Pharmaceutical Development
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
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April 2007
Pharmaceutical Development
Developing formulation and manufacturing process
Presenter:
János Pogány, pharmacist, PhD
pogany.janos@chello.hu
WHO expert
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April 2007
Abbreviations
API
EoI
FDC
FPP
GMP
ICH
MA
PQP
TRS
Active Pharmaceutical Ingredient
Expression of Interest
Fixed-Dose Combination
Finished Pharmaceutical Product
Good Manufacturing Practices
International Conference on Harmonization
Marketing Authorization
PreQualification Project
Technical Report Series of WHO
Red → emphasis
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Slide 3 of 45
Green → WHO
April 2007
Violet → ICH region
Pharmaceutical Development
Outline 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
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April 2007
Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Objective, guidelines
Interchangeability (IC)
INTERCHANGEABILITY (IC) OF MULTISOURCE
FPPs = THERAPEUTICAL EQUIVALENCE WITH
A COMPARATOR (REFERENCE) FPP =
PHARMACEUTICAL EQUIVALENCE (PE) +
BIOEQUIVALENCE (BE)
IC = PE + BE
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April 2007
Pharmaceutical equivalence
 Products are pharmaceutical equivalents1 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 equivalence, including
stability equivalence (and packaging equivalence)
 WHO-GMP (manufacturing process equivalence)
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April 2007
Focus on paediatric dosage forms






Epivir (lamivudine) 10 mg/ml oral solution
Retrovir (zidovudine) 100 mg/10 ml oral solution
Sustiva (efavirenz) 30 mg/ml oral solution
Viramune (nevirapine) 50 mg/5 ml oral suspension
Zerit (stavudine) 200 mg powder for oral solution
Powder for oral suspension, capsules, film-coated tablets
and chocolate pastilles can also be considered
Once safe and effective doses are established, generic FPPs can be
developed and bioequivalence demonstrated
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April 2007
Pharmaceutical development
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)
Product and process development
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April 2007
C
O
N
T
I
N
U
O
U
S
I
M
P
R
O
V
E
M
E
N
T
Guidelines 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.)
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April 2007
Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Desk research
Nevirapine 50mg/5 ml oral suspension
Information 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
specifications
http://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
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April 2007
Information 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).

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April 2007
Nevirapine is highly stable
Viramune 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 years
The 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 childresistant 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
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April 2007
Viramune 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.
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April 2007
Viramune 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.
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April 2007
Clinical information

Nevirapine was readily absorbed (> 90 %) after oral administration in healthy
volunteers and in adults with HIV-1 infection.

A 3-way crossover study 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.
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April 2007
Clinical 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.
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April 2007
Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Generic pharmaceutical
product and process development
Pharmaceutical development for generics
 Product target profile (PTF) is different:
– Innovator PTP is based on clinical studies
– Generic FPP targets the innovator FPP
 Multisource FPP manufacturers must be highly skilled in
product development
 The chances of developing a bioequivalent generic product can
be significantly increased by using the formulation of the
innovator. The lowest risk strategy for the development of an
interchangeable multisource FPP is to copy the innovator FPP.
 Manufacturing processes are the same for innovators and
generic manufacturers.
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April 2007
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)
–
–
–
–
–
–
–
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Assay: 99.9% of labelled amount (LA)
Methylparaben (HPLC): 0.18% w/v
Propylparaben (HPLC): 0.02% w/v
Total related substances: 0.03%
Specific gravity (at 25oC): 1.150
Viscosity (at 25oC): 1,150 cPs
pH: 5.80
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April 2007
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
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April 2007
Innovator product – bench marking (3)
Time (minutes)
% API dissolved
 Dissolution profile (% LA)
(hypothetical figures)
5
27
10
42
15
55
20
65
 Apparatus: USP II (paddle,
25rpm)
 Medium: 0.1N HCl
 Volume: 900ml

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30
76
45
88
60
92
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April 2007
http://www.accessdata.fda.gov/scripts/cder/diss
olution/dsp_SearchResults_Dissolutions.cfm
downloaded on 13 March 2007
Innovator product – bench marking (4)
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
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April 2007
Pharmaceutical development protocol
 API experiments
– Solubility at 37 oC
– Particle size distribution
– Density
 Formulation experiments
– Screening laboratory batches with different proportions of excipients to
match innovator dissolution
– Stress testing of the selected composition
– Compatibility with excipients
– Antimicrobial effectiveness test according to PhEur
 Packing materials
– Dimensions and tolerances of packing components
– Precision and accuracy of the dosing syringe
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April 2007
Product-specific physical API properties
Introduction of
the API starting
material(s) into
process
Production
of intermediate(s)
Isolation and
purification
Physical
processing and
packaging
PhInt specifications + residual solvents from APIMF.
Product-specific physical properties depend on crystallization and subsequent
physical processing. Density and particle size distribution of Nevirapine Hemihydrate
are critical quality 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.
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April 2007
Stress stability testing - Nevirapine
Stress type
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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
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April 2007
Solubility of nevirapine hemihydrate at 37oC
pH
Dissolved material (mg/ml)
(hypothetical figures)
1.2
2.75
2.1
0.28
3.0
0.08
4.5
0.06
6.8
0.06
7.2
0.06
8.0
0.06
Nevirapine Hemihydrate belongs to BCS Class 2 (low solubility, high permeability).
Solubility data are also important for cleaning validation
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April 2007
Dissolution profiles of innovator and generic FPPs
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)
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April 2007
60
70
80
90
Selected generic composition (hypothetical figures)
Ingredients
 Nevirapine hemihydrate
mg/5ml
51.7
 Excipients
–
–
–
–
–
–
–
–
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Carbomer 934P
Methyl parahydroxybenzoate
Propyl parahydroxybenzoate
Sorbitol
Sucrose
Polysorbate 80
Sodium hydroxide
Purified water
to make
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April 2007
8.0
10.0
1.0
800.0
700.0
3.0
q.s.
5.0 ml
Compatibility with excipients
Nevirapine Hemihydrate in solid state – illustrative example: heat
Stress
Condition
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)
Observations
Assay:
SI1:
D1:
Total unspecified:
Total impurities:
Assay:
SI1:
D2:
Total unspecified:
Total impurities:
To do: stress testing the dose-proportional mixture of the APIs in aqueous medium.
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April 2007
Risk assessment matrix – illustrative
Milling
Wetting
Weighing
API
API
Vehicle
Wet
milling
Filling
Packing
Dissolution
Assay
Degradation
Content
uniformity
Stability
 physical
 microbial
pH
Not critical to Q
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April 2007
Potentially
critical to Q
Monitoring
strategy
Critical to Q
Control strategy
Process 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
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April 2007
Proposed 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
– Propylparaben: 98 to 102% of LA
[End of shelf life: 80 to 102% of LA]
[End of shelf life: 80 to 102% of LA]
 Assay: 95.0 to 105.0% of LA
End-of shelf-life acceptance limits for assay should not be proposed at this stage.
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April 2007
Scale 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
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April 2007
High-shear batch mixer and in-line mixer
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April 2007
Dissolution (and bioequivalence) batch
Innovator FPP
Generic FPP
Dissolution test
3 batches
Production batch, or
NLT 1/10 of final size
Select a batch showing
intermediate dissolution
Reference product
Test product
Dissolution profile
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April 2007
Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Special features of FDCs
4-FDC antituberculosis FPP
Originator FPP in ICH region
 None
FPP in current (14th) List Essential Medicines




Rifampicin
Isoniazid
Pyrazinamide
Ethambutol
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April 2007
150 mg
75 mg
400 mg
275 mg
4FDC-TB tablets exposed to
40°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
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April 2007
A 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.
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April 2007
Critical quality variables
1. 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.
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Slide 42 of 45
April 2007
Main 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.
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April 2007
Science- and risk-based approach means:
There will be no weak eye in the pharmaceutical development chain
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April 2007
THANK YOU
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April 2007