Development, safety and stability of biotechnological and biological products

1. Development, Safety and Stability of
Biotechnological and Biological Products
Prof. Dr. Basavaraj K. Nanjwade M. Pharm., PhD
Principal Scientist
Research and Development
Troy Life Sciences
Bangalore-560064, Karnataka, India
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2. CONTENT
1. Active substance
2. Excipients and other non-active constituents
3. Overages
4. Physico chemical or Biophysical Paramenters
5. Liquid and Semi-solid Formulations
6. Solid dosage forms
7. Other Dose Forms
8. Packaging materials
9. Manufacturing process
10. Safety Pharmacology and Toxicology
11. Stability of the active substance
12. Stability of the formulated product
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3. INTRODUCTION
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5. Active substance
Compatibility
• Proteins can interact chemically with the formulation
excipients present in the finished product.
• Potential interactions between the primary packaging.
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6. Active substance
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Formulation
Stability
Safety

7. Excipients and other non-active
constituents
1. Compatibility of excipients with other excipients.
2. Where novel constituents are used in the
manufacture of the product.
3. A new substance introduced as a constituent will be
regarded in the same way as a new active ingredient.
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8. Excipients and other non-active
constituents
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9. Overages
• Overages are primarily employed to cover losses during
manufacture of active substances.
• Overages could be included in the formulation of certain
biological/biotechnological products.
• Any overages to be included should also take into
account.
• It should also be remembered that over dosage may be
introduced.
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10. Overages
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11. Physico chemical parameters
1. pH:
• Evidence should be presented to show that the effect
of pH within the range specified in a formulation has
been properly investigated.
• The pH profile of an active substance may be useful
in investigating the bioavailability of products
administered by the oral route.
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12. Physico chemical or BioPhysical
2. Characterization
• Adequate characterisation using modern
physico-chemical and biophysical methods.
• Biological activity such as active sites,
receptor and ligand binding sites and the
features responsible for signal transduction.
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13. Physico chemical parameters
3. Other parameters:
• Depending on the formulation, such parameters
as dissolution and redispersion, particle size
distribution, aggregation, rheological properties,
etc.
• In the formulation of parenteral products,
consideration may have to be given to such
factors as tonicity adjustment, globule size of
emulsions, particle size and shape as well as
changes in crystal form, viscosity and/or
syringeability etc.
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14. Physico chemical parameters
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15. Liquid and Semi-solid
Formulations
• Antimicrobial preservatives
• Antioxidants
• Athers including surfactants, solvents, chelators,
permeability enhancers, tablet lubricants, release
modifers etc.
• This is particular important for product to be
administered intravenously.
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16. Liquid and Semi-solid
Formulations
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17. Solid dosage forms
• The capacity for chemical incompatibilities or
instability is clearly less significant in solids
than in liquid or semi-solid media.
• Differing physical properties of active
substances and excipients may also lead to
uneven distribution and alteration in drug
delivery to the target site.
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18. Solid dosage forms
1. Homogeneity:
• Mixing processes are normally required to ensure
even distribution of the active substance.
• Studies carried out at the development stage can
provide a useful prediction of validation protocols
applied to large-scale mixing processes.
• Routine testing should be supported by development
studies, especially for highly potent substances
present in low concentration in a formulation.
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19. Solid dosage forms
2. Performance testing
• The performance can be considered as an indicator of
the delivery of a drug from the dose form to the target
site and will depend upon the type of dose form and
the route of administration.
• Release of an active substance from a dose form may
be immediate e.g. suppositories, conventional release
tablets or modified in some way either by altering rate
or site of release (prolonged or delayed release).
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20. Solid dosage forms
2.1. Disintegration testing
• Disintegration testing is normally applied to each
finished batch of oral solid dose forms and also to
suppositories or at an intermediate stage.
• Such testing is intended to demonstrate the effective
break-up of the solid formulation (performance of the
disintegrant) after administration.
• Since many solid dose forms disintegrate rapidly, an
individually validated limit needs to be set.
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21. Solid dosage forms
2.2. Dissolution
• The actual amount of drug liberated from the dose
form into an aqueous reservoir in vitro is intended to
reflect the in vivo behaviour of the product.
• In practice in vivo behaviour is dependent on a
number of factors making in-vivo in-vitro correlation
difficult.
• Nevertheless the dissolution test provides a useful
range of data and the investigation of dissolution
characteristics should routinely be applied to all solid
dose forms at the development phase.
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22. Solid dosage forms
a) Conventional release preparations:
Dissolution tests should be performed during
development and stability studies in order to
establish whether such testing would need to be
included routinely in the finished product
specification.
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23. Solid dosage forms
b) Modified release preparations
• The choice of dissolution test conditions and release
rates adopted for assessing batch reproducibility
needs to be justified.
• This should take account of in vivo studies carried
out to establish the release and absorption profile of
the product and would, if feasible, consist of a study
correlating in vitro release rates to in vivo results to
allow meaningful standards to be set for in vitro
testing.
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24. Solid dosage forms
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25. Other Dose Forms
1. Transdermal patches
2. Pressured metered dose preparation for
inhalation
3. Dry powder for inhalation
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26. Other Dose Forms
1. Transdermal patches:
• Transdermal patches systems are designed to provide
a delivery of active substance through intact skin with
a constant systemic absorption rate.
• Drugs intended to be incorporated into transdermal
systems require an appropriate combination of
physicochemical properties, potency, biocompatibility
and clinical need.
• In particular, attention should be focused on the
matrix reservoir and adhesive materials to exclude the
possibility of incompatibility with the active
substance.
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27. Transdermal patches
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28. Other Dose Forms
2. Pressured metered dose preparation for inhalation
• The particle size of the drug substance used in
suspension formulations and the qualities of the
proposed propellant co-solvent and surfactant should
be carefully examined in the light of the desired
function.
• The propellant may interact with the active substance
altering the physical/ chemical properties
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29. Pressured metered dose
preparation for inhalation
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30. Other Dose Forms
3. Dry powder for inhalation
• These may be either single dose or multidose.
• Since the dose delivered may depend upon the air
flow rate, this should be investigated both in vitro and
in vivo.
• Attempts should be more to correlate the results of in
vitro testing with those batches showing acceptable
performance in vivo.
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31. Dry powder for inhalation
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32. Packaging materials
• Primary packaging should be justified including
appropriate considerations for the safety.
• Appropriate studies should be performed to
demonstrate the integrity of the container and closure.
• A possible interaction between product and container
may need to be considered
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33. Packaging materials
1. Sorption to container
2. Leaching
3. Dose reproducibility
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34. Packaging materials
1. Sorption to container:
• Sorption of the active constituent(s) and additive(s)
from liquid or semi-solid formulations if relevant to
safety and stability.
• These phenomena are known to occur with rubber
closures and with both glass and plastic containers
and administration sets.
• In extreme cases sorption can lead to permeation
through the container walls.
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35. Packaging materials
2. Leaching:
• Data should be presented to show that there is no
significant leaching of any pack component, into
liquid or finely divided solid preparations over the
shelf life period, where such leaching could give rise
to safety concerns.
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36. Packaging materials
3. Dose reproducibility:
• If a dosing device is used e.g. dropper pipette, pen
injection device etc.
• Evidence should be presented that a reproducible and
accurate dose of the product.
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37. Manufacturing process
• Biologicals or biotechnological products are
distinguishable from their chemically synthesized
counterparts with respect to their manufacturing
process and its impact on the drug product quality
and safety.
• The quality of biologicals is defined by the chosen
production and manufacturing process.
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38. Manufacturing process
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Generic monoclonal antibody production scheme

39. Manufacturing process
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40. Safety Pharmacology and
Toxicology
• Safety pharmacology studies measure functional
indices of potential toxicity.
• These functional indices may be investigated in
separate studies or incorporated in the design of
toxicity studies.
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41. Stability of the active substance
• Due to the hierachical nature of protein structure, there will
usually be more than one mechanism of degradation, be it
physical or chemical.
• In this regard, the degradation pathways, including their
mechanisms and kinetics, where applicable, should be
established by an appropriate array of physico- or bio-
chemical methods.
• For DNA based products, the stability of the active principle
should be investigated with respect to its degradation
kinetics relating to, for example, depurination and b-
elimination.
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42. Stability of the formulated
product
• Because of the lability inherent in certain
biological/biotechnological products, appropriate
quantity or quantities of suitable excipients, supported
by experimental data, are frequently incorporated into
the formulated or finished product.
• The stability of the formulated product or the drug
substance under various process conditions, such as
lyophilisation, should be investigated in order to
optimise the formulation with respect to the amount
of, for example, lyoprotectant required to preserve the
integrity of the drug substance.
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43. REFERENCES
1. www.ich.org
2. www.fda.gov
3. www.eudra.org/emea.html
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THANK YOU
E-mail: nanjwadebk@gmail.com