12 BioPharm International
®
Emerging Therapies eBook September 2023 www.biopharminternational.com
Cell
and
Gene
Therapies
they do for any drug substance. However, when they
are being used in the manufacture of advanced med-
icines such as cell and gene therapies, plasmids are
typically defined as starting materials, and there are
fewer regulatory requirements.
As these products are still in their relative infancy,
the regulatory landscape continues to evolve in par-
allel to the science and technology that underpins
their development. When plasmids are used as part
of a manufacturing process, a company must describe
the quality principles applied to control their safety
and quality in the Control of Materials section of the
Common Technical Document.
The regulator will assess the quality of the starting
material in the context in which it is being consid-
ered, whether this is for a marketing authorization, a
variation application, or an application to run a clini-
cal trial. The EU guidance is, arguably, the most-well
defined, and the European Medicines Agency (EMA)
has published guidance on the principles of GMP for
the manufacture of starting materials of biological
origin used to transfer genetic material for the man-
ufacturing of advanced therapies (1). This guidance
clarifies the fact that EudraLex Volume 4 part IV (2) is
applicable to plasmids and provides manufacturers
with a methodolog y to identif y the minimum re-
quirements in the quality management system, risk
management product development, production, and
quality control when defining the principles of GMP
for the plasmids. For manufacturers, this highlights
the need for a risk-based approach to be adopted.
When used in this way, there is no requirement
for a GMP cer tif icate, or for a qualif ied person to
release plasmids in the European Union, or for rou-
tine inspections. Contract development and manu-
facturing organizations will typically manufacture
different grades of plasmid, with increasing levels of
GMP control, enabling a customer to select the grade
that most closely matches the GMP principles high-
lighted by their risk assessment.
Growing demand
The rapid growth in cell and gene therapies has in-
creased demand for pDNA significantly, with the
market exceeding current supply. This demand is ex-
pected to continue to grow, with projections showing
that it will expand by approximately 20% between
now and 2030 (3).
Advances in manufacturing capabilities and effi-
ciencies are already helping to increase supply. Ini-
tially, processes included time-consuming manual
steps, increasing the risks of contamination and
low-quality products, resulting in significant vari-
ability between batches. Over time, the introduction
of new technologies and single-use reactors have
greatly improved efficiency, yield, purity, and con-
sistency, with automation and a tight control of pro-
cess parameters having a critical role. Quality control
systems have also played their part in ensuring the
consistency and safety of the final product.
In the coming years, further advances are inevita-
ble, and greater scalability, as has been witnessed with
more mature biologic products, will enable plasmids
to be produced at a reduced cost. Better process effi-
ciency could help too, with continuous or semi-con-
tinuous processes potentially reducing waste, and
advances in purification technologies should afford
increased yields of products that have higher purity
and greater consistency.
Research and development of better-performing
bacterial strains offer further benefits, particularly if
they are able to produce particularly challenging se-
quences. Novel delivery strategies of advanced thera-
pies may also lead to a decrease in the quantity of pDNA
required for a number of applications, which alongside
efficiency in manufacturing and decreased costs, could
contribute to accelerating the development of thera-
pies, allowing patients to access them more quickly.
References
1. EMA. Questions and Answers on the Principles of
GMP for the Manufacturing of Starting Materials of
Biological Origin Used to Transfer Genetic Material
for the Manufacturing of ATMPs. EMA.europa.eu,
Feb. 24, 2021.
2. Eu ropea n Com m i s sion. G ood M a nu f ac t u r i ng
Practice (GMP) Guidelines. EudraLex Volume 4.
EC.europa.eu (accessed July 19, 2023).
3. Grand View Research. Plasmid DNA Manufactur-
ing Market Size, Share and Trends Analysis Report
by Disease (Cancer, Infect ious Diseases), by Grade
(R&D, GMP), by Application, by Development Phase,
and Segment Forecasts, 2023–2030. Market Report,
November 2022. ■
The rapid growth
in cell and gene
therapies has
increased demand
for [plasmid] DNA
significantly, with the
market exceeding
current supply.
