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| Slide 1 of 45 April 2007

Training Workshop onPharmaceutical Development withfocus on Paediatric Formulations

Protea Hotel

Victoria Junction, Waterfront

Cape Town, South Africa

Date: 16 to 20 April 2007

Pharmaceutical Development


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Developing formulation and manufacturing process

Presenter: Jnos Pogny, pharmacist, PhD

[email protected]

WHO expert
mailto:[email protected]:[email protected]


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Abbreviations

API Active Pharmaceutical Ingredient

EoI Expression of Interest

FDC Fixed-Dose Combination

FPP Finished Pharmaceutical Product

GMPGood Manufacturing Practices

ICH International Conference on Harmonization

MA MarketingAuthorization

PQP PreQualification Project

TRS Technical Report Series of WHO

Red emphasis Green WHO Violet ICH region


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Outline and Objectives of presentation

Objective, guidelines

Literature and patent survey

Generic pharmaceutical product and process development

assessors viewof a science- and risk-based approach Laboratory scale

Pilot plant

Production plant

Presentation of dossier for prequalification

Continuous improvement

Main points again


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Training Workshop onPharmaceutical Development with

focus on Paediatric Formulations

Objective, guidelines


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Interchangeability (IC)

INTERCHANGEABILITY (IC)OF MULTISOURCE

FPPs = THERAPEUTICAL EQUIVALENCE

WITH A COMPARATOR (REFERENCE) FPP=

PHARMACEUTICAL EQUIVALENCE (PE)+

BIOEQUIVALENCE (BE)

IC=PE+ BE


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Pharmaceutical equivalence

Products are pharmaceutical equivalents1if they contain the same molar amount of the same active pharmaceutical

ingredient(s)

in the same dosage form

if they meetcomparable standards, and

if they are intended to be administered by the same route

1Pharmaceutical equivalence does not necessarily imply therapeutic equivalence, asdifferences in the excipients and/or the manufacturing process and some other variables canlead to differences in product performance.

Pharmaceutical development equivalence, including

stability equivalence (and packaging equivalence)

WHO-GMP(manufacturing process equivalence)


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Focus on paediatric dosage forms

Epivir (lamivudine) 10 mg/ml oral solution Retrovir (zidovudine) 100 mg/10 ml oral solution

Sustiva(efavirenz) 30 mg/ml oral solution

Viramune (nevirapine) 50 mg/5 ml oral suspension

Zerit (stavudine) 200 mg powder for oral solution

Powder for oral suspension, capsules, film-coated tablets

and chocolate pastilles can also be considered

Once safe and effective doses are established, generic FPPs can bedeveloped and bioequivalence demonstrated


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QualificationStage ValidationStage

Key elements Design & C Installation Operation Prospective Concurrent

Facilitiesand Engineering phase Manufacturing Start-Up

Equipment

(ValidationProtocols) (Batch Records and Validationdocumentation)

Preparatory phase Design (laboratory) Scale-Up (pilot plant) Production

(Validationof (Critical attributes (process optimization (final batch size,

analytical and formula screening) and stability batch reproducible

methods) biobatch) quality)

Product and process development

Pharmaceutical development

C

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Guidelines used in PQP

Annex 6.Validation of manufacturing processes, in WHOTRS No. 863 (1996).

WHO Guidelineon Submission of Documentation forPrequalification of Multi-source (Generic) FinishedPharmaceutical Products (FPPs)Used in the Treatment of

HIV/AIDS, Malaria and Tuberculosis.3.2 PharmaceuticalDevelopment

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. Itidentifies elements/operations within the system that render it vulnerable.)


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Desk research

Nevirapine 50mg/5 ml oral suspension


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Information on Nevirapine

The synthesis of the two crystal formsis similar until the final drying step

Impurity profileis well characterised. Impurities arising from synthesis have been

toxicologically qualified

The API is milledin order to obtain an acceptable particle sizedistribution

The API is non-hygroscopic

No polymorphic changes were observedunder stressed conditions

No degradation productshave been detected during stability testing

Batch analysis dataconfirm that nevirapine hemihydrate complies with thespecificationshttp://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdf

http://www.fda.gov/cder/ogd/rld/20933s3.PDF

Nevirapine is official inthe PhInt
http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdfhttp://www.fda.gov/cder/ogd/rld/20933s3.PDFhttp://www.fda.gov/cder/ogd/rld/20933s3.PDFhttp://www.fda.gov/cder/ogd/rld/20933s3.PDFhttp://www.fda.gov/cder/ogd/rld/20933s3.PDFhttp://www.fda.gov/cder/ogd/rld/20933s3.PDFhttp://www.fda.gov/cder/ogd/rld/20933s3.PDFhttp://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdfhttp://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdfhttp://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdfhttp://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdfhttp://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdf


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Information on Nevirapine

Nevirapineis lipophilic(partition coefficient83) and is essentially nonionized at

physiologic pH.

As a weak base (pKa2.8), Nevirapine is

showing increased solubility at acidic pH

values.

Source: Meck Index

Aqueous solubility(anhydrate) (90g/ml at

25C).

Nevirapine ishighly stable


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Viramune 50 mg/5 ml oral suspension

Oral suspension containing 10 mg/ml of nevirapine as 10.35 mg/ml Nevirapine

Hemihydrateas theAPI. Excipients: Carbomer, methyl parahydroxybenzoate, propyl

parahydroxybenzoate, sorbitol, sucrose, polysorbate 80, sodium hydroxide andpurified water. (FDA excipient list: Carbomer 934P).

Shelf life: 3 yearsThe product should be used within 2 months of opening.

No special precautions for storage

Nature and contents of containerWhite HDPE bottle with two piece child-resistant closure (outer shell white HDPE, inner shell natural polypropylene) withLDPE foam liner. Each bottle contains 240 ml of oral suspension.Clear polypropylene 5-ml dispensing syringe(0.2 ml graduations) with siliconerubber piston seal.Clear low density polyethylene bottle-syringe adapter.

http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdf

http://www.fda.gov/cder/ogd/rld/20933s3.PDF

Nevirapine oral suspension monograph (PhInt) is being developed
http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdfhttp://www.fda.gov/cder/ogd/rld/20933s3.PDFhttp://www.fda.gov/cder/ogd/rld/20933s3.PDFhttp://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdf


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The HDPE bottlematerial is inert and was shown to be compatiblewith the activesubstance and other ingredients of the formulation.

The levels of preservatives have been correlated with antimicrobial effectivenesstested according to PhEur

Acceptable data demonstrating the precision and accuracy of the dosing syringewere provided.

Synthesis impurities are not degradants and not part of FPP specifications

The method of preparation of the oral suspension is standard for this form andhas been adequately described. Validation data presented on three productionbatches manufactured using three different lots of nevirapineanhydrous (?) wereadequate to demonstrate that the process is under control and ensures bothbatch-to-batch reproducibility and compliance with standard specifications. Tests

at release are standard and ensure reproducible clinical performance of theproduct.


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Stabilitydata up to 18 months for the newly recapped oralsuspension and 24 months with the old pulpboard liner confirmedthe physical and chemical stability of the oral suspension and theantimicrobial efficacy of the preservative. These results support ashelf life of 24 months. Long-term stability data will be submitted onongoing basis.

An in-use stability studydesigned to mimic the delivery of 2 mldose, which represents one of the lowest projected doses, twice aday, using the delivery device intended for marketing has beenperformed.

An additional studyis presented on the stability of the product

exposed to freeze-thaw conditions. On the basis of results fromboth studies, the claimed in-use shelf life of 60 dayswith no specialstorage precautions is supported.


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Clinical information

Nevirapine was readily absorbed (> 90 %) after oral administration in healthy

volunteers and in adults with HIV-1 infection.

A 3-way crossover study comparedthe bioavailability from threeproduction/commercial scale batches with varying dissolution profiles. All threebatches were bioequivalent with respect to systemic exposure (AUC). Thesignificantly different values for Cmax and tmax were considered not to beclinically relevant.

In studies 1100.1231 and 1100.896 in which the suspension was administereddirectly using a syringe, it was demonstrated that the suspension and tabletformulations were comparably bioavailablewith respect to extent of absorption.In study 1100.1213 the suspension was administered in a dosing cup withoutrinsing. The suspension intended for marketing was bioequivalent to thesuspension used during clinical trials but was not bioequivalent to the marketed

tablets. This could be attributed to incomplete dosing of the two suspensionssince there was about 13 % of the dose remaining in the cup.


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Clinical information

It has been later determined in a single dose study in 9 patients aged between 9

months and 14 yearsadministered after an overnight fast (3 patients per doselevel equivalent to 7.5 mg/m, 30.0 mg/m and 120.0 mg/m).

Based on adult experience, a comparable lead-in period of two weeks wassuggested for paediatric population.A 4 mg/kg dose is proposed for all childrenregardless the age. Although no particular study has been performed to find theoptimal lead-in dose, this dose was considered acceptable considering the

enzyme induction to achieve initial antiretroviral activity.

The final recommended dosesfor the different ages are therefore the following:

Patients from 2 months to 8 years, 4 mg/kg once daily for 2 weeks followed by7 mg/kg bid

Patients from 8 years to 16 yearsare 4 mg/kg once daily followed by 4-mg/kgbids.


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Generic pharmaceutical

product and process development


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Pharmaceutical development for generics

Product target profile (PTF) is different:

Innovator PTP is based on clinical studies

Generic FPP targets the innovator FPP

Multisource FPP manufacturers must be highly skilled in

product development

The chances of developing a bioequivalent generic product can

be significantly increased by using the formulation of the

innovator. The lowest risk strategy for the development of an

interchangeable multisource FPP is to copy the innovator FPP.

Manufacturing processes are the same for innovators and

generic manufacturers.


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Innovator suspensionbench marking (1)

Sample confirmation Batch numbers

Shelf life: 3 years and within 2 months of opening. Storage instructions: No special precautions for storage

Container and closure system: as per EPAR

QC analysis(hypothetical figures) Assay: 99.9% of labelled amount (LA)

Methylparaben (HPLC): 0.18% w/v

Propylparaben (HPLC): 0.02% w/v

Total related substances: 0.03%

Specific gravity (at 25oC): 1.150

Viscosity (at 25oC): 1,150 cPs

pH: 5.80


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Innovator suspensionbench marking (2)

The composition suggests that:

Sucrose and sorbitol are used

to adjust the density of the

medium

Carbomer 934P is used toadjust viscosity

Polysorbate is a wetting agent

Sodium hydroxide is used toadjust the pH to 5.8


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Innovator productbench marking (3)

% API dissolved(hypothetical figures)

Time (minutes)

275

4210

5515

6520

7630

8845

9260

Dissolution profile (% LA)

Apparatus: USP II (paddle,

25rpm)

Medium: 0.1N HCl

Volume: 900ml

http://www.accessdata.fda.gov/scripts/cder/diss

olution/dsp_SearchResults_Dissolutions.cfm

downloaded on 13 March 2007
http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfmhttp://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfmhttp://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfmhttp://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm


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Innovator productbench marking (4)




pH 6.8 bufferpH 4.5 bufferpH 1.2 bufferTime (minutes)

2215275

27254210

3536551542426520

49487630

57498845

65499260765010090

Dissolution profile (% LA), Apparatus: USP II (paddle, 25rpm), Volume: 900mlDifferent speeds to be investigated


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Pharmaceutical development protocol

API experiments

Solubility at 37 oC

Particle size distribution

Density

Formulation experiments Screening laboratory batches with different proportions of excipients to

match innovator dissolution

Stress testing of the selected composition

Compatibility with excipients

Antimicrobial effectiveness test according to PhEur

Packing materials Dimensions and tolerances of packing components

Precision and accuracy of the dosing syringe


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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

PhInt specifications + residual solvents from APIMF.

Product-specific physical properties depend on crystallization and subsequent

physical processing. Density and particle size distribution of Nevirapine Hemihydrate

are critical quality attributesof the API. Acceptance criteria are established by

measurement of particle size of innovators API in suspension and through the

similarity of dissolution profiles of innovator and generic products.


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Stress stability testing - Nevirapine

Stress type Conditions Assay (%)

Control 25oC 99.8

36% HCl 80oC, 40 min. 72.0

5N NaOH 80o

C, 2h 20 98.6

30% w/w H2O2 80oC, 2h 20 98.6

Heat 130oC, 49h 101.5

Light 500W/m2

, 68h 101.7

Water 25oC, 92% RH, 91h 101.2


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Solubility of nevirapine hemihydrate at 37oC

pH Dissolved material (mg/ml)(hypothetical figures)

1.2 2.75

2.1 0.28

3.0 0.08

4.5 0.06

6.8 0.06

7.2 0.06

8.0 0.06

Nevirapine Hemihydrate belongs to BCS Class 2 (low solubility, high permeability).

Solubility data are also important for cleaning validation


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Dissolution profiles of innovator and generic FPPs

M

ea

n

%

A

P

I

d

i

s

s

o

l

v

e

d

Time (minutes)

innovator

generic

Similarity

factor, f2=73

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80 90


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Selected generic composition (hypothetical figures)

Ingredients mg/5ml Nevirapine hemihydrate 51.7

Excipients Carbomer 934P 8.0

Methyl parahydroxybenzoate 10.0 Propyl parahydroxybenzoate 1.0

Sorbitol 800.0

Sucrose 700.0

Polysorbate 80 3.0

Sodium hydroxide q.s. Purified water to make 5.0 ml


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Compatibility with excipients

Nevirapine Hemihydrate in solid stateillustrative example: heat

Stress Treatment Observations

Assay:

SI1:

D1:

Total unspecified:

None Initial values API

Total impurities:

Assay:

SI1:

D2:

Total unspecified:

Heat

API is mixed with excipient, the

mixture is wetted and a thin layer ofthe powder blend is kept at 60C for

4 weeks in a Petri dish (open

system) Total impurities:

To do: stress testingthe dose-proportional mixture of the APIs in aqueous medium.


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Risk assessment matrixillustrative

Not critical to Q Potentially

critical to Q

Monitoring

strategy

Critical to Q

Control strategy

Milling

API

WeighingWetting

API

VehicleWet

milling

Filling Packing

Dissolution

Assay

Degradation

Contentuniformity

Stability

physical microbial

pH


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Process development

Selection of process: standard for oral aqueous suspensions

The progress frompre-formulation formulation pilotmanufacture(not less than 1/10th of production batch) production

scale(approved batch size) manufacture should be shown in the

dossier submitted for prequalification to be logical, reasoned and

continuous.

A pilot batchis manufactured by a procedure fully representative ofand simulating that to be applied to a full production scale batch.

Manufacture of primary batchesin the proposed container and

closure systems for: Bioequivalence and dissolution studies

Regulatory stability studies ( including in-use stability study and an additional

study under freeze-thaw conditions.)

Prospective validationof bioequivalence, dissolutionand stability batches


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Proposed FPP specifications

Description

Identification (HPLC) Dissolution (UV): Q = 70% in 45 minutes

pH = 4.86.2

Deliverable volume Average fill volume: NLT 240 ml

Fill volume variation: should meet PhInt requirements Related substances: not tested

Preservative content (HPLC) Methylparaben: 98 to 102% of LA [End of shelf life: 80 to 102% of LA] Propylparaben: 98 to 102% of LA [End of shelf life: 80 to 102% of LA]

Assay: 95.0 to 105.0% of LA

End-of shelf-life acceptance limits for assay should not be proposed at this stage.


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Scale up activities

Stability protocolis prepared

A large number of samples is tested from pilot scale batches to

establish provisional acceptance limits for the control of critical

process parameters (prospective validation, IPC limits) in order to

define design space (process knowledge)and control strategy(risk

mitigation)that encompasses aspects of scale, environmental

aspects of site, packaging, as well as final product stability. Theprocess will be well understood when:

all critical sources of variabilityhave been identifiedand explained

variabilityis managedby the process

product quality attributescan be accurately and reliably predicted

Validation protocolis written

Dossieris submittedfor prequalification


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High-shear batch mixer and in-line mixer


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Innovator FPP Generic FPP

Dissolution test

3 batchesProduction batch, or

NLT 1/10 of final size

Reference product Test product

Select a batch showing

intermediate dissolution

Dissolution (and bioequivalence) batch

Dissolution profile


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Special features of FDCs


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4-FDC antituberculosis FPP

Originator FPP in ICH region

None

FPP in current (14th) List Essential Medicines

Rifampicin 150 mg

Isoniazid 75 mg

Pyrazinamide 400 mg

Ethambutol 275 mg


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4FDC-TB tablets exposed to40C/75%RH for one week

Two differentproducts. Bleeding may start after moreexposure to stress testing without packing material. (Source:

North-West University, South Africa)

Control on left Control on left


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A typical incompatibility

Magnesium stearate is incompatiblewith salts of weak

bases and strong acids, such as:

Amodiaquine hydrochloride

Ethambutol hydrochloride

Mefloquine hydrochloride

because the formed MgCl2 is highly hygroscopic (the

hexahydrate is also deliquescent) and, as a result, the

lubricant properties of magnesium stearate alsochange.


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Critical quality variables

1. The formulation is hygroscopic, sensitive to lightand unstable (reaction between

rifampicin and isoniazid).2. Moisture contentof FPP and intermediates (granules and uncoated tablets).

3. Ethambutol.2HCl provides acidic conditionsto accelerate reaction between rifampicin

and isoniazid.

4. Packing materialsare critical for stability.

5. Compatibility of APIs with each other and withexcipients6. Stress stability testing of the final formulation

7. Controloftemperatureand RHduring the manufacturing process

8. Heavy-duty compression machine.

9. Validation batchesand annual product review reports.

10.Stability testing of the FPP to include visual inspection, assay, impurities and

degradants(in particular isonicotinyl hydrazone), LOD, hardness, and other

attributes.


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Main points again

Pharmaceutical development is an essential part of applications for

prequalification.

Desk research gives valuable information for generic pharmaceuticalproduct and process development for paediatric formulations.

FPP-specific quality and processability requirements are integratedinto the API specifications during pharmaceutical developmentstudies.

A science- and risk-based pharmaceutical development of genericFPPs provides a high level of assurance for interchangeability withthe innovator product.

Manufacturing process design and optimization identifies the criticalattributes whose control leads to the batch-to-batch consistency ofquality.


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Science- and risk-based approach means:

There will be no weak eye in the pharmaceutical development chain


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THANK YOU

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