How to optimise commercial-scale ATMP manufacturing through automation

This is the second part of our series, "The ATMP Manufacturer's Guide to Commercialisation and cGMP Compliance".

The first article in the ATMP series focused on the standardised production platform that supports ATMP manufacturing at various scales.

In this piece, we will address how much these efforts benefit your operations. With a strong continuous automation strategy, you can scale faster, ensure compliance, and optimise product quality and reproducibility based on a standardised production platform.

Among other biologics manufacturers, ATMP manufacturers are particularly well situated to benefit from this strategy. Allogeneic cell therapy manufacturers, but especially autologous cell therapy manufacturers, can benefit as they face the scalability challenges of working with small batches for a single patient. Leveraging automation to aid this process is not a nice-to-have, but a must-have.

In this article, we highlight how you can use automation to start a robust, sustainable ATMP manufacturing process. The automation pyramid serves as a road map for these steps.

1. Defining the automation pyramid
An automation pyramid visually represents the automation levels that are possible in any complex manufacturing environment. Especially in ATMP manufacturing, the automation pyramid can provide scalability and flexibility, even for particularly small batch sizes. The base of the pyramid is formed from the operational technology levels, which provides support for the information level at the top.

Automation is becoming increasingly important in commercial ATMP facilities because it can simplify and eliminate manual steps and data recording. These manual steps are prone to human error and place manufacturers at serious regulatory and operational risk. Additionally, manual steps contribute to immense overhead and operational costs.

The automation pyramid enables scalability, continuous compliance, and flexibility by harmonising data and mitigating production inefficiencies. However, this data automation and harmonisation is especially critical for ATMP small product batches from a quality perspective and in business operations.

Nearly 50% of cell therapy manufacturers surveyed in last year's Horizons report indicated they were targeting automation and inline analytics to reduce costs. Automation-driven process closure was further cited as a cost-reduction strategy by one-fifth of respondents.

2. Key benefits for ATMP manufacturers
The automation pyramid facilitates the reduction of regulatory risks for ATMP facilities and the continuous optimisation of the manufacturing process using real-time data-driven insights.

The biggest advantage of the automation strategy is to achieve business stability at scale. For ATMP manufacturers, in particular, a digitised and automated facility is essential to ensure this stability.

Additional benefits are:

Compliance
FDA 21 CFR Part 11 and EU GMP Annex 11 regulations that apply to commercial ATMP manufacturing can be incorporated at the very beginning of the automation pyramid. This ensures that all data is assigned, legible, complete and consistent, original, accurate, and available (ALCOA+ principles).

Continuous optimisation
ATMP manufacturers, compared to traditional biologics manufacturers, do not have predictability in their manufacturing results. Additionally, they often have to work with starting material from patients, who are often in very poor health, requiring continuous, accurate, and proactive monitoring.

Advanced technologies such as artificial intelligence (AI) and machine learning (ML) can help manufacturers optimise processes while delivering the same therapeutic benefits to patients, as these systems are capable of capturing and analysing large volumes of manufacturing data. In order to take advantage of AI technologies without fully integrating automation, it is important to collect historical data that can be integrated into the systems to form the basis for continuous improvement.

3. The hierarchy of the automation pyramid
The automation pyramid is divided into five levels. The lower levels are called the operating technology of the pyramid and focus on measuring and controlling results in the manufacturing facility. The upper levels form the information technology level, which deals with controlling decisions, as well as tracking the manufacturing process through automation.

a) Operational technology levels

Level 0: Sensors and actuators
This level is the foundation that enables measurements in the first place. All sensors are integrated in this level, which can record pressure, pH-value, temperature, and other basic data, as well as spectroscopy, which can measure the density of viable cells and more.

Level 1: Automation
The subsequent Level 1 handles the control of the data collected in Level 0 and inserts them into a distributed control system (DCS) to activate certain operations (e.g., switching on a pump).

Level 2: Monitoring, control, and data acquisition (SCADA)
After the collected data has been integrated into a system, this level is now used to retrieve correlations (status of devices) or to manage alarm systems. This level provides information about the status of the system through the stored data.

b) Transfer level

Level 3: Manufacturing execution system (MES)
The third level documents and tracks the automated processes involved over the product's entire manufacturing process via MES. While some companies treat MES as part of the operational level, others classify it as information technology.

c) Information technology level

Level 4: Enterprise resource planning (ERP)
The fourth level enables seamless business operations. The ERP consolidates all the data and insights from previous levels that help manufacturers multiply the complexity of numerous patient-specific batches.

4. Process automation within the pyramid's foundation
By creating and automating a standardised process platform, ATMP manufacturers can address challenges at a scale and adapt their processes to new conditions. Due to small batch sizes, the production line is utilised much more, and a lot of inputs and outputs occur. An automated process platform is easier to maintain here and offers more flexibility for adjustments.

The benefits of process automation are vast:

a) Reduced regulatory risk
Experience with automated technologies shows that, especially in ATMP manufacturing, some risks can be reduced through process closure and automation approaches. As a result, it can support regulatory compliance.

b) Fewer lab tests and batch releases in real-time
Automation can monitor critical quality attributes (CQAs) and critical process parameters (CPPs) in real time by enabling accurate in-line data collection via PATs and smart meters. Deviations can thus be registered more quickly, and adjustments made before batches have to be disposed of, resulting in lower costs for sick patients.

c) Standardising to the next level
Each change between different products or batches generates costs in terms of programming and validation effort, which can be significantly reduced through standardisation and automation.

d) Improved modularity and scalability
With the help of automation, an ATMP manufacturer can quickly pivot when product pipelines need to be expanded, or batch numbers suddenly increase.

e) Building for the future
Once your automation infrastructure is established, you can adopt and enable new technologies as they become available and reduce costs in doing so.

5. Impacts on manufacturing at the top of the pyramid

A searchable database with electronic batch records (EBR) helps ATMP manufacturers get the right data to the right place in real time. This automation strategy helps investigate and understand dependencies between the facility, the quality laboratory, and the final product.

In the upper levels of the automation pyramid, the focus is on the MES, which, if implemented early and procedures documented, can have a significant impact on costs, technology transfer, and validation experience.

The benefits of implementing an MES early are clear:

a) Traceability and back-tracking, supply chain and cold chain monitoring
Drug quality is critical for ATMP patients. Through automation, individual ATMP processing steps can be tracked and traced to ensure proper cooling and quality control measures have been taken.

b) Continuous regulatory compliance
Manufacturing data must be 100% up to date to comply with cGMP standards. In the EWC, this data is always up to date, stored, or logged by a controlled unit.

c) Streamlined process control
Some ATMPs must pass in-process control (IPC) tests within the manufacturing process to ensure the consistency and quality of the final product. IPCs are useful to ensure that these requirements are achieved and that bottlenecks can be identified and eliminated at an early stage.

d) Insightful data analytics
The data science team also benefits from the automated capture and harmonisation of data (process, lab test, and manufacturing data), enabling them to create more insightful models.

6. Types of data going through the automation pyramid

ATMP manufacturers generate a significant amount of data; therefore, they need a well-thought-out data strategy to harmonise this information. These data types include:

• Process data (temperature, PH value, etc.)
• Lot numbers and consumables data
• Chain of custody and cold chain data
• Metadata and contextual data
• Quality control data
• Environmental monitoring data

The first step in a data strategy should be set up according to the FAIR principle (Findable, Accessible, Interoperable, and Retrievable), so that it becomes a single, cohesive ecosystem where everything runs in a controlled manner.

ATMP manufacturers that implement data automation early in the clinical phase are more likely to ensure a smooth technology transfer and optimised control at scale.

Optimised cGMP manufacturing starts with the automation pyramid

Eliminating manual steps can help ATMP manufacturers create consistency of process and quality data, reduce labour dependencies, and build the foundation for scalable and future-proof manufacturing. However, those who benefit most are the patients for whom these treatments can be key to survival.

About the authors

Michela Castellani-Kleinschroth is a process specialist at CRB Group. She holds a doctorate in Biochemistry from Goethe University, Frankfurt, Germany. Castellani-Kleinschroth has extensive experience leading tech transfers within intercultural, cross-functional teams to achieve realisation of clinical trials suites and GMP compliant production. She is a local expert for Tech Transfer from process development to cGMP manufacturing and is well networked within the Phacilitate. Castellani-Kleinschroth is also an active member of ISPE, ESCGT, and the CGT Circle. She participates in the ISPE “Women in Pharma” Chapter to support women in the pharma industry.

David Estapé David Estapé is senior fellow, biopharmaceutical process, at CRB Group, and is a recognised biotechnology thought leader. Throughout his career, he has led or supported design and provided GMP consulting services for clients within the biotech, vaccine, and blood plasma pharmaceutical industries. With a strong interest in new technologies and regulatory trends, Estapé participates heavily in organisations like BioPhorum and the International Society for Pharmaceutical Engineering.

Ryan Thompson is senior specialist, Industry 4.0, at CRB Group, and brings more than 17 years of experience successfully leading companies and projects through their digital transformation. He believes the purpose of Industry 4.0 is to achieve more with less. Thompson’s experience spans the pharmaceutical, food and beverage, and consumer packaged goods industries. He specialises in process and batch automation, data modelling and infrastructure, MES platforms, ERP integrations, FDA regulations such as 21 CFR Part 11, and a vast net of automation platforms and smart manufacturing tools and technologies. Thompson is Six Sigma Green Belt certified and a Google Cloud certified Cloud Digital Leader. He received his Bachelor of Applied Science in Mechanical Engineering at the University of Toronto.