All manufacturing environments struggle with some degree of complexity in pursuing digital transformation (DX) initiatives to strengthen operations in a modern era defined by highly competitive markets and unprecedented supply chain disruptions. Yet perhaps no production setting is more challenging to transform than pharmaceutical manufacturing. 

Longstanding challenges in pharma production include highly complex processes involving sensitive ingredients that often require sterile production environments controlling for temperature, humidity and other conditions. On top of that, biopharma manufacturing is subject to strict regulations, given the fact that what’s being produced are life-saving medicines that must remain safe and effective for patients who take them.

Now there’s even more pressure on pharmaceutical companies as they seek to tackle more than  7,000 rare diseasesthat have emerged in recent decades and now affect one out of every 10 Americans. To meet this challenge, pharmaceutical manufacturers are pivoting towards more flexible factory operations to support the production of a wider variety of specialized drugs and therapeutics. Rather than focus on large-scale bulk manufacturing, these producers are instead working on smaller batch highly targeted treatments.

In the face of these challenges, life sciences manufacturers are learning to adapt a broader Industry 4.0 transformation trend in manufacturing to suit the particular needs of their own sector. By implementing what has been termed Pharma 4.0 transformations, drug producers are finding ways to rise to the moment by building highly efficient and flexible factories. Powered by real-time data and modular “plug-and-play” equipment and infrastructure, these facilities are changing the game in the drive to produce more drugs, more quickly for the diverse populations who need them.

The Rise of Pharma 4.0: Expanding Production Capabilities for an Expanding HealthCare Need 
Pharma 4.0 is an ambitious initiative characterized by the International Society for Pharmaceutical Engineering (ISPE). It involves the highly-specialized customization to the life sciences sector of Industry 4.0 transformation strategies that are happening elsewhere in manufacturing. And so, to understand Pharma 4.0, it’s first necessary to understand Industry 4.0. 

Manufacturers across many different sectors are pursuing Industry 4.0 transformations characterized by intelligent digitization and enhanced quality, variety and availability of data generated across production systems. Within these scalable and multi-cloud environments are advanced IoT, edge and related technologies, with powerful artificial intelligence (AI) and machine learning (ML) algorithms for robust analytics that enable real-time visibility and precision control of the entire production and supply chain ecosystem.

The Industry 4.0 playbook can be applied to pharmaceutical production as well, provided the modernization effort is adequately tailored to the demanding manufacturing requirements that are unique to the sector. Hence the advent of Pharma 4.0, for which the ISPE developed a series of 12 foundational “theses” to define the concept:

1.     Pharma 4.0 extends/describes the Industry 4.0 Operating Model for medicinal products.
2.     In contrast to common Industry 4.0 approaches, Pharma 4.0 embeds health regulations and best practices.
3.     Pharma 4.0 breaks down silos in organizations by building bridges between industry, regulators and healthcare and all other stakeholders.
4.     For the next Generation Medicinal Products, Pharma 4.0 is THE enabler and business case.
5.     For the established products, Pharma 4.0 offers new business cases.
6.     Investment calculations for Pharma 4.0 require innovative approaches for business case calculations.
7.     Prerequisite for Pharma 4.0 is an established PQS and controlled processes & products.
8.     Pharma 4.0 is not an IT Project.
9.     The Pharma 4.0 Operating Model incorporates next to IT also the organizational, cultural, processes & resources aspects.
10.  The Pharma 4.0 Maturity Model allows aligning the organizations operating model for innovative and established industries, suppliers and contractors to an appropriate desired state.
11.  Pharma 4.0 is not a must, but a competitive advantage. Missing Pharma 4.0 might be a business risk.
12.  When moving from blockbusters to niche products and personalized medicines, Pharma 4.0 offers new ways to look at business cases.

The effectiveness of each Pharma 4.0 transformation will be determined by how well these principles are backed up by a comprehensive plan for implementing transformation efforts in a biopharma company’s specific manufacturing environment. As discussed, modernization must align with the evolution away from large-scale global production, in favor of more localized, small-batch drug development. This requires the production environment to be highly digital and highly flexible, which means unprecedented data agility is mission critical.  

Keep in mind that 45% of manufacturing executives already specify the inability to access data as a key barrier to solving their challenges. In modern pharma manufacturing, those challenges are more pronounced, given the more flexible and diverse pharma production environments needed in order to handle frequent changeovers and parallel development of multiple drugs in a single factory. Because of this, life sciences production environments require transformations that ensure real-time management, analytics and reporting on vastly higher volumes and varieties of data.

Bringing Flexibility to Production Through “Plug-and-play” Factory Design
The most effective Pharma 4.0 transformations for today’s fast-shifting requirements to manufacture a wider range of drugs are those designed to bring what’s known as “plug-and-play” flexibility on the production floor. It’s just like it sounds: what used to be permanently anchored machinery and infrastructure, is now capable of being moved quickly at will. 

The factory of the future can be reconfigured in just minutes or hours, with components able to be swapped out to accommodate new production scenarios. This same flexibility also allows cleaning cycles to happen conveniently away from the production environment, dramatically reducing the need for costly pauses in operations for clean-in-place activities. For example, it can take up to two days to clean and sterilize a traditional stainless steel reactor; by contrast, a flexible factory can use modular infrastructure and single use materials, such as tubing and reactor bags, to shorten that changeover period to just a couple hours. 

A key enabler of this flexibility involves modernized distributed control systems (DCS) that support plug-and-play connectivity though docking stations for mobile equipment. Quality, safety and compliance are assured with the help of dedicated IP addresses for each piece of equipment so, as equipment is moved and reconfigured, the DCS employs a failsafe system that forbids controls for any piece of equipment that’s docked in the wrong location.

Additional efficiency and quality are made possible by standardized data structures that give workers access to real-time data in a common format. As one example, an ERP system can be set up for two way communication up and down the chain of individual equipment, raw materials and end products. For example, one processing line or inspection system can produce multiple terabytes of data each day. Successfully mining this data for temperature deviations, refrigeration exposure time or other abnormal events can minimize the time batches are held before release. With easily accessible quality insights, you can use analytics to realize proactive process improvements and productivity.

Throughout, a modernized DCS helps speed time to market by streamlining the path of new drugs from lab to factory. Many research laboratories are employing modern DCS solutions on small bioreactors in their labs, and are gaining regulatory approval under this process. In fact there has been a 206% increase of patents issued from the Technology Transfer Office in the past decade. This trend means the ability to seamlessly transfer new technologies into factory operation will only become more critical over time. 

Better Compliance Through Better Manufacturing Execution Systems (MES)
Lengthy compliance activities drive up the cost of production operations while product sits waiting to be shipped. This time and expense are unacceptable in an industry pressured to lower overall drug costs. The good news is that the Pharma 4.0 efforts we’ve been discussing are also game-changers for compliance, especially when modernization of manufacturing execution systems (MES) is part of the picture. 

That’s because auditing is no longer a static process. Global laws and regulations surrounding patient care require extensive, digitally integrated documentation of pharmaceutical production. This directive is made more daunting to satisfy in flexible manufacturing scenarios where the production managers must scale up production, run smaller batch sizes and increase changeovers. Amid such challenges, quality and compliance can be maintained by implementing a modern, integrated MES that can help the organization both adhere to regulations and drive profitability.

Some of the must-have capabilities in a modernized MES should include a comprehensive electronic batch record (EBR) that captures complete product genealogy, facilitates review by exception and connects with any anti-counterfeiting serialization systems that are part of the manufacturing ecosystem. Just as critical for success is a role-based recipe management approach that is optimized for each stage of a recipe lifecycle and that drives time to results for every user. 

Strong data integrity is also needed to ensure that production or documentation errors do not result in wasted product, contamination or potential recalls. Well-designed in-process quality data collection and analytics can turn weeks of review into real-time-release, with no quarantine required. The right MES can bring unified integration from ERP to the shop floor, enable real-time quality dashboards, enhance order-completion data and greatly reduced time to qualify. 

The best MES solutions will support high quality and strong compliance of flexible manufacturing practices enterprise-wide. These gains are no small matter for a highly-regulated industry that demands strict adherence to regulations, no matter how dynamic and scalable the production environment may be. There’s also a powerful effect on workforce utilization, as the ability to collect and analyze real-time data helps pharma manufacturing stakeholders from the shop floor to the top floor collaborate and make better decisions while achieving compliance.

The Many Benefits of Pharma 4.0 Transformation 
Pharmaceutical manufacturers that stay the course through the Pharma 4.0 journey by thoroughly modernizing their DES, MES and other critical systems will reap powerful benefits in the form of more efficient operations, significant cost savings and accelerated time to market. Pretested and validated equipment allow for more economical investments and modular equipment setup in factories that reduces the need for square footage and hard piping for utilities. These combined factors can speed ramp-up times to as little as six months. 

Such benefits are far from hypothetical. They’ve already been proven in demanding, real-life production settings. For example, one biopharmaceuticals giant faced skid control obsolescence, poor data visibility and alarms that led to excess downtime. With the transition from a traditional to modern DCS, the company went from a half dozen communication-related alarms per week, to zero in the first two months of operation. The company achieved added operational improvements from a “family” code approach that cut skid validation time in half, and a more granular level of visibility into the entire production ecosystem has reduced troubleshooting to as little as two minutes.

In another use case, a major pharmaceutical producer needed to quickly increase production to meet global demand. Their answer was an MES that eliminated time consuming, error-prone paper-based documentation. This helped increase efficiencies, reduce costs and ensure compliance in real time. Their processes are now 100% paperless – resulting in fewer errors, up to 10% savings on labor costs and a 50% reduction in product and management review times.

These and other real-world examples demonstrate how a flexible and future-focused information infrastructure that brings together information technology (IT) and operation technology (OT) can ensure key process data is no longer siloed. As scalable analytics tools convert raw data into customized, actionable information on an ongoing basis, production systems continually provide contextualized insights around quality, batch deviations and other critical indicators that enhance quality compliance and conformity at a lower cost. This helps increase output and decrease inventory, all while improving process workflows, asset utilization, time-to-market and revenue generation.

Conclusion
Biopharma manufacturers face all the challenges of Industry 4.0 transformation, plus the additional task of adapting transformation to an evolving, flexible manufacturing scenario necessary to address the growing number of rare diseases that require a wider and more powerful variety of medicines to treat. Thankfully, Pharma 4.0 transformation can deliver the level of flexibility, efficiency and quality assurance in manufacturing that’s needed to satisfy this important societal need. 

Dan UpDyke is the Life Sciences Strategic Marketing Manager for Rockwell Automation. With a background that includes system integration, product management, and industry marketing, UpDyke has 25 years of combined process control experience across industries including pharmaceuticals, biotech, medical devices, and specialty chemicals.