2006.01.09. Pogány - Guilin 1/57

WHO Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence with a focus

on artemisinines

János Pogány, pharmacist, Ph.D. consultant to WHO

Guilin, China, 10 January 2006E-mail: pogany@t-online.hu

Pharmaceutical quality by design and development

2006.01.09. Pogány - Guilin 2/57

Abbreviations

API Active Pharmaceutical Ingredient

BP British Pharmacopoeia

FDC Fixed-Dose Combination

FPP Finished Pharmaceutical Product

ICH International Conference on Harmonization

PhEur European Pharmacopoeia

PhInt International Pharmacopoeia

USP United States Pharmacopeia

2006.01.09. Pogány - Guilin 3/57

Subjects for discussion1. DESIGN (product-specific research)

Desk research API (specifications, stress stability testing, etc.) FPP (pre-formulation, stability studies, etc.)

2. DEVELOPMENT (manufacturing process) Laboratory Pilot plant Production plant

3. Main points again

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

3.2.2 Information from literature (Desk research)

2006.01.09. Pogány - Guilin 5/57

EOI – Oral Preparations Artesunate* + Amodiaquine Artemether* + Lumefantrine* Artesunate* + Mefloquine Artesunate* + SP (sulphadoxine / pyrimethamine)

* No comparator at the beginning * High-risk API

+ ... FDC or co-blistered (co-packaged) FPPsAll oral FPPs include paediatric formulations.(EOI is included in the Notes Page of this and the subsequent slides)

2006.01.09. Pogány - Guilin 6/57

EOI – Other dosage forms Artemether Injection and rectal FPPs Artemotil (arteether) Injection Artesunate Injection and rectal FPPs Only FPPs listed in the EOI are discussed.

2006.01.09. Pogány - Guilin 7/57

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. Not included in the current EOI.

2006.01.09. Pogány - Guilin 8/57

Artemether

Practically insoluble in water Artemether injection is an

oily soulution

The API, the capsules, the tablets and the injection are official in the Ph. Int.

2006.01.09. Pogány - Guilin 9/57

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

2006.01.09. Pogány - Guilin 10/57

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

2006.01.09. Pogány - Guilin 11/57

Metabolism of Artemether and Artesunate

2006.01.09. Pogány - Guilin 12/57

AmodiaquineAmodiaquine Hydrochloride USP, C20H22ClN3O.2HCl.2H2O. Merck Index: pH of 1% aqeous solution is from 4.0 to 4.8.

2006.01.09. Pogány - Guilin 13/57

Mefloquine hydrochloride

Has an optically active carbon

Very slightly soluble in water

Has no reactive functional groups under general environmental conditions

2006.01.09. Pogány - Guilin 14/57

Lumefantrin

2006.01.09. Pogány - Guilin 15/57

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 bound of artesunate is liable to hydrolysis. The non-artemisinin APIs in the EoI are chemically stable.

2006.01.09. Pogány - Guilin 16/57

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.

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

2006.01.09. Pogány - Guilin 18/57

3.2.1 Company research and developmentThe 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).

2006.01.09. Pogány - Guilin 19/57

Qualification Stage Validation Stage

Key elements Design & C Installation Operation Prospective Concurrent

Facilities and Engineering phase Manufacturing Start-Up

Equipment

(Validation Protocols) (Batch Records and Validation documentation)

Product and Process Design (formulation) Scale-Up Production

(Validation of (Critical attributes (process optimization (final batch size,

analytical and Stability Testing) and pilot batches) reproducible

methods) quality)

Quality Development

2006.01.09. Pogány - Guilin 20/57

Product-specific physical API properties

Introduction of

the API starting

material(s) into

process

Production

of intermediate(s) 

Isolation and

purification

Physical processing

and packaging

Product-specific physical properties depend on crystallization

and subsequent physical processing.

2006.01.09. Pogány - Guilin 21/57

Potentially critical attributes of API

Key physicochemical characteristics:1. Solubility over the physiological pH range (e.g., BCS, dissolution testing,

cleaning validation)

2. Octanol-water partition (BCS)

3. Particle size (pharmaceutical and bioequivalence, processability)

4. Polymorphic or solid state form (if relevant)

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.

2006.01.09. Pogány - Guilin 22/57

Solubility of artesunatepH Dissolved material (mg/ml)

1 1,9

5 1,5

6 3,5

7 10,2

8 12,2

2006.01.09. Pogány - Guilin 23/57

Degradation of artesunate in aqueous solution

Conditions Time (h) Degradation (%)

Water 2 0

0.1N HCl 2 74

0.1N NaOH 2 100

2006.01.09. Pogány - Guilin 24/57

Relationship between permeability coefficient and octanol-water partition

1 Prednisolone

...

3 Dexamethazone

...

9 Dexamethazone-acetate

...

11 Progesterone

2006.01.09. Pogány - Guilin 25/57

Particle sizeWhen 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.

2006.01.09. Pogány - Guilin 26/57

Potentially critical attributes of APICross 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.

2006.01.09. Pogány - Guilin 27/57

Rate of water absorption as a function of RH

0,20

0,25

0,30

0,35

0,40

0,451 4 7 10 13 16 19 22 25 28

Lg time, t (3 min. units)

Lg

RH

, %

35%

55%

75%

100%

2006.01.09. Pogány - Guilin 28/57

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.

2006.01.09. Pogány - Guilin 29/57

Compatibility of APIs in FDCs

Artemether + Lumefantrine

Artesunate + Amodiaquine.2HCl

Artesunate + Mefloquine.HCl

Artesunate + Sulphadoxine/Pyrimethamine (SP)

2006.01.09. Pogány - Guilin 30/57

Compatibility of the API with excipients and diluents

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 of the drug product with reconstitution diluents should be addressed, e.g. in Artesunate injection.

2006.01.09. Pogány - Guilin 31/57

Selection of excipients - TalcTime (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

2006.01.09. Pogány - Guilin 32/57

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 6’30’’ 7’40’’ 10’50’’

Dissolution (%, 15’) 96.6 95.6 96.7

2006.01.09. Pogány - Guilin 33/57

Selection of binder and solvent

Povidone, water (W), ethanol (E) W-E W E

Granules

LOD(%) 0.8 0.9 0.8

Median diameter (μm) 186 179 184

Tablets

Average weight (mg) 626 624 628

Hardness (kp) 13.3 11.2 12.9

Friability (%) 0.5 0.5 0.4

Disintegration time 7’4’’ 2’10’’ 6’35’’

Dissolution (%, 15’) 95.6 96.3 75.7

2006.01.09. Pogány - Guilin 34/57

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”.

2006.01.09. Pogány - Guilin 35/57

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.

2006.01.09. Pogány - Guilin 36/57

Dissolution testing 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 rpm3. Twelve units of each product in all 3 media4. Dissolution samples collected at short intervals, e.g.

10, 15, 20, 30, 45 and 60 minutes Analyse samples for all APIs, when applicable

2006.01.09. Pogány - Guilin 37/57

Hypothetical dissolution profile of a 2-FDC FPP

020406080

100120

0 15 30 45 60

minutes

% d

isso

lved Series1

Series2

Series3

Series4

2006.01.09. Pogány - Guilin 38/57

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.

2006.01.09. Pogány - Guilin 39/57

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

2006.01.09. Pogány - Guilin 40/57

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

2006.01.09. Pogány - Guilin 41/57

4FDC-TB tablets exposed to40°C/75%RH for one week

Two different products. “Bleeding” may start after more exposure to stress testing without packing material. (North-West University, South Africa)

Control on left Control on left

2006.01.09. Pogány - Guilin 42/57

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.

2006.01.09. Pogány - Guilin 43/57

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.

2006.01.09. Pogány - Guilin 44/57

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.

2006.01.09. Pogány - Guilin 45/57

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).

2006.01.09. Pogány - Guilin 46/57

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.

2006.01.09. Pogány - Guilin 47/57

Pivotal batchesA 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.

2006.01.09. Pogány - Guilin 48/57

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.

2006.01.09. Pogány - Guilin 49/57

Manufacturing Process Development 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).

2006.01.09. Pogány - Guilin 50/57

Manufacturing Process Development The selection, the control, and any improvement

of the manufacturing process described in 3.5 Manufacturing process should be explained.

Appropriateness of the equipment used for the intended product(s) should be discussed.

Process development studies should provide the basis for process improvement, process validation, continuous process verification (where applicable), and any process control requirements.

2006.01.09. Pogány - Guilin 51/57

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.

2006.01.09. Pogány - Guilin 52/57

CompressionTabletting machine BB3 BB3 β-Press

Granules, (Mg-stearate %) 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

Friability (%) 0.3 0.5 0.8

Disintegration time 6’48’’ 14’19’’ 8’14’’

Dissolution (%, 15’) 99.5 76.7 92.0

2006.01.09. Pogány - Guilin 53/57

Film-coating conditionsSpraying 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

2006.01.09. Pogány - Guilin 54/57

Film-coating results

Quality parameterPilot batch 1 Pilot batch 2

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 3’40’’ 5’32’’ 1’44’’ 2’46’’

Dissolution (15’, %) - 93 - 98

2006.01.09. Pogány - Guilin 55/57

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.

2006.01.09. Pogány - Guilin 56/57

Literature1. 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).

2006.01.09. Pogány - Guilin 57/57

THANK YOU

谢谢 !