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| 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
| Slide 2 of 45 April 2007
Pharmaceutical DevelopmentPharmaceutical DevelopmentPharmaceutical DevelopmentPharmaceutical Development
Developing formulation and manufacturing process
Presenter: János Pogány, pharmacist, PhD
WHO expert
| Slide 3 of 45 April 2007
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
| Slide 4 of 45 April 2007
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
| Slide 6 of 45 April 2007
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
| Slide 7 of 45 April 2007
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)
| Slide 8 of 45 April 2007
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
| Slide 9 of 45 April 2007
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
| Slide 10 of 45 April 2007
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.)
Training Workshop on Training Workshop on Pharmaceutical Development with Pharmaceutical Development with focus on Paediatric Formulationsfocus on Paediatric Formulations
Desk research
Nevirapine 50mg/5 ml oral suspension
| Slide 12 of 45 April 2007
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
| Slide 13 of 45 April 2007
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
| Slide 14 of 45 April 2007
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
| Slide 15 of 45 April 2007
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.
| Slide 16 of 45 April 2007
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.
| Slide 17 of 45 April 2007
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.
| Slide 18 of 45 April 2007
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.
Training Workshop on Training Workshop on Pharmaceutical Development with Pharmaceutical Development with focus on Paediatric Formulationsfocus on Paediatric Formulations
Generic pharmaceutical product and process development
| Slide 20 of 45 April 2007
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.
| Slide 21 of 45 April 2007
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
| Slide 22 of 45 April 2007
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
| Slide 23 of 45 April 2007
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
| Slide 24 of 45 April 2007
Innovator product – bench marking (4)Innovator product – bench marking (4)Innovator product – bench marking (4)Innovator product – bench marking (4)
% API dissolved (hypothetical figures)
% API dissolved (hypothetical figures)
% 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
| Slide 25 of 45 April 2007
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
| Slide 26 of 45 April 2007
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.
| Slide 27 of 45 April 2007
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
| Slide 28 of 45 April 2007
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
| Slide 29 of 45 April 2007
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
| Slide 30 of 45 April 2007
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
| Slide 31 of 45 April 2007
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.
| Slide 32 of 45 April 2007
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
| Slide 33 of 45 April 2007
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
| Slide 34 of 45 April 2007
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.
| Slide 35 of 45 April 2007
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
| Slide 36 of 45 April 2007
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
| Slide 37 of 45 April 2007
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
Training Workshop on Training Workshop on Pharmaceutical Development with Pharmaceutical Development with focus on Paediatric Formulationsfocus on Paediatric Formulations
Special features of FDCs
| Slide 39 of 45 April 2007
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
| Slide 40 of 45 April 2007
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
| Slide 41 of 45 April 2007
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.
| Slide 42 of 45 April 2007
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.
| Slide 43 of 45 April 2007
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.
| Slide 44 of 45 April 2007
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