (blister)
List such products, where considered necessary
*
Products available for inspection/testing
Description/appearance of reference products
Product A: Red oblong film-coated tablets, etc.
Packaging / pack sizes
HDPE bottles (100s?), 3 x 10 blisters (alu/alu?)?
*
Storage requirements /shelf life
From SmPC or PIL
Published product specific excipients
From SmPCs (also available on internet)
Document known incompatibilities with APIs
*
Published formulas
Formulas are published for older products in standard works and journals (see next page)
Official product monographs
2 HPLC assay methods for all four APIs
Dissolution test for all four APIs
Related substances (degradants) not included
Safety & efficacy information
Typical books for formulation and excipients:
S. K. Niazi. Handbook of Pharmaceutical Manufacturing Formulations. CRC Press, Boca Raton (current edition):
Volume 1. Compressed Solid Products
Volume 2. Uncompressed Solid Products
Volume 3. Liquid Products
Volume 4. Semisolid Products
Volume 6. Sterile Products
*
API information
Nomenclature
INN, USAN, Systematic name , CAS, etc. from e.g. Merck Index for each API (standard)
General physical properties
Discuss/tabulate properties of each API in terms of the guidance for dossier requirements, with special attention to unique API properties, e.g.
Rifampicin (pseudo) polymorphism and dissolution
Hygroscopicity of ethambutol 2HCl
*
Compedial monograph(s)
Stability & degradation routes
Stress data and mild conditions from literature in:
- solution and solid state
API/API and API/excipient interactions
Conclusions and precautions with respect to intended product
*
Possible BCS classification
Biowaivers (in vitro dissolution instead of bioequivalence studies) for immediate release solid orals (tablets, capsules) are not in current prequalification guidelines.
Biowaivers used for demonstration of equivalence of lower vs higher strength in proportional similar formulations.
*
Recommendations
File hard copies of all sources in support of the Product Profile Report
The data in the Product Profile Report can be used inter alia:
To form the basis of development pharmaceutics & to identify further experimental investigations
To alert the development team of possible problems
To identify monograph & analytical shortcomings
*
Rifampicin 150 mg
Isoniazid 75 mg
Pyrazinamide 400 mg
*
Rifampicin
Reaction with Isoniazid
isonicotinyl hydrazone major decomposition product
Light sensitive
*
hydrolysis
Isoniazid
3-Formylrifamycin (from rifampicin)
Ethambutol hydrochloride (2HCl)
Creates slightly acidic conditions
*
Isonicotinyl hydrazone (3-(isonicotinylhydrazinomethyl) rifamycin)
This is major decomposition product in tablets containing rifampicin and isoniazid
Series of articles by dr. S. Singh et al. (NIPER), e.g.
S. Singh, T. T. Mariappan, N. Sharda, S. Kumar & A. K. Chakraborti. The reason for an increase in decomposition of rifampicin in the presence of isoniazid under acid conditions. Pharm. Pharmacol. Commun., 6, 405-410 (2000)
*
4FDC-TB tablets exposed to 40°C/75%RH for one week
Two products. “Bleeding” may start after more exposure (in-house)
Control on left Control on left
1.bin
2.bin
Prevent oxidation & hydrolysis
Protect product from moisture and oxygen
Non-permeable packaging
Avoid repackaging
Light protection
*
Polymorph I
Polymorph II
Amorphous form
Five commercial samples (A to E) in examples:
Sample A: Form II
Sample B: Form II
Sample E: Form II
*
Middle: Sample C (Form II + amorph – intensity drop)
Bottom: Amorphous form (no pattern)
*
Profiles of all samples are similar
Dissolves immediately in 0.1 M hydrochloric acid
*
Profiles A, B & E are similar (f2 ≥ 50)
Profiles C & D are similar (f2 ≥ 50) - dissolution incomplete
Profiles A, B, E dissimilar from profiles C,D (f2 < 50)
A, B, E
Profiles C & D are similar (f2 ≥ 50) - dissolution incomplete
Profiles A, B, E dissimilar from profiles C,D (f2 < 50)
A, B, E
Dissolution rate is not different in 0.1 M HCl
Presence of amorphous form slows down dissolution at higher pH (f2 test)
Incomplete dissolution after 65 minutes !!
May fail USP tolerance at pH 6.8 (75% in 45 min.) ??
Agglomeration / wettability?
Reference:
*
Polymorphism – important situations
When it has a significant effect on the rate of dissolution of the API in water and biological fluid, that may affect the absorption of the API
Of special importance for practically insoluble APIs
When it can affect the manufacturing process, e.g. in the case of flow properties
*
BCS classification (1)
High solubility: Highest dose strength of API should be soluble in ≤ 250 ml water at 37ºC over the pH range 1.0-7.5.
High permeability: Absolute bioavailability ≥ 90 % (presently) - apart from specific permeability studies
Limiting factors for biowaivers (see FDA & EMEA)
Class
Solubility
Permeability
1
High
High
2
Low
High
3
High
Low
4
Low
Low
Data from:
M Lindenberg, S. Kopp, J. B. Dressman. Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. Eur. J. Pharm. Biopharm., 58, 265-278 (2004)
None of other TBs (mainly for injection, thus not classified) in 5th inv. for EOI in publication – a number of ARVs are
API (INN)
Three media - 900 ml or less - all at 37°C
1. Buffer pH 1.2, SGF without enzymes or 0.1M HCl
2. Buffer pH 4.5
Twelve units of each product in all 3 media
Dissolution samples collected at short intervals, e.g.
10, 15, 20, 30, 45 and 60 minutes
Analyse samples for all APIs
*
Biowaiver dissolution studies (2)
Evaluation of dissolution data
The profiles of the test and reference products must be similar in all three media for considering a biowaiver (for not doing BE)
The profiles of the two products in a particular medium is considered similar:
If the similarity factor f2 ≥ 50 (see FDA/EMEA for calc)
Not all values can be considered for calculation of f2 (see EMEA guideline) – only one point beyond 85% dissolution, for both APIs (point zero also excluded)
If both products show ≥ 85% dissolution in 15 minutes
*
Formulation selection. Comparison of different lab / development batches with innovator product.
Important for comparison of pivotal batches to demonstrate in vitro similarity
Aids in selecting FPP dissolution conditions/specification
Bioequivalence support
Biowaiver studies not in current prequalification guidelines.
Post-approval changes
Four manufacturers (A, B, C & D)
Dissolution conditions:
Pull times: 10, 15, 20, 30, 45 & 60 minutes
*
Chart3
0
0
10
10
15
15
20
20
30
30
45
45
60
60
Dissolution (%)
DISSOLUTION Wyeth: Myambutol-INH Forte tablets Batch P3 Ethambutol 2HCl (400 mg) & Isoniazid (150 mg) Medium: Phosphate buffer pH 6.8
0
0
34.01
29.46
41.38
37.62
50.08
47.44
64.15
63.3
78.56
79.68
91
95.29
Cadila
0
0
60.59
56.73
79.71
78.02
90.27
90.55
98.42
100.17
98.54
101.54
99.42
101.82
Schazoo
Dissolution (%)
DISSOLUTION Schazoo: Schazobutol-H tablets Batch SHT 18 Ethambutol HCl (400 mg) & Isoniazid (150 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Lupin
DISSOLUTION Lupin: Ethambutol HCl & Isoniazid tablets Batch X4320 Ethambutol HCl (800 mg) & Isoniazid (300 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
34.01
60.59
60.58
93.61
41.38
79.71
77.14
99.32
50.08
90.27
86.71
99.46
64.15
98.42
96.95
99.36
78.56
98.54
101.55
99.34
91
99.42
103.07
99.77
Isoniazid
Wyeth
Cadila
Schazoo
Lupin
0
0
0
0
0
10
29
57
55
87
15
38
78
72
96
20
47
91
84
99
30
63
100
97
100
45
80
102
104
101
60
95
102
105
102
Isoniazid
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
DISSOLUTION 2FDC TABLETS API: Isoniazid Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Chart1
0
0
10
10
15
15
20
20
30
30
45
45
60
60
Dissolution (%)
DISSOLUTION Wyeth: Myambutol-INH Forte tablets Batch P3 Ethambutol 2HCl (400 mg) & Isoniazid (150 mg) Medium: Phosphate buffer pH 6.8
0
0
34.01
29.46
41.38
37.62
50.08
47.44
64.15
63.3
78.56
79.68
91
95.29
Cadila
0
0
60.59
56.73
79.71
78.02
90.27
90.55
98.42
100.17
98.54
101.54
99.42
101.82
Schazoo
Dissolution (%)
DISSOLUTION Schazoo: Schazobutol-H tablets Batch SHT 18 Ethambutol HCl (400 mg) & Isoniazid (150 mg) Medium: Phosphate buffer pH 6.8
0
0
60.58
54.5
77.14
72.07
86.71
84.18
96.95
96.64
101.55
103.58
103.07
104.82
Lupin
DISSOLUTION Lupin: Ethambutol HCl & Isoniazid tablets Batch X4320 Ethambutol HCl (800 mg) & Isoniazid (300 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
34.01
60.59
60.58
93.61
41.38
79.71
77.14
99.32
50.08
90.27
86.71
99.46
64.15
98.42
96.95
99.36
78.56
98.54
101.55
99.34
91
99.42
103.07
99.77
Isoniazid
Wyeth
Cadila
Schazoo
Lupin
0
0
0
0
0
10
29
57
55
87
15
38
78
72
96
20
47
91
84
99
30
63
100
97
100
45
80
102
104
101
60
95
102
105
102
Isoniazid
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
DISSOLUTION 2FDC TABLETS API: Isoniazid Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Chart4
0
0
10
10
15
15
20
20
30
30
45
45
60
60
Dissolution (%)
DISSOLUTION Wyeth: Myambutol-INH Forte tablets Batch P3 Ethambutol 2HCl (400 mg) & Isoniazid (150 mg) Medium: Phosphate buffer pH 6.8
0
0
34.01
29.46
41.38
37.62
50.08
47.44
64.15
63.3
78.56
79.68
91
95.29
Cadila
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Schazoo
Dissolution (%)
DISSOLUTION Schazoo: Schazobutol-H tablets Batch SHT 18 Ethambutol HCl (400 mg) & Isoniazid (150 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Lupin
DISSOLUTION Lupin: Ethambutol HCl & Isoniazid tablets Batch X4320 Ethambutol HCl (800 mg) & Isoniazid (300 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
34.01
60.59
60.58
93.61
41.38
79.71
77.14
99.32
50.08
90.27
86.71
99.46
64.15
98.42
96.95
99.36
78.56
98.54
101.55
99.34
91
99.42
103.07
99.77
Isoniazid
Wyeth
Cadila
Schazoo
Lupin
0
0
0
0
0
10
29
57
55
87
15
38
78
72
96
20
47
91
84
99
30
63
100
97
100
45
80
102
104
101
60
95
102
105
102
Isoniazid
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
DISSOLUTION 2FDC TABLETS API: Isoniazid Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Chart5
0
0
10
10
15
15
20
20
30
30
45
45
60
60
Dissolution (%)
DISSOLUTION Wyeth: Myambutol-INH Forte tablets Batch P3 Ethambutol 2HCl (400 mg) & Isoniazid (150 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Cadila
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Schazoo
Dissolution (%)
DISSOLUTION Schazoo: Schazobutol-H tablets Batch SHT 18 Ethambutol HCl (400 mg) & Isoniazid (150 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Lupin
DISSOLUTION Lupin: Ethambutol HCl & Isoniazid tablets Batch X4320 Ethambutol HCl (800 mg) & Isoniazid (300 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
34.01
60.59
60.58
93.61
41.38
79.71
77.14
99.32
50.08
90.27
86.71
99.46
64.15
98.42
96.95
99.36
78.56
98.54
101.55
99.34
91
99.42
103.07
99.77
Isoniazid
Wyeth
Cadila
Schazoo
Lupin
0
0
0
0
0
10
29
57
55
87
15
38
78
72
96
20
47
91
84
99
30
63
100
97
100
45
80
102
104
101
60
95
102
105
102
Isoniazid
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
DISSOLUTION 2FDC TABLETS API: Isoniazid Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
A
B,C
D
Chart6
0
0
0
0
10
10
10
10
15
15
15
15
20
20
20
20
30
30
30
30
45
45
45
45
60
60
60
60
0
0
0
0
29.46
56.73
54.5
86.65
37.62
78.02
72.07
96.13
47.44
90.55
84.18
98.82
63.3
100.17
96.64
100.06
79.68
101.54
103.58
100.73
95.29
101.82
104.82
101.56
Wyeth
Dissolution (%)
DISSOLUTION Wyeth: Myambutol-INH Forte tablets Batch P3 Ethambutol 2HCl (400 mg) & Isoniazid (150 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Cadila
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Schazoo
Dissolution (%)
DISSOLUTION Schazoo: Schazobutol-H tablets Batch SHT 18 Ethambutol HCl (400 mg) & Isoniazid (150 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Lupin
DISSOLUTION Lupin: Ethambutol HCl & Isoniazid tablets Batch X4320 Ethambutol HCl (800 mg) & Isoniazid (300 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
34.01
60.59
60.58
93.61
41.38
79.71
77.14
99.32
50.08
90.27
86.71
99.46
64.15
98.42
96.95
99.36
78.56
98.54
101.55
99.34
91
99.42
103.07
99.77
Isoniazid
Wyeth
Cadila
Schazoo
Lupin
0
0
0
0
0
10
29
57
55
87
15
38
78
72
96
20
47
91
84
99
30
63
100
97
100
45
80
102
104
101
60
95
102
105
102
Isoniazid
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
DISSOLUTION 2FDC TABLETS API: Isoniazid Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Chart7
0
0
0
0
10
10
10
10
15
15
15
15
20
20
20
20
30
30
30
30
45
45
45
45
60
60
60
60
0
0
0
0
34.01
60.59
60.58
93.61
41.38
79.71
77.14
99.32
50.08
90.27
86.71
99.46
64.15
98.42
96.95
99.36
78.56
98.54
101.55
99.34
91
99.42
103.07
99.77
Wyeth
Dissolution (%)
DISSOLUTION Wyeth: Myambutol-INH Forte tablets Batch P3 Ethambutol 2HCl (400 mg) & Isoniazid (150 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Cadila
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Schazoo
Dissolution (%)
DISSOLUTION Schazoo: Schazobutol-H tablets Batch SHT 18 Ethambutol HCl (400 mg) & Isoniazid (150 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Lupin
DISSOLUTION Lupin: Ethambutol HCl & Isoniazid tablets Batch X4320 Ethambutol HCl (800 mg) & Isoniazid (300 mg) Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Isoniazid
Wyeth
Cadila
Schazoo
Lupin
0
0
0
0
0
10
29
57
55
87
15
38
78
72
96
20
47
91
84
99
30
63
100
97
100
45
80
102
104
101
60
95
102
105
102
Isoniazid
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
DISSOLUTION 2FDC TABLETS API: Isoniazid Medium: Phosphate buffer pH 6.8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Evaluation of dissolution data
The dissolution profiles of the APIs in a particular product are similar (this holds for all 4 products)
Both APIs are highly soluble (BCS definition)
The products show different dissolution rates
Dissolution rate A > B ≈ C >> D
Disintegration (min) 7 11 11 21
Dissolution rate related to disintegration time
f2 values show that B & C have similar profiles
Dissolution method discriminating
*
Feb 2005
Some conclusions
Get to know you product through systematic desk research, e.g. Product Profile Report
Physical properties of APIs may be important for low soluble APIs, e.g. polymorphism & particle size
Powder dissolution testing may be useful for sourcing
Consider important API properties and API-API interactions, especially in FDCs in formulation
Packaging to be non-permeable and light protective
Biowaiver type dissolutions are important in:
Choice of formulation vs comparator
Comparison of pivotal batches
Setting product dissolution specifications