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J. Luo et al.
15.3.6 Identify Model Output andModel Selection
Two factors to decide before modeling are to identify the model output (target vari­able) and identify the unit of analysis. As discussed above, the main purpose is to reduce the titer variability of the production culture to make the production culture titer a default candidate for model output. However, reviewing the production cul­ture has shown that there are known factors that will affect titer (e.g., production culture duration). To remove the known culture duration effect, instead of titer, a growth indicator (integrated viable packed-cell volume at xed culture duration of x hours: ivPCVx) was also used as a model output. This is because there is a linear relationship observed between titer and ivPCV at harvest and data availability (i.e., time course date of PCV measurement is available, but no time course date for titer). Other normalizations based on process characterization could be used to remove the known factor from modeling. In this specic example, the unit of analysis is each run when inoculum train culture starts. As shown in Fig.15.2, there are many seed train cultures connected to each inoculum train culture. Therefore, a method to aggregate seed train information to run level is needed to build the model.
Once the team identied which is the target variable and the desired outcome of the model (e.g., if the intent of the model is diagnostics analytics or predictive ana­lytics), a model was recommended by the DS team. Because the manufacturing process could benet from both (target variable and desired outcome) to identify factors for growth/titer improvement and to predict the titer of culture for down­stream processing, a random forest model with explainable articial intelligence (AI) was used in this study. The random forest model was selected based on its strong prediction accuracy. It is good at capturing complex non-linear relationships in the data while being fairly robust to noise. To better interpret the complex and predictive models, an explainable AI (e.g., Shapley additive explanation [SHAP]) was used to generate insights [19]. When running the model, a vefold cross­validation was used. This is to reduce overtting of the available dataset and make the model outcome more robust to the broader dataset. The overall modeling pro­cess runs on Google cloud platform. The results were summarized in a global fea­ture importance plot for each model iteration, with the top 20 features, and their impact on scale and direction based on the SHAP value. To further understand the feature effect and model performance, the training and test sets R2, partial depen­dence plot, scatter plot, and trend stability were also reviewed.
15.3.7 Model Insights
As with many data analyses, the rst model often identies what was already known to process SMEs. Therefore, model iterations are a must-to-have for the ADA pro­cess. The review of hypotheses and the model outputs is ongoing through the model iteration phase, which helps to create new hypotheses as well as ne-tune and
15 Advanced Data Analytics Application inBiomanufacturing Processes
Table 15.5 Example of model insights and potential actions
Hypothesis
Outcome
Process insight Conrm Seed train status
Falsied Effect of sampling
New Effect of sampling
New Effect of kitted
New Raw material
Operational insight Conrm Measurement
description Learning Potential action
impacts production culture [18]
volume impacts pH measurement
time close to the shift change time
medium storage time
attribute
variation of the ofine analyzer
Evidenced by process understanding, conrmed through modeling
Sample volume variation observed but does not correlate with pH measurement
Aggregate data in different ways through modeling
Longer kitted medium storage correlates with reduced growth
Important to include raw material test data. Different model outputs (even highly correlated) could provide different insights
Evidence by a small dataset, conrmed through modeling
Select better seed train culture to source large-scale runs
Since the model veried the variation, recommend best practice for sampling volume
Build the knowledge into future resource planning, allocation
Avoid longer storage time through planning
Follow up with the vendor to understand raw material variability and any vendor manufacturing process change. Assess if specication change is needed
Establish a monitoring program
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prioritize them. In turn, it will provide direction of ongoing DE work (e.g., which data sources to link, what kind of features to create).
Table 15.5 shows a few examples of insights generated from this model exercise. This exercise provided an opportunity to verify or falsify previous hypotheses and create new insights (features not previously analyzed) on both process and opera­tional perspectives.
15.4 Conclusion andDiscussion
Leverage modeling for process and product understanding, monitoring, trouble­shooting, prediction, and process control improvement is the trend for bioprocess­ing. Different statistical models can be used in different stages of the lifecycle. Advanced data analytics program should be considered for ongoing commercial manufacturing.
A multi-disciplinary team of bioprocess experts, data engineers, data scientists, and IT specialists, in collaboration with skilled consultants were able to employ
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advanced data analytics techniques to identify contributing sources of variation and actionable insights for a complex and unsolved culture performance problem.
By utilizing a structured but agile approach, the team was able to extract, cleanse, ingest, and process 800GB of data from 11 disparate data sources into a cloud envi­ronment to evaluate more than 100 independent hypotheses. More than 500 plots to support exploratory data analysis were generated, reviewed, and a complex model used to iteratively evaluate hypotheses leading to new “actionable insights” and proposed interventions. Several of the new insights had not been previously discov­ered or documented during process design or from multiple years of univariate monitoring of commercial manufacturing campaigns. More than 100 runs have been executed after implementing some of the changes proposed. The normalized titer for 95% of those runs ranges from 0.97 to 1.17, which is ~6% improved on upstream productivity on Process A.Furthermore, the potential for future optimiza­tion of culture performance is bolstered by the addition of the complex model as an additional tool to complement the formal CPV program.
For complex investigations seeking root causes for process performance or prod­uct quality variation, in some cases, questions can go unasked and unanswered because of the complexity and scope of data required to evaluate a specic hypoth­esis. A key benet of developing ADA capability is to accelerate the iterative cycle of asking and answering structured questions and quantifying the likelihood of potential causal factors contributing to the variation in the chosen target (response) variable. Even when evaluation of a hypothesis does not result in a “smoking gun,” the documentation of “non-effects” provides evidence to rule out factors, sharpens the focus, adds to the body of process/product knowledge, and deepens the quality and thoroughness of the investigation. Establishing data pipelines and improved ADA skills holds promise for increasing hypothesis evaluation productivity, thereby bolstering institutional knowledge and problem solving speed.
In addition, the established platform and internal capability enable the building of unit operation or holistic process models, integrating with existing and new PAT devices with soft sensors, driving bioprocess digitization, and revolutionizing biomanufacturing.
Acknowledgments The authors would like to thank Mckinsey/Quantam-Black for guidance in the project execution and support in building the internal capability. The authors would also like to thank Sally Kline, Lisa Vulliet, Karen Roque, Juan Melendez, Cristen Peterson, Veronica Carvalhal, Luis Avila, Duyen Tran, Michael Siani-Rose, Ann Rea, Ulrike Strauss, Ravi Medandrao, Paul Paczuski, Jason Gu, and Daniel Coleman for their contributions to the project.

References

1. FDA Guidance for Industry (2011) Process validation: general principles and practices
2. Möller J, Pörtner R (2017) Chapter 5: Model-based design of process strategies for cell culture bioprocesses: state of the art and new perspectives. In: New insights into cell culture technol­ogy. InTech, pp157–172
15 Advanced Data Analytics Application inBiomanufacturing Processes
3. Horvath B, Mun M, Laird MW (2010) Characterization of a monoclonal antibody cell culture production process using a quality by design approach. Mol Biotechnol 45(3):203–206
4. Jayakumar M (2013) When and how to use Plackett-Burman experimental design. https://
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5. Royall RM (1986) The effect of sample size on the meaning of signicance tests. Am Stat 40(4):313–315
6. McNeish D (2016) On using Bayesian methods to address small sample problems. Struct Equ Model Multidiscip J 23(5):750–773
7. Melchers RE, Beck AT (2018) Structural reliability analysis and prediction. Wiley
8. Fujiwara Y, Miyawaki Y, Kamitani Y (2009) Estimating image bases for visual image recon­struction from human brain activity. Adv NIPS 22:576–584
9. Stenling A, Ivarsson A, Johnson U, Lindwall M (2015) Bayesian structural equation modeling in sport and exercise psychology. J Sport Exerc Psychol 37:410–420
10. Rodgers M, Oppenheim R (2019) Ishikawa diagrams and Bayesian belief networks for con­tinuous improvement applications. TQM J 31(3):294–318
11. Breiman L (2001) Statistical modeling: the two cultures. Stat Sci 16(3):199–231
12. Eriksson L, McCready C (2018) Characterizing a bioprocess with advanced data analytics. Modeling at various stages of the data analytics continuum aids scale comparison of a bioreac­tor. BioPharm Int 31(3):18–23
13. Vamathevan J, Clark D, Czodrowski P, Dunham I, Ferran E, Lee G (2019) Application of machine learning in drug discovery and development. Nat Rev Drug Discov 18(6):463–477
14. Ayon D (2016) Machine learning algorithms: a review. IJCSIT J 7(3):1174–1179
15. Yuk IH, Russell S, Tang Y, Hsu WT, Mauger JB, Aulakh RP, Luo J, Gawlitzek M, Joly JC (2015) Effects of copper on CHO cells: cellular requirements and product quality consider­ations. Biotechnol Prog 31(1):226–238
16. Stichbury J (2019) Kedro: a new tool for data science, June 4. https://towardsdatascience.com/
kedro- prepare- to- pimp- your- pipeline- f8f68c263466
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18. Tung M, Tang D, Wang S-H, Zhan D, Kiplinger K, Pan S, Jing Y, Shen A, Ahyow P, Snedecor B, Gawlitzek M, Misaghi S (2018) High intracellular seed train BiP levels correlate with poor production culture performance in CHO cells. Biotechnol J 13:1700746
19. Molnar C (2019) Interpretable machine learning, a guide for making black box models explain­able, November 17. https://christophm.github.io/interpretable- ml- book/index.html
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Part VIII
Biopharmaceutical Regulatory CMC
Chapter 16
Overview ofComplexities ofGlobal CMC Regulatory Affairs
KatherineArch-Douglas, NathalieDubois, StephenMayer, RichPelt, andAndrewNelson
Abstract As the technologies within the biopharmaceutical industry evolve so
does the global chemistry, manufacturing, and control (CMC) regulatory environ­ment with ever-present complexity of gaining regulatory approvals around the world for new products for patients. From the earliest pharmaceutical laws in the 1900s to the inception of the International Council for Harmonization (ICH) to the transfer of regulatory oversight of well-characterized biologics from CBER (Center for Biologics Evaluation and Research) to CDER (Center for Drug Evaluation and Research), there has been a continuum of regulatory growth and oversight to ensure compliance and safety of all products globally. Every country and/or region has a separate health authority (HA) that oversees commercial licensure and clinical stud­ies for all biopharmaceuticals. History, regional laws, regional cultures, and resources are many of the factors that inuence the regulatory environment around the world, and all HAs must be engaged appropriately for successful global rollouts of biopharmaceuticals.
Keywords International Council for Harmonisation (ICH) · Health Authority (HA) · Biopharmaceutical · Regulatory · Commercial · Clinical
K. Arch-Douglas · S. Mayer Global Regulatory Sciences CMC, Pzer Inc., Pearl River, NY, USA
N. Dubois Global Regulatory Sciences CMC, Pzer Inc., Brussels, Belgium
R. Pelt (*) · A. Nelson Global Regulatory Sciences CMC, Pzer Inc., Sanford, NC, USA e-mail: Rich.peltiii@pzer.com
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_16
457© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
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16.1 Introduction

Every industry has its own semantics (e.g., set of terms, acronyms, abbreviations, and hyphenations) that facilitate workow processes of a particular discipline. The biopharmaceutical industry is denitely no slouch when it comes to its own seman­tics and it is often very complex and can vary across the regions of the globe. In order to nd success in the biopharmaceutical industry we need to understand the regulatory jargon of the industry, and also appreciate the complexities in how bio­pharmaceutical products are regulated by various health authorities (HAs) globally. This is especially true when we consider the time, cost, and risks associated with developing a biopharmaceutical product.
A biopharmaceutical product can take 10–15years to develop and almost 90% of drug candidates in development fail before becoming a marketed product [1]. This is a huge risk for any potential drug development, especially considering that research published in 2016 found that the estimated research and development (R&D) costs associated with developing a new pharmaceutical product from dis­covery through development and to product launch was upward of 2.8 billion dol­lars [2].
Throughout the remainder of this chapter, we will begin to discuss the complexi­ties associated with global regulatory affairs. The content discussed in the various underlying sections will only touch the surface of what you will come to see is a very diverse and agile eld. As we overview the various regulatory bodies and their regulations, laws, and guidances, you will begin to understand the language that is biopharmaceutical global regulatory affairs.
16.1.1 Regulatory Bodies inMajor Markets
A major challenge in global regulatory affairs is to put together a core dossier that can be leveraged in multiple markets; this adds to the complexity of what should and should not be included when you build your regulatory strategy as there is a need to consider multiple health authorities’ (HAs) country regulations. Flushing out this global regulatory strategy early can reduce submission timelines, unneces­sary additional authoring, and potential extra costs associated with what would oth­erwise be country-specic documentation for each dossier put forward. Country-specic documentation is not always avoidable and is sometimes manda­tory such as in Module 1 of Common Technical Documentation (CTD) Pyramid put forward by the International Council for Harmonization (ICH) (more on ICH and CTD later in this chapter), but that does not mean that there are not places in a regu­latory dossier where synergies can be in place.
So, with this in mind, as a regulatory affairs professional working for a pharma­ceutical company, it is important to understand how the major markets are
16 Overview ofComplexities ofGlobal CMC Regulatory Affairs
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structured and what their regulatory requirements are: this works to your benet in two ways. One, major markets are usually associated with the highest prot margins available for a biopharmaceutical manufacturer, and, two, many smaller or develop­ing markets rely on approvals from reference HA markets, in this case markets such as the United States or the European Union (EU).
Below is a brief summary of some of the major HA organizations and clinical trial and license application processes.
16.1.1.1 United States
The U.S. Food and Drug Administration (FDA) is an agency within the Department of Health and Human Services and “… is responsible for protecting
the public health by assuring the safety, efcacy and security of human and veterinary drugs, biological products, medical devices, our nation’s food sup­ply, cosmetics, and products that emit radiation. FDA is also responsible for advancing the public health by helping to speed innovations that make medi­cines more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medicines and foods to maintain and improve their health….” The FDA is subsequently organized into
multiple centers and ofces:
• Ofce of the Commissioner (OC)
• Ofce of Foods and Veterinary Medicine
• Ofce of Global Regulatory Operations and Policy
• Ofce of Regulatory Affairs (ORA)
• Ofce of Operations
• Ofce of Policy, Planning, Legislation, and Analysis
• Ofce of Medical Products and Tobacco
• Center for Biologics Evaluation and Research (CBER)
• Center for Devices and Radiological Health (CDRH)
• Center for Drug Evaluation and Research (CDER)
• Center for Tobacco Products
• Ofce of Special Medical Programs
• Ofce of Combination Products
• Oncology Center of Excellence (Operates across CDER, CBER, CDRH)
The Center for Biologics Evaluation and Research has eight ofces and is responsible for regulation of biological and related products including blood, vac­cines, allergenics, tissues, and cellular and gene therapies. The Ofce of Vaccines Research and Review (OVRR) is within CBER.
The Center for Drug Evaluation and Research has various ofces and is respon­sible for regulation of over-the-counter and prescription drugs, including biological therapeutics and generic drugs.