APR March 2024 - 20

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FORMULATION AND DEVELOPMENT
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* The distribution plot is imported into GUSSI software (freely
distributed by UT Southwestern Medical Center) which
determines the relative concentration of the different species
(area under the curve) and the sedimentation coefficients for
each species observed.
Each of these steps was subjected to a risk analysis to determine
required mitigation for GMP analyses.
GMP Implementation
1. Optima AUC Onboard Computer - Use within
GMP through Mitigation Strategies
The PostgreSQL database for storing the raw data constitutes an
open-source object-relational database management system and
thus poses a potential risk of unauthorized users accessing it and
obtaining data (lack of cybersecurity). This risk can easily be mitigated
by not connecting the AUC onboard PC directly to the internet, but
rather connecting it to a secondary computer used for Intermediate
data saving.
The Optima AUC onboard computer also does not provide security
against unauthorized/authorized users. The system provides three
access levels (user, data management and service) that all lack
attributability. By allowing analysts only access to the user level and
requiring analyst user access be subjected to secondary witness
documentation, any acquired GMP data becomes attributable to fulfill
the respective ALCOA+ principle. A similar approach is taken for the
Optima v.1.11 Service engineer account, used by vendors only, which
enables vendors to change the date, time, system configuration,
instrument settings, and delete raw data. In addition, the vendor pin
cannot be changed by PPD Laboratory services. To mitigate this access
security risk, our support services personnel act as a secondary witness
and document and oversee all vendor visits.
To further limit access to the data acquired on the AUC onboard
computer, the linked intermediate data saving PC is minimally
configured for the purpose of creating and saving AUC methods and
downloading data for transfer to our data backup system. Access
to this capability is limited to a designated group of users within a
security group, which is comprised of our approved AUC analysts.
Data downloading is also witnessed by a second analyst. Since this
requires modify and write access to the folder on the intermediate
data saving PC, a five-minute schedule to sweep the compressed
raw data into a secure back-up location was implemented to protect
against data deletion or modification. Data processing is only allowed
on a secondary processing PC to which the raw data have been
downloaded from the secure backup location. Secondary witnessing is
applied to this process as well. To protect against deletion of processed
data, the directory contents are swept in 30-minute intervals to a
secure backup location.
Any risk mitigation regarding data security as well as secondary
witnessing is governed by our standard operation procedure governing
the operation, calibration and maintenance of the Optima AUC.
20 |
| March 2024
2. Data Rationale for Use of SEDFIT and GUSSI in
AUC Analyses as a GMP Application
AUC is a classical (Svedberg and Rinde 19248
), yet contemporary
(Uchimaya et al. 20169) technique for the characterization of
macromolecular and colloidal particles in solution. As described
in numerous recent reviews, book chapters and monographs (see,
for instance, Uchimaya et al. 2016; Schuck et al. 2016;10
Patel et al.
2016),11 AUC permits the separation of the components of a solute
sample in the centrifugal field, as well as the characterization of their
individual solution properties and, even, their interactions. The basis
of the sedimentation velocity (SV) experiments is mathematically
captured by the Lamm equation (Lamm, 1929),12
which describes
the sedimentation and diffusion of particles in a sector-shaped cell.
The relationship between the solvent and physical properties of
sedimenting particles is defined by the Svedberg equation. Analysis
of AUC data can be performed with or without the application of
modeling-based approaches to extract particle properties. A review
by Edwards et al. 202013
listed the following available free software for
use in SV-AUC: DCDT+, SVEDBERG, SEDANAL, SEDFIT and UltraScan III.
Of the listed software options, only SEDANAL, SEDFIT and UltraScan
III provide a numerical approach to fitting the Lamm equation to the
AUC raw data. SEDANAL analysis, as well as the approximate (nonnumerical)
SVEDBERG analysis require user-selected species models,
for which, in our opinion, the impact of potential user bias on the
final analysis results is not known. Only SEDFIT14
and UltraScan III15
(freely distributed by University of Texas Health Science Center)
provide a continuous distribution analysis of species with different
sedimentation coefficients, which represents the data desired by our
clients. This can be either a proportion of empty and (genetic material)
filled AAV capsids and their mean sedimentation coefficients or in
the case of protein aggregate analysis their relative percentage and
approximate molecular weights.
UltraScan III is a sophisticated AUC analysis software due to its
advanced data analysis and extensive modeling capabilities, while the
UltraScan LIMS system provides web-based access to the database and
supercomputing functionality. To avoid web-based data analysis for
client confidentiality (or other) reasons, UltraScan-in-a-box provides
the means to run the AUC data analysis locally.
SEDFIT on the other hand, while not validated to cGMP standards
(including IQ/OQ/PQ), is a software tool for the biophysical analysis of
macromolecular assembly which would be considered a reliable source
as it has been widely used by academic groups for more than 20 years
and gained popularity in the industry in the last five years or so.
While SEDFIT provides the sedimentation distribution analysis raw
data, it is used in conjunction with GUSSI,16
which can illustrate
the output of SEDFIT and perform simple calculations from the
sedimentation velocity data. This includes areas under the curve
analysis for the determination of relative distributions, like percent
empty capsules.17
Our evaluation of these two software (UltraScan and SEDFIT/GUSSI)

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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