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Digital Manufacturing for Regulated Industries
Pharmaceutical and biotech manufacturers face a number of unique challenges in the digital era. While other industries continue to leverage new technologies and significantly boost productivity through continuous process improvements, regulated industries often lag behind due to a relatively slower adoption rate. Stringent requirements for documentation, data integrity, and process validation consume so much of a company’s bandwidth that there are few resources left to devote to continuous improvement efforts.
Despite all of this friction to change, modern solutions enable new opportunities through which manufacturers can rethink the way their operations are run. Several technologies can be deployed to automate tedious tasks or error-proof processes by augmenting technicians.
By connecting physical and digital systems, manufacturers can ensure data integrity, increase production visibility, and make data-driven decisions to continuously improve their operations.
This guide provides a comprehensive overview of digital manufacturing for the pharmaceutical industry — highlighting specific strategies, use cases, and case studies.
Consider this your roadmap for building digital capabilities in regulated industries.
What is Pharma 4.0?
Defining Pharma 4.0
Pharma 4.0 is a framework for adapting digital strategies to the unique context of pharmaceutical manufacturing.
In practical terms, this framework introduces more connectivity, increased productivity, simplified compliance, and the ability to leverage production information to respond to problems as they emerge.
The term was trademarked by the International Society for Pharmaceutical Engineers (ISPE) to align target components and enablers to this term, and to provide best practices for accelerating digital maturation across the pharmaceutical industry.
The Pharma 4.0 framework advocates a holistic approach — outlining priorities for business, IT, and manufacturing throughout a drug product’s lifecycle.
They strive to help organizations achieve “business goals by operating faster, reducing costs, and being more competitive and agile.”
Pharma 4.0 is more than just an approach to digital technologies: It’s a shift in mindset. Manufacturers need to find new ways to identify problems and implement advanced technology to increase efficiency and effectiveness in meeting compliance requirements.
From connecting workers to introducing more human-centric workflows to driving shifts in company culture, humans are at the core of Pharma 4.0. As such, companies must do more than automating processes.
In order to achieve this level of operation, you must consider the following:
The elimination of paper-based processes and paper documentation
The elimination of data silos with better communication across the lifecycle of drugs
A lower-touch relationship with regulatory bodies as data collection and sharing improves
A shift to a risk-based and integrated approach for validation
The implementation of a holistic control strategy tied to validation
The increased focus on data for quality assurance and compliance
Pharma 4.0 envisions a manufacturing paradigm that allows manufacturers to be agile, iterate quickly, connect resources and workers, and ultimately produce more quality products with better patient outcomes.
Steps to Reach Pharma 4.0
Stages of Digital Maturity
One of the Pharma 4.0 operating model enablers is digital maturity. Broadly speaking, there are six stages of digital maturity as outlined in Industrie 4.0 Maturity Index. Managing the Digital Transformation of Companies – UPDATE 2020. In order to achieve full digital maturity, the transformation must begin now — starting with computerization to make operations more efficient.
At the highest level of maturity, companies will be self-adapting — with the ability to withstand turbulent economic times and shift business objectives quickly to seize opportunities.
To ensure success, manufacturers must take a methodical approach in which each stage builds upon the previous one:
1. Computerization: The first stage of maturity is to automate simple manual processes by introducing digital technology. The goal is to find repetitive tasks that would be better performed by computers — creating the basis for a digital infrastructure.
2. Connectivity: Data silos currently exist because IT, OT, and communication systems are often not in sync with each other. Through system integration, data can flow seamlessly throughout your organization — enabling staff members to accomplish tasks more efficiently.
3. Visibility: This is the area in which many manufacturers will start to see incremental improvements. Connected people, machines, and processes create a substantial digital record of production that can be used to make real-time, data-driven decisions.
4. Transparency: With more data, new insights about complex systems become available. Advanced analytics provide you with evolving opportunities for improvement.
5. Predictability: Detail production records enable manufacturers to correct problems before they happen.
6. Adaptability: Systems anticipate problems and initiate the proper action by themselves. At their most advanced, these systems become autonomous and self-correcting.
We’re far from a reality in which pharmaceutical manufacturing lines detect problems and self-correct. But this trajectory from a baseline of digitization and connectivity to sophisticated, predictive systems is one that manufacturers can take steps to achieve now.
With the right strategy in place, that future might not be so far away. Pharmaceutical manufacturers can experience significant gains by finding small opportunities for digitization and beginning there.
Bringing Industry 4.0 to Pharma
Outlining a strategy for digital transformation or finding small, scalable opportunities for improvement aren’t trivial tasks.
If the goal is to become an autonomous, self-correcting system, the question becomes: How do we get there?
The answer is adopting an agile approach, leaning towards a steady evolution that will result in revolutionary productivity gains. Start making changes now and evolve often; do not wait for the big bang. You will miss the train!
Industry 4.0 Fundamentals
While Industry 4.0 is often defined as a suite of technologies converging on the modern shop floor, there are a few concepts that tie them all together.
The first is the Industrial Internet of Things (IIoT). More than a technology, IIoT refers to the networking of disparate items, sensors, and people across a manufacturing facility. This connectivity creates a more holistic picture of manufacturing processes and helps to eliminate data silos.
The other key concept is cyber-physical systems (CPS). CPS are networks that combine human and machine inputs to create better communication and support between the different actors in a factory. In simpler terms, CPS are connected systems that help support humans on the shop floor by contextualizing their activity across the digital and physical domains of manufacturing.
CPS help people make better decisions, find new opportunities for improvement, optimize resource allocation, and improve quality by creating more responsive working systems. With CPS, humans work hand-in-hand with digital manufacturing systems.
Together, IIoT and CPS enable a bottom-up approach to pharmaceutical manufacturing. Hierarchical control models require more information before implementing changes. With IIoT and CPS, control is emergent.
By emergent, we mean new patterns emerge as digital systems operate in harmony. Specifically, the increased quantity and quality of information enables manufacturers to identify local problems in real time and to adapt their improvements accordingly.
Accepting emergence means accepting that we can’t have all of the answers prior to letting the system run and sampling its output. Working with emergence is key to creating value through evolution, not revolution.
Data Integrity by Design
Data integrity is one of the areas in which Pharma 4.0 can contribute the most. In fact, the ISPE outlines “Data Integrity by Design” as a desired outcome of digital maturity.
Despite knowing this, many pharmaceutical companies continue to rely on error-prone, paper-based documentation. During manufacturing, engineers record machine states, batch information, and production schedules in paper forms. These logs are labor intensive, prone to transcription error, and difficult to reference. Mistakes caught at the end of the process often leave few options available for corrections.
With Pharma 4.0 solutions, manufacturers can implement process checks on the most critical data and catch deviations in real time. This makes it possible to manufacture with a right-the-first-time approach — saving time in exception handling.
How to Leverage a Composable Platform to Solve Local Problems
There’s a common fear that pivoting from paper-based workflows to a Pharma 4.0-driven facility requires overhauling your systems and implementing massive, monolithic software to improve efficiency. However, the market is shifting towards more flexible, adaptable systems — and the force driving this change is composability.
Composable software is a system made by combining “building blocks" that add flexibility and additive value to the software’s functionality. This system structure is advantageous because it reduces the risk of change while enabling operational agility.
Currently, monolithic solutions require customizations or point solutions to fill in any functionality gaps. They also force your processes to work around their generic solutions. With a composable solution, however, pharmaceutical companies can build their own solution that fits their unique processes.
These solutions also enable citizen development. Many composable systems tend to have no-code capabilities, which accelerate the software development cycle and empower process experts to build solutions for specific use cases, giving the power to those that understand the problems best. Some use case opportunities could be error-proofing workflows with digital work instructions, requesting 21 CFR Part 11-compliant eSignatures during workflows, and creating customizable dashboards to gain real-time operational visibility.
The future is composable because unlike a monolithic system — which requires costly customizations and lengthy implementation times — composable software has a faster time-to-value, letting pharmaceutical companies think big, start small, and move fast.
Let’s look at some ways that manufacturers are already creating value with Pharma 4.0 solutions.
Electronic logbooks automatically document relevant production information — streamlining a manual process while dramatically improving data integrity. These logbooks can compile and integrate information from machines and operators, expanding process visibility. Further, electronic logs can integrate photos, notes, reason codes, device history records, and locations — providing a more holistic record of production than paper-based forms.
Electronic logbooks ensure that information is attributable, legible, contemporaneous, original, and accurate (ALCOA).
Because these logs are digital, they can be easily accessed to prove compliance.
Many line clearance processes are complex, time-intensive changeovers. With paper-based processes, workers may spend a significant amount of time looking for the next step or validating the execution of the previous one, reducing the amount of time they have to actually progress through the procedure.
Interactive, digital line clearance applications can make line clearance easier to navigate. Digital, IoT-enabled work instructions guide users through SOPs — increasing efficiency while ensuring that work is performed correctly and validated automatically. The applications record how long each step of the process takes, serving to improve process visibility and enable engineers to locate areas for process improvement. Because these apps are collecting and communicating data in real time, engineers can view process status as work unfolds, leading to reduced downtime and more effective scheduling.
Electronic Batch Records
Batch record reviews require aggregating and reviewing a substantial quantity of manufacturing data and process documentation.
Much of the labor spent in the review process comes from identifying incorrect or illegible entries and correcting records so that all production information is available for a given batch.
With Pharma 4.0 tools, manufacturers can make data collection and validation a continuous, seamless part of the manufacturing process. Information about manufacturing processes is automatically collected as operators and machines work, and all data is thereby attributable, legible, contemporaneous, original, and accurate.
When it’s time for a batch record review, the necessary information is accessible and easy to read. Manufacturers can spend more time ensuring the quality of a product and less time correcting transcription errors. With more data available, it’s easier to flag items to review by exception.
The greatest barrier to process improvement in pharmaceutical manufacturing isn’t always regulatory constraints. In many cases, it can be a lack of process visibility.
With IoT devices and human-centric manufacturing applications, manufacturers can break complex processes into their constituent steps, creating a granular picture of how workers perform on the line. The applications let engineers track individual operators' performance at each step. This lets engineers identify situations in which more training may be necessary. It also helps them differentiate between poor operator performance and poor process design.
In our experience, many of these changes are incremental and can yield significant gains in quality and efficiency without triggering an audit or requiring revalidation.
Clean Room Monitoring
IIoT makes it possible to respond to changes in environmental conditions as they develop. This capability saves a significant amount of time in monitoring clean rooms that normally require a technician onsite who undergoes a gowning and sanitization process, records the information on paper, and documents the data in a computer. Connected sensors can detect when conditions may exceed established thresholds and alert technicians to take the proper action before interrupting production.
Training for Regulated Environments
Many manufacturing processes require a significant investment in training. This challenge is further exacerbated during periods of high employee turnover, which result in a loss of expert knowledge on the team. Training can be slow, as manufacturers often have a difficult time replicating real-life production scenarios in their training programs. Lengthy training times are expensive, deflate productivity, and reduce quality if technicians aren’t trained properly.
Using manufacturing apps, manufacturers can design Pharma-specific training applications to get employees on the line fast. Engineers can break multi-stage processes into their constituent parts with targeted modules and embed media like videos and images to help convey information to different styles of learners. If it’s not possible to take workers off the line during reskilling periods, training applications can be configured to facilitate on-the-job training (OJT).
Manufacturers can even simulate processes by running training apps in a staging environment using Workspaces. This sets up a separate environment that allows you to track operator performance without having training data impact your production data.
Big Data Analytics
Manufacturers generate a truly massive quantity of data in the course of operations daily. Yet most of this data isn’t used as the basis for production insights. This is because it can be too unwieldy or unstructured to be valuable (also referred to as “Data Rich, Information Poor,” or DRIP).
One of the promises of Pharma 4.0 is the enhanced interpretation of the data collected throughout a product’s lifecycle. With advances in artificial intelligence (AI) and machine learning, systems are better able to parse and find connections within large data sets.
Digitizing Paper Logbooks to Increase Data Accessibility
A top 10 pharmaceutical manufacturer still used paper logbooks to capture information during daily operations. This generated massive amounts of data that can only be accessed in clean rooms. Through an internal study, this pharmaceutical manufacturer realized that they were spending hours a week putting on PPE and sanitizing just to enter a clean room to retrieve data from paper. This was unacceptable.
The pharmaceutical manufacturer implemented Tulip’s electronic logbook solution to automatically capture data and error-proof their workflows — allowing them to save time and increase productivity. These logbooks are able to log who completes the task, where, and when in an auditable trail.
By using drop-down menus, the manufacturer has made data capture faster and easier. Now that this information is fully digital, the department manager is able to access all of the data in their equipment logbooks from multiple rooms — from anywhere, at any time.
Reducing Line Changeover Time by 80%
Another manufacturer used Pharma 4.0 techniques to improve a complex line changeover. This process took 14 days to complete because operators needed to navigate through an 80-page paper SOP, document each step to create an auditable trail, and report their progress for the next shift of operators to take over. If a step was skipped or an error was made, the fix could be extremely costly and time-consuming.
This company used digital work instructions to guide operators step-by-step with embedded images and videos for clarity. These work instructions can be dynamically configured with “if-this-then-that” logic to account for branching decision points in the changeover process. Critical process parameters and values were automatically logged into the application data with timestamps and eSignatures to comply with GxP practices.
By making this process more human-centric, the pharmaceutical company was able to reduce the burden of documentation and error-proof their workflows. The operators no longer needed to manually record information on paper, so they were more focused on getting the task right the first time.
An added benefit of digitizing their operations was the ability to track line changeover processes in real time. The next shift was ready to pick up on any outstanding tasks with actionable next steps — and managers gained production visibility into their progress.
Industry 4.0 Unlocks Pharma 4.0
The pharmaceutical manufacturing industry is evolving at a rapid speed.
While the FDA and manufacturers both envision a world in which compliance is a lower touch, collaborative exercise — balancing continuous improvement with compliance will remain essential for years to come.
The promise of Pharma 4.0 lies in its ability to unlock new potential for productivity and quality while making compliance a seamless part of the manufacturing process.
Manufacturers who take the necessary steps to embrace a digital future now stand to benefit from seamless compliance, but it doesn’t need to stop there.
By adopting a Pharma 4.0 strategy, you can increase connectivity, efficiency, and agility.
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