Workshop on GMP and Quality Assurance of
Multisource Tuberculosis Medicines
Kuala Lumpur – Malaysia
21-25 February 2005
Pharmaceutical
Research and Development
Considerations
Theo Dekker, D.Sc., consultant to WHO
Research Institute for Industrial Pharmacy
North-West University, Potchefstroom, South Africa
iiftgd@puk.ac.za
Feb 2005
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TG Dekker – WHO, Malaysia
Abbreviations
API
BCS
BP
CEP
EOI
FDC
FPP
ICH
Int.Ph.
R&D
TB
XRPD
USP
Feb 2005
Active pharmaceutical ingredient
Biopharmaceutics classification system
British Pharmacopoeia
EU certificate of suitability
Expression of interest
Fixed dose combination
Finished pharmaceutical product
International Conference on Harmonization
International Pharmacopoeia
Research and development
Tuberculosis
X-ray powder diffractogram
United States Pharmacopeia
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TG Dekker – WHO, Malaysia
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
Feb 2005
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TG Dekker – WHO, Malaysia
Pharmaceutical R&D
1. Learn about the product through desk research:



Don’t try to reinvent the wheel
Collect & analyse available information on e.g. APIs,
formulas, excipients, compatibility, stability, dosage form,
strength, packaging & analysis
Compile a Product Profile Report
2. Development according to plan, including:





Feb 2005
Preformulation studies
Formula / dosage form development & packaging
Comparative dissolution against comparator FPP
Accelerated stability
Final formula / manufacturing process
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TG Dekker – WHO, Malaysia
Topics for discussion
1. Desk research – Product Profile Report
2. The FDCs anti-tuberculosis tablets – a problem mix

API-API interactions of particular importance
3. Solid state properties of APIs

Rifampicin as example
4. Biowaiver type of comparative dissolutions




Feb 2005
Formulation development & comparison of pivotal
batches
Setting product dissolution specifications
Pre-BE control
Post-approval changes
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TG Dekker – WHO, Malaysia
Product profile report
 Objective




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

Feb 2005
4FDC anti-tuberculosis tablets
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TG Dekker – WHO, Malaysia
Typical product profile report (1)
PRODUCT UNDER CONSIDERATION
 4FDC anti-tuberculosis solid oral dosage form
Reference product(s) information
1. Category

Anti-tuberculosis agent
2. WHO model list of essential drugs (current)

Rifampicin 150 mg, Isoniazid 75 mg, Pyrazinamide 400 mg & Ethambutol 2HCl 275 mg
3. Prequalification EOI requirement (current)

Feb 2005
As for WHO model list – as tablets
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TG Dekker – WHO, Malaysia
Typical product profile report (2)
4. Prequalified products according to current list



Wyeth Pakistan - tablet (blister)
Lupin India – tablet (blister, HDPE bottle)
Sandoz – tablet (blister)
5. Public assessment reports available

None (FDA, EPAR, WHOPAR)
6. Comparator product (bio-section)


Sandoz (registered in Sweden)? Clarify
Combination of loose tablets? Clarify
7. Other products with “marketing authorisation”

Feb 2005
List such products, where considered necessary
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TG Dekker – WHO, Malaysia
Typical product profile report (3)
8. Products available for inspection/testing


Wyeth Pak, Lupin, Sandoz, others
Comparator for comparing dissolution profiles
9. Description/appearance of reference products


Especially the prequalified products (i.a. for
patient compliance)
Product A: Red oblong film-coated tablets, etc.
10. Packaging / pack sizes


Feb 2005
Prequalified products important (see website)
HDPE bottles (100s?), 3 x 10 blisters (alu/alu?)?
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TG Dekker – WHO, Malaysia
Typical product profile report (4)
11. Storage requirements /shelf life


Especially the prequalified 4FDC tablets
From SmPC or PIL
12. Published product specific excipients




Feb 2005
Tabulate for all prequalified/registered products
where available (table for comparative purposes)
Public assessment reports (not available for the
4FDC tablets)
From SmPCs (also available on internet)
Document known incompatibilities with APIs
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TG Dekker – WHO, Malaysia
Typical product profile report (5)
13. Published formulas

Formulas are published for older products in
standard works and journals (see next page)
14. Official product monographs




USP 28 (always current) for 4FDC
2 HPLC assay methods for all four APIs
Dissolution test for all four APIs
Related substances (degradants) not included
15. Safety & efficacy information


Feb 2005
Requirements for BE studies
Comparator product(s)
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TG Dekker – WHO, Malaysia
Typical product profile report (6)
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
Handbook of Pharmaceutical Excipients. A.H. Kibbe, ed.
3rd edition. American Pharmaceutical Association,
Washington, 2000 (Pharmaceutical Press, London)
Feb 2005
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TG Dekker – WHO, Malaysia
Typical product profile report (7)
API information
16. Nomenclature

INN, USAN, Systematic name , CAS, etc. from
e.g. Merck Index for each API (standard)
17. General physical properties




Feb 2005
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
Comparison of solubilities (analytically important)
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TG Dekker – WHO, Malaysia
Typical product profile report (8)
18. Compedial monograph(s)

BP/Ph.Eur., Int.Ph. and USP for all 4 APIs
19. Stability & degradation routes





Feb 2005
Compile expert report for each of the 4 APIs
Stress data and mild conditions from literature in:
- solution and solid state
API/API and API/excipient interactions
Storage conditions and optimal analytical stability
Conclusions and precautions with respect to
intended product
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TG Dekker – WHO, Malaysia
Typical product profile report (9)
20. Possible BCS classification


Feb 2005
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.
FDA and EMEA guidelines exist for classification
“rules”, dissolution requirements and similarity of
profiles
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TG Dekker – WHO, Malaysia
Typical product profile report (10)
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
Feb 2005
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TG Dekker – WHO, Malaysia
4FDC tablets – a problem mix (1)
Composition in current Essential Drug List
 Rifampicin
 Isoniazid
 Pyrazinamide
 Ethambutol 2HCl
 Total API weight
 Typical tablet weight
Feb 2005
150 mg
75 mg
400 mg
275 mg
900 mg
~ 1.3 g
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TG Dekker – WHO, Malaysia
4FDC tablets – a problem mix (2)
Rifampicin
 Oxidation (quinone & N-oxide)
 Protect from air exposure
 Hydrolysis (3-formylrifamycin & 25-desacetyl)
 Wet granulation / drying a potential problem?
 Reaction with Isoniazid
 3-(isonicotinylhydrazinomethyl)rifamycin or more
commonly known as isonicotinyl hydrazone
 isonicotinyl hydrazone major decomposition product
 Light sensitive
 Product to be protected from light exposure
Feb 2005
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TG Dekker – WHO, Malaysia
4FDC tablets – a problem mix (3)
Rifampicin
hydrolysis
oxidation
Feb 2005
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hydrolysis
TG Dekker – WHO, Malaysia
4FDC tablets – a problem mix (4)
Isoniazid
 Reacts with aldehydes/reducing sugars
 Sugar & lactose to be avoided in formulation !!
 3-Formylrifamycin (from rifampicin)
Ethambutol hydrochloride (2HCl)
 Hygroscopic
 Absorbs water for reaction in tablets
 Creates slightly acidic conditions
 pH of 2% w/v solution: 3.7-4.0 (BP)
 The acidic conditions enhance rifampicin/isoniazid
reaction (isonicotinyl hydrazone formation)
Feb 2005
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TG Dekker – WHO, Malaysia
4FDC tablets – a problem mix (5)
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)
 The reactions shown on next slide are from the above
publication
Feb 2005
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TG Dekker – WHO, Malaysia
4FDC tablets – hydrazone formation
Feb 2005
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TG Dekker – WHO, Malaysia
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
Feb 2005
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TG Dekker – WHO, Malaysia
4FDC-TB tablets
preventative/protective measures
 Formulation - no sugar/lactose (isoniazid)
 Separate granulation of rifampicin & isoniazid
 Rifampicin as powder (not granulate)?
 Prevent oxidation & hydrolysis
 Low water content of tablet (USP ≤ 3.0%)
 Protect product from moisture and oxygen
 Non-permeable packaging
 Do not remove from primary packaging
 Avoid repackaging
 Light protection
 Differential formulation, e.g. delayed release &
immediate release in one tablet ??
Feb 2005
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TG Dekker – WHO, Malaysia
Rifampicin solid state properties
 Rifampicin exist is 3 solid state forms:



Polymorph I
Polymorph II
Amorphous form
 Commercial material contains:


Polymorph II (predominantly)
Mixture of polymorph II and amorphous form
 Five commercial samples (A to E) in examples:
Sample A: Form II
Sample B: Form II
Sample C: Form II + amorph
Sample D: Form II + amorph
Sample E: Form II
Feb 2005
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TG Dekker – WHO, Malaysia
Rifampicin - SEM photos
Feb 2005
Sample A
Sample D
Form II
Form II + amorph
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TG Dekker – WHO, Malaysia
Rifampicin -XRPDs
Top:
Middle:
Bottom:
Feb 2005
Sample A (Form II – sharp signals)
Sample C (Form II + amorph – intensity drop)
Amorphous form (no pattern)
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TG Dekker – WHO, Malaysia
Rifampicin – powder dissolution (1)
Medium: 0.1 M hydrochloric acid
 Profiles of all samples are similar
 Dissolves immediately in 0.1 M hydrochloric acid
Feb 2005
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TG Dekker – WHO, Malaysia
Rifampicin – powder dissolution (2)
Medium: Phosphate buffer pH 7.4
A, B, E
(form II)
C, D
Form II + Amorph
 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)
Feb 2005
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TG Dekker – WHO, Malaysia
Rifampicin – powder dissolution (3)
Medium: Water
A, B, E
(form II)
C, D
(form II + amorph)
 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)
Feb 2005
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TG Dekker – WHO, Malaysia
Rifampicin - solid state conclusions
1. Solid state forms identifiable by means of XRPD
2. Dissolution rate is not different in 0.1 M HCl
3. 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?
4. Comparative powder dissolution powerful tool for
supplier selection
Reference:

Feb 2005
S. Q. Henwood, M. M. de Villiers, W. Liebenberg, A.P.
Lötter. Solubility and dissolution properties of generic
rifampicin raw materials. Drug Dev. & Ind. Pharm. 26,
403-408 (2000) (Research Institute for Industrial Pharm.)
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TG Dekker – WHO, Malaysia
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
 Where the properties differs to such extent that
different forms can be used in different dosage forms
(nevirapine: anhydrate in tablets and the hemihydrate
in suspensions)
Feb 2005
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TG Dekker – WHO, Malaysia
BCS classification (1)
Class
1
2
Solubility
High
Low
Permeability
High
High
3
4
High
Low
Low
Low
 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)
Feb 2005
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TG Dekker – WHO, Malaysia
BCS classification (2)
Data from:
API (INN)
Rifampicin
Isoniazid
Pyrazinamide
Ethambutol 2HCl
Class
2 (tentative)
1 (tentative)
1
3 (tentative)
 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
Feb 2005
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TG Dekker – WHO, Malaysia
Biowaiver dissolution studies (1)
Conditions
1. Three media - 900 ml or less - all at 37°C




2.
3.
4.
1. Buffer pH 1.2, SGF without enzymes or 0.1M HCl
2. Buffer pH 4.5
3: Buffer pH 6.8 or SIF without enzymes
Water may be used additionally (not instead of)
Paddle at 50 or basket at 100 rpm
Twelve units of each product in all 3 media
Dissolution samples collected at short intervals, e.g.


Feb 2005
10, 15, 20, 30, 45 and 60 minutes
Analyse samples for all APIs
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TG Dekker – WHO, Malaysia
Biowaiver dissolution studies (2)
Evaluation of dissolution data
1. The profiles of the test and reference products
must be similar in all three media for considering
a biowaiver (for not doing BE)
2. 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
Feb 2005
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TG Dekker – WHO, Malaysia
Biowaiver type dissolution application
1. Important during development studies



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
2. Bioequivalence support


Ideal pre-bioequivalence control - profile similarity with
comparator product good indication of BE
Biowaiver studies not in current prequalification
guidelines.
3. Post-approval changes
Feb 2005
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TG Dekker – WHO, Malaysia
Comparative dissolution example
Example
 Ethambutol hydrochloride/Isoniazid 400/150 mg
Tablets
 Four manufacturers (A, B, C & D)
 Dissolution conditions:
 Paddle, 50 rpm
 Phosphate buffer pH 6.8, 500 ml, undegassed, 37ºC
 Pull times: 10, 15, 20, 30, 45 & 60 minutes
 Source: T.G. Dekker, E.Swanepoel, A-M Redelinghuys & E.C.
van Tonder - unpublished
Feb 2005
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TG Dekker – WHO, Malaysia
Ethambutol 2HCl & Isoniazid Tabs (1)
Product B
120
120
100
100
Dissolution (%)
Dissolution (%)
Product A
80
Ethambutol HCl
60
Isoniazid
40
80
60
40
Ethambutol HCl
20
20
Isoniazid
0
0
0
10
20
30
40
50
60
70
10
20
30
40
50
60
70
Withdrawal time in minutes
Withdrawal time in minutes
Feb 2005
0
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TG Dekker – WHO, Malaysia
Ethambutol 2HCl & Isoniazid Tabs (2)
Product C
Product D
100
100
Dissolution (%)
120
Dissolution (%)
120
80
60
40
80
60
40
Ethambutol HCl
Ethambutol HCl
20
20
Isoniazid
Isoniazid
0
0
0
10
20
30
40
50
60
70
Withdrawal time in minutes
Feb 2005
0
10
20
30
40
50
60
70
Withdrawal time in minutes
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TG Dekker – WHO, Malaysia
Ethambutol 2HCl & Isoniazid Tabs (3)
All 4 products
API: Isoniazid
All 4 products
API: Ethambutol
120
120
A
80
B,C
60
40
D
20
100
Dissolution (%)
Dissolution (%)
100
80
60
40
20
0
0
0
10
20
30
40
50
60
0
70
Withdrawal time in minutes
Feb 2005
10
20
30
40
50
60
70
Withdrawal time in minutes
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TG Dekker – WHO, Malaysia
Ethambutol 2HCl & Isoniazid Tabs (4)
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
 Typical type of results during pharmaceutical R&D
Feb 2005
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TG Dekker – WHO, Malaysia
Some conclusions
1. Get to know you product through systematic desk
research, e.g. Product Profile Report
2. Physical properties of APIs may be important for low
soluble APIs, e.g. polymorphism & particle size

Powder dissolution testing may be useful for sourcing
3. Consider important API properties and API-API
interactions, especially in FDCs in formulation

Packaging to be non-permeable and light protective
4. Biowaiver type dissolutions are important in:





Feb 2005
Choice of formulation vs comparator
Comparison of pivotal batches
Setting product dissolution specifications
Pre-BE control
Post-approval changes
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TG Dekker – WHO, Malaysia