PharmDesign QualityDevelopment

WHO Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence with a focus on artemisinines
Pharmaceutical quality by design and development

Jnos Pogny, pharmacist, Ph.D. consultant to WHO Tanzania, 22 August 2006 E-mail: pogany.janos@chello.hu
2006.08.22.
Pogny - Dar es Salaam
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Abbreviations
API DRA EoI FDC FPP GMP ICH MA PQIF Active Pharmaceutical Ingredient Drug Regulatory Authority Expression of Interest Fixed-Dose Combination Finished Pharmaceutical Product Good Manufacturing Practices International Conference on Harmonization Marketing Authorization Pharmaceutical Quality Information Form
Green WHO
Yellow emphasis
2006.08.22.
Blue ICH region

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Subjects for discussion

1.
DESIGN (product-specific research)

Desk research API (specifications, stress stability testing, etc.) FPP (pre-formulation, screening stability studies, etc.)
2.
DEVELOPMENT [FPP and manufacturing process (same for innovator and generic FPPs)]

Laboratory Pilot plant (dissolution equivalence, stability and bioequivalence studies, tentative FPP specifications, prospective validation) Production plant (concurrent validation)
3.
Main points again

2006.08.22. Pogny - Dar es Salaam
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Applicable guidelines
Annex 6. Validation of manufacturing processes, in WHO
TRS No. 863 (1996).

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) ICH Q9 Quality risk management (E.g., FMEA might be used to
analyze a manufacturing operation and its effect on product or process. It identifies elements/operations within the system that render it vulnerable.)
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WHO guidelines
Annex 7 - Multisource (generic) pharmaceutical products:
guidelines on registration requirements to establish interchangeability, in WHO TRS, No. 937, 2006 Annex 8 - Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms (ibid) Annex 11 - Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products, in WHO Technical Report Series, No. 902, 2002 Annex 5 - Guidelines for registration of fixed-dose combination medicinal products, in WHO TRS, No. 929, 2005
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Related WHO guidelines

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 Guidance on Variations to a Prequalified Dossier
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EOI Scope of presentation

Artesunate* + Amodiaquine Artemether* + Lumefantrine* Artesunate* + Mefloquine Artesunate* + SP (sulphadoxine / pyrimethamine) * No comparator at the beginning * High quality-risk API
+ ... FDC or co-blistered (co-packaged) FPPs All oral FPPs include paediatric formulations.
(EOI is included in the Notes Page of this and the subsequent slides)
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EOI Scope of presentation

Artemether Injection and rectal FPPs
Artemotil (arteether) Injection Artesunate Injection and rectal FPPs
Only FPPs listed in the EOI are discussed.
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Qualification Stage Key elements Design & C Installation Operation
Validation Stage Prospective Concurrent
Facilities and Equipment
Engineering phase
Manufacturing Start-Up
(Validation Protocols)
(Batch Records and Validation documentation)
Product and Process (Validation of analytical methods)
Design (laboratory) (Critical attributes and formula screening)
Scale-Up (pilot plant) (process optimization and stability batch biobatch)
Production (final batch size, reproducible quality)
Quality Development
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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
3.2.1 Information from literature (Desk research)
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
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Artemisinin
Active antimalarial constituent of the traditional Chinese
medicinal herb 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. Not included in the current EOI.
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Artenimol
Practically insoluble in
water. Slightly soluble in ethanols and dichloromethane.

Both the API and the
tablets are official in the Ph. Int.

Not included in the
current EOI
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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
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Metabolism of Artemether and Artesunate
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Amodiaquine
Amodiaquine Hydrochloride USP, C20H22ClN3O.2HCl.2H2O. Merck Index: pH of 1% aqeous solution is from 4.0 to 4.8.
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Mefloquine hydrochloride
Has an optically active
carbon Very slightly soluble in water Has no reactive functional groups under general environmental conditions
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Lumefantrin
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Pharmaceutical information
Artemisinin derivatives may have - or -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 bound of artesunate is liable to hydrolysis. The non-artemisinin APIs in the EoI are chemically stable.
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Biopharmaceutical information
The internal peroxide bound is fundamental for antimalarial
activity.
Artemisinin has a

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.
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References
1. 2.
Monographs from the Merck Index, 13th edition (2001).

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).
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3.2.2 Company R & D Laboratory scale
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).
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API properties
Potentially critical attributes of API

Cross reference to stress testing (forced degradation):
1. 2. 3. 4. 5. 6.
Sensitivity to temperature (wet granulation, sterilization) Sensitivity to moisture (wet granulation, hygroscopicity) Sensitivity to light (packing materials) Sensitivity to oxidation (inert gas atmosphere in ampoules) Sensitivity to pH (FDC with HCL salts of weak bases) Sensitivity to metal ions (internal peroxide bond)
Expected degradants, manufacturing conditions, etc. This information is partially available from the OP of the DMF
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Product-specific physical API properties
Introduction of the API starting material(s) into process
Production
Isolation and purification
of intermediate(s)
Physical processing and packaging
Product-specific physical properties depend on crystallization and subsequent physical processing.

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Potentially critical attributes of API

Key physicochemical characteristics:
Polymorphic or solid state form (amorphous, hydrate, solvate) 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.
1. 2.
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Solubility of artesunate
pH
1
Dissolved material (mg/ml)

1,9
5
6 7 8
1,5
3,5 10,2 12,2
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Stress-testing of artesunate in aqueous solution

Conditions
Water 0.1N HCl 0.1N NaOH
Time (h)
2 2 2
Degradation (%)
0 74 100
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Particle size
When the solubility of an API is less than 0.1 mg/ml 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.
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Effect of Particle Size on Dissolution
Dissolution profiles in USP apparatus 2 at 50 rpm and pH 4.5 for product produced with different particle size of the API 2006.08.22. Pogny - Dar es Salaam
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Dissolution Profile of Viramune and Generic Nevirapine Tablets on the Indian Market
USP Type II / 0.01N HCl 50 RPM / 900 ml 120
% Drug Dissolved
100 80 60 40 20 0
F2
20 73
Time (Min) Viramune B.No.992633B Brand C B.No.C00139 Ranbaxy B.No.(1024)17
xxxxxxx
0 0.0 0.0 0.0
10 83.3 34.3 88.9
20 96.6 51.3 97.6
30 97.7 61.2 99.2
45 99.7 70.8 99.7
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Dissolution profile testing
2. 3. 4.
Three media - 900 ml or less - all at 37C 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) 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, when applicable
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Rate of water absorption as a function of RH

0,45 0,40
Lg RH, %
35% 0,35 0,30 0,25 0,20 55% 75% 100%
10
13
16
19
22
25
Lg time, t (3 min. units)
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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.
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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.
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Compatibility of APIs in FDCs

Artemether + Lumefantrine
Artesunate + Amodiaquine.2HCl* Artesunate + Mefloquine.HCl* Artesunate + Sulphadoxine/Pyrimethamine (SP)
*Co-blistering, or bi-layered tablets
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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.
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Selection of excipients - Talc

Time (week) Talc A Salicylic acid, % Talc B Salicylic acid, %
0
4 8 12
2006.08.22.
0.10
0.32 0.41 0.80
0.10
5.85 13.00 28.50
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Pre-formulation
Dissolution testing*
Dissolution testing is used for the selection of the formulation and comparison of the dissolution profiles with that of the innovator product and clinical batches. This should be a basic strategy in pharmaceutical development to maximize the chances of bioequivalence. Limits should be set for each API in fixed-dose FPPs.
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.
*Supplement 1 to the Generic Guideline.

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Selection of tablet mass

Composition
API (mg) Excipients (mg)
A
500 200
B
500 125
C
500 56
Tablet mass (mg):

Granules, LOD (%) Median diameter (m) Tablets, hardness (kp)
700
0,9 194 12.8
625
0,8 186 13.3
556
0,8 189 12.4
Friability (%)
Disintegration time Dissolution (%, 15)
0.7
630 96.6
0.5
740 95.6
0.5
1050 96.7
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Selection of binder and solvent

Povidone, water (W), ethanol (E) Granules
LOD(%) Median diameter (m) 0.8 186 0.9 179 0.8 184
W-E
Tablets
Average weight (mg) Hardness (kp) Friability (%) 626 13.3 0.5 624 11.2 0.5 628 12.9 0.4
Disintegration time
Dissolution (%, 15)
74
95.6
210
96.3
635
75.7
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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.
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Artemether injection
Possible design and development issues: Selection of oil. Heat stability of the oil and the oily solution of artemether (standard conditions for dry heat sterilization: NLT 160oC, two hours) Alternatively, sterile filtration under aseptic conditions.
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Artesunate injection
In the treatment of severe malaria, intravenous artesunate is
more rapidly acting than intravenous quinine in terms of parasite clearance, is safer, and is simpler to administer, but whether it can reduce mortality is uncertain.
Every 60mg vial contained anhydrous artesunic acid, which

we dissolved in 1mL 5% sodium bicarbonate and then mixed with 5mL of 5% dextrose before injecting as a bolus into an indwelling intravenous cannula. www.thelancet.com Vol366 August 27, 2005
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4-FDC antituberculosis FPP

Originator FPP in ICH region None FPP in current Essential Drug List Rifampicin 150 mg Isoniazid 75 mg Pyrazinamide 400 mg Ethambutol 275 mg
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4FDC-TB tablets exposed to 40C/75%RH for one week

Two different products. Bleeding may start after more exposure to stress testing without packing material. (NorthWest University, South Africa) Control on left Control on left
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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.
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Special attention in assessment

Compatibility of APIs with each other and with
excipients. Stress stability of the final formulation. Equilibrium moisture content of granules and uncoated tablets. Control of temperature and RH during the manufacturing process.
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Special attention in assessment

Specifications and sampling of the primary packing
materials. Heavy-duty compression machine. Validation batches and annual product review reports. Stability testing of the FPP to include visual inspection, assay, impurities and degradants (in particular isonicotinyl hydrazone), water, hardness, and other attributes.
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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:

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).
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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.
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Manufacturing process development

Laboratory scale
Selection of FPP and manufacturing process

Qualitative information
Composition (innovator) Experimental methods
Tablets, hard capsules and powders

Wet granulation Dry granulation, or Direct compression Film coating
Primary packing Different strengths with the same composition

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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.
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Compression
Tabletting machine
BB3
0.25
1.5 341 605 10.9 0.3
BB3
0. 50
1.5 341 607 9.7 0.5
-Press
0.50
1.5 341 599 7.3 0.8
Granules, (Mg-stearate %)
LOD (%) Median diameter (m) Tablets Average weight (mg) Hardness (kp) Friability (%)
Disintegration time
Dissolution (%, 15)
648
99.5
1419
76.7
814
92.0
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Film-coating conditions
Spraying conditions Film-coater Nozzle (mm) Spraying pressure (psi) Inlet temperature (oC) Outlet temperature (oC) Spray rate (g/min) Drum speed (rpm) Pilot batch 1 Manesty 0.8 40/25 81 45 36 8 Pilot batch 2 Manesty 0.8 40/25 71 44 26 10
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Film-coating results
Pilot batch 1 Quality parameter Weight increase (%) Appearance Mean thickness (mm) Hardness (kp) Friability (%) Disintegration time Dissolution (15, %) 4.25 9.2 0.3 340 Core Coated 2.12 good 4.28 14.7 0 532 93 4.34 8.7 0.44 144 Pilot batch 2 Core Coated 2.04 good 4.37 10.8 0 246 98
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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.
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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. 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).
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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.
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The remaining steps

Pharmaceutical equivalence and bioequivalence
with innovator product has been demonstrated Production batches validated Compilation of the dossier for prequalification Prequalification procedure GMP inspection Listing the FPP on the PQ website
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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.
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THANK YOU
2006.08.22.
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WHO Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence with a focus on artemisinines

Pharmaceutical quality by design and development

Pogny - Dar es Salaam

Blue ICH region

Subjects for discussion

DESIGN (product-specific research)

Main points again

TRS No. 863 (1996).

Pogny - Dar es Salaam

Related WHO guidelines

Pogny - Dar es Salaam

EOI Scope of presentation

Pogny - Dar es Salaam

EOI Scope of presentation

Only FPPs listed in the EOI are discussed.

Pogny - Dar es Salaam

Qualification Stage Key elements Design & C Installation Operation

Validation Stage Prospective Concurrent

Facilities and Equipment

(Batch Records and Validation documentation)

Product and Process (Validation of analytical methods)

Design (laboratory) (Critical attributes and formula screening)

Scale-Up (pilot plant) (process optimization and stability batch biobatch)

Production (final batch size, reproducible quality)

Pogny - Dar es Salaam

3.2.1 Information from literature (Desk research)

Pogny - Dar es Salaam

medicinal herb Artemisia annua L., Compositae

Artemisia annua makes only one configuration (Identification)

Ph. Int. Not included in the current EOI.

Pogny - Dar es Salaam

water. Slightly soluble in ethanols and dichloromethane.

tablets are official in the Ph. Int.

Pogny - Dar es Salaam

Metabolism of Artemether and Artesunate

Pogny - Dar es Salaam

Pogny - Dar es Salaam

Pogny - Dar es Salaam

Pogny - Dar es Salaam

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.

Pogny - Dar es Salaam

Monographs from the Merck Index, 13th edition (2001).

Pogny - Dar es Salaam

3.2.2 Company R & D Laboratory scale

3.2.1 Company research and development

Potentially critical attributes of API

Pogny - Dar es Salaam

Product-specific physical API properties

Introduction of the API starting material(s) into process

Isolation and purification

Physical processing and packaging

Product-specific physical properties depend on crystallization and subsequent physical processing.

Potentially critical attributes of API

Dissolved material (mg/ml)

Pogny - Dar es Salaam

Stress-testing of artesunate in aqueous solution

Pogny - Dar es Salaam

Pogny - Dar es Salaam

Effect of Particle Size on Dissolution

Time (Min) Viramune B.No.992633B Brand C B.No.C00139 Ranbaxy B.No.(1024)17

0 0.0 0.0 0.0