Transcript Finished Pharmaceutical Products (FPPs)

Evaluation of Quality and Interchangeability of
Medicinal Products
Training Workshop for Evaluators
from National Medicines Regulatory
Authorities in East African
Community
Dar Es Salaam, Tanzania
Date: 10 to 14 September 2007
Slide 1 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Evaluation of Quality and Interchangeability of
Medicinal Products
3.0 Finished Pharmaceutical Products

Presenter:
3.2 Pharmaceutical Development
Deus K. Mubangizi, pharmacist, MSc(Pharm.)
[email protected], [email protected]
Chief Inspector of Drugs, National Drug Authority
WHO expert
Slide 2 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
3.2 Pharmaceutical Development
Outline of presentation
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Applicable Guidelines
Aim of Pharmaceutical Development
Dossier data requirements on pharmaceutical development
Pre-formulation studies
 Phyisco-chemical characteristics of the API
 Stress stability of the API
Choice of excipients
Choice of formulation and compatibility (Example of 4FDC FPP)
Choice of manufacturing process
 Lab scale
 Pilot scale
Dissolution testing
Details of batches studied
Container closure system
Microbiology attributes
Examples of ACTS
Summary of main points
Slide 3 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Applicable guidelines
 WHO 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. 3.2 Pharmaceutical Development
 ICH Q8 Pharmaceutical Development (Nov.
2005)
Slide 4 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.2. Pharmaceutical development
The aim is to build a quality product by design.
1.
DESIGN (product-specific research)
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Desk research
API (specifications, stress stability testing, etc.)
FPP (pre-formulation, screening stability studies, etc.)
DEVELOPMENT [FPP and manufacturing process (same for innovator and
generic FPPs)]
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Laboratory
Pilot plant (dissolution equivalence, stability and bioequivalence studies,
tentative FPP specifications, prospective validation)
Production plant (concurrent validation)
Slide 5 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
General considerations
 The marketing of a new multisource FPP in the ICH
region may cost USD 1 to 2 millions and may take a time
of three to 5 years.
 The lowest risk strategy for the development of an
interchangeable multisource FPP is to copy the innovator
FPP.
 Multisource FPP manufacturers must be highly skilled in
product and process development
Slide 6 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.2. Pharmaceutical development
The section should contain information on the development studies
conducted to establish that
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the dosage form,
the formulation,
the manufacturing process,
the container closure system,
microbiological attributes and
storage and usage instructions
are appropriate for the purpose specified in the dossier.
Slide 7 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
3.2.1 Company research and development
The Pharmaceutical Development section should contain information on the
development studies conducted to establish that the dosage form, the
formulation, manufacturing process, container closure system, microbiological
attributes and usage instructions are appropriate for the purpose specified in the
application. The studies described here are distinguished from routine control
tests conducted according to specifications.
The summary should highlight the evolution of the formulation design from initial
concept up to the final design and it should also take into consideration the
choice of drug product components (e.g., the properties of the drug substance,
excipients, container closure system, the manufacturing process, and, if
appropriate, knowledge gained from the development of similar drug product(s).
Slide 8 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.2. Pharmaceutical development (pre-formulation)
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Physico-chemical characteristics of the APIs
– solubility
(composition)
– water content
(stability)
– hygroscopicity (stability)
– particle size
(solubility, bioavailability, suspension properties,
stability …)
– polymorphism (solubility, bioavailability, stability)
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Data obtained from literature : Books, Journals, International
Pharmaceutical Abstracts, Chemical Abstracts, Analytical Abstracts,
Internet ……
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Experimental data
(if necessary)
Slide 9 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Particle size
When the solubility of an API is less than 0.1
mg/ml (>10,000ml/g, practically insoluble) and
does not change with pH in the physiological
range, then the optimisation 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
(>1,000ml/g, very slightly soluble).
Slide 10 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Potentially critical attributes of API
Key physicochemical characteristics:
1.
Polymorphic or solid state form (amorphous, hydrate, solvate)
2.
Solubility at 37 oC over the physiological pH range (e.g., BCS,
dissolution testing, cleaning validation)
3.
Permeability (octanol-water partition) (BCS)
4.
Crystal habit, particle shape and size (pharmaceutical and
bioequivalence, processability)
5.
Bulk density, untapped and tapped (processability)
6.
Flowability (processability)
7.
Color, olor, taste, consistency (choice of dosage form)
should be discussed and supported by experimental data.
Slide 11 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Potentially critical attributes of API
Cross reference to stress testing (forced degradation):
1.
Sensitivity to temperature (wet granulation, sterilization)
2.
Sensitivity to moisture (wet granulation, hygroscopicity)
3.
Sensitivity to light (packing materials)
4.
Sensitivity to oxidation (inert gas atmosphere in ampoules)
5.
Sensitivity to pH (FDC with HCL salts of weak bases)
6.
Sensitivity to metal ions (internal peroxide bond)
Expected degradants, manufacturing conditions, etc.
This information is partially available from the OP of the DMF
Slide 12 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.2. Pharmaceutical development (choice of excipients)
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Intended function of each excipient
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Criteria
– compatibility of excipients with API(s),
– characteristics of the excipients (water content, particle size, flowability, density,
rheological behaviour…)
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Particularly : other non active constituents (lowest acceptable
concentration to be chosen e.g. concentration of parabens as
preservatives)
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Experimental data needed.
Slide 13 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
EXCIPIENTS - STARCH
 All starches are hygroscopic and rapidly absorb atmospheric
moisture. Approximate equilibrium moisture content values at 50%
relative humidity are:
 11% FOR MAIZE (CORN) STARCH,
 18% FOR POTATO STARCH,
 14% FOR RICE STARCH, AND
 13% FOR WHEAT STARCH.
 Between 30-80% relative humidity, corn starch is the least
hygroscopic starch and potato starch is the most hygroscopic
starch.
Slide 14 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.2. Pharmaceutical development (choice of formulation and
compatibility)
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Compatibility of APIs with the excipients
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Compatibility of APIs between each other in case of fixed
dose combinations
See example of 4 FDC for TB products
Slide 15 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example: 4 FDC FPP
3.2. Pharmaceutical development (choice of formulation and compatibility)
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Each tablet contains 4 APIs
. Rifampicin ………………. 150 mg
. Isoniazid …………………. 75 mg
. Pyrazinamid …………….. 400 mg
. Ethambutol 2HCl…………275 mg
. Excipients ………………..
Slide 16 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example: 4 FDC FPP
3.2. Pharmaceutical development (choice of formulation and compatibility)
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Rifampicin
Oxidation (quinone & N-oxide)
– Protect from air exposure
Hydrolysis (3-formylrifamycin & 25-desacetyl)
– Wet granulation/drying a potential problem ?
Reaction with Isoniazid
– Produces 3-(isonicotinylhydrazinomethyl) rifamycin or more commonly known
as isonicotinyl hydrazone.
Light sensitive
– Product to be protected from light exposure
Slide 17 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example: 4 FDC FPP
3.2. Pharmaceutical development (choice of formulation and compatibility)
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Isoniazid
Reacts with aldehydes/reducing sugars
– Sugar & lactose to be avoided in formulation !!
– 3-formylrifamycin (from rifampicin)
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Ethambutol hydrochloride (2HCl)
Hygroscopic
– Absorbs water reactions in tablets.
Creates slightly acidic conditions
– The acidic conditions enhance reaction between rifampicin and
isoniazid (isonicotinyl hydrazone formation)
Slide 18 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example: 4 FDC FPP
3.2. Pharmaceutical development (preventive/protective measures)
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Formulation – no sugar/lactose (isoniazid)
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Separate granulation of rifampicin & isoniazid (limit contact)
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Rifampicin as powder (not granulate) ?
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Prevent oxidation & hydrolysis
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Low water content of tablet
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Protect product from moisture and oxygen
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Film coating,
Non-permeable packaging
Light protection
Slide 19 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example: 4 FDC FPP, Critical quality variables
1. The formulation is hygroscopic, sensitive to light and
unstable.
2. Moisture content of FPP and intermediates.
3. Ethambutol.2HCl provides acidic conditions to accelerate
decomposition between rifampicin and isoniazid.
4. Packing materials are critical for stability.
Slide 20 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Manufacturing process
development
Laboratory scale
Selection of FPP and manufacturing process
Qualitative information
 Composition (innovator)
 Experimental methods
Tablets, hard capsules and powders
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Wet granulation
Dry granulation, or
Direct compression
Film coating
Primary packing
Different strengths with the same composition
Slide 22 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Manufacturing Process Development
The progress from pre-formulation (size:1x) → formulation (10x) →
pilot manufacture (100x but not less than 100,000 capsules or
tablets) → production scale (approved batch size) manufacture
should be shown in the dossier submitted for prequalification to be
logical, reasoned and continuous.
A pilot batch is manufactured by a procedure fully representative of
and simulating that to be applied to a full production scale batch.
Slide 23 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.2. Pharmaceutical development (choice of the manufacturing
process)
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Parameters : characteristics of the APIs, dosage form,
composition…. .
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Rational behind the choice
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Justification of the overage (if any)
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Identification of the critical steps
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In Process Control (IPC)
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Selection and optimisation of manufacturing process
Slide 24 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Overages in the formulation
Information should be provided on the
1. amount of overage,
2. reason for the overage (e.g., to compensate for
expected and documented manufacturing losses), and
3. justification for the amount of overage (API but not
EXCIPIENT).
The overage should be included in the amount of drug
substance listed in the batch formula.
Slide 25 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Compression
Tabletting machine
BB3
Granules, (Mg-stearate %)
β-Press
BB3
0.25
0. 50
0.50
LOD (%)
1.5
1.5
1.5
Median diameter (μm)
341
341
341
Tablets
Average weight (mg)
605
607
599
Hardness (kp)
10.9
9.7
7.3
0.3
0.5
0.8
Disintegration time
6’48’’
14’19’’
8’14’’
Dissolution (%, 15’)
99.5
76.7
92.0
Friability (%)
Slide 26 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Film-coating conditions
Spraying conditions
Pilot batch 1
Pilot batch 2
Manesty
Manesty
0.8
0.8
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-coater
Nozzle (mm)
Spraying pressure (psi)
Slide 27 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Film-coating results
Pilot batch 1
Quality parameter
Core
Pilot batch 2
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
3’40’’
5’32’’
1’44’’
2’46’’
Dissolution (15’, %)
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93
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98
Slide 28 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Manufacturing process
development
Pilot plant scale
Primary (exhibit) 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 appropriate.
Slide 30 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Manufacturing Process Development
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Significant differences between the manufacturing processes
used to produce batches for pivotal clinical trials (safety, efficacy,
bioavailability, bioequivalence) or primary stability studies and the
process described in 3.5 Manufacturing process should be
discussed.
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The information should include, for example,
– the identity (e.g., batch number) and use of the batches produced (e.g.,
bioequivalence study batch number),
– the manufacturing site,
– the batch size, and
– significant equipment differences (e.g., different design, operating
principle, size).
Slide 31 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Manufacturing Process Development
 An assessment of the ability of the process to reliably produce a
product of the intended quality e.g., the performance of the
manufacturing process under
– different operating conditions,
– at different scales, or
– with different equipment can be provided.
 Unsatisfactory processes must be modified and improved until a
validation exercise proves them to be satisfactory.
 An understanding of process robustness can be useful in risk
assessment and risk reduction.
Slide 32 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.2. Pharmaceutical development (dissolution testing)
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To study dissolution operating conditions (media, pH, rotation, …)
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To develop a discriminatory dissolution method
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Comparative dissolution testing is a tool, mandatory in development
pharmaceutics section of the dossier in PQ, See Supplement 1
– Help in selection of the formulation
 compare formulation(s) with innovator product,
 a basic strategy in development to maximize the chances of bioequivalence
– Comparison of pivotal batches to commercial batches/ post-approval changes
– Setting of dissolution specifications
Slide 33 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Dissolution profile testing
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Three media - 900 ml or less - all at 37°C
– Buffer pH 1.2, SGF without enzymes or 0.1M HCl
– Buffer pH 4.5
– Buffer pH 6.8 or SIF without enzymes
 Water may be used additionally (not instead of)
2.
Paddle at 50 or basket at 100 rpm
3.
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, when applicable
Slide 34 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Quality dossier / Section 3
Finished Pharmaceutical Product (FPP)
3.2. Pharmaceutical development (details of batches studied)
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Provide a summary of development of the FPP from preformulation to production scale.
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Provide a comparison of formulas (tabulated form) of :
– bio-batche(s) (clinical/bioequivalence),
– development batches,
– stability batches,
– batches for validation/production
Slide 35 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Special requirements
In case of tablets designed with a score line, information
should be given whether or not reproducible dividing of the
tablets has been shown. e.g. „the scoreline is only to
facilitate breaking for ease of swallowing and not to divide
into equal doses”, „the tablet can be divided into equal
halves”.
Slide 36 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Container closure system
 The choice and rationale for selection of the container closure
system for the commercial product [described in 3.10
Container/closure system(s) and other packaging] should be
discussed.
 The data should include details on:
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tightness of closure.
protection of the contents against external factors.
container/contents interaction (e.g. sorption, leaching).
influence of the manufacturing process on the container (e.g. sterilisation
conditions).
Slide 37 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Microbiological attributes
 The microbiological attributes of the FPP should be discussed in
this section. The discussion should include, for example:
– The rationale for performing or not performing microbial limits testing
for non-sterile FPPs (e.g., Decision Tree #8 in ICH Q6A
Specifications).
– Antimicrobial preservative effectiveness should be demonstrated
during development.
Slide 38 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example of Artemisinin Based Combinations
Slide 39 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example of ACTs: Artemisinin
 Active antimalarial constituent of the traditional Chinese
medicinal herb 青蒿素 Artemisia annua L., Compositae
 Artemisinin has seven (7) centers of assymetry but
Artemisia annua makes only one configuration
(Identification)
 Practically insoluble in water
 The bond energy of the O-O bond is ~30 kcal/mol
 When the peroxide comes into contact with high iron
concentrations, the molecule becomes unstable and
"explodes" into free radicals.
 The API, the capsules and the tablets are official in the
Ph. Int.
Slide 40 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example of ACTs: Artenimol
 Practically insoluble in water.
Slightly soluble in ethanols
and dichloromethane.
 Both the API and the tablets
are official in the Ph. Int.
Slide 41 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example of ACTs: Artesunate
 Very slightly soluble in water
 The ester linkage is in alpha
configuration.
 Both the API and the tablets
are official in the Ph. Int.
 Two functional groups are
liable to decomposition
Slide 42 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example of ACTs: Metabolism of Artemether and Artesunate
Slide 43 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example of ACTs: Amodiaquine
Amodiaquine Hydrochloride USP, C20H22ClN3O.2HCl.2H2O. Merck Index: pH
of 1% aqeous solution is from 4.0 to 4.8.
Slide 44 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example of ACTs: Mefloquine hydrochloride
 Has an optically active carbon
 Very slightly soluble in water
 Has no reactive functional
groups under general
environmental conditions
Slide 45 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example of ACTs: Lumefantrin
Slide 46 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example of ACTs: Pharmaceutical information
 Artemisinin derivatives may have α- or β-configuration and each of
them can exist in two conformations. The literature does not reveal
any impact of the geometric isomerism on efficacy, safety or quality
of artemisinins.
 The internal peroxide bound is the most reactive part of the
molecule. When the peroxide comes into contact with high iron
concentrations, the molecule becomes unstable and "explodes"
into free radicals.
 The ester bond of artesunate is liable to hydrolysis.
 The non-artemisinin APIs mentioned above are chemically stable.
Slide 47 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example of ACTs: Biopharmaceutical information
 The internal peroxide bound is fundamental for antimalarial activity.
 Artemisinin has a
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poor solubility in both water and oil,
short pharmacological half life,
high first-pass metabolism, and
poor oral bioavailability.
 Its lactol ethers –artemether and arteether– are soluble in oils.
 The lactol hemiester –artesunate– is slightly soluble in water and soluble
at a basic pH.
Slide 48 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example of ACTs: References
1.
Monographs from the Merck Index®, 13th edition (2001).
2.
Xuan-De Luo and Chia-Chiang Shen: The Chemistry,
Pharmacology and Clinical Applications of Qinghaosu (Artemisinin) and
its Derivatives (Med. Research Reviews, Vol. 7, No.1, 29-52 (1987).
3.
The International Pharmacopoeia, 3rd ed., Volume 5, 185-233,
WHO, Geneva (2003).
Slide 49 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example of ACTs: Compatibility of APIs in FDCs
 Artemether + Lumefantrine
 Artesunate + Amodiaquine.2HCl*
 Artesunate + Mefloquine.HCl*
 Artesunate + Sulphadoxine/Pyrimethamine (SP)
*Co-blistering, or bi-layered tablets
Slide 50 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Example of ACTs: Compatibility of the API with excipients and diluents
 Select innovator excipients (WHOPAR, EPAR, Section 6.1)
 Magnesium stearate is incompatible with salts of weak
bases and strong acids (e.g. Amodiaquine.2HCl)
because the formed MgCl2 is highly hygroscopic and,
as a result, its lubricant properties also change.
 The compatibility and in-use stability of the FP with
reconstitution diluents should be addressed, e.g. in
Artesunate injection.
Slide 51 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
Main points again
 Development pharmaceutics is an essential part of applications for
prequalification.
 Desk research gives valuable design and development information.
 The specifications of an API are finalized during pharmaceutical
development studies.
 FPP design, characterization and selection should follow a scientific
methodology.
 Manufacturing process design and optimization identifies the critical
attributes whose control leads to the batch-to-batch consistency of
quality.
Slide 52 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007
THANK YOU
Slide 53 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007