The European Agency for the Evaluation of Medicinal Products
Evaluation of Medicines for Human Use

London, 21 October 1999
CPMP/BWP/328/99

COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS
(CPMP)

DEVELOPMENT PHARMACEUTICS FOR BIOTECHNOLOGICAL
AND BIOLOGICAL PRODUCTS (CPMP/BWP/328/99)

ANNEX TO NOTE FOR GUIDANCE ON DEVELOPMENT
PHARMACEUTICS (CPMP/QWP/155/96)

DISCUSSION IN THE BIOTECHNOLOGY WORKING February 1999
PARTY (BWP)

TRANSMISSION TO THE CPMP February 1999

RELEASE FOR CONSULTATION March 1999

DEADLINE FOR COMMENTS September 1999

RESUBMITTED TO BWP September 1999

TRANSMISSION TO THE CPMP October 1999

FINAL ADOPTION BY THE CPMP October 1999

DATE FOR COMING INTO OPERATION April 2000

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EMEA 1999 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged

DEVELOPMENT PHARMACEUTICS FOR BIOTECHNOLOGICAL
AND BIOLOGICAL PRODUCTS

(ANNEX TO NOTE FOR GUIDANCE ON DEVELOPMENT PHARMACEUTICS)

1. INTRODUCTION

Whilst some of the issues illustrated in the Note for Guidance on Development Pharmaceutics have
been elaborated primarily for products containing chemical active substances, the principles stated
therein may be applicable to biological or biotechnological products.

2. GENERAL CONSIDERATIONS
There are, however, underlying physico-chemical differences between biological/biotechnological
products and chemically synthesised products, for example, lability and complexity inherent in
biotechnological and biological substances.. These differences may necessitate special
pharmaceutical and biopharmaceutical considerations during the research and development
programme.
This document, therefore, focuses on formulation or pre-formulation studies which should be
considered in the course of the development of a suitable dosage form for active principles produced
by biological or biotechnological means. The objective of these studies is to develop a stable
formulation which ensures, by means of appropriate stability indicating assays, that the integrity of the
active moiety is preserved both biologically and chemically for i) the intended medicinal use, ii) during
the manufacturing process and iii) throughout the defined shelf-life. Furthermore, process parameters
which can influence consistency of the product during scale-up should also be carefully evaluated.
As far as the development pharmaceutics of biological/biotechnological products is concerned, three
important inter-related areas should be carefully considered, namely, aspects relating to stabilisation,
compatibility and biological activity in any pre-formulation or formulation studies. This document
should be read in conjunction with any relevant CPMP guidance notes.

3. SPECIFIC CONSIDERATIONS
3.1 Characterisation
Adequate characterisation using modern physico-chemical and biophysical methods appropriate to
the nature and properties of the active substances, excipients and the formulated products should be
carried out including those relating to molecular size, charge and surface properties. These studies
are intended to describe structural elements responsible for the biological activity such as active sites,
receptor and ligand binding sites and the features responsible for signal transduction. They can also
indicate the relevant parameters which can potentially impact on the in vivo disposition of the
product following administration including those intended for site specific delivery.
Any physico-chemical interactions between the active principle and its excipients should also be
carefully investigated. In the case of certain viral and bacterial vaccines, physico-chemical or
biophysical characterisation may not be adequate and biological characterisation, e.g.
immunogenicity determination, should be considered, where appropriate.

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3.2 Manufacturing process
Biologicals or biotechnological products are distinguishable from their chemically synthesised
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.
Minor changes in the process can affect the quality of the drug product and therefore the
development of the manufacturing process is of paramount importance for biologicals, be they
vaccines, biotechnological or blood products or oligonucleotide therapeutics such as DNA vaccines
and gene therapy products. Manufacturing parameters which can impact on the quality and stability
of the drug substance in a formulated product as indicated previously, e.g. pH, heat, shear, should be
carefully investigated as part of the development strategy to ensure consistency. Where over-fill is
necessary to ensure that adequate amount of the active substance is administered to the patient, e.g.
pre-filled syringe formulation, satisfactory justification should be provided with relevant supporting
evidence.
Because of their physico-chemical properties, it is usually not possible to terminally sterilise the
biological products in the final container by autoclaving. In most instances, they are sterilised by
membrane filtration prior to filling. In this context, manufacture the product under defined, well-
controlled aseptic conditions is deemed sufficient.

3.3 Overages
As a result of stability considerations, overages could be included in the formulation of certain
biological/biotechnological products, e.g. vaccines, to ensure that the required biological activity or
potency is maintained throughout the entire shelf-life under the prescribed storage conditions. Any
overages to be included should also take into account the variability of the bioassay method
employed to determine the potency of the product particularly where an in vivo biological assay is
required for such determination.

3.4 Compatibility
Substantial evidence exists that proteins can interact chemically with the formulation excipients
present in the finished product, for example, the formation of adducts which are potentially
immunogenic.
Potential interactions between the primary packaging and the product itself should be investigated in
any products development programme in order to minimise any decrease in the potency or biological
activity of the finished product arising as a result of sorption during storage. Since proteins are
amphiphilic polyelectrolytes, they exhibit some degree of surface activity. In this regard, adsorption
denaturation can take place through i) diffusion of the native protein molecules to the interface and
their subsequent adsorption ii) uncoiling of the polypeptide chains at the interface and iii) aggregation
of the surface denatured protein into coagulum.
Where the formulated product is presented as a powder for injection in two-chamber cartridges for
reconstitution, e.g. growth hormone, special attention should be paid to ensure correct re-constitution
of the powder or its homogeneous resuspendability and dosage uniformity in the case of a
suspension. This should form the basis of the instructions for use in the appropriate sections of the
leaflet and summary of product characteristics.
Compatibility with another active substance(s) in combination should also be carefully considered,
for example, combination vaccines for subcutaneous, intramuscular or oral use. There are examples
of both live attenuated vaccines, e.g. measles, mumps and rubella, and inactivated vaccines, e.g.
DTP and Hib, where combining components has altered the antigenicity of the individual elements.
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The clinical relevance of any untoward findings should be fully addressed. The effect of adjuvant on
mounting the appropriate immunogenic response should be carefully considered.

3.5 Stability of the active substances
In any pre-formulation studies, it is important to establish the stability of the active principle. In the
case of a protein molecule, for it to retain its biological functions, it usually must adopt the correct
conformation to render it biologically active for the target receptor(s). 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 β-elimination.
The results obtained can be useful in determining how the formulation, and conditions employed in
the manufacturing process and storage, including those relating to changes in temperature, pH, salt,
pressure and shear, will impact on the integrity of the molecule such that degradation can be
minimised.

3.6 Stability of the formulated product
For routine stability testing, reference is made to ICH Q5C Note for Guidance on stability testing for
biotechnological products.
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. This is intended to render the active moiety more stable, for
example, with respect to its primary or tertiary structure, both of which may have direct impact on
the biological activity of the final product e.g. coagulation factors. Such changes may arise during the
manufacturing process and/or during storage.
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.
Excipients and/or reagents used in the manufacture or formulation of drug substances or products
may be of human or animal origin. It is desirable that in development pharmaceutics work on labile
biological products such as live attenuated vaccines, alternatives to the use of materials of human or
animal origin should be developed and evaluated for use in production and in formulation. Substitute
for albumin as an excipient, where possible, should be investigated.

CPMP/BWP/328/99 draft 3/3
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