APR March 2024 - 11

« BIOPHARMACEUTICALS
Columns
Chromatographic media are not widely available in pre-sterilized
column format. It is more usual for packed columns to be sanitized
with NaOH at a molarity that the medium will withstand. For most
columns and for some modern Protein A resins such as MabSelect
PrismA™ resin, this is 1N NaOH. Sanitizing in place with NaOH is not
as desirable, as it can be difficult to destroy microorganism spores
that can be highly resistant to NaOH. Additionally, during sanitization,
the downstream flow path may be exposed to bioburden. For these
reasons, pre-sterilization of columns is an active area of research.3
However, for batch processes, the risks of using chromatography with
sanitization (rather than pre-sterilization) have been well managed
over the years, with some suppliers moving to highly controlled
manufacturing environments.
Microbial testing
Despite efforts to create a completely closed process and minimize
microbial contamination, testing is still required. Endotoxin testing
is probably the least problematic of such release tests. Limulus
amoebocyte lysate (LAL)-based methods are well established and
relatively fast. Alternative approaches are also under development.
Bioburden is more of an issue. Microorganism testing as described in
USP chapter 61 is more prolonged.4
The main element of the chapter
is a plate count assay that requires up to 14-day incubation times on
agar plates. This is a major pain point for lot release. Additionally, it
poses another problem, as contamination detection takes such a
long time it offers no opportunity to correct a process if bioburden is
beginning to appear.
Similarly to bioburden testing, viral contamination testing currently
involves cell tissue culture with protracted incubation times. Thus,
rapid detection methods are an active area of interest, and the lead
alternative involves next-generation sequencing (NGS). While this
approach is faster, it involves a significant amount of data analysis
and poses substantial problems with respect to process validation for
GMP.5
data. Overall, microbial testing represents the main analytical issue to
continuous manufacturing and releasing lots in a timely manner.
Cleanroom requirements
The proposed improvements to the flow path may enable development
of a fully closed manufacturing process, which in turn would eliminate
the risk of adventitious agents entering through the manufacturing
environment. A potential positive impact of such a closed process
would be the reduced requirements for a cleanroom classification,
which would greatly reduce cost and facility complexity. Fully
closed processes could potentially be operated in open 'ballrooms'.
Additionally, there would be no need to physically segregate the
pre- and post-viral removing steps (e.g., the operations before and
after virus filtration). However, fully defining the requirements and
validation for a closed system remains a challenge.6
The location of the individual unit operations in an enclosure or
secondary container could essentially create a secondary environment
to house the closed flow path. Controlling that secondary environment
would further reduce the risk of contamination and may provide the
confidence to locate a continuous bioproduction capability outside a
traditional cleanroom environment.
User Experience
The challenges for users of continuous systems go beyond the
standard 21 CFR part 11 requirements: " Persons who use open systems
to create, modify, maintain, or transmit electronic records shall employ
procedures and controls designed to ensure the authenticity, integrity,
and, as appropriate, the confidentiality of electronic records... " .7
This
entails different login credentials and software abilities for different
operators, supervisors, and process engineers that are standard for
manufacturing processes. However, a continuous process poses
new challenges that require further development of the software.
Programming systems to operate in unison for days or weeks is more
challenging. It also requires development at both the unit operation
and process levels. Thus, the manufacturing equipment may be best
viewed holistically as a single system. For operators to set up and
perform processes, enhanced programmability may be a necessity
to minimize errors and ensure compatibility of the unit operation
outputs throughout the process. Additionally, a user-friendly graphical
interface with real-time data monitoring will be required for operators
to monitor the process and see if any part of it is starting to head out
of specification.
Data Management
It remains to be seen how regulatory authorities will accept such
One of the advantages of continuous processing is the ability to
reduce the size of equipment and consumables through rapid
cycling. From a data perspective, rapid cycling can be a double-edged
sword. On the positive side, having more process data enables earlier
identification of when the system starts to deviate from control, so that
early intervention can be deployed to keep all product in specification.
On the negative side, operating for long periods of time creates a datamanagement
problem. Sensors, for example, can take measurements
with millisecond frequency. This would generate a vast amount of
data after multiple weeks of continuous processing, which then must
be stored, managed, and presented in the batch report. Reporting
by exception - focusing on occasions where the actual data differ
from the prediction - would be the most likely path forward. Luckily,
the large amounts of data generated would enable a more complete
statistical analysis. This is a key area where digital twins of the process
could be highly impactful.
Another challenge with data management is tying data together from
different systems and sources. Here it will be important to employ a
data historian and be able to timestamp and reconnect data that is
generated later through analytics and offline sampling. This challenge
is exaggerated for continuous processing due to the longer processing
times and increased amount of data generated.
www.americanpharmaceuticalreview.com |
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»

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APR March 2024

Table of Contents for the Digital Edition of APR March 2024

Message from the Editor
Editorial Advisory Board
BIOPHARMACEUTICALS - Getting to GMP-Quality Biotherapeutics From Today’s Bench-Scale Continuous Manufacturing Systems: A Gap Analysis
MICROBIOLOGY - Critical Behavioral Attributes and the Application of COM-B Framework in Aseptic Processing
FORMULATION AND DEVELOPMENT - Use of AUC in AAV Analysis in a GMP Setting
FORMULATION AND DEVELOPMENT - Precision Medicine in Clinical Trials: A Statistical Perspective
An Interview with Dan Smithey, PhD President & CEO, Serán
FORMULATION AND DEVELOPMENT - Still Early Days for AI in Drug Discovery...Says Who?
QC Corner - Enhancing Material and Equipment Availability in Production Isolators
BIOPHARMACEUTICALS - Technologies for Aseptic Filling: The Choice is Clear
Vendor Viewpoint - Data Integrity and Rapid Micro Methods: Transforming to a Modern Microbiology Lab
MICROBIOLOGY - Bacterial Spore Formers in Disinfectant Efficacy Testing
Partner Perspective - Nanoparticle Technologies: Enablers for Ocular Drug Delivery
DRUG DELIVERY - Your Nails and You
DRUG DEVELOPMENT - Battling Exorbitance: High Costs in Sickle Cell Gene Therapies and the Imperative of Global Patient Registries for Equity
FORMULATION AND DEVELOPMENT - How Pharma Companies Are Solving Regulatory Challenges with AI-based Technology
Event Preview - CPHI North America
Event Preview - Excipient World 2024
P.I.N. Points
Advertiser's Index
APR March 2024 - CoverTip01
APR March 2024 - CoverTip02
APR March 2024 - Cover1
APR March 2024 - Cover2
APR March 2024 - 1
APR March 2024 - 2
APR March 2024 - 3
APR March 2024 - 4
APR March 2024 - 5
APR March 2024 - Message from the Editor
APR March 2024 - Editorial Advisory Board
APR March 2024 - BIOPHARMACEUTICALS - Getting to GMP-Quality Biotherapeutics From Today’s Bench-Scale Continuous Manufacturing Systems: A Gap Analysis
APR March 2024 - 9
APR March 2024 - 10
APR March 2024 - 11
APR March 2024 - 12
APR March 2024 - 13
APR March 2024 - MICROBIOLOGY - Critical Behavioral Attributes and the Application of COM-B Framework in Aseptic Processing
APR March 2024 - 15
APR March 2024 - 16
APR March 2024 - 17
APR March 2024 - 18
APR March 2024 - FORMULATION AND DEVELOPMENT - Use of AUC in AAV Analysis in a GMP Setting
APR March 2024 - 20
APR March 2024 - 21
APR March 2024 - 22
APR March 2024 - 23
APR March 2024 - FORMULATION AND DEVELOPMENT - Precision Medicine in Clinical Trials: A Statistical Perspective
APR March 2024 - 25
APR March 2024 - 26
APR March 2024 - 27
APR March 2024 - An Interview with Dan Smithey, PhD President & CEO, Serán
APR March 2024 - 29
APR March 2024 - 30
APR March 2024 - FORMULATION AND DEVELOPMENT - Still Early Days for AI in Drug Discovery...Says Who?
APR March 2024 - 32
APR March 2024 - 33
APR March 2024 - QC Corner - Enhancing Material and Equipment Availability in Production Isolators
APR March 2024 - 35
APR March 2024 - BIOPHARMACEUTICALS - Technologies for Aseptic Filling: The Choice is Clear
APR March 2024 - 37
APR March 2024 - 38
APR March 2024 - 39
APR March 2024 - Vendor Viewpoint - Data Integrity and Rapid Micro Methods: Transforming to a Modern Microbiology Lab
APR March 2024 - 41
APR March 2024 - MICROBIOLOGY - Bacterial Spore Formers in Disinfectant Efficacy Testing
APR March 2024 - 43
APR March 2024 - Partner Perspective - Nanoparticle Technologies: Enablers for Ocular Drug Delivery
APR March 2024 - 45
APR March 2024 - 46
APR March 2024 - 47
APR March 2024 - DRUG DELIVERY - Your Nails and You
APR March 2024 - 49
APR March 2024 - 50
APR March 2024 - 51
APR March 2024 - DRUG DEVELOPMENT - Battling Exorbitance: High Costs in Sickle Cell Gene Therapies and the Imperative of Global Patient Registries for Equity
APR March 2024 - 53
APR March 2024 - 54
APR March 2024 - 55
APR March 2024 - FORMULATION AND DEVELOPMENT - How Pharma Companies Are Solving Regulatory Challenges with AI-based Technology
APR March 2024 - 57
APR March 2024 - Event Preview - CPHI North America
APR March 2024 - 59
APR March 2024 - Event Preview - Excipient World 2024
APR March 2024 - 61
APR March 2024 - P.I.N. Points
APR March 2024 - 63
APR March 2024 - Advertiser's Index
APR March 2024 - Cover3
APR March 2024 - Cover4
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