1 TG Dekker – WHO, Malaysia Feb 2005 Pharmaceutical Research and Development Considerations...

1 TG Dekker – WHO, MalaysiaFeb 2005

PharmaceuticalResearch and Development

Considerations

Workshop on GMP and Quality Assurance of

Multisource Tuberculosis MedicinesKuala Lumpur – Malaysia

21-25 February 2005

Theo Dekker, D.Sc., consultant to WHOResearch Institute for Industrial Pharmacy

North-West University, Potchefstroom, South [email protected]


Abbreviations

API Active pharmaceutical ingredientBCS Biopharmaceutics classification systemBP British PharmacopoeiaCEP EU certificate of suitabilityEOI Expression of interestFDC Fixed dose combinationFPP Finished pharmaceutical productICH International Conference on HarmonizationInt.Ph. International PharmacopoeiaR&D Research and developmentTB TuberculosisXRPD X-ray powder diffractogramUSP United States Pharmacopeia


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


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


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 Formulation development & comparison of pivotal

batches Setting product dissolution specifications Pre-BE control Post-approval changes


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


Typical product profile report (1)

PRODUCT UNDER CONSIDERATION 4FDC anti-tuberculosis solid oral dosage form

Reference product(s) information1. Category

Anti-tuberculosis agent

2. WHO model list of essential drugs (current) Rifampicin 150 mg, Isoniazid 75 mg, Pyrazin-

amide 400 mg & Ethambutol 2HCl 275 mg

3. Prequalification EOI requirement (current) As for WHO model list – as tablets



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



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?)?



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



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)



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)



API information16.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)



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



20.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.

FDA and EMEA guidelines exist for classification “rules”, dissolution requirements and similarity of profiles



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


4FDC tablets – a problem mix (1)

Composition in current Essential Drug List

Rifampicin 150 mg Isoniazid 75 mg Pyrazinamide 400 mg Ethambutol 2HCl 275 mg Total API weight 900 mg Typical tablet weight ~ 1.3 g



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



hydrolysis Rifampicin

oxidation hydrolysis



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)



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


4FDC tablets – hydrazone formation


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


4FDC-TB tabletspreventative/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 ??


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 IISample C: Form II + amorphSample D: Form II + amorphSample E: Form II


Rifampicin - SEM photos

Sample A Sample DForm II Form II +

amorph


Rifampicin -XRPDs

Top: Sample A (Form II – sharp signals)Middle: Sample C (Form II + amorph – intensity drop)Bottom: Amorphous form (no pattern)


Rifampicin – powder dissolution (1)

Medium: 0.1 M hydrochloric acid

Profiles of all samples are similar Dissolves immediately in 0.1 M hydrochloric acid



Medium: Phosphate buffer pH 7.4

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(form II)

C, DForm II + Amorph



Medium: Water

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(form II)

C, D(form II + amorph)


Rifampicin - solid state conclusions

1. Solid state forms identifiable by means of XRPD2. Dissolution rate is not different in 0.1 M HCl3. 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.

Lötter. Solubility and dissolution properties of generic rifampicin raw materials. Drug Dev. & Ind. Pharm. 26, 403-408 (2000) (Research Institute for Industrial Pharm.)


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)


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


BCS classification (2)

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) Class

Rifampicin 2 (tentative)

Isoniazid 1 (tentative)

Pyrazinamide 1

Ethambutol 2HCl 3 (tentative)


Biowaiver dissolution studies (1)

Conditions1. 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 3: Buffer pH 6.8 or SIF without enzymes

Water may be used additionally (not instead of)2. Paddle at 50 or basket at 100 rpm3. Twelve units of each product in all 3 media4. 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 data1. 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


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


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


Ethambutol 2HCl & Isoniazid Tabs (1)

Product B

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

Withdrawal time in minutes

Dis

solu

tio

n (

%)

Ethambutol HCl

Isoniazid

Product A

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70


Dis

solu

tio

n (

%)

Ethambutol HCl

Isoniazid



Product C

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70


Dis

solu

tio

n (

%)

Ethambutol HCl

Isoniazid

Product D

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70


Dis

solu

tio

n (

%)

Ethambutol HCl

Isoniazid



All 4 productsAPI: Isoniazid

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70


Dis

solu

tio

n (

%)

All 4 productsAPI: Ethambutol

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70


Dis

solu

tio

n (

%)

A

B,C

D



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


Some conclusions1. Get to know you product through systematic desk

research, e.g. Product Profile Report2. 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

1 TG Dekker – WHO, Malaysia Feb 2005 Pharmaceutical Research and Development Considerations...

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