PuK - Process Technology & Components 2024

Pumps and Systems
Diaphragm metering pumps
Production of biomolecules for pharmaceuticals
Diaphragm metering pumps prove their
worth for critical mixing tasks in industrial
oligonucleotide production
Dr. Hans-Joachim Johl
The size of oligonucleotides lies between
that of small, low-molecular-weight
active pharmaceutical
ingredients (APIs) and high-molecular-weight
active pharmaceutical ingredients
such as mAbs (monoclonal
antibodies). Production facilities
for the manufacture of oligonucleotides
must be able to handle flammable,
toxic compounds as well as
meet hygienic standards to ensure
biological integrity. Above all, however,
they must be flexible and able
to be scaled up from pilot plants
so that they can ideally synthesize
and purify a wide variety of drugs.
In addition to standardized platform
technologies, customer-specific
GMP-compliant systems are
also needed. Diaphragm metering
pumps in these systems can meet
the challenges of extreme chemical
syntheses in the upstream process
and also be used in contamination-free
downstream processes.
The flexible production of toxic and
flammable fluid mixtures with widely
varying flow rate requirements is
particularly important here.
From rare diseases to chronic indications,
the demand for oligonucleotide-based
drugs is steadily increasing.
Oligonucleotides are short, small
(= oligo) sections of genetic sequences
(RNA and DNA). Nucleotides are
the building blocks of nucleic acids
occurring in DNA and RNA chains. Oligonucleotides
are therefore among
the most important components of
modern molecular biology. One of
the most important ways of producing
oligonucleotides with modified
nucleotides for therapeutic purposes
is industrial DNA and RNA synthesis.
In contrast to the frequently used,
biopharmaceutically produced drugs
that target proteins, oligonucleotides
target disorders in the genetic
code that are the cause of specific
diseases. This makes them predestined
for the treatment of previously
incurable rare diseases, including
neuronal diseases. The first antisense
oligonucleotide drug was approved in
1998 as Fomivirsen, under the trade
name Vitravene, for the treatment of
CMV virus in AIDS patients. 1 Several
others followed, including Partisiran,
approved in 2018 under the trade
name Onpattro, a lipid nanoparticleformulated
drug that is one of the
newer oligonucleotide therapies for
polyneuropathy. Although various
oligonucleotide drugs have already
been approved by the authorities,
they have not yet been established
on an industrial commercial scale.
Many other drugs are currently in the
clinical phase prior to industrial production
and are therefore the focus
of ongoing research efforts, which
increasingly include economic and
quantitative aspects.
Challenge: Economical production
of oligonucleotides
As a result, many specialized companies
are focusing on efficient and safe
GMP production of oligonucleotides
using suitable production facilities.
The aim is to maximize yield while
maintaining high purity. This means
that manufacturers of active pharmaceutical
ingredients are faced with
the task of making their own production
processes more and more economical
and robust so that they can
be scaled up from laboratory or pilot
scale to industrial GMP production
with the highest possible yield in synthesis
and downstream steps, without
sacrificing quality or neglecting
economic aspects.
An important step for oligonucleotide
processes is known as media
dilution, where the concentrations
of a synthesized solution are
adjusted. More concentrated storage
solutions are continuously di-
Fig. 1: Production facilities for the manufacture of oligonucleotides must be able to handle
flammable, toxic compounds as well as meet hygienic standards to ensure biological
integrity. (Source: LEWA)
20 PROCESS TECHNOLOGY & COMPONENTS 2024