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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 1
Training Workshop on Pharmaceutical Development
with focus on Paediatric Formulations
Tallinn
15-19th October 2007
Pharmaceutical DevelopmentPharmaceutical Development
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 2
Pharmaceutical DevelopmentPharmaceutical Development
Pharmaceutical Development of Finished Pharmaceutical
Products (FPPs)
Presenter: Susan Walters
Email: [email protected]
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 3
The Australian view of the worldThe Australian view of the world
We are here!
This place isn’t too
bad either!
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 4
What Australia gave to the world (1)What Australia gave to the world (1)
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 5
What Australia gave to the world (2)What Australia gave to the world (2)
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 6
Pharmaceutical Development of FPPsPharmaceutical Development of FPPs
Outline of presentation
We will:
Look at the development process as a whole & consider its objectives
Review relevant guidelines
Review sources of information
Go through a worked example
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 7
Objectives of Pharmaceutical Development : What is the purpose?
Objectives of Pharmaceutical Development : What is the purpose?
From the perspective of a generic manufacturer, the objective is to develop a product that is:
of appropriate quality &
interchangeable with the innovator brand (so we can avoid expensive & time-consuming studies of safety & efficacy)
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 8
Objectives of Pharmaceutical Development : What is the purpose?
Objectives of Pharmaceutical Development : What is the purpose?
From the perspective of the manufacturer of a new dosage form &/or strength (eg a paediatric dosage form), the objective is to develop a product that is:
Of appropriate quality, &
Of appropriate dosage form & strength, &
Either has been shown to be safe & effective for the claimed indications & patient population or has been shown to pharmacokinetically interchangeable with a brand that has been shown to be safe & effective for the claimed indications & patient population
However safety & efficacy is outside the scope of this presentation so I will deal only with generics that contain the same API in the same dosage form & strength as the innovator
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 9
Define drug & dosage regime for the paediatric indication
Development of a paediatric dosage form
Select a dosage form & strength
Consider:· Suitable routes of administration· Suitable dosage forms
Consider suitable, formulations & manufacturing
procedures
Prepare early batches & test relevant characteristics including:· Dissolution rate· Stability · Pilot BE study if necessary
Sources of possible formulations & manufacturing procedures:· Innovator excipients· Your company’s prior experience· Commercially available formulations &
manufacturing procedures · WHO ‘starting-point’ formulations
Apply optimization techniques/validate
formulation & method of manufacture
Decide final formulation, method of manufacture &
packaging
Conduct:· Confirmatory stability studies· Confirmatory dissolution studies· Final BE study if needed
Review literature data &/orconduct own studies
Consider pharmacokinetic characteristics of API including:· Half life, Cmax, AUC · BCS classification if oral
route is intendedDetermine & prepare for studies likely to be required relating to BABE
Submit application for prequalification
Determine:· Relevant
physicochemical characteristics of API
· Stability of API under stress conditions
· Compatibility of API with common excipients
Define design space
Prepare draft prescribing information
Review literature data &/orconduct own studies
Finalise prescribing information
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 10
Product & process development (sorry don’t know the source of this diagram)
Product & process development (sorry don’t know the source of this diagram)
CONTINUOUS IMPROVEMENT
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 11
Terminology – from ICH Q1A(R2) 2003 (stability)
Terminology – from ICH Q1A(R2) 2003 (stability)
- Production batch:– A batch of a drug substance or drug product manufactured at production scale
by using production equipment in a production facility as specified
- Pilot scale batch:– A batch of a drug substance or drug product manufactured by a procedure fully
representative of and simulating that to be applied to a full production scale batch. For solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger.
- Laboratory scale batch [not an ICH definition]- A batch smaller than pilot scale that is manufactured for development purposes
Remember that scale-ups must be validated – batch characteristics may change during scale-up
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 12
Relevant non-WHO guidelinesRelevant non-WHO guidelines
ICH Q8 Pharmaceutical Development (2005)
ICH Q9 Quality Risk Management (Nov 2005)
ICH Q10 DRAFT Pharmaceutical Quality System (May 2007)
Note for guidance on Process Validation CHMP/QWP/848/96 (EU 2001)
– An elderly guideline but informative & helpful
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 13
Relevant WHO guidelinesRelevant WHO guidelines
Pharmaceutical Development, Section 3.2 of 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, WHO PQP (2005)
Extension of the WHO List of Stable (not easily degradable ARV) APIs, Supplement 2 (Rev 1) to 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, WHO PQP (2005)
Supplementary guidelines on Good Manufacturing Practices: Validation, Annex 4 to WHO TRS 937 (2006)
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 14
Some relevant journalsSome relevant journals
Pharmaceutical Technology
Pharmaceutical Technology Europe
Pharmaceutical Industry
Pharmaceutical Development and Technology
Drug Development & Industrial Pharmacy
Pharmaceutical Manufacturing
Dissolution Technologies - A free on-line journal at http://www.dissolutiontech.com/
European Journal of Pharmaceutics and Biopharmaceutics
Pharmazie in Unserer Zeit (often in German)
S.T.P. Pharma Pratiques (often in French)
Pharmaceutisch Weekblad (often in German)
It is often possible to obtain access to journals via university on-line databases
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 15
Some relevant websitesSome relevant websites
http://www.who.int/medicines/en/. – WHO medicines program.
http://mednet3.who.int/prequal/ – WHO prequalification program.
http://www.ich.org– ICH website
http://www.emea.europa.eu/htms/human/humanguidelines/background.htm– European guidelines for human medicines
http://www.fip.org/www2/sciences/index.php– international Pharmaceutical Federation: Pharmaceutical Sciences
section
http://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm– Dissolution methods for drug products
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 16
How can we optimise the possibility of developing an acceptable product? - 1How can we optimise the possibility of developing an acceptable product? - 1
Form a development team– Include staff with experience in formulation, manufacturing, quality control, stability testing
Prepare a development plan, set goals & timelines, & monitor progress with regular meetings (eg weekly in the first instance)
Make use of experienced staff within your company, especially in relation to manufacturing equipment & procedures
Review the literature for information on:– Chemical & physicochemical properties of the API(s)– Information on the innovator product
Conduct experiments to fill in the gaps in information, – Especially concerning API properties & compatibilities
If possible, use the same excipients as the innovator. – Less likely to encounter problems with compatibility, stability, bioequivalence
If possible, use standard manufacturing procedures with which your company has experience
– More likely to achieve suitable dissolution properties & reproducible manufacturing
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 17
How can we optimise the possibility of developing an acceptable product? - 2How can we optimise the possibility of developing an acceptable product? - 2
BOTTOM LINE:– Ensure our product meets WHO criteria for quality, stability &
interchangeability– Ensure our product has similar dissolution characteristics as
the innovator at various pH– May need to confirm bioequivalence with the innovator
• See Annex 8 to WHO TRS 937 (2006) Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 18
What are the chemical & physicochemical properties of API(s) that we need to know, or are at least useful?
What are the chemical & physicochemical properties of API(s) that we need to know, or are at least useful?
Solubility at various pH
Acid or base?
pKa & partition coefficient
Stability under stress (eg oxygen, moisture, acid etc)
Compatibility with common excipients
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 19
What literature should we look for?What literature should we look for?
Look for……
A WHOPAR, if one is available for your product– See http://mednet3.who.int/prequal/default.htm. Look for WHO Public Assessment Reports under
Quick Links on the RH side of the page
Innovator documentation. – Can often be found on the innovator website. – The prescribing information is especially useful & often includes a list of excipients.
A drug approval package (DAP) via http://www.fda.gov/cder/foi/nda/
An EPAR (European Public Assessment Report)
An official monograph in the Ph Int
A monograph in Clarke’s Analysis of Drugs and Poisons, published by The Pharmaceutical Press (latest edition 2004).
A monograph in The Merck Index, published by CambridgeSoft (latest edition 2001).
Regulatory information– See for example the WHO information line [email protected].
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 20
Case study: A new brand of Nevirapine 50mg/5 ml oral suspension - 1
Case study: A new brand of Nevirapine 50mg/5 ml oral suspension - 1
Why do we need to know the chemical structure?
To determine whether the active is an acid, base or neutral
To assist in devising assay procedures
To determine likely compatibilities/incompatibilities – Based on a knowledge of organic chemistry
To inform other decisions & predictions that are based on chemistry
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 21
Case study: A new brand of Nevirapine 50mg/5 ml oral suspension - 2
Case study: A new brand of Nevirapine 50mg/5 ml oral suspension - 2
We plan to develop a paediatric product that contains the same active in the same dose & dosage form as an existing paediatric product.
The innovator is Boehringer Ingelheim. The innovator brand name is Viramune® 50 mg/5mL oral suspension.
The product under development is a multisource (generic) product.
The quality, safety & efficacy of the existing product have been established.
The product will be an oral suspension containing 50mg of nevirapine in each 5mL. The drug is present as an equivalent quantity of the hemihydrate API.
– Note that the API is often a salt or solvate of the active ingredient. In this case the API is the hemihydrate of nevirapine.
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 22
What useful sources of information did we find?
An EPAR at http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdf
A drug approval package (DAP) at http://www.fda.gov/cder/foi/nda/98/20-933_20-636S009_Viramune.htm
A letter of approval at http://www.fda.gov/cder/ogd/rld/20933s3.PDF
An official monograph in the Ph Int.
A monograph in Clarke’s Analysis of Drugs and Poisons, published by The Pharmaceutical Press 2004.
A monograph in The Merck Index, published by CambridgeSoft 2001.
Regulatory information concerning a possible impurity in the API. See http://www.medicalnewstoday.com/articles/82050.php
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 23
What useful information did we find? - 1What useful information did we find? - 1
Nevirapine is lipophilic (partition coefficient
83) & is essentially nonionized at
physiological pH
As a weak base (pKa 2.8), nevirapine
shows increased solubility at acidic pH
The aqueous solubility (of the anhydrate)
is 90μg/ml at 25°C
Nevirapine is generally stable when
stressed
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 24
What useful information did we find? - 2What useful information did we find? - 2
There are two crystal forms of the API
No polymorphic changes were observed under stressed conditions
The API (hemihydrate) is non-hygroscopic
The synthesis of the two crystal forms is similar until the final drying step
The impurity profile is well characterised
Impurities arising from the synthesis have been toxicologically qualified
No degradation products were detected during stability testing of the API
The API is milled in order to obtain an acceptable particle size distribution for the suspension
Nevirapine is official in the Ph Int
Batch analysis data confirmed that nevirapine hemihydrate complies with the specifications
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 25
What useful information did we find? - 3 What useful information did we find? - 3
The innovator markets an oral suspension (Viramune ® 50 mg/5 ml) containing nevirapine (present as the hemihydrate at 10.35 mg/ml).
– That is….the active is nevirapine & the API is nevirapine hemihydrate
Excipients in the innovator formulation are: – Carbomer 934P (synthetic high molecular weight crosslinked polymers of
acrylic acid), methyl & propyl hydroxybenzoates, sorbitol, sucrose, polysorbate 80, NaOH, purified water.
The shelf life of the innovator is 3 years. – The product should be used within 2 months of opening (‘in-use’ stqbility).
The innovator has no special precautions for storage
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 26
What useful information did we find? - 4 What useful information did we find? - 4
The innovator’s container is a 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.
Included with the innovator product is a clear polypropylene 5-ml dispensing syringe (0.2 ml graduations) with silicone rubber piston seal, & a clear low density polyethylene bottle-syringe adapter.
See http://www.emea.europa.eu/humandocs/PDFs/EPAR/Viramune/109697en6.pdf
http://www.fda.gov/cder/ogd/rld/20933s3.PDF
A monograph (Ph Int) is being developed for the FPP, nevirapine oral suspension
– NB check the WHO website for the latest information
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 27
What useful information did we find? - 5What useful information did we find? - 5
The HDPE bottle is inert & has been shown to be compatible with the active substance & other ingredients of the innovator’s formulation.
% content of antimicrobial preservatives has been correlated with antimicrobial effectiveness when tested according to Ph Eur methodology
Acceptable data are available to demonstrate the precision & accuracy of the innovator’s dosing syringe
None of the synthesis impurities are degradants
The method of preparation of the oral suspension is standard for this dosage form & has been well described. Validation data presented for three production batches manufactured using three different lots of nevirapine demonstrated that the process is under control & ensures both batch-to-batch reproducibility & compliance with standard specifications. Tests at release are typical & ensure reproducible performance of the product.
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 28
What useful information did we find? - 6What useful information did we find? - 6
Stability data are available for up to 18 months for the innovator. Long-term stability data have been promised on an ongoing basis.
An in-use stability study has been performed that mimics delivery of a 2mL dose, representing one of the lowest projected doses using the delivery device intended for marketing
An additional study has been conducted on the stability of the product exposed to freeze-thaw conditions
On the basis of results from these studies, an in-use shelf life of 60 days with no special storage precautions is claimed
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 29
What useful information did we find? – 7What useful information did we find? – 7
In vivo data provided by the innovator included the following :
Nevirapine is readily absorbed (> 90 %) after oral administration in healthy volunteers & in adults with HIV-1 infection.
A 3-way crossover study comparing the bioavailability of three production/commercial scale batches that had varying dissolution profiles showed that all three batches were bioequivalent with respect to systemic exposure (AUC). The statistically significantly different values for Cmax and tmax were considered not to be clinically relevant.
In studies in which the suspension was administered directly using a syringe, it was demonstrated that the suspension & tablet formulations were comparably bioavailable with respect to extent of absorption.
In a study in which 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 was attributed to incomplete dosing of the two suspensions since there was about 13 % of the dose remaining in the cup.
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 30
What useful information did we find? – 8What useful information did we find? – 8
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 of 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 following doses were approved:– Patients from 2 months to 8 years, 4mg/kg once daily for 2
weeks followed by 7mg/kg twice daily – Patients from 8 years to 16 years, 4 mg/kg once daily followed
by 4mg/kg twice daily
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 31
Benchmarking the innovator – 1(these slides were taken from a presentation by János Pogány )
Benchmarking the innovator – 1(these slides were taken from a presentation by János Pogány )
Obtain a sample for confirmation of characteristics– 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)– Methylhydroxy benzoate (HPLC): 0.18% w/v– Propylhydroxy benzoate (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
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 32
Benchmarking the innovator - 2Benchmarking the innovator - 2
The qualitative 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
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 33
Benchmarking the innovator – 3Our tests show…..
Benchmarking the innovator – 3Our tests show…..
Time (minutes)% API dissolved (hypothetical figures)
527
1042
1555
2065
3076
4588
6092
Dissolution profile (% labeled strength)
Apparatus: USP II (paddle, 25rpm)
Medium: 0.1N HCl
Volume: 900ml
See http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm downloaded on 13 March 2007
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 34
Benchmarking the innovator - 4 Our tests show…..
Benchmarking the innovator - 4 Our tests show…..
% 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
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 35
Pharmaceutical development protocolPharmaceutical development protocolAPI experiments
– Particle size distribution
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 Ph Eur
Packing materials– Dimensions and tolerances of packing components– Precision & accuracy of the dosing syringe
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 36
Product-specific API propertiesProduct-specific API properties
Ph Int specifications + limits on residual solvents from API manufacture
Product-specific physical properties depend on crystallization and subsequent physical processing. Density and particle size distribution of nevirapine hemihydrate are critical quality attributes. Acceptance criteria are established by measurement of particle size of innovator’s API in suspension & through the similarity of dissolution profiles of innovator and generic products.
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 37
Undertake stress testing of the APIif not already available in existing documentation
Undertake stress testing of the APIif not already available in existing documentation
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
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 38
Solubility of nevirapine hemihydrate at 37oC If not already available in existing documentation
Solubility of nevirapine hemihydrate at 37oC If not already available in existing documentation
Note: Nevirapine hemihydrate belongs to BCS2 (low solubility, high permeability)
– See Annex 8 to WHO TRS 937 (2006) Solubility data are also important for cleaning validation
0.282.1
0.067.2
0.068.0
0.066.8
0.064.5
0.083.0
2.751.2
Dissolved material (mg/ml)
(hypothetical figures)
pH
0.282.1
0.067.2
0.068.0
0.066.8
0.064.5
0.083.0
2.751.2
Dissolved material (mg/ml)
(hypothetical figures)
pH
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 39
Dissolution profiles of innovator & generic FPPsHypothetical data
Dissolution profiles of innovator & generic FPPsHypothetical data
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
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 40
Selected generic composition Hypothetical numbers
Selected generic composition Hypothetical numbers
Ingredients mg/5mlNevirapine hemihydrate 51.7
Excipients– Carbomer 934P 7.0– Methyl parahydroxybenzoate 9.0 – Propyl parahydroxybenzoate 0.9– Sorbitol 900.0– Sucrose (!) 500.0– Polysorbate 80 4.0– Sodium hydroxide q.s.– Purified water to make 5.0 ml
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 41
Proposed FPP specificationsA hypothetical set of limits
Proposed FPP specificationsA hypothetical set of limits
Description: including at least colour, texture, odour Identification (HPLC) Dissolution (UV): Q = 70% in 45 minutes pH = 5.0 – 6.1 Deliverable volume
– Average fill volume: NLT 240 ml– Fill volume variation: Meets Ph Int requirements
Related substances: NMT 0.1% of any one imp & NMT 0.3% total imps
Preservative content (HPLC)– Methylparaben: 98 to 102% of labeled strength– Propylparaben: 98 to 102% of labeled strength
Assay: 95.0 to 105.0% of labeled strength
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 42
Compatibility with excipientsMay not need to do this if use only the same excipients as the
innovator
Compatibility with excipientsMay not need to do this if use only the same excipients as the
innovator
Nevirapine hemihydrate in solid state – illustrative example: heat
Stress Condition
Treatment Observations Assay: Impurity 1: Impurity 2: Total unspecified imps:
None Initial values API
Total impurities: Assay: Impurity 1: Impurity 2: Total unspecified imps:
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:
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 43
Development of manufacturing process Development of manufacturing process
Select a standard process for oral aqueous suspensions, if possible using our existing method
Manufacture a lab scale batch– If necessary make adjustments & manufacture another lab scale batch
When satisfied with the formulation, manufacture a pilot scale batch– If necessary make adjustments & manufacture another pilot scale batch– Recollect that a pilot batch is manufactured by a procedure fully representative of and
simulating that to be applied to a full production scale batch Manufacture primary* batches in the proposed container & closure systems for:
– Bioequivalence & dissolution studies– Regulatory stability studies
• Iincluding an in-use stability study & a stress study under freeze-thaw conditions– Validation of bioequivalence, dissolution & stability batches
*Primary as defined in WHO/ICH guidelines
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 44
Development of manufacturing process Development of manufacturing process
Note that the progress from pre-formulation to formulation to pilot manufacture to production scale manufacture should be described in the PQP dossier & shown to be logical, reasoned & continuous
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 45
Scale up activitiesScale up activities Test a large number of samples from pilot scale batches to
establish provisional acceptance limits for the control of critical process parameters (prospective validation, in-process control limits) in order to define the design space* & a control strategy that encompasses batch scale, equipment, packaging, as well as final product stability. The process will be well understood when:
– all critical sources of variability have been identified & explained– variability is managed by the process– product quality attributes can be accurately & reliably predicted
A validation protocol is written
* See ICH Q8, Q9 & draft Q10 for further explanation
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 46
Dissolution & bioequivalence testingDissolution & bioequivalence testing
Innovator FPP Generic FPPConduct a dissolution test
on at least 3 batchesSelect a production batch, orone NLT 1/10th of final size
Reference product Test product
Select a batch showing intermediate dissolution
Dissolution profile
Bioequivalence study
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines 15-19 October 2007Slide 47
Pharmaceutical Development Summary and conclusion
Pharmaceutical Development Summary and conclusion
The probability of producing a product that is:
- Of high quality
- Stable
- Consistent from batch to batch, &
- Bioequivalent to the innovator
can be significantly improved by employing a planned & systematic approach to product development, & using all the information that has been published