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The WHO has since issued an EUL to ten vaccine products (Comirnaty,
Vaxzevria, Covishield, COVID-19 Vaccine by Janssen-Cilag Int NV, Spikevax,
Inactivated COVID-19 Vaccine [Vero Cell], CoronaVac, Covaxin, Covovax, and
Nuvaxovid).
K. Arch-Douglas et al.
16.4.4 Examples ofGlobal Regulatory Challenges During
aPandemic
In order for a manufacturer to market their product in a country, they must ensure
they are in compliance with local country laws and regulations. This is a challenge
when you consider the dossier mentioning the need to alleviate concerns for a single
board of health. However, when you consider the complexities of alleviating those
same concerns across 50 or 80 plus countries, that regulatory challenge exacerbates
ten-fold.
Every major change that a manufacturer makes (e.g., increasing batch size,
extending shelf-life, or increasing the amount of manufacturing sites) to their dossier must receive approval or concurrence from every country’s board of health in
which the drug is registered.
There are some boards of health that require a single license per drug product
manufacturing site; they may also require a new license for a different concentration
or formulation of that same drug (such as dosing concentration changes for pediatric indications or changing product formulation from a liquid drug product to a
lyophilized drug product as a means of increasing product shelf-life). Having to
maintain ve or six licenses for a single country adds to the increased regulatory
burden on manufacturers. The increased burden could be having to submit different
submission packages across the various licenses for the same change. There could
also be parallel queries received across licenses, as well as parallel commitments
across licenses, all needing to be managed, authored, and submitted within very
specic timeframes.
During the COVID-19 pandemic, many countries understood this added burden
and made new guidances or even changed laws to alleviate the burden so that they
could receive vaccine doses at a rapid rate.
Many global boards of health rely on a reference market to leverage for submission approvals. In many cases that reference market is either the European Union
(EU) or the United States. During a pandemic, the manufacturer and the country
may prefer global harmonization for their dossiers and may attempt to align global
market dossier packages with either the United States or the EU.This would allow
the manufacturer to rapidly submit supplements, amendments, or variations, removing the need to customize a submission for specied markets on an individualized
basis. The country using the EU conditional marketing authorization as a reference
market dossier in turn may require the manufacturer to submit EU queries, specic
obligations, and recommendations as commitments to maintain conditional use of
16 Overview ofComplexities ofGlobal CMC Regulatory Affairs
471
the drug in their country. In the case of the COVID-19 pandemic, this was more
prevalent as the FDA and EMA were openly collaborating together with other countries to help facilitate COVID-19 vaccine development; this included specic obligations and recommendations to manufacturers with other countries.
The COVID-19 pandemic was and continues to be the most globally collaborative therapeutic, diagnostic, and vaccine development effort in human history. It is
because of this global collaboration from various governments, regulatory entities,
private businesses, philanthropists, and global health organizations that we were
able to see companies like Pzer and Moderna develop and successfully launch a
viable vaccine candidate with very high efcacy in under a year—something that
until December of 2020 had never been done in the modern biopharmaceutical age.
References
1. https://www- sciencedirect- com.eu1.proxy.openathens.net/science/article/pii/S22113835
22000521
2. DiMasi JA, Grabowski HG, Hansen RW (2016) Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ 47:20–33. https://doi.org/10.1016/j.
jhealeco.2016.01.012. Epub 2016 Feb 12. https://pubmed.ncbi.nlm.nih.gov/26928437/
3. https://admin.ich.org/sites/default/les/2021- 02/CTD_triangle_color_Proofread.pdf
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013036/pdf/pone.0096513.pdf
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291398/pdf/05- 0979.pdf
6. Bourla A (2022) Moonshot—inside Pzer’s nine-month race to make the impossible possible.
HarperCollins Publishers
7. https://pubmed.ncbi.nlm.nih.gov/32191675/
8. https://www.fda.gov/emergency- preparedness- and- response/mcm- legal- regulatory-
and- policy-framework/emergency- use- authorization
9. Secretary of Health and Human Services Alex M.Azar. Determination that a public health
emergency exists (January 31, 2020, renewed April 21, 2020). Available at https://www.phe.
gov/emergency/news/healthactions/phe/Pages/default.aspx
10. https://www.fda.gov/news- events/fda- voices/fda- and- ema- collaborate- facilitate- sars- cov- 2-
vaccine- development
11. https://www.fda.gov/media/139638/download
12. https://www.fda.gov/media/142749/download
13. https://www.ema.europa.eu/en/human- regulatory/marketing- authorisation/
conditional- marketing- authorisation
14. https://www.who.int/teams/regulation- prequalification/eul#:~:text=The%20WHO%20
Emergency%20Use%20Listing,by%20a%20public%20health%20emergency
Chapter 17
CMC Considerations forContinuous
Bioprocess Design, Development,
andManufacturing
Yanhuai(Richard)Ding andMargaret(Peggy)Marino
Abstract This chapter describes monoclonal antibody (mAb) continuous biopro-
cess (CBP) from design, implementation to manufacturing based on the scientic
understanding of mAb physicochemical properties, proven bioprocessing principles, available technologies, chemistry, manufacturing, and control (CMC) considerations, current industrial practices, regulatory guidelines, challenges, potential
solutions, and future perspectives. The discussion addresses the conventional, intensied, integral, and/or fully automated end-to-end mAb CBP manufacturing process
from cell line development (CLD); cell culture process development (e.g., upstream
process); protein purication process development (e.g., downstream process); analytical method development, qualication, and validation for process performance;
and product quality monitoring and control perspectives. The increasing interest in
the application of CBP in biopharmaceutical manufacturing is associated with
increased mAb market demand, demonstrated process consistency and product
quality, and potential cost of goods (COGs) reduction. Some unprecedented challenges of CBP application are discussed. Some innovative technologies are assessed
with practical solutions proposed. A case study is presented and discussed regarding
a owthrough mode of cation exchange chromatography for potential CBP implementation. The goal of this chapter is to propose a design and establish a fully
automated CBP platform for an end-to-end mAb production from cell culture to
drug substance (DS) formulation. Finally, the CBP technology is proposed for other
bioprocess and manufacturing such as adeno-associated virus (AAV) vector for
gene therapy.
Y. Ding (*)
CMC Drug Substance/Drug Product, EvolveImmune Therapeutics, Branford, CT, USA
e-mail: yanhuai.ding@evolveimmune.com
M. Marino
Downstream Process Development & Manufacturing, AnaptysBio, San Diego, CA, USA
K. Gadamasetti, S. A. Kolodziej (eds.), Bioprocessing, Bioengineering
and Process Chemistry in the Biopharmaceutical Industry,
https://doi.org/10.1007/978-3-031-62007-2_17
473© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
474
Y. Ding and M. Marino
Keywords Continuous bioprocess · Chemistry · manufacturing · and control ·
Critical quality attribute · Drug substance · Monoclonal antibody · Adenoassociated virus
17.1 Introduction
Continuous manufacturing (CM) has been used for petrochemical, chemical, pharmaceutical, and food processing for decades [1, 2]. CM can provide consistent
product quality; cleaner, more exible, and higher process efciency; automation,
low in-process hold times, and sample conditioning; smaller footprint for equipment and facility; and lower operating cost of goods (COGs) [3, 4]. The CM concept has been applied for continuous bioprocess (CBP) as well for small molecule
production such as amino acids, vitamins, peptides, and antibiotics [5]. Currently,
the continuous processes for small molecule manufacturing have been applied for
Orkambi and Symdeko for cystic brosis treatment (Vertex 2015) and Prezista for
HIV treatment (Janssen 2016) [6].
However, CBP application to large molecule biologics (e.g., monoclonal antibody [mAb]) manufacturing has been slow to adopt in the industry due to several
challenges. The challenges include: (A) mAb biologic complexity; (B) cell line and
mAb stability; (C) manufacturing raw material properties and variability; (D) lack
of CBP-designated systems for effective and robust process performance monitoring and control; (E) immature CBP-designated analytical systems and methods for
real-time product quality monitoring and control; (F) lack of CBP-specialized
process- related hardware and software; and (G) lack of sufcient nancial resources,
and scientists and engineers with CBP expertise and experience.
Conventional mAb drug substance (DS) manufacturing starts from Master Cell
Bank (MCB) or Working Cell Bank (WCB) vial thaw followed by seeding train
expansion, cell culture production, bulk cell harvest, clarication, purication, and
nal DS formulation. The cell culture process is conducted in batch, fed-batch,
hybrid fed-batch, or perfusion mode [7–9]. The mAb purication framework is
mainly carried out in a unit-by-unit operational manner [10]. In-process sample and
nal DS testing is primarily conducted by ofine assays, which are labor intensive,
time consuming, and do not provide real-time supportive data. The conventional
process has intrinsic drawbacks associated with lower productivity and efciency,
less automation and robust control, higher waste generation, higher COGs from
operational to capital expenditure, and larger equipment and facility footprint. In
contrast, CBP implementation is an effective strategy to overcome these drawbacks
per current industrial needs.
17 CMC Considerations for Continuous Bioprocess Design, Development…
475
17.2 Regulatory Guidance, Expectations,
andSupport forCBP
FDA has been collaborating with both industry and academia to assess new technology applications for CM [11], analytical method improvement, and microbial control (Fig.17.1). To accelerate CM application in biopharmaceuticals, FDA supports
the quality by design (QbD) and process analytical technology (PAT) approaches
[12, 13].
QbD is a systematic, risk-based, holistic, proactive, and continuous improvement
approach for pharmaceutical development from discovery, development to manufacture of drugs [14, 15]. The key considerations from QbD are: (1) product knowledge including quality target product prole (QTPP), dose form, formulation, and
stability; (2) process design including unit operation, in-process control (IPC), and
critical process parameter (CPP) assessment; and (3) product quality control strategy including critical quality attributes (CQAs) and real-time testing with predetermined acceptance criteria and specication.
PAT framework supports innovative pharmaceutical development, manufacturing, and quality assurance [16]. It includes designing, analyzing, and controlling
manufacturing through timely measurements of CQAs and critical performance
attributes (CPAs) from raw material, in-process material to process control
(Fig.17.2) in a timely manner (e.g., in-, on-, or at-line monitoring and control). The
PAT implementation can provide the scientic basis for establishing regulatory
specications. It also enhances continuous process improvement and product quality control [16]. Regulatory authorities support an enhanced and innovative
Fig. 17.1 New strategies and approaches supported by FDA for product manufacturing and quality improvement
476
Y. Ding and M. Marino
PAT
FrameQork
Fig. 17.2 PAT-A framework for innovative pharmaceutical development, manufacturing, and
quality assurance from FDA
bioprocessing with more exible, compatible, and disposable technology for simpler process procedure and better product quality control [13].
Standard Guide for Application of Continuous Quality Verication (ASTM)
E2537 provides guidance for process validation and continuous process verication, which is aligned with ICH Q8 and Q9. ASTM E2537 provides a guidance for
continuous process monitoring, measuring, and analyzing; risk evaluation and mitigation; process variable reduction; capability adjustment; and enhancement for
product lifecycle quality monitoring, control, and improvement. This guidance is a
valuable source document for CBP implementation.
17 CMC Considerations for Continuous Bioprocess Design, Development…
477
17.3 Current Industrial Practice formAb Production
mAb therapeutics not only improve human quality of life but also generate billions
in revenue each year for the biopharmaceuticals industry [17]. Over 80 therapeutic
mAbs have been approved by global regulatory authorities [17, 18]. To bring a mAb
candidate from discovery to commercialization, it is necessary for a biopharmaceutical company to spend a signicant amount of money (e.g., hundreds of millions of
US dollars), time (e.g., ≥10years), and resources to complete essential activities
from chemistry, manufacturing, and control (CMC), clinical trials to regulatory lings and approval.
Figure 17.3 illustrates a roadmap of mAb drug development from research to
commercialization. Current mAb production is primarily carried out in a batchmode including both upstream process (USP) and downstream process (DSP). The
batch-mode has its intrinsic limitations as described previously; however, scientists
and engineers from academia and biopharmaceutical industry are investigating
alternative approaches from an intensied process [19], an integral process [4, 7], a
hybrid process [20] to a fully automated bioprocess [21].
Research & Process Development (PD)
.
.
.
.
.
.
.
.
.
Process Characterizaon (PC)
.
.
.
.
Process Validaon (PV)
Commercializaon and Post-commercial
.
.
.
.
.
Improvement (PCI)
Fig. 17.3 Roadmap of mAb drug development from research to commercialization
478
Y. Ding and M. Marino
17.3.1 Cell Line Development: TheFoundation
ofBiologics Development
17.3.1.1 Antibody DNA Sequence andGene Construction
Figure 17.4 illustrates a ow diagram for a typical mAb cell line development
(CLD) process. The gene sequence of a mAb candidate can be identied and determined by Xenomouse hybridoma (e.g., Herceptin), phage display (e.g., Humira),
transgenic mouse (e.g., Stelara), or single B-cell (e.g., HIV neutralization antibody)
[18, 22]. The hybridoma technique, which has been the most widely used approach,
has led to the majority of mAbs (48 out of 80mAbs) approved on the market [18,
23]. The antibody heavy chain and light chain variable (VH and VL) region cDNA
sequence can be generated by reverse transcription polymerase chain reaction
(RT-PCR) from the isolated mRNA [24]. The determined variable region from each
gene can be humanized by complementarity-determining region (CDR)-grafting
and codon optimization followed by the assessment of afnity, functional potency,
and stability of the mAb [24].
In addition to hybridoma technology, antibody phage display (APD) has been
also used for therapeutic antibody discovery and development [25]. The APD
approach is based on the pioneer work from Smith (1985) and Parmley (1988) for
peptide expression followed by John McCafferty and Gregory Winter [26–28] for
mAb engineering. The APD approach includes DNA library construction (e.g.,
mRNA, RT-PCR, cDNA), phagemid generation, phage display, and genetic analysis
(Figs.17.5 and 17.6).
The aim of antibody gene sequencing and construction is to determine heavy
chain and light chain gene sequence, which is genetically stable with optimal afnity, specicity, stability, immunogenicity, and developability properties. It is the
foundation for the development of all biologics and a critical step, which enables
USP development and manufacturing (Fig.17.7).
Fig. 17.4 Flow diagram for mAb cell line development
17 CMC Considerations for Continuous Bioprocess Design, Development…
479
.Phage display
.CDR-graing.Hybridoma
.Transgenec mice
.Single B cell
VHand V
.Anity,
.Potency
.Genec stability
.Developability
L
Sewuence
determinaon
Codon
opmizaon
Humanizaon
Vector
construcon
.Promoter
.Enhancer
.Metabolic marker
.Anbiocs marker
Fig. 17.5 Key considerations for mAb gene sequencing and vector construction
Fig. 17.6 Clone selection procedure and key considerations
17.3.1.2 Clone Selection
Once the mAb gene sequences including the signal peptide sequence for the heavy
chain and light chains are determined, each sequence is synthesized and subcloned
into an expression vector (Fig.17.4). The vector contains the promoter/enhancer for
mRNA transcription, translation, maturation, and selective markers (Fig.17.5). The
optimal expression vector and host cell line are crucial for the target mAb gene
expression, cell culture process development, and manufacturing [29].
There are different types of expression vectors currently used in the industry. For
example, CHOZN® GS−/-with ubiquitous chromatin opening elements (UCOE®)
can minimize gene silencing and mutation for high productivity (e.g., 3–10g/L
titer) (Millipore Sigma). The pXC Multigene vector is designed for expressing