Chapter 6: Gene Therapy and Viral Vectors: An Overview on Current Trends
54
Chemistry, Manufacturing, and Control
Gene therapy products are novel treatments and
complex biological products and, as a result, pose
multiple challenges for sponsors involved in their
development and manufacturing. Establishing
controls and standards are the building blocks of
developing a robust manufacturing paradigm for
these revolutionary therapeutic options. Health
authorities across the globe, realizing the poten-
tial of gene therapy, have partnered with sponsors
and supported the development of gene therapy
products by releasing guidance documents with
current thinking and recommendations regarding
chemistry, manufacturing, and control (CMC)
information that is essential for product devel-
opment and regulatory submissions. Examples of
these guidance documents and a brief description
of their scope and objective are provided below
guidance also applies to combination products
that contain gene therapy in combination with a
device, drug, or other biological.
• January 2020 FDA guidance on chemis-
try, manufacturing, and control (CMC)
information for human gene therapy inves-
tigational new drug applications (INDs)
provides sponsors developing gene therapy
products with recommendations regarding
CMC information submitted in an IND.
FDA also provides guidance on product
development and the expectation around
CMC requirements for the investigational
product’s safety, identity, quality, purity, and
strength (including potency). The recom-
mendations are effectively grouped as eCTD
modules with appropriate contents to aid
sponsors when completing the sections for
filing an IND.30
• January 2020 FDA guidance on human gene
therapy for hemophilia provides recommen-
dations to sponsors mainly on the clinical
aspects of developing human gene therapy
products for the treatment of hemophilia.
The guidance also covers preclinical consid-
erations and CMC expectations to support
development of gene therapy products
for the treatment of hemophilia. CMC
expectations were like those described in
the previous guidance and no indication of
specific nuances were described.31
• January 2020 FDA guidance on human
gene therapy for rare diseases provides
recommendations to sponsors developing
human gene therapy products focusing on
a rare disease, which is defined in the US as
one that affects fewer than 200,000 people.
The guidance outlines CMC, preclinical,
and clinical considerations where there may
be feasibility issues related to the size of
the affected population. Uniqueness of the
gene therapy products combined with the
limited study population may compound the
challenges faced in the development of gene
therapy products. While the general phi-
losophy around CMC for developing gene
therapy products remain the same as those
described in general, aspects such as fewer
lots manufactured and insufficient samples
make it hard to develop or design critical
quality attributes based on clinical outcomes.
The guidance also outlines challenges in
establishing critical process parameters
and the importance of implementing these
parameters early in the product development
timeline. The preclinical program should be
designed to support the development of a
robust analytical strategy including potency
assays to guide the clinical development of
gene therapy products for rare disorders.32
• January 2020 FDA guidance on human
gene therapy for retinal disorders provides
recommendations to sponsors developing
human gene therapy products for retinal
disorders. In addition to the general CMC
guidelines applicable for gene therapy prod-
ucts, special considerations specific to retinal
products, such as formulation for small
volume and endotoxin limits, are discussed.
Purity factors, such as particulate matter, and
the evaluation of compatibility of the drug
product with the delivery system are also
discussed.33 Other product-specific guid-
ance with CMC recommendations include
preparation of IDEs and INDs for products
intended to repair or replace knee cartilage
and considerations for allogeneic pancreatic
islet cell products.34
54
Chemistry, Manufacturing, and Control
Gene therapy products are novel treatments and
complex biological products and, as a result, pose
multiple challenges for sponsors involved in their
development and manufacturing. Establishing
controls and standards are the building blocks of
developing a robust manufacturing paradigm for
these revolutionary therapeutic options. Health
authorities across the globe, realizing the poten-
tial of gene therapy, have partnered with sponsors
and supported the development of gene therapy
products by releasing guidance documents with
current thinking and recommendations regarding
chemistry, manufacturing, and control (CMC)
information that is essential for product devel-
opment and regulatory submissions. Examples of
these guidance documents and a brief description
of their scope and objective are provided below
guidance also applies to combination products
that contain gene therapy in combination with a
device, drug, or other biological.
• January 2020 FDA guidance on chemis-
try, manufacturing, and control (CMC)
information for human gene therapy inves-
tigational new drug applications (INDs)
provides sponsors developing gene therapy
products with recommendations regarding
CMC information submitted in an IND.
FDA also provides guidance on product
development and the expectation around
CMC requirements for the investigational
product’s safety, identity, quality, purity, and
strength (including potency). The recom-
mendations are effectively grouped as eCTD
modules with appropriate contents to aid
sponsors when completing the sections for
filing an IND.30
• January 2020 FDA guidance on human gene
therapy for hemophilia provides recommen-
dations to sponsors mainly on the clinical
aspects of developing human gene therapy
products for the treatment of hemophilia.
The guidance also covers preclinical consid-
erations and CMC expectations to support
development of gene therapy products
for the treatment of hemophilia. CMC
expectations were like those described in
the previous guidance and no indication of
specific nuances were described.31
• January 2020 FDA guidance on human
gene therapy for rare diseases provides
recommendations to sponsors developing
human gene therapy products focusing on
a rare disease, which is defined in the US as
one that affects fewer than 200,000 people.
The guidance outlines CMC, preclinical,
and clinical considerations where there may
be feasibility issues related to the size of
the affected population. Uniqueness of the
gene therapy products combined with the
limited study population may compound the
challenges faced in the development of gene
therapy products. While the general phi-
losophy around CMC for developing gene
therapy products remain the same as those
described in general, aspects such as fewer
lots manufactured and insufficient samples
make it hard to develop or design critical
quality attributes based on clinical outcomes.
The guidance also outlines challenges in
establishing critical process parameters
and the importance of implementing these
parameters early in the product development
timeline. The preclinical program should be
designed to support the development of a
robust analytical strategy including potency
assays to guide the clinical development of
gene therapy products for rare disorders.32
• January 2020 FDA guidance on human
gene therapy for retinal disorders provides
recommendations to sponsors developing
human gene therapy products for retinal
disorders. In addition to the general CMC
guidelines applicable for gene therapy prod-
ucts, special considerations specific to retinal
products, such as formulation for small
volume and endotoxin limits, are discussed.
Purity factors, such as particulate matter, and
the evaluation of compatibility of the drug
product with the delivery system are also
discussed.33 Other product-specific guid-
ance with CMC recommendations include
preparation of IDEs and INDs for products
intended to repair or replace knee cartilage
and considerations for allogeneic pancreatic
islet cell products.34