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Workshop on Quality Assurance and GMP of multisource HIV/AIDS medicines


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Title: Workshop on Quality Assurance and GMP of multisource HIV/AIDS medicines

Workshop on Quality Assurance and GMP of
multisource HIV/AIDS medicines
Pharmaceutical Research and Development Quality
by design
  • János Pogány, pharmacist, PhD,
  • consultant to WHO
  • Shanghai, 01 March 2005
  • E-mail

Abbreviations and Notes
  • API Active pharmaceutical ingredient
  • FDC(s) fixed-dose combination(s)
  • FPP(s) Finished pharmaceutical product(s)
  • RD Research and development
  • Text in green refers to WHO documents or
  • Text in yellow indicates a quality assessment
  • Text in light blue highlights key words

Subjects for Discussion
  • Desk research Indinavir
  • Submission of pharmaceutical RD data
  • Research (Laboratory scale)
  • API (specifications, stress stability testing,
  • FPP (
  • Development (Pilot scale)
  • Manufacture (Production scale)
  • Conclusions

What can we learn from the European Public
Assessment Report(s) EPAR(s)?

Indinavir - Chemistry
  • Indinavir is a chiral molecule with 5 stereogenic
    centers and is used as a single isomer, the
  • The primary degradation pathway for indinavir
    sulfate for both solid state and solution is
    amide bond hydrolysis to form lactone and
    aminoindanol. The degradation is humidity and
    temperature dependent.
  • Indinavir is highly hygroscopic at relative
    humidities above 60 . Indinavir Sulfate
    monoethanolate converts to hydrate with the loss
    of ethanol upon exposure to moist air.

Indinavir Physicochemistry
  • It has two pKb values 6.2 and 3.8
  • Aqueous solubility is 100mg/ml at room
    temperature but the solubility decreases at
    higher pH.
  • Partition coefficient octanol/water (log P) is
    2.7 at pH 7.

Indinavir - Biology
  • Early clinical studies revealed a more
    reproducible absorption when indinavir was
    administered as the sulfate salt compared with
    the free base.
  • The bioavailability of indinavir is good
    (approximately 60 , peak plasma concentration is
    0.8 0.3 hours), which facilitates
    pre-formulation and formulation research.
  • Toxico-pharmacological information suggests that
    indinavir pharmaceutical forms may be
    manufactured in multiproduct plants.

Indinavir - Preformulation
  • In view of indinavir sulfates moisture and
    temperature sensitivity, poor flowability and
    relatively loose bulk density, a dry granulation
    formulation with acceptable compressibility and
    consistent fill volume during encapsulation was
  • Anhydrous lactose was selected as a filler and
    binding aid because of its low moisture content,
    non hygroscopicity and good compactibility.
  • Magnesium stearate provides the lubrication
    required for machinability.

Quality of inactive ingredients
  • Both capsule manufacturers have provided
    assurance that gelatin used will be obtained only
    from BSE-free countries (BSE bovine (animal)
    spongiform encephalopathy).
  • The same assurance could be required for
    magnesium stearate, or stearic acid and its
    derivatives in general.

Crixivan Capsules
  • Indinavir, as sulfate 100mg 200mg
  • Lactose, anhydrous 37mg 74mg
  • Magnesium stearate ? ?
  • Indinavir, as sulfate 333mg 400mg
  • Lactose, anhydrous 124mg 149mg
  • Magnesium stearate ? ?

Indinavir Packing Materials
  • CRIXIVAN 100 mg hard capsules are supplied in
    HDPE bottles with a polypropylene cap and a foil
    induction cap.
  • CRIXIVAN 400 mg hard capsules are supplied in
    all-aluminium blisters.

Indinavir Labeling
  • HDPE bottles keep the container tightly closed
    in order to protect from moisture. Do not remove
    the desiccant canister from the bottle.
  • Blister packs store in the original package in
    order to protect from moisture.
  • Note that the storage temperature is not

Indinavir Stability of Capsules
  • No degradation other than the lactone and the
    aminoindanol were observed in any of the stressed
    capsules. The aminoindanol is produced in
    equimolar amount to the lactone.
  • Shelf life
  • 24 months for CRIXIVAN capsules in blisters.
  • 36 months for CRIXIVAN capsules in HDPE bottles.

Indinavir Scale up
  • The formulation intended for market has remained
    unchanged throughout the development program.
    Studies showed that the quality of the finished
    product is not compromised by the scale-up in
  • Flowability and bulk density of granules are
    important/critical parameters for weight

Indinavir Scale up
  • The manufacturing process is carried out under
    GMP at controlled humidity of the air in the
    manufacturing areas associated with roller
    compaction, milling and encapsulating.
  • HVAC system should maintain a relative humidity
    of 33 at 25oC.
  • The result of the manufacturing process
    development is a stable product with low
    batch-to-batch variation with the finished
    product specification.

Indinavir Quality control
  • The specifications of the FPP cover the
  • Appearance of the capsules,
  • Identity,
  • Assay of drug substance,
  • Dose uniformity,
  • Dissolution test,
  • Test on degradation product and
  • Moisture content.

Indinavir Quality control
  • At release,
  • an assay limit of 95-105
  • lactone impurity is not more than 0.3.
  • Batch analyses data for several pilot scale lots
    used in clinical, safety and stability studies
    are submitted and demonstrate a consistent
    quality of the product and compliance with the
    stated specifications.

Indinavir Quality control
  • At the end of shelf life,
  • an assay limit of 93-105 and
  • lactone impurity is not more than 1.5.
  • The stability studies of the FPP show that the
    drug product is stable when stored in the
    original container, tightly closed and protected
    from humidity.
  • Submission of full time stability data on
    production batches of the finished product is
    part of the follow-up measures.

Indinavir Literature
  • CPMP/589/96 Committee for Proprietary Medicinal
    Products (CPMP) European Public Assessment Report
    (EPAR) The European Agency for the Evaluation of
    Medicinal Products, 7 Westferry Circus, Canary
    Wharf, London E14 4HB, UK
  • Additional sources of information
  • United States patent No. 5,413,999
  • Literature search on chemistry of indinavir.

Guideline on Submission of Documentation for
Prequalification of Multi-source
(Generic) Finished Pharmaceutical Products
(FPPs) Used in the Treatment of HIV/AIDS, Malaria
and Tuberculosis

Objective of Pharmaceutical RD
  • The Pharmaceutical RD section presents the
    knowledge gained through the application of
    scientific approaches, and risk management, to
    the development of a FPP and its manufacturing
    process. It is first submitted in the original
    marketing application and can be updated to
    support new knowledge gained over the lifecycle
    of a product.
  • The studies described here are distinguished from
    routine control tests conducted according to

  • Laboratory scale R D

Physicochemical and physical properties of API
  • Physicochemical
  • hygroscopicity
  • solubility
  • water content
  • polymorphism
  • permeability
  • Physical
  • particle size
  • bulk density (g/100ml)
  • flowability
  • color, olor, taste
  • consistency

Equilibrium Moisture Content
  • At relative humidities (RHs) lt100, a solid API
    (that does not form crystalline compounds with
    water) will loose some bound and all its unbound
    water until it is in equilibrium with the
    surrounding atmosphere. The sum of both these
    moistures is the free moisture of the API
    (granules) at the specified RH.

Rate of Water Absorption at Different RHs
Solubility of Zidovudine at 25oC
pH Dissolved material (mg/ml)
3.0 21
4.0 20
5.3 20
6.0 21
7.0 22
Distilled water 20
8.0 21
Relationship between Permeability Coefficient and
Octanol-Water Partition
  • 1 Prednisolone
  • ...
  • 3 Dexamethazone
  • ...
  • 9 Dexamethazone-acetate
  • ...
  • 11 Progesterone

NORVIR (Ritonavir) EPAR/CPMP /527/96
  1. No polymorphism observed at the time of first
    submission (only form I hard capsules and oral
    solution registered)
  2. Failure in dissolution during stability studies
    for hard capsules
  3. Emergence of form II (contamination of form I)
  4. Production of hard capsules discontinued
  5. Development and registration of soft capsules

Particle Size
  • When the solubility of an API is less than 0.1
    mg/ml, the optimization of the particle size
    during preformulation may be critical to efficacy
    or pharmaceutical equivalence. Other researchers
    believe that particle size may be critical at a
    solubility of 1 mg/ml or less.

Effect of Particle Size on Dissolution
Screening of Compositions
  • Compatibility of an API with the excipients and
    the APIs with each other in FDCs is studied in
    open system stress stability experiments, e.g.,
    60-80 oC, 100 RH.
  • Regulatory stability studies of the final
    composition are frequently initiated in the
    pharmaceutical R D laboratory.

Compatibility of Acetylsalicylic Acid with
Time (week) Talc A Talc B
Salicylic acid, Salicylic acid,
0 0.10 0.10
4 0.32 5.85
8 0.41 13.00
12 0.80 28.50
Triomune - WHOPAR
  • Experimental studies showed chemical
    incompatibility for the lamivudine with stavudine
    and nevirapine with stavudine combination.
    Lamivudine with nevirapine showed no change
    indicating that they are compatible. Stavudine
    was found incompatible with both the drugs,
    indicated by the brown colouration and increase
    in the impurities.
  • Therefore it was decided to separate stavudine
    from the other two drugs. Hence the formulation
    was proposed to be bilayered tablet formulation,
    where stavudine is in one layer and lamivudine
    nevirapine in other layer. Thus contact of
    stavudine with the other two drugs was minimised.

Dissolution Test and Profile
  • A (discriminating) dissolution test method should
    be developed for the final composition of the
  • Limits should be set for each API in fixed-dose
  • The dissolution method should be incorporated
    into the stability and quality control programs.
  • Multipoint dissolution profiles of both the test
    and the reference FPPs should be compared.

Dissolution Profile of Viramune and Generic
Nevirapine Tablets on the Indian Market
Hypothetical Dissolution Profile of a 2-FDC FPP
Pivotal Batches
  • A tabulated summary of the compositions of the
    clinical, bioequivalence, stability and
    validation FPP batches together with
    documentation (batch number, batch size,
    manufacturing date and certificate of analysis at
    batch release) and a presentation of dissolution
    profiles must be provided.
  • Results from comparative in vitro studies (e.g.,
    dissolution) or comparative in vivo studies
    (e.g., bioequivalence) should be discussed when

Excipients Lactose (L)
  • Different grade, different physical properties
  • Angle of repose 32- 47o (Specs.)
  • Bulk density 0.34 0.80 g/cm3 (Specs.)
  • Bulk density (tapped) 0.41 0.95 g/cm3
  • Flowability (spray processed) 4.1 g/s (Specs.)
  • Hygroscopicity L monohydrate is stable in air at
    room temperature. Anhydrous L may absorb
  • Moisture content L monohydrate contains approx.
    5 w/w water of crystallization

Excipients Lactose (L)
  • Solubility in water
  • 1 in 4.63 at 25 oC
  • 1 in 3.14 at 40 oC
  • 1 in 2.04 at 50 oC
  • 1 in 1.68 at 60 oC
  • 1 in 1.07 at 80 oC
  • Particle size distribution depends on grade.
  • Stability may develop brown colouration ( 80
  • Incompatibility APIs with a primary amine group
    (base catalysed), aminophylline and amphetamines.

Packaging Materials
  • Moisture-impermeable containers glass ampoules,
    vials closed with rubber stoppers and fixed with
    metal caps, aluminium/aluminium blisters, high
    density polyethylene (HDPE) or glass bottles
    fitted with metal metal or HDPE closures, etc.
  • Moisture-permeable containers polyvinyl chloride
    (PVC) blisters, low density polyethylene (LDPE)
    bottles, HDPE bottles fitted with polypropylene
  • Specifications of packaging materials should
    include thickness and permeability coefficient.

Development of a film-tablet manufacturing process
  • Pilot scale experiments

Justification of Film-coating
  1. Mask bitter taste of the tablets
  2. Reduce skin contact (risk of allergy)
  3. Improve colour uniformity
  4. Facilitate packaging

Results of API Stress Stability Testing
Initial assay 98.1
Storage conditions Assay ()
50oC 99.9
60oC 98.4
70oC 99.9
30oC/90RH 100.2
40oC/90RH 100.1
LIGHT 93.3
  • API is soluble in water, it can be easily
    granulated, compression results in good tablets
    with a rapid dissolution rate. There is no need
    for particle size reduction.
  • API is compatible with all excipients, including
    film-coating inactive ingredients.
  • Decomposition of API in UV and artificial
    daylight is not accelerated by the excipients.

Selection of Tablet Mass
Composition A B C
API (mg) 500 500 500
Excipients (mg) 200 125 56
Tablet mass (mg) 700 625 556
Granules, LOD () 0,9 0,8 0,8
Median diameter (µm) 194 186 189
Tablets, hardness (kp) 12.8 13.3 12.4
Friability () 0.7 0.5 0.5
Disintegration time 630 740 1050
Dissolution (, 15) 96.6 95.6 96.7
Solvent Selection for Binder
Povidone, water (W), ethanol (E) W-E W E
Granules Granules Granules Granules
LOD() 0.8 0.9 0.8
Median diameter (µm) 186 179 184
Tablets Tablets Tablets Tablets
Average weight (mg) 626 624 628
Hardness (kp) 13.3 11.2 12.9
Friability () 0.5 0.5 0.4
Disintegration time 74 210 635
Dissolution (, 15) 95.6 96.3 75.7
Compression Speed
Tabletting machine BB3 BB3 ß-Press ß-Press
Granules, (Mg-stearate ) 0.25 0. 50 0.50 0.50
LOD () 1.5 1.5 1.5 1.5
Median diameter (µm) 341 341 341 341
Tablets Tablets Tablets Tablets Tablets
Average weight (mg) 605 607 607 599
Hardness (kp) 10.9 9.7 9.7 7.3
Friability () 0.3 0.5 0.5 0.8
Disintegration time 648 1419 1419 814
Dissolution (, 15) 99.5 76.7 76.7 92.0
Film-coating Parameters
Spraying conditions Pilot batch 1 Pilot batch 2
Film-coater Manesty Manesty
Nozzle (mm) 0.8 0.8
Spraying pressure (psi) 40/25 40/25
Inlet temperature (oC) 81 71
Outlet temperature (oC) 45 44
Spray rate (g/min) 36 26
Drum speed (rpm) 8 10
Film-coating Results
Quality parameter Pilot batch 1 Pilot batch 1 Pilot batch 2 Pilot batch 2
Quality parameter Core Coated Core Coated
Weight increase () 2.12 2.04
Appearance good good
Mean thickness (mm) 4.25 4.28 4.34 4.37
Hardness (kp) 9.2 14.7 8.7 10.8
Friability () 0.3 0 0.44 0
Disintegration time 340 532 144 246
Dissolution (15, ) - 93 - 98
Choice of Container
  • Amber glass bottles with LDPE snap-fitting caps,
  • Amber PVC/aluminium foil blister packs
  • General principle
  • Packaging should be selected to ensure the
  • quality of the FPP throughout its shelf life.

Pharmaceutical R D Process includes Transfer of
Technology to the Production Plant
  • Production scale experiments with validation

Validation protocol and report
  • Data should be submitted in the application for
    prequalification demonstrating the validity of a
    given process.
  • Formal studies of production scale batches
    (normally not less than three consecutive
    batches) are required before the product is
    placed on the market.
  • Where validation data on production scale batches
    are not provided with the application, the
    applicant should submit the validation protocol.
  • Following completion of the programme, a
    validation report should be generated for
    examination by WHO.

Main points again
  • Pharmaceutical R D is an essential part of
    applications for Marketing Authorization.
  • Desk research gives valuable information.
  • Laboratory scale studies should identify critical
    product quality attributes.
  • FDCs require particular tests.
  • Packing materials should also be selected through
    documented experiments.

Main points again
  • Pilot plant experiments should provide the basis
    for process optimisation, process validation and
    process control requirements.
  • Validation batches at production scale should
    establish the critical process parameters (e.g.,
    granulation end point, drying temperature) that
    should regularly be monitored or controlled to
    guarantee batch-to-batch consistency of quality.