Pharmaceutical Research and Development Considerations

1
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 iiftgd_at_puk.ac.za
2
Abbreviations

• 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 on Harmonization
• Int.Ph. International Pharmacopoeia
• RD Research and development
• TB Tuberculosis
• XRPD X-ray powder diffractogram
• USP United States Pharmacopeia

3
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

4
Pharmaceutical RD

• 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
• Development according to plan, including
• Preformulation studies
• Formula / dosage form development packaging
• Comparative dissolution against comparator FPP
• Accelerated stability
• Final formula / manufacturing process

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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

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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

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Typical product profile report (1)

• PRODUCT UNDER CONSIDERATION
• 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

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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

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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?)?

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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

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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)

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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)

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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)

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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

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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

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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

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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

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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

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4FDC tablets a problem mix (3)

• hydrolysis
  Rifampicin
• oxidation
  hydrolysis

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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)

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4FDC tablets a problem mix (5)

• Isonicotinyl hydrazone (3-(isonicotinylhydrazinome
  thyl)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

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4FDC tablets hydrazone formation
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4FDC-TB tablets exposed to 40C/75RH for one week

• Two products. Bleeding may start after more
  exposure (in-house)
• Control on left Control on left

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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 ??

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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

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Rifampicin - SEM photos

• Sample A Sample D
• Form II Form II amorph

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Rifampicin -XRPDs

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

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Rifampicin powder dissolution (1)

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

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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
  lt 50)

A, B, E(form II)
C, DForm II Amorph
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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
  lt 50)

A, B, E(form II)
C, D(form II amorph)
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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
• 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.)

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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)

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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
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BCS classification (2)

• Data from
• M Lindenberg, S. Kopp, J. B. Dressman.Classificat
  ion 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)
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Biowaiver dissolution studies (1)

• Conditions
• 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)
• 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

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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

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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

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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

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Ethambutol 2HCl Isoniazid Tabs (1)

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Ethambutol 2HCl Isoniazid Tabs (2)
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Ethambutol 2HCl Isoniazid Tabs (3)
A
B,C
D
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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 gt B C gtgt 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 RD

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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