Pharmaceutical Development
Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Tallinn
15-19th October 2007
Slide 1
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Pharmaceutical Development
Pharmaceutical Development of
Finished Pharmaceutical Products
(FPPs)
Slide 2
Presenter:
Susan Walters
Email:
susanw@netspeed.com.au
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
The Australian view of the world
We are
here!
This place
isn’t too
bad either!
Slide 3
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
What Australia gave to the world (1)
Slide 4
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
What Australia gave to the world (2)
Slide 5
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Pharmaceutical 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
Slide 6
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
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)
Slide 7
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
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
Slide 8
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Development of a paediatric dosage form
Define drug & dosage regime for the paediatric indication
Consider:
·
Suitable routes of administration
·
Suitable dosage forms
Review literature
data &/or
conduct own studies
Consider pharmacokinetic
characteristics of API
including:
·
Half life, Cmax, AUC
·
BCS classification if oral
route is intended
Determine & prepare for
studies likely to be required
relating to BABE
Determine:
·
Relevant
physicochemical
characteristics of API
·
Stability of API under
stress conditions
·
Compatibility of API with
common excipients
Review literature
data &/or
conduct own studies
Select a dosage form &
strength
Sources of possible formulations &
manufacturing procedures:
·
Innovator excipients
·
Your company’s prior experience
·
Commercially available formulations &
manufacturing procedures
·
WHO ‘starting-point’ formulations
Consider suitable,
formulations &
manufacturing
procedures
Prepare draft
prescribing
information
Prepare early batches & test relevant
characteristics including:
·
Dissolution rate
·
Stability
·
Pilot BE study if necessary
Define design space
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
Submit application for
prequalification
Slide 9
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Finalise
prescribing
information
Product & process development
(sorry don’t know the source of this diagram)
Qualification Stage
Key elements
Design & C Installation
Facilities and
Engineering phase
Validation Stage
Operation
Prospective
Concurrent
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
biobatch)
quality)
methods)
Slide 10
Product and process development
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
CONTINUOUS
IMPROVEMENT
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, onetenth 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
Slide 11
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Relevant 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
Slide 12
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Relevant WHO guidelines
 Pharmaceutical Development, Section 3.2 of Guideline on
Submission of Documentation for Prequalification of Multisource (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)
Slide 13
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Some 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
Slide 14
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Some 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
Slide 15
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
How 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
Slide 16
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
How 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
Slide 17
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
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
Slide 18
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
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
–
Slide 19
See for example the WHO information line e-drug@healthnet.org.
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
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
Slide 20
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
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.
Slide 21
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
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/98/20933_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
Slide 22
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
What 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
Slide 23
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
What 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
Slide 24
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
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
Slide 25
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
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
Slide 26
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
What 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.
Slide 27
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
What 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
Slide 28
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
What 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.
Slide 29
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
What 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
Slide 30
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
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)
–
–
–
–
–
–
–
Slide 31
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 2007
Benchmarking 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
Slide 32
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Benchmarking the innovator – 3
Our tests show…..
Time (minutes)
% API dissolved
(hypothetical figures)
Slide 33
 Dissolution profile (% labeled
strength)
5
27
10
42
 Apparatus: USP II (paddle,
25rpm)
15
55
 Medium: 0.1N HCl
20
65
 Volume: 900ml
30
76
45
88
60
92
See
http://www.accessdata.fda.gov/scripts/cder/diss
olution/dsp_SearchResults_Dissolutions.cfm
downloaded on 13 March 2007
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Benchmarking the innovator - 4
Our tests show…..
Time (minutes)
5
10
15
20
30
45
60
90
% API dissolved
% API dissolved
% API dissolved
(hypothetical figures)
(hypothetical figures)
(hypothetical figures)
pH 1.2 buffer
27
pH 4.5 buffer
15
pH 6.8 buffer
22
42
55
65
25
36
42
27
35
42
76
88
92
48
49
49
49
57
65
100
50
76
Dissolution profile (% LA), Apparatus: USP II (paddle, 25rpm), Volume: 900ml – Different speeds to be investigated
Slide 34
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Pharmaceutical development protocol
API 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
Slide 35
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Product-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.
Slide 36
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Undertake stress testing of the API
if not already available in existing documentation
Stress type
Conditions
Assay (%)
Control
25o C
99.8
36% HCl
80o C, 40 min.
72.0
5N NaOH
80o C, 2h 20’
98.6
30% w/w H2O2
80o C, 2h 20’
98.6
Heat
130o C, 49h
101.5
Light
500W/m2, 68h
101.7
Water
25o C, 92% RH, 91h
101.2
Slide 37
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Solubility of nevirapine hemihydrate at 37oC
If not already available in existing documentation
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
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
Slide 38
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Dissolution profiles of innovator & generic FPPs
Hypothetical data
M
e
a
n
%
A
P
I
d
i
s
s
o
l
v
e
d
120
100
▀ innovator
80
▀ generic
60
Similarity
factor
f2=73
40
20
0
0
10
20
30
40
50
Time (minutes)
Slide 39
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
60
70
80
90
Selected generic composition
Hypothetical numbers
Ingredients
 Nevirapine hemihydrate
mg/5ml
51.7
 Excipients
–
–
–
–
–
–
–
–
Slide 40
Carbomer 934P
Methyl parahydroxybenzoate
Propyl parahydroxybenzoate
Sorbitol
Sucrose (!)
Polysorbate 80
Sodium hydroxide
Purified water
to make
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
7.0
9.0
0.9
900.0
500.0
4.0
q.s.
5.0 ml
Proposed FPP specifications
A 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
Slide 41
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Compatibility with excipients
May not need to do this if use only the same excipients as the
innovator
Nevirapine hemihydrate in solid state – illustrative example: heat
Stress
Condition
Slide 42
Treatment
None
Initial values API
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)
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Observations
Assay:
Impurity 1:
Impurity 2:
Total unspecified imps:
Total impurities:
Assay:
Impurity 1:
Impurity 2:
Total unspecified imps:
Total impurities:
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
Slide 43
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
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
Slide 44
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Scale 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
Slide 45
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
Dissolution & bioequivalence testing
Innovator FPP
Generic FPP
Conduct a dissolution test
on at least 3 batches
Select a production batch, or
one NLT 1/10th of final size
Select a batch showing
intermediate dissolution
Reference product
Test product
Dissolution profile
Bioequivalence study
Slide 46
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007
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
Slide 47
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines 15-19 October 2007