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Prior to nomination into full development, a candidate drug
should undergo a phase traditionally called preformulation.
Preformulation is the physiochemical characterization of the
solid and solution properties of compounds.
Preformulation encompasses all studies enacted on a new drug
compound in order to produce useful information for
subsequent formulation of a stable and biopharmaceutically
suitable drug dosage form.
These should focus on those physiochemical properties of new
compound that could effect drug performance and development
of an efficacious dosage form.
“ A phase of a research and development process
where the preformulation scientist characterizes the
physical , chemical and mechanical properties of a
new drug substance in order to develop stable , safe
and effective dosage forms”
 To establish the physico-chemical properties of a new
 To establish the data on drug-excipient compatibility
 To establish API ‘s kinetic rate profile.
1. Q1A(R2) Stability Testing of New Drug Substances and
Products (Issued 11/2003, Posted 11/20/2003);
2. Q1B Photo stability Testing of New Drug Substances and
Products (Issued 11/1996, Reposted 7/7/1998);
3. Q1C Stability Testing for New Dosage Forms (Issued
5/9/1997, Posted 3/19/1998);
4. Q1D Bracketing and Matrixing Designs for Stability Testing of
New Drug Substances and Products (Issued 1/2003, Posted
5. Q3A Impurities in New Drug Substances (Issued 2/10/2003,
6. Q3B(R) Impurities in New Drug Products (Issued 11/2003, Posted
7. Q3C Impurities: Residual Solvents (Issued 12/24/1997, Posted 12/30/1997);
8. Q3C Tables and Lists (Posted 11/12/2003);
9. Q6A International Conference on Harmonization; Guidance on Q6A
Specifications: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances (12/29/2000);
10. Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients (Issued 8/2001, Posted 9/24/2001).
Physicochemical and biological properties that might need to be examined
Water content,
Particle size,
Crystal properties,
Biological activity, and
These properties could be inter-related and might need to be
considered in combination. Some of these properties can
change with time and require time studies.
To evaluate the potential effect of the physicochemical
properties of the drug substance on the performance of the drug
product, the ICH Q6A Specifications: Test Procedures and
Acceptance Criteria for New Drug Substances and New Drug
One purpose of these comprehensive guidelines it to prepare for compliance
with PROCESS ANALYTICAL TECNOLOGY (PAT), a recent initiative of
the Food and Drug Administration (FDA; Ref. 1).
PAT is intended to encourage drug makers to build quality into their
development processes so they can anticipate the impact of changes on a
final formulation.
Although PAT is voluntary, the initiative is designed to promote a better
understanding, among drug manufacturers, of the mechanics of their
processes so that they can avoid failures and minimize the amount of testing
required at the end of production.
Preformulation studies support PAT by providing more information on an
active pharmaceutical ingredient’s (API) characteristics to facilitate
downstream efficiency and success.
Drug manufacturers can eventually submit their documents to a special PAT
group within the FDA, which can expedite regulatory approval.
The FDA considers PAT to be a system for designing,
analyzing, and controlling manufacturing through timely
measurements (i.e., during processing) of critical quality and
performance attributes of raw and in-process materials and
processes, with the goal of ensuring final product quality.
The goal of PAT is to enhance the understanding and control
the manufacturing process, which is consistent with our current
drug quality system
This guidance facilitates innovation in development,
manufacture, and quality assurance by focusing on process
understanding. These concepts are applicable to all
manufacturing situations.
In January 2004, the U.S. FDA issued a guideline for botanical
The information discussed in section VII.A.1 of the guideline
pertains to the initiation of characterization of the drug substance.
It is important for the safe conduct of clinical trials to ensure the
proper identity of botanical raw materials used in the trials.
As there is no history of experience in United States with botanical
raw materials marketed only outside the United States, a certificate
of authenticity of the plant and plant parts should be provided for
such materials.
A trained professional who is competent to determine authenticity
should sign this certificate.
The general method of preparation is provided under Sec312.
The EMEA provides the following guidelines for herbal (botanical as listed
in United States) products:
Guidance on Quality of Herbal Medicinal Products (CPMP/CVMP
adopted July 01).
• CPMP/QWP/2820/00 (EMEA/CVMP/815/00) Note for Guidance on
Specifications: Test procedures and Acceptance Criteria for Herbal
Drugs, Herbal Drug Preparations and Herbal Medicinal Products
(CPMP/CVMP adopted July 01).
If no monograph for the herbal drug is given in a
pharmacopoeia referred in directives 75/318/European
economic community(EEC)and81/852/EEC
Annexure 1
Analytical procedures not given in a Pharmacopeia should be
validated in accordance with the ICH guideline “ validation of
analytical procedures; methodology” (CPMPICH/281/95) and
The information may be supplied either as part of the
marketing authorization application or with the help of
European drug master file procedure.
Proteins may be identified through genomics/proteomics
activities or through more traditional medical research.
One of the most challenging aspects of developing protein
pharmaceuticals is dealing with and overcoming the inherent
physical and chemical instabilities of proteins.
Marketing considerations arise early in product development
fro monoclonal antibodies(MAb’s).
Typically MAb’s are needed at higher doses and are normally
delivered ‘IV’.
Thus, MAb’s must be available at high concentrations
at which they are viscous, making them difficult to administer
preformulation activity that needs to be considered ia a
concentration study investigating solubility behavior, effect of
conc. on viscosity, increased potential for aggregation.
disagreement over preservatives in food and drugs
may present problem at the preformulation stage.
US,EU and Japanese compendia standards differ regarding
the timing of anti microbial tests for preservatives
E.g.: Japan does not accept phenol, where it is commonly used in
European union is known to have the toughest acceptance
criteria for preservatives.
The USFDA provides a detailed description of the
characterization of the substances obtained by
recombinant DNA technique.
Several guidelines of the ICH and other guidelines at
the USFDA provide additional information on stability
testing of biological products.
A clear description of the drug substance should be
provided which may include any of the following:
Chemical structure
Molecular weight
Molecular formula
Information from specific tests regarding
identity, purity, stability and consistency of manufacture
of the drug substance should be provided.
Amino acid analysis
Amino acid sequencing
Peptide mapping
Determination of disulphide linkage
Application should include description of
- Relevant invitro and invivo biological testing
- Bioassays
- Storage conditions
- Study protocols
- Results supporting this section
 Hand
Book of Preformulation