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Chapter 15: Global Regulatory Strategy
perspective, the CMC development program
must consider many aspects, including develop-
ment phase and regional requirements.
A global CMC strategy should be inte-
grated and linked with the overall global
product strategy to ensure suitably formulated
product is available to meet a particular devel-
opment stage’s requirements.
The three key factors influencing the CMC
development program are quality, time and cost.
All these factors are related, and the chosen
pathway also will depend on the business’s risk
tolerance. For example, an organization initially
may choose to save time to get the first patient
for a given clinical study. However, in the end,
that decision may incur higher costs and addi-
tional time or even result in a product profile that
is less acceptable to patients (e.g., short storage
conditions due to lack of stability data).
Initially, a non-GMP drug substance is
acceptable for nonclinical studies, provided the
impurity profile does not increase a toxicity risk
that might not occur at later development stages
when impurity limits are tighter. Frequently, only
the drug substance is required for initial pharma-
cology and toxicology studies. However, formu-
lation effects must be evaluated, and the drug
product may be required for nonclinical studies if
the product required a complex formulation due
to the drug substance’s physicochemical prop-
erties, e.g., low solubility, membrane permea-
bility, stability or interactions with formulation
excipients.
As the product moves into clinical stud-
ies, the CMC strategy must take clinical trial
product requirements into account in countries
where studies are planned. In most countries,
full GMP compliance is required for all clinical
study phases. However, some countries, including
Australia, allow use of a non-GMP product for a
first-in-human study in healthy volunteers.
The drug product presentation also must be
consistent with the clinical development strategy
to ensure the dosage form and dose unit meet
protocol requirements. Early in development, it
is recognized clinical studies may be conducted
with a simple formulation, but later clinical
studies should be conducted with the product
planned for marketing. If significant manufac-
turing or formulation changes are made late in
development, bridging studies may be required to
confirm the changes have not altered the prod-
uct’s safety or efficacy profile.
Other clinical study CMC considerations
include requirements for a placebo product
identical in appearance to the active product for
use in double-blind studies. Placebo development
may be challenging if the active drug substance
has characteristics difficult to emulate with an
inactive substance, e.g., smell or taste.
Many countries are members of the Phar-
maceutical Inspection Convention and Phar-
maceutical Inspection Cooperation Scheme
(PIC/S), which provides a GMP guide for
medicinal products. Annex 13 sets out require-
ments for clinical trial product manufacturing
and labeling. This guide can assist the CMC
team in planning the clinical trial product man-
ufacturing program and core labels however, the
team always should be aware of the geographic
locations in which studies will be conducted and
individual country- and study-specific require-
ments. In some countries, e.g., India, patient
labels and information are required to be in the
local language, meaning up to six local languages
must be accommodated. Clinical trial supply
availability is a key factor in study start-up
times and should be coordinated with the
clinical development team. Batch records may
be required for study approval, but manufacture
timing should ensure, as far as possible, sufficient
stability data are available to avoid the need to
change batches during the study.
As the product development program moves
closer to market, it is important the CMC team
understands the regulatory filing strategy, desired
product profile for patients and priority target
countries to ensure regulatory dossier CMC sec-
tions meet both the format and content require-
ments for each country. International Council
on Harmonisation (ICH) guidelines assist and
enable manufacturers to develop a core CMC
Chapter 15: Global Regulatory Strategy
perspective, the CMC development program
must consider many aspects, including develop-
ment phase and regional requirements.
A global CMC strategy should be inte-
grated and linked with the overall global
product strategy to ensure suitably formulated
product is available to meet a particular devel-
opment stage’s requirements.
The three key factors influencing the CMC
development program are quality, time and cost.
All these factors are related, and the chosen
pathway also will depend on the business’s risk
tolerance. For example, an organization initially
may choose to save time to get the first patient
for a given clinical study. However, in the end,
that decision may incur higher costs and addi-
tional time or even result in a product profile that
is less acceptable to patients (e.g., short storage
conditions due to lack of stability data).
Initially, a non-GMP drug substance is
acceptable for nonclinical studies, provided the
impurity profile does not increase a toxicity risk
that might not occur at later development stages
when impurity limits are tighter. Frequently, only
the drug substance is required for initial pharma-
cology and toxicology studies. However, formu-
lation effects must be evaluated, and the drug
product may be required for nonclinical studies if
the product required a complex formulation due
to the drug substance’s physicochemical prop-
erties, e.g., low solubility, membrane permea-
bility, stability or interactions with formulation
excipients.
As the product moves into clinical stud-
ies, the CMC strategy must take clinical trial
product requirements into account in countries
where studies are planned. In most countries,
full GMP compliance is required for all clinical
study phases. However, some countries, including
Australia, allow use of a non-GMP product for a
first-in-human study in healthy volunteers.
The drug product presentation also must be
consistent with the clinical development strategy
to ensure the dosage form and dose unit meet
protocol requirements. Early in development, it
is recognized clinical studies may be conducted
with a simple formulation, but later clinical
studies should be conducted with the product
planned for marketing. If significant manufac-
turing or formulation changes are made late in
development, bridging studies may be required to
confirm the changes have not altered the prod-
uct’s safety or efficacy profile.
Other clinical study CMC considerations
include requirements for a placebo product
identical in appearance to the active product for
use in double-blind studies. Placebo development
may be challenging if the active drug substance
has characteristics difficult to emulate with an
inactive substance, e.g., smell or taste.
Many countries are members of the Phar-
maceutical Inspection Convention and Phar-
maceutical Inspection Cooperation Scheme
(PIC/S), which provides a GMP guide for
medicinal products. Annex 13 sets out require-
ments for clinical trial product manufacturing
and labeling. This guide can assist the CMC
team in planning the clinical trial product man-
ufacturing program and core labels however, the
team always should be aware of the geographic
locations in which studies will be conducted and
individual country- and study-specific require-
ments. In some countries, e.g., India, patient
labels and information are required to be in the
local language, meaning up to six local languages
must be accommodated. Clinical trial supply
availability is a key factor in study start-up
times and should be coordinated with the
clinical development team. Batch records may
be required for study approval, but manufacture
timing should ensure, as far as possible, sufficient
stability data are available to avoid the need to
change batches during the study.
As the product development program moves
closer to market, it is important the CMC team
understands the regulatory filing strategy, desired
product profile for patients and priority target
countries to ensure regulatory dossier CMC sec-
tions meet both the format and content require-
ments for each country. International Council
on Harmonisation (ICH) guidelines assist and
enable manufacturers to develop a core CMC