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Pharmaceutical Research and Development Considerations. Workshop on GMP and Quality Assurance of Multisource Tuberculosis Medicines Kuala Lumpur – Malaysia 21-25 February 2005. Theo Dekker, D.Sc., consultant to WHO Research Institute for Industrial Pharmacy

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pharmaceutical research and development considerations

PharmaceuticalResearch and Development Considerations

Workshop on GMP and Quality Assurance of

Multisource Tuberculosis Medicines

Kuala Lumpur – Malaysia

21-25 February 2005

Theo Dekker, D.Sc., consultant to WHO

Research Institute for Industrial Pharmacy

North-West University, Potchefstroom, South Africa


API Active pharmaceutical ingredient

BCS Biopharmaceutics classification system

BP British Pharmacopoeia

CEP EU certificate of suitability

EOI Expression of interest

FDC Fixed dose combination

FPP Finished pharmaceutical product

ICH International Conference onHarmonization

Int.Ph. International Pharmacopoeia

R&D Research and development

TB Tuberculosis

XRPD X-ray powder diffractogram

USP United States Pharmacopeia

the perspective
The perspective
  • Pharmaceutical R & D provides the foundation of the activities aimed at ensuring thatthe 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
Pharmaceutical R&D
  • Learn about the product through desk research:
    • Don’t try to reinvent the wheel
    • Collect & analyseavailable 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
    • Formula / dosage form development & packaging
    • Comparative dissolution against comparator FPP
    • Accelerated stability
    • Final formula / manufacturing process
topics for discussion
Topics for discussion
  • 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
product profile report
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
Typical product profile report (1)


  • 4FDC anti-tuberculosis solid oral dosage form

Reference product(s) information

  • 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
typical product profile report 2
Typical product profile report (2)
  • Prequalified products according to current list
    • Wyeth Pakistan - tablet (blister)
    • Lupin India – tablet (blister, HDPE bottle)
    • Sandoz – tablet (blister)
  • Public assessment reports available
    • None (FDA, EPAR, WHOPAR)
  • Comparator product (bio-section)
    • Sandoz (registered in Sweden)? Clarify
    • Combination of loose tablets? Clarify
  • Other products with “marketing authorisation”
    • List such products, where considered necessary
typical product profile report 3
Typical product profile report (3)
  • Products available for inspection/testing
    • Wyeth Pak, Lupin, Sandoz, others
    • Comparator for comparing dissolution profiles
  • Description/appearance of reference products
    • Especially the prequalified products (i.a. for patient compliance)
    • Product A: Red oblong film-coated tablets, etc.
  • Packaging / pack sizes
    • Prequalified products important (see website)
    • HDPE bottles (100s?), 3 x 10 blisters (alu/alu?)?
typical product profile report 4
Typical product profile report (4)
  • Storage requirements /shelf life
    • Especially the prequalified 4FDC tablets
    • From SmPC or PIL
  • 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
typical product profile report 5
Typical product profile report (5)
  • Published formulas
    • Formulas are published for older products in standard works and journals (see next page)
  • 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
  • Safety & efficacy information
    • Requirements for BE studies
    • Comparator product(s)
typical product profile report 6
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)
typical product profile report 7
Typical product profile report (7)

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
    • Comparison of solubilities (analytically important)
typical product profile report 8
Typical product profile report (8)
  • Compedial monograph(s)
    • BP/Ph.Eur., Int.Ph. and USP for all 4 APIs
  • 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
typical product profile report 9
Typical product profile report (9)
  • 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
typical product profile report 10
Typical product profile report (10)


  • 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
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
4fdc tablets a problem mix 2
4FDC tablets – a problem mix (2)


  • 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
4fdc tablets a problem mix 3
4FDC tablets – a problem mix (3)

hydrolysis Rifampicin

oxidation hydrolysis

4fdc tablets a problem mix 4
4FDC tablets – a problem mix (4)


  • 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)
4fdc tablets a problem mix 5
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
4fdc tb tablets exposed to 40 c 75 rh for one week
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 tablets preventative protective measures
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 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

rifampicin sem photos
Rifampicin - SEM photos

Sample A Sample D

Form II Form II + amorph

rifampicin xrpds
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
Rifampicin – powder dissolution (1)

Medium: 0.1 M hydrochloric acid

  • Profiles of all samples are similar
  • Dissolves immediately in 0.1 M hydrochloric acid
rifampicin powder dissolution 2
Rifampicin – powder dissolution (2)

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

rifampicin powder dissolution 3
Rifampicin – powder dissolution (3)

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
Rifampicin - solid state conclusions
  • Solid state forms identifiable by means of XRPD
  • 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?
  • Comparative powder dissolution powerful tool for supplier selection


    • 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
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
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)
bcs classification 2
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
biowaiver dissolution studies 1
Biowaiver dissolution studies (1)


  • 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 usedadditionally (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.
    • 10, 15, 20, 30, 45 and 60 minutes
    • Analyse samples for all APIs
biowaiver dissolution studies 2
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
biowaiver type dissolution application
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

Bioequivalence support

Ideal pre-bioequivalence control - profile similarity with comparator product good indication of BE

Biowaiver studies not in current prequalification guidelines.

Post-approval changes

Biowaiver type dissolution application
comparative dissolution example
Comparative dissolution 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 4
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
some conclusions
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
    • Pre-BE control
    • Post-approval changes