Slide 1 of 53D.K. Mubangizi, Dar Es Salaam Sept. 2007 Training Workshop for Evaluators from National Medicines Regulatory Authorities in East African Community.

Slide 1 of 53 D.K. Mubangizi, Dar Es Salaam Sept. 2007

Training Workshop for Evaluators from National

Medicines Regulatory Authorities in East African

Community

Dar Es Salaam, Tanzania

Date: 10 to 14 September 2007

Evaluation of Quality and Interchangeability of Medicinal Products





3.0 Finished Pharmaceutical Products

3.2 Pharmaceutical Development

Presenter: Deus K. Mubangizi, pharmacist, MSc(Pharm.)

[email protected], [email protected]

Chief Inspector of Drugs, National Drug Authority

WHO expert

mailto:[email protected]

mailto:[email protected]


3.2 Pharmaceutical Development3.2 Pharmaceutical Development

Outline of presentation

– 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


Applicable guidelinesApplicable 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)


Quality dossier / Section 3Finished Pharmaceutical Product (FPP)


3.2. Pharmaceutical development

The aim is to build a quality product by design.

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)


General considerationsGeneral 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




3.2. Pharmaceutical development

The section should contain information on the development studies conducted to establish that

– 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.


3.2.1 Company research and development3.2.1 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).




3.2. Pharmaceutical development (pre-formulation)

Physico-chemical characteristics of the APIs– solubility (composition)– water content (stability)– hygroscopicity (stability)– particle size (solubility, bioavailability, suspension properties,

stability …)– polymorphism (solubility, bioavailability, stability)

Data obtained from literature : Books, Journals, International Pharmaceutical Abstracts, Chemical Abstracts, Analytical Abstracts, Internet ……

Experimental data (if necessary)


Particle sizeParticle 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).


Potentially critical attributes of APIPotentially 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.


Potentially critical attributes of APIPotentially 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




3.2. Pharmaceutical development (choice of excipients)

Intended function of each excipient

Criteria – compatibility of excipients with API(s),– characteristics of the excipients (water content, particle size, flowability, density,

rheological behaviour…)

Particularly : other non active constituents (lowest acceptable concentration to be chosen e.g. concentration of parabens as preservatives)

Experimental data needed.


EXCIPIENTS - STARCHEXCIPIENTS - 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.




3.2. Pharmaceutical development (choice of formulation and compatibility)

Compatibility of APIs with the excipients

Compatibility of APIs between each other in case of fixed dose combinations

See example of 4 FDC for TB products


Example: 4 FDC FPPExample: 4 FDC FPP


Each tablet contains 4 APIs

. Rifampicin ………………. 150 mg

. Isoniazid …………………. 75 mg

. Pyrazinamid …………….. 400 mg

. Ethambutol 2HCl…………275 mg

. Excipients ………………..




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




Isoniazid

Reacts with aldehydes/reducing sugars– Sugar & lactose to be avoided in formulation !!– 3-formylrifamycin (from rifampicin)

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)



3.2. Pharmaceutical development (preventive/protective measures)

Formulation – no sugar/lactose (isoniazid)

Separate granulation of rifampicin & isoniazid (limit contact)

Rifampicin as powder (not granulate) ?– Prevent oxidation & hydrolysis

Low water content of tablet

Protect product from moisture and oxygen– Film coating,– Non-permeable packaging

Light protection


Example: 4 FDC FPP, Critical quality variablesExample: 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.

Manufacturing process development

Laboratory scale


Selection of FPP and manufacturing processSelection 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


Manufacturing Process DevelopmentManufacturing 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.




3.2. Pharmaceutical development (choice of the manufacturing process)

Parameters : characteristics of the APIs, dosage form, composition…. .

Rational behind the choice

Justification of the overage (if any)

Identification of the critical steps

In Process Control (IPC)

Selection and optimisation of manufacturing process


Overages in the formulation 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.


CompressionCompression

Tabletting machineBB3BB3β-Press

Granules, (Mg-stearate %)0.250. 500.50

LOD (%) 1.51.51.5

Median diameter (μm)341341341

Tablets

Average weight (mg)605607599

Hardness (kp)10.99.77.3

Friability (%)0.30.50.8

Disintegration time6’48’’14’19’’8’14’’

Dissolution (%, 15’)99.576.792.0


Film-coating conditionsFilm-coating conditions

Spraying conditionsPilot batch 1Pilot batch 2

Film-coaterManestyManesty

Nozzle (mm)0.80.8

Spraying pressure (psi)40/2540/25

Inlet temperature (oC)8171

Outlet temperature (oC)4544

Spray rate (g/min)3626

Drum speed (rpm)810


Film-coating resultsFilm-coating results

Quality parameterPilot batch 1Pilot batch 2

CoreCoatedCoreCoated

Weight increase (%)2.122.04

Appearancegoodgood

Mean thickness (mm)4.254.284.344.37

Hardness (kp)9.214.78.710.8

Friability (%)0.300.440

Disintegration time3’40’’5’32’’1’44’’2’46’’

Dissolution (15’, %)-93-98

Manufacturing process development

Pilot plant scale


Primary (exhibit) batchesPrimary (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.



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).



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.




3.2. Pharmaceutical development (dissolution testing)

To study dissolution operating conditions (media, pH, rotation, …)

To develop a discriminatory dissolution method

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


Dissolution profile testingDissolution 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 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




3.2. Pharmaceutical development (details of batches studied)

Provide a summary of development of the FPP from pre-formulation to production scale.

Provide a comparison of formulas (tabulated form) of :

– bio-batche(s) (clinical/bioequivalence),

– development batches,

– stability batches,

– batches for validation/production


Special requirementsSpecial 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”.


Container closure system 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 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.


Example of Artemisinin Based Combinations


Example of ACTs: ArtemisininExample 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.


Example of ACTs: ArtenimolExample 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.


Example of ACTs: ArtesunateExample 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


Example of ACTs: Metabolism of Artemether and ArtesunateExample of ACTs: Metabolism of Artemether and Artesunate


Example of ACTs: AmodiaquineExample of ACTs: Amodiaquine

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


Example of ACTs: Mefloquine hydrochlorideExample of ACTs: Mefloquine hydrochloride

Has an optically active carbon

Very slightly soluble in water

Has no reactive functional groups under general environmental conditions


Example of ACTs: LumefantrinExample of ACTs: Lumefantrin


Example of ACTs: Pharmaceutical informationExample 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.


Example of ACTs: Biopharmaceutical informationExample of ACTs: 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.


Example of ACTs: ReferencesExample 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).


Example of ACTs: Compatibility of APIs in FDCsExample 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


Example of ACTs: Compatibility of the API with excipients and diluents 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.


Main points againMain 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.


THANK YOUTHANK YOU

Slide 1 of 53D.K. Mubangizi, Dar Es Salaam Sept. 2007 Training Workshop for Evaluators from National Medicines Regulatory Authorities in East African Community.

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