Production environments are linked to the quality and volume output of the end product. Global life sciences advanced solutions director Greg Weddle and Paul Watts, operations lead - process and GxP, of Johnson Controls discuss how, when it comes to creating optimal conditions within pharmaceutical manufacturing environments, a full understanding of process cycles is vital.
A clear understanding of the manufacturing process and its rules, together with internal and external factors, is essential to maximising investment to output potential.
One of the best examples of plant management stems from corn. This example of a plant environment has more parallel points than just the name. An ear of corn sits connected to its stalk. This stalk and its leaves will manage the environment for the production of the ear, as well as deliver required raw materials to the production process.
The stalk, roots and leaves are designed to manage the variability of the product, independent of its environment: the field. Environmental conditions - such as day/night cycles, sun, moisture, temperature, wind and soil - experienced throughout the corn production cycle will determine the plant's output.
Too little rain early in the corn's development triggers a programme within each plant that influences the number of rows the ear establishes, while similar conditions occurring later in the process trigger events determining the length of an ear and the number of kernels in a row. In a similar vein, if an extreme heat wave hits after tassels appear, this limits the lifespan of pollen, which can affect kernel development.
Accurate output prediction is what farmers, governments, traders and brokers need to manage their businesses. The plant does what it can to assure every kernel is produced successfully (quality control), but the plant's volume output (production) is limited by the timing of field conditions.
Other similarities between the corn plant and a pharmaceutical production plant include isolation from contaminants, protection from insects and rodents, managed temperature and humidity, and the need for raw materials (water, nutrients/compounds and excipients) and energy (sun/fuels).
What can pharmaceutical manufacturers learn from this parallel with corn? The same thing that farmers and researchers have learned: the more you know about the process cycles of your product, the better you can manage its quality and productivity. Determining such 'requirements' of production success sounds simple but is, in reality, a challenge.
Table 1 compares the output of pharma manufacturing plants with that of other industries and worldclass factories. Measures such as stockturn, on time in full (OTIF) and right first time (RFT) are of the highest interest in the analysis, as they point directly to output efficiencies and what is possible, where OTIF is a direct measure of the product available to sales and competitive shelf advantage.
The reality of developing requirements in support of any production design or run is complicated by the separation of researcher to architect, preconceived views of the designers, and the current understanding of the science/chemistry and mechanics of the product. Defining a mechanism to capture the elements of manufacturing success and then interpreting those into a 'bricks-and-mortar' facility, with all the right systems and controls in place to assure the product's quality and productivity, is one key to success.
Having spent 30 years at Johnson Controls, designing and delivering environments that support the process of converting one thing to another, global life sciences advanced solutions director Greg Weddle is familiar with the dos and don'ts. To him, Johnson Controls represents over 100 years of controls and automation technologies and, as he began working with those sages of systems experience and translated their analogue systems tricks into lines of code, a whole new world opened up.
When, later in his career, Weddle moved into the pharmaceutical industry, he tackled the concept of 'regulated' space. Early in the industry's lifetime, facility and production environments had generally escaped the scrutiny of regulators. Other industries, however, had already grown to understand the relationship between optimal control of environmental conditions and production success.
Successes and failures seemed to be defined by facility and automation designers' full understanding of the process and product they were trying to support. Weddle saw facilities so misaligned to the needs of the product that they never entered operation; buildings that were 90% built, only to find the product failed Phase III clinical trials or could be manufactured more effectively elsewhere; and 'wants' rather than 'needs' drive spiralling costs and add unnecessary complications to designs, so that facilities could not be built successfully.
On the operations side, he witnessed first-hand how facility and production managers struggled to get what they needed from operations; automation capabilities that were never fully commissioned; innovative design concepts during the build get thrown out by operations teams that could not understand or see the innovation that had been delivered to them; and, of course, facilities and systems that simply missed the mark of the product need.
In 2002, Dr Janet Woodcock of FDA CDER introduced the idea of risk-based compliance to the pharmaceutical industry in a bid to convince the industry to break with its traditional rigid construct of design and operations, influenced by rote compliance procedures, and bring innovations into facilities and operations. At this time, Weddle started looking at these facilities from the aspect of business risk. This risk-based view, known as FRAME (Facility Risk Assessment Methodology for the Enterprise), tied the reliability of the facility, utility, compliance and equipment to the consequence of the product. This statistically objective and economically focused approach led him to the true nature of what is important to a plant manager or CEO.
FRAME bridges the gap between what can be achieved in automation and system design, and what is needed to support product and lifecycle compliance needs. By bringing together the product inventor, production, materials management, facility, automation, compliance and operations experts with those that know the risk and revenue profile, the impact of facility design, and operations on revenue and profits can be objectively measured. What is possible and what is practical is now an equation, instead of being decided by the loudest voice in the room.
Johnson Controls operates critical facilities as well as manufacturing processes, and understands the process not just from an engineering perspective - in terms of nuts and bolts, flanges, bursting discs and filter dryers - but also from a chemical process perspective. This has enabled its engineering teams to move away from a 'we ask, you do' mentality to a more 'this is what we need; what's the best way we can do this?' type of approach. This understanding has transformed service delivery from a very transactional service to that of an integrated process.
In the context of a primary manufacturing plant, productivity has often been 'trumped' by the complexity of the chemistry, and the need to handle all production internally under client control, which was the traditional paradigm. The last few years have seen that paradigm challenged from a number of fronts, including the global financial markets, as a result of difficulties in developing medicines for complex medical needs, patent expiries, and a lack of blockbuster-style drugs to replenish the pharma pipeline. The net effect has seen the pharma industry turn away from internal control and manufacture, and towards competitive outsourcing, cost reduction and risk-based approaches that five to ten years ago would not have been entertained. In addition, a further significant internally driven focus has applied pressure within the business to maximise patents and the potential additional revenue that can be harvested from efficient operations. Within this focus, the supply chain to patient and, by extension, the manufacture of drug substances have also come under scrutiny.
The effect of this paradigm shift is seen across manufacturing, as new strategic drivers focus on cost and time reduction (reducing the product-to-patient time; knowledge transfer from the lab to scale-up areas (reducing the need to re-engineer processes suitable for scale-up); increasing yields; and manufacturing only the required amount of drug (reduction/removal of overages) - all in a compliant, safe and efficient manner.
Such drivers impact upon how engineering teams are supplied and service is delivered in these regulated spaces. Over the last two to three years, there has been greater focus on embedding client teams within the process, so that they are involved from the moment the drug is confirmed to be manufactured by the lab/product development team, right through to the point that it is packed and shipped to the patient.
Within primary, secondary and sterile operations, Johnson Controls' engineering teams are more involved in addressing these strategic drivers than ever before, and this new way of working can have a profound impact on them. For example, primary manufacturing's focus on shortening the traditional operation reconfiguration set-up and strip-down times has reduced overall product cycles and increased manufacturing reliability, driving down the average cost of a batch without compromising quality. The intensive use of lifecycle asset and business-driven maintenance, continuous improvement, root cause analysis and other methodology has proven to effectively reduce the engineering incidents, rework and associated delays traditionally attributed to process and engineering equipment. In essence, optimising the overall equipment effectiveness (OEE) and plant productivity as a whole can be achieved primarily through the use of these tools and initiatives.
To ensure the success of these cross-functional teams, a set of rules, a disciplined process, and tools that gather key knowledge and resolve dependencies are needed. Be prepared to discuss the options openly when it comes to production and facility needs, including geographic selections, tax position, energy/sustainability targets, product timing and disposable production methods. Be open to sharing the answers you don't yet have, be they product revenues/volumes, the science of the process or compliance/approval challenges.
Table 2 presents an example of the process and discipline that Johnson Controls has developed to manage and publish this data collection step, the output of which is user or product requirements.
Environmental and process conditions may include temperature, pressure, humidity, weight and particulate count, depending on the space or process design. These conditions will generally vary in line with the type of space (lab, animal room, production suite or warehouse) or process (dry, wet, lyophilisation, open/closed, chemical, mechanical or biologic). The required conditions may be driven by regulatory concerns, or scientific, operational and/or financial/business factors. In any case, it is important to capture its driver and test the requirement against the 'need' or 'want' bucket. Remember: needs simplify, but wants complicate.
Driving success means matching the availability and timing of a manufacturing space and line to product demand. Put simply, availability translates to the ability to deliver within the user and product requirements, before and during the production process. The categories of management are defined by each individual process, but will extend themselves to reference standards used in calibrations; the ability to prove standard operating procedures are followed, up and downstream; material verification; process cleaning and testing; automation system tests; change control management; business continuity plans; and communication to verify utilities continuity, product order details, delivery and batch information.
Productivity is improved by starting with measures: the predicted productivity target against what is delivered, adjusted and repeated. If your Sigma analysis tells you that your process is out of control, you must return to control before assigning success to a process change. Measuring the impact of process changes upon productivity depends on your ability to isolate the impact of that change. When measuring inputs, outputs and environmental conditions, trends emerge; arranging these trends by business consequence priority and then systematically addressing high-impact variables will improve productivity.
These following statements are key lessons and truths that every manufacturer should know:
Both types of plant - the green one and the one made of bricks and mortar - reflect the designer: one has flaws and the other doesn't. From the green plant, pharma manufacturers can learn the lessons of simplicity of design, the benefits of 'needs' over 'wants', the importance of flexibility and, of course, that a detailed knowledge of the process provides the timing of impactful intervention.