| slide 1 of 45 april 2007 training workshop on pharmaceutical development with focus on paediatric...

| Slide 1 of 45 April 2007

Training Workshop on Pharmaceutical Development

with focus on Paediatric Formulations

Protea Hotel

Victoria Junction, Waterfront

Cape Town, South Africa

Date: 16 to 20 April 2007

Pharmaceutical DevelopmentPharmaceutical DevelopmentPharmaceutical DevelopmentPharmaceutical Development


Pharmaceutical DevelopmentPharmaceutical DevelopmentPharmaceutical DevelopmentPharmaceutical Development

Developing formulation and manufacturing process

Presenter: János Pogány, pharmacist, PhD

[email protected]

WHO expert

mailto:[email protected]


AbbreviationsAbbreviationsAbbreviationsAbbreviationsAPI Active Pharmaceutical Ingredient EEoIoI EExpression oof IInterest FDC Fixed-Dose CombinationFPP Finished Pharmaceutical ProductGMPGMP GGood MManufacturing PPracticesICHICHIInternational CConference on HHarmonizationMA Marketing AuthorizationPQPPQP PPreQQualification PProjectTRSTRS TTechnical RReport SSeries of WHOof WHO

Red Red →→ emphasis emphasis Green Green →→ WHO WHO Violet Violet →→ ICH region ICH region


Pharmaceutical DevelopmentPharmaceutical DevelopmentPharmaceutical DevelopmentPharmaceutical DevelopmentOutline and Objectives of presentation

Objective, guidelines

Literature and patent survey

Generic pharmaceutical product and process development –assessors view of a science- and risk-based approach

– Laboratory scale – Pilot plant – Production plant – Presentation of dossier for prequalification – Continuous improvement

Main points again

Training Workshop on Training Workshop on Pharmaceutical Development with Pharmaceutical Development with focus on Paediatric Formulationsfocus on Paediatric Formulations

Objective, guidelines


Interchangeability (IC)Interchangeability (IC)Interchangeability (IC)Interchangeability (IC)

INTERCHANGEABILITY (IC)INTERCHANGEABILITY (IC) OF MULTISOURCE

FPPs = THERAPEUTICAL EQUIVALENCE THERAPEUTICAL EQUIVALENCE

WITH A COMPARATOR (REFERENCE) FPPWITH A COMPARATOR (REFERENCE) FPP =

PHARMACEUTICAL EQUIVALENCEPHARMACEUTICAL EQUIVALENCE (PEPE) +

BIOEQUIVALENCE (BE)

ICIC = PEPE + BE


Pharmaceutical equivalencePharmaceutical equivalencePharmaceutical equivalencePharmaceutical equivalence

Products are pharmaceutical equivalentsProducts are pharmaceutical equivalents11 if they contain the– same molar amount of the same active pharmaceutical

ingredient(s)– in the same dosage form– if they meet comparable standards, and– if they are intended to be administered by the same route

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

Pharmaceutical development equivalencePharmaceutical development equivalence, including stability , including stability equivalence (and packaging equivalence)equivalence (and packaging equivalence)

WHO-GMPWHO-GMP (manufacturing process equivalence)(manufacturing process equivalence)


Focus on paediatric dosage formsFocus on paediatric dosage formsFocus on paediatric dosage formsFocus 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 be developed and bioequivalence demonstrated


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)

Preparatory phase 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)

Product and process development

Pharmaceutical developmentPharmaceutical developmentPharmaceutical developmentPharmaceutical developmentCONTINUOUS IMPROVEMENT


Guidelines used in PQPGuidelines used in PQPGuidelines used in PQPGuidelines used in PQP 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.)


Desk research

Nevirapine 50mg/5 ml oral suspension


Information on NevirapineInformation on NevirapineInformation on NevirapineInformation on Nevirapine The synthesis of the two crystal forms is similar until the final drying step

Impurity profile is well characterised. Impurities arising from synthesis have been toxicologically qualified

The API is milled in order to obtain an acceptable particle size distribution

The API is non-hygroscopic

No polymorphic changes were observed under stressed conditions

No degradation products have been detected during stability testing

Batch analysis data confirm that nevirapine hemihydrate complies with the specificationshttp://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdf http://www.fda.gov/cder/ogd/rld/20933s3.PDF

Nevirapine is official in the PhInt

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

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


Information on NevirapineInformation on NevirapineInformation on NevirapineInformation on Nevirapine

Nevirapine is lipophilic (partition coefficient

83) and is essentially nonionized at

physiologic pH.

As a weak base (pKa 2.8), Nevirapine is

showing increased solubility at acidic pH

values.

Source: Meck Index

Aqueous solubility (anhydrate) (90μg/ml at

25°C).

Nevirapine is highly stable


VViramuneiramune 50 mg/5 ml oral suspension 50 mg/5 ml oral suspensionVViramuneiramune 50 mg/5 ml oral suspension 50 mg/5 ml oral suspension Oral suspension containing 10 mg/ml of nevirapine as 10.35 mg/ml Nevirapine

Hemihydrate as the API. Excipients: Carbomer, methyl parahydroxybenzoate, propyl

parahydroxybenzoate, sorbitol, sucrose, polysorbate 80, sodium hydroxide and purified 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 container White HDPE bottle with two piece child-

resistant closure (outer shell white HDPE, inner shell natural polypropylene) with LDPE foam liner. Each bottle contains 240 ml of oral suspension.Clear polypropylene 5-ml dispensing syringe (0.2 ml graduations) with silicone rubber 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






VViramuneiramune 50 mg/5 ml oral suspension 50 mg/5 ml oral suspensionVViramuneiramune 50 mg/5 ml oral suspension 50 mg/5 ml oral suspension The HDPE bottle material is inert and was shown to be compatible with the

active substance and other ingredients of the formulation.

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

Acceptable data demonstrating the precision and accuracy of the dosing syringe were 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 and has been adequately described. Validation data presented on three production batches manufactured using three different lots of nevirapine anhydrous (?) were adequate to demonstrate that the process is under control and ensures both batch-to-batch reproducibility and compliance with standard specifications. Tests at release are standard and ensure reproducible clinical performance of the product.


VViramuneiramune 50 mg/5 ml oral suspension 50 mg/5 ml oral suspensionVViramuneiramune 50 mg/5 ml oral suspension 50 mg/5 ml oral suspension

Stability data up to 18 months for the newly recapped oral suspension and 24 months with the old pulpboard liner confirmed the physical and chemical stability of the oral suspension and the antimicrobial efficacy of the preservative. These results support a shelf life of 24 months. Long-term stability data will be submitted on ongoing basis.

An in-use stability study designed to mimic the delivery of 2 ml dose, which represents one of the lowest projected doses, twice a day, using the delivery device intended for marketing has been performed.

An additional study is presented on the stability of the product exposed to freeze-thaw conditions. On the basis of results from both studies, the claimed in-use shelf life of 60 days with no special storage precautions is supported.


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

volunteers and in adults with HIV-1 infection.

A 3-way crossover study compared the bioavailability from three production/commercial scale batches with varying dissolution profiles. All three batches were bioequivalent with respect to systemic exposure (AUC). The significantly different values for Cmax and tmax were considered not to be clinically relevant.

In studies 1100.1231 and 1100.896 in which the suspension was administered directly using a syringe, it was demonstrated that the suspension and tablet formulations were comparably bioavailable with respect to extent of absorption. In study 1100.1213 the suspension was administered in a dosing cup without rinsing. The suspension intended for marketing was bioequivalent to the suspension used during clinical trials but was not bioequivalent to the marketed tablets. This could be attributed to incomplete dosing of the two suspensions since there was about 13 % of the dose remaining in the cup.


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

months and 14 years administered after an overnight fast (3 patients per dose level equivalent to 7.5 mg/m², 30.0 mg/m² and 120.0 mg/m²).

Based on adult experience, a comparable lead-in period of two weeks was suggested for paediatric population. A 4 mg/kg dose is proposed for all children regardless the age. Although no particular study has been performed to find the optimal lead-in dose, this dose was considered acceptable considering the enzyme induction to achieve initial antiretroviral activity.

The final recommended doses for the different ages are therefore the following:

Patients from 2 months to 8 years, 4 mg/kg once daily for 2 weeks followed by 7 mg/kg bid

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


Generic pharmaceutical product and process development


Pharmaceutical development for genericsPharmaceutical development for genericsPharmaceutical development for genericsPharmaceutical 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.


Innovator suspension – bench marking (1)Innovator suspension – bench marking (1)Innovator suspension – bench marking (1)Innovator suspension – bench 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


Innovator suspension – bench marking (2)Innovator suspension – bench marking (2)Innovator suspension – bench marking (2)Innovator suspension – bench marking (2)

The composition suggests that:

Sucrose and sorbitol are used to adjust the density of the medium

Carbomer 934P is used to adjust viscosity

Polysorbate is a wetting agent

Sodium hydroxide is used to adjust the pH to 5.8


Innovator product – bench marking (3)Innovator product – bench marking (3)Innovator product – bench marking (3)Innovator product – bench marking (3)

Time (minutes)% API dissolved (hypothetical figures)

527

1042

1555

2065

3076

4588

6092

Dissolution profile (% LA)

Apparatus: USP II (paddle, 25rpm)

Medium: 0.1N HCl

Volume: 900ml

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

http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm

http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm


Innovator product – bench marking (4)Innovator product – bench marking (4)Innovator product – bench marking (4)Innovator product – bench marking (4)

% API dissolved (hypothetical figures)



Time (minutes)pH 1.2 bufferpH 4.5 bufferpH 6.8 buffer

5271522

10422527

15553635

20654242

30764849

45884957

60924965

901005076Dissolution profile (% LA), Apparatus: USP II (paddle, 25rpm), Volume: 900ml – Different speeds to be investigated


Pharmaceutical development protocolPharmaceutical development protocolPharmaceutical development protocolPharmaceutical 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


Product-specific physical API propertiesProduct-specific physical API propertiesProduct-specific physical API propertiesProduct-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 subsequentphysical processing. Density and particle size distribution of Nevirapine Hemihydrate are critical quality attributes of the API. Acceptance criteria are established by measurement of particle size of innovator’s API in suspension and through the similarity of dissolution profiles of innovator and generic products.


Stress stability testing - NevirapineStress stability testing - NevirapineStress stability testing - NevirapineStress stability testing - Nevirapine

Stress typeConditionsAssay (%)

Control25o C 99.8

36% HCl80o C, 40 min. 72.0

5N NaOH 80o C, 2h 20’ 98.6

30% w/w H2O280o C, 2h 20’ 98.6

Heat130o C, 49h 101.5

Light 500W/m2, 68h 101.7

Water 25o C, 92% RH, 91h 101.2


Solubility of nevirapine hemihydrate at 37Solubility of nevirapine hemihydrate at 37ooCCSolubility of nevirapine hemihydrate at 37Solubility of nevirapine hemihydrate at 37ooCC

pHDissolved material (mg/ml)(hypothetical figures)

1.22.75

2.10.28

3.00.08

4.50.06

6.80.06

7.20.06

8.00.06

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

Solubility data are also important for cleaning validation


Dissolution profiles of innovator and generic FPPsDissolution profiles of innovator and generic FPPsDissolution profiles of innovator and generic FPPsDissolution profiles of innovator and generic FPPs

Mean % API

dissolved

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


Selected generic composition Selected generic composition (hypothetical figures)Selected generic composition 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


Compatibility with excipientsCompatibility with excipientsCompatibility with excipientsCompatibility with excipients

Nevirapine Hemihydrate in solid state – illustrative example: heat

Stress Condition

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 of the powder blend is kept at 60°C for 4 weeks in a Petri dish (open system) Total impurities:

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


Risk assessment matrix – illustrative Risk assessment matrix – illustrative Risk assessment matrix – illustrative Risk assessment matrix – illustrative

Not critical to Q Potentially critical to QMonitoring strategy

Critical to QControl strategy

Milling API

Weighing Wetting

API Vehicle

Wet milling

Filling Packing

Dissolution Assay Degradation Content uniformity

Stability physical microbial pH


Process developmentProcess developmentProcess developmentProcess development Selection of process: standard for oral aqueous suspensions The progress from pre-formulation → formulation → pilot

manufacture (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 batch is manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch.

Manufacture of primary batches in 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 validation of bioequivalence, dissolution and stability batches


Proposed FPP specificationsProposed FPP specificationsProposed FPP specificationsProposed FPP specifications Description Identification (HPLC) Dissolution (UV): Q = 70% in 45 minutes pH = 4.8 – 6.2 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.


Scale up activitiesScale up activitiesScale up activitiesScale up activities Stability protocol is 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. The process will be well understood when:

– all critical sources of variability have been identified and explained– variability is managed by the process– product quality attributes can be accurately and reliably predicted

Validation protocol is written Dossier is submitted for prequalification


High-shear batch mixer and in-line mixerHigh-shear batch mixer and in-line mixerHigh-shear batch mixer and in-line mixerHigh-shear batch mixer and in-line mixer


Innovator FPP Generic FPP

Dissolution test3 batches

Production batch, orNLT 1/10 of final size

Reference product Test product

Select a batch showing intermediate dissolution

Dissolution (and bioequivalence) batchDissolution (and bioequivalence) batchDissolution (and bioequivalence) batchDissolution (and bioequivalence) batch

Dissolution profile


Special features of FDCs


4-FDC antituberculosis FPP4-FDC antituberculosis FPP4-FDC antituberculosis FPP4-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


4FDC-TB tablets exposed to4FDC-TB tablets exposed to40°C/75%RH for one week40°C/75%RH for one week

4FDC-TB tablets exposed to4FDC-TB tablets exposed to40°C/75%RH for one week40°C/75%RH for one week

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

Control on left Control on left


A typical incompatibilityA typical incompatibility A typical incompatibilityA typical incompatibility

Magnesium stearate is incompatible with 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 also change.


Critical quality variablesCritical quality variablesCritical quality variablesCritical quality variables1. The formulation is hygroscopic, sensitive to light and unstable (reaction between

rifampicin and isoniazid).

2. Moisture content of FPP and intermediates (granules and uncoated tablets).

3. Ethambutol.2HCl provides acidic conditions to accelerate reaction between rifampicin and isoniazid.

4. Packing materials are critical for stability.

5. Compatibility of APIs with each other and with excipients

6. Stress stability testing of the final formulation

7. Control of temperature and RH during the manufacturing process

8. Heavy-duty compression machine.

9. Validation batches and 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.


Main points againMain points againMain points againMain points again Pharmaceutical development is an essential part of applications for

prequalification.

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

FPP-specific quality and processability requirements are integrated into the API specifications during pharmaceutical development studies.

A science- and risk-based pharmaceutical development of generic FPPs provides a high level of assurance for interchangeability with the innovator product.

Manufacturing process design and optimization identifies the critical attributes whose control leads to the batch-to-batch consistency of quality.


Science- and risk-based approach means:Science- and risk-based approach means:Science- and risk-based approach means:Science- and risk-based approach means:

There will be no weak eye in the pharmaceutical development chain


THANK YOUTHANK YOU

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pharmaceutical equivalents

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oral solution powder

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