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

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
2

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

TG Dekker WHO, Malaysia

Pharmaceutical R&D
1.

Learn about the product through desk research:

Dont 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:

Preformulation studies
Formula / dosage form development & packaging
Comparative dissolution against comparator FPP
Accelerated stability
Final formula / manufacturing process

Feb 2005

TG Dekker WHO, Malaysia

Topics for discussion

1.
2.
3.

4.

Feb 2005

Desk research Product Profile Report

The FDCs anti-tuberculosis tablets a problem mix
API-API interactions of particular importance
Solid state properties of APIs
Rifampicin as example
Biowaiver type of comparative dissolutions
Formulation development & comparison of pivotal
batches
Setting product dissolution specifications
Pre-BE control
Post-approval changes

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
4FDC anti-tuberculosis tablets

Feb 2005

TG Dekker WHO, Malaysia

Typical product profile report (1)

PRODUCT UNDER CONSIDERATION

4FDC anti-tuberculosis solid oral dosage form

Reference product(s) information

1.
2.

3.

Category
Anti-tuberculosis agent
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)
As for WHO model list as tablets

Feb 2005

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

List such products, where considered necessary

Feb 2005

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

Prequalified products important (see website)
HDPE bottles (100s?), 3 x 10 blisters (alu/alu?)?
Feb 2005

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
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

Feb 2005

10

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
Requirements for BE studies
Comparator product(s)
Feb 2005

11

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

12

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
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)
Feb 2005

13

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
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

Feb 2005

14

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

15

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

16

TG Dekker WHO, Malaysia

4FDC tablets a problem mix (1)

Composition in current Essential Drug List

Feb 2005

Rifampicin
Isoniazid
Pyrazinamide
Ethambutol 2HCl
Total API weight
Typical tablet weight

17

150 mg
75 mg
400 mg
275 mg
900 mg
~ 1.3 g

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

18

TG Dekker WHO, Malaysia

4FDC tablets a problem mix (3)

Rifampicin
hydrolysis

oxidation
Feb 2005

19

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

20

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

21

TG Dekker WHO, Malaysia

4FDC tablets hydrazone formation

Feb 2005

22

TG Dekker WHO, Malaysia

4FDC-TB tablets exposed to

40C/75%RH for one week
Two products. Bleeding may start after more exposure (inhouse)
Control on left

Feb 2005

Control on left

23

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

Feb 2005

Light protection
Differential formulation, e.g. delayed release &
immediate release in one tablet ??
TG Dekker WHO, Malaysia
24

Rifampicin solid state properties

Feb 2005

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

25

TG Dekker WHO, Malaysia

Rifampicin - SEM photos

Feb 2005

Sample A

Sample D

Form II

Form II + amorph

26

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)

27

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

28

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

29

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

30

TG Dekker WHO, Malaysia

Rifampicin - solid state conclusions

1.
2.

Solid state forms identifiable by means of XRPD

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:
S. Q. Henwood, M. M. de Villiers, W. Liebenberg, A.P.
Ltter. Solubility and dissolution properties of generic
rifampicin raw materials. Drug Dev. & Ind. Pharm. 26,
403-408 (2000) (Research Institute for Industrial Pharm.)
Feb 2005

31

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

32

TG Dekker WHO, Malaysia

BCS classification (1)

Class

Solubility

Permeability

High

High

Low

High

High

Low

Low

Low

High solubility: Highest dose strength of API should be

soluble in 250 ml water at 37C over the pH range 1.07.5.
High permeability: Absolute bioavailability 90 %
(presently) - apart from specific permeability studies
Limiting factors for biowaivers (see FDA & EMEA)
Feb 2005
TG Dekker WHO, Malaysia
33

BCS classification (2)

API (INN)

Class

Rifampicin

2 (tentative)

Isoniazid

1 (tentative)

Pyrazinamide

Ethambutol 2HCl

3 (tentative)

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
Feb 2005

34

TG Dekker WHO, Malaysia

Biowaiver dissolution studies (1)

Conditions
1. Three media - 900 ml or less - all at 37C
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)
2.
3.

Paddle at 50 or basket at 100 rpm

Twelve units of each product in all 3 media

4.

Dissolution samples collected at short intervals, e.g.

10, 15, 20, 30, 45 and 60 minutes
Analyse samples for all APIs

Feb 2005

35

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

36

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

37

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, 37C
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

38

TG Dekker WHO, Malaysia

Ethambutol 2HCl & Isoniazid Tabs (1)

Feb 2005

39

TG Dekker WHO, Malaysia

Ethambutol 2HCl & Isoniazid Tabs (2)

Feb 2005

40

TG Dekker WHO, Malaysia

Ethambutol 2HCl & Isoniazid Tabs (3)

A
B,C
D

Feb 2005

41

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

42

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:

Choice of formulation vs comparator
Comparison of pivotal batches
Setting product dissolution specifications
Pre-BE control
Post-approval changes

Feb 2005

43

TG Dekker WHO, Malaysia