2006.08.22. Pogány - Dar es Salaam 1/66 WHO Training Workshop on Pharmaceutical Quality, GMP and...

2006.08.22. Pogány - Dar es Salaam 1/66

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

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

Tanzania, 22 August 2006E-mail: [email protected]

Pharmaceutical quality by design and development


AbbreviationsAPI Active Pharmaceutical Ingredient DRA Drug Regulatory Authority EoI Expression of Interest FDC Fixed-Dose CombinationFPP Finished Pharmaceutical Product GMP Good Manufacturing PracticesICH International Conference on HarmonizationMA Marketing AuthorizationPQIF Pharmaceutical Quality Information FormYellow → emphasis Green → WHO Blue → ICH region


Subjects for discussion1. 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


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.)


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


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


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) FPPsAll oral FPPs include paediatric formulations.(EOI is included in the Notes Page of this and the subsequent slides)


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.


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 (laboratory) Scale-Up (pilot plant) Production

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

analytical and formula screening) and stability batch reproducible

methods) biobatch) quality)

Quality Development

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


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.


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


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


Metabolism of Artemether and Artesunate


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


Mefloquine hydrochloride

Has an optically active carbon

Very slightly soluble in water

Has no reactive functional groups under general environmental conditions


Lumefantrin


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.


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.


References1. 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).



Tuberculosis

3.2.2 Company R & D

Laboratory scale


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).



Tuberculosis

API properties


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.

This information is partially available from the OP of the DMF


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.


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.


Solubility of artesunatepH Dissolved material (mg/ml)

1 1,9

5 1,5

6 3,5

7 10,2

8 12,2


Stress-testing of artesunate in aqueous solution

Conditions Time (h) Degradation (%)

Water 2 0

0.1N HCl 2 74

0.1N NaOH 2 100


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.


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


Dissolution Profile of Viramune and Generic Nevirapine Tablets on the Indian Market

USP Type II / 0.01N HCl 50 RPM / 900 ml

0

20

40

60

80

100

120

Time (Min)Viramune B.No.992633BBrand C B.No.C00139Ranbaxy B.No.(1024)17

0 10 20 30 450.0 83.3 96.6 97.7 99.70.0 34.3 51.3 61.2 70.80.0 88.9 97.6 99.2 99.7

% D

rug

Dis

so

lve

d

F2

20

73xxxxxxx


Dissolution profile 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


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%


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.


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.


Compatibility of APIs in FDCs

Artemether + Lumefantrine

Artesunate + Amodiaquine.2HCl*

Artesunate + Mefloquine.HCl*

Artesunate + Sulphadoxine/Pyrimethamine (SP)

*Co-blistering, or bi-layered tablets


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.


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



Tuberculosis

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.


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


Selection of binder and solvent

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

Granules

LOD(%) 0.8 0.9 0.8


Tablets

Average weight (mg) 626 624 628

Hardness (kp) 13.3 11.2 12.9

Friability (%) 0.5 0.5 0.4


Dissolution (%, 15’) 95.6 96.3 75.7


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”.


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.


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


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


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


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.


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.


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.


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).


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.

Manufacturing process development

Laboratory scale


Selection of FPP and manufacturing processQualitative 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


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.


CompressionTabletting machine BB3 BB3 β-Press

Granules, (Mg-stearate %) 0.25 0. 50 0.50

LOD (%) 1.5 1.5 1.5


Tablets

Average weight (mg) 605 607 599

Hardness (kp) 10.9 9.7 7.3

Friability (%) 0.3 0.5 0.8


Dissolution (%, 15’) 99.5 76.7 92.0


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


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

Manufacturing process development

Pilot plant scale


Primary (exhibit) 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.


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).


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.


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


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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