Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	Data analytics software and machine learning capabilities give pharmaceutical manufacturers new tools to move beyond preventive maintenance into predictive and prescriptive maintenance, which promises to be more effective and save time and money. 

spoke with Dennis Belanger, director of Operational Certainty Consulting at Emerson, about these new methods. 

What is the difference between preventive, predictive, and prescriptive maintenance? What do you see as the trend in maintenance of equipment in pharma manufacturing?

Today, prescriptive maintenance is being adopted by best-in-class pharma manufacturers to drive better production through more informed decision making. Prescriptive maintenance uses Big Data analytics to find patterns or anomalies in large amounts of seemingly unrelated data-understanding and evaluating the performance of a process or system rather than measuring the condition of a single piece of equipment. Finding these indicators can help organizations identify areas of good and bad performance that might be impossible to identify through standard monitoring procedures. The prescriptive element comes in when organizations can associate a corrective action or adjustment to the anomalies and provide specific actions to take to minimize or stop the failure.

	Many organizations still use preventive and predictive maintenance, and there is an important distinction between them. Preventive maintenance tasks are performed on a fixed schedule or a metric such as run hours or cycles. Preventive tasks inspect assets or bring them back to a certain condition and typically require a scheduled system shutdown. Preventive maintenance tasks should only be used when it is not possible to detect failure modes in a timely manner with predictive monitoring solutions  because they provide only few weeks’ notice of potential failure. Filter changes, leak inspections, and alignment checks are good candidates for preventive maintenance.

	Predictive maintenance uses technology to monitor and trend an asset to detect change in conditions that might indicate a future problem. Maintenance data are collected regularly while equipment is running, through manual rounds or through devices installed at the collection site. Predictive maintenance eliminates the need to schedule a shutdown and provides a better indication of the actual condition of equipment. Predictive technologies have become quite popular because they can provide early indication of potential asset failure-typically allowing many months of advance warning, which supports organizations’ planning of turnarounds and scheduled outages to minimize overall downtime. Vibration analysis, infrared testing, and condition monitoring are all common examples of predictive maintenance technologies widely used today.

What are some best practices for using predictive maintenance?

One of the best practices a pharma organization can apply is to perform a maintenance strategy analysis using a failure modes and effects analysis (FMEA). This analysis would typically incorporate critically ranking information and will ultimately show an organization where best to apply the resources of a predictive maintenance program to have the strongest impacts. Often, organizations view predictive maintenance as a costly expense and use it only sparingly on their most critical assets, but applying it more widely can result in much higher savings if the application is properly targeted. Top quartile performers typically use vibration analysis on 80–90% of their rotating equipment. These organizations know that predictive maintenance is approximately 50% less costly than preventive maintenance, while still providing a much better indication of potential failure. Moreover, online predictive maintenance can also provide earlier detection of issues, making it easier to plan repairs, which typically cuts repair costs by 40–50%.

How are models for maintenance developed, and how can they be best used?

Common assets and systems typically have common problems and impacts on a business. Emerson uses these commonalities as a starting point to develop models that can be used hundreds or thousands of times across many clients with minimal customization. Organizations can use these models to effectively and efficiently simulate common assets such as compressors, distillation columns, heat exchangers, pumps, valves, generators, and turbines, making advanced analytics more achievable and sustainable. 

	Many models for high-impact, known problems can be applied across industries or organizations because the models are built for common equipment. As Emerson expands solutions to address business problems for complex systems and processes, more specific models are possible and will be useful to target a company or plant’s unique environment. When individual systems begin to vary greatly in configuration, engineering design, age, and monitoring techniques, there are more complex custom solutions that can be built from scratch and can deliver end user-specific insights. 

What is the importance of detecting and addressing issues in real time?

The importance of detecting issues in real time is linked to the duration between the detection of a failure mode and the onset of a problem. For example, some electrical failures occur in a matter of minutes. Such a failure would require real-time or near-real-time detection to provide enough time for maintenance to intervene. On the other hand, failure modes such as bearing deterioration may take months to go from detection to failure. When the time to failure is that long, more intermittent monitoring may be appropriate. 

	While monitoring every piece of equipment in real time would be nice, an organization would need to be able to handle the volumes of data such monitoring would generate. Understanding that time to failure dictates real-time detection in only a handful of cases, most organizations opt to monitor many assets in near real-time or even using periodic readings, which still allows them plenty of time to react to problems.

	If you are going to spend the effort and resources setting up and maintaining infrastructure to detect issues in real time, then you also need to be able to act in real time. Detection is only a part of the picture. Organizations also need to examine the established work management process so that significant lead time translates to timely and precise action. 

	Examples of addressing equipment failures

Can you give some examples of detecting and addressing equipment failure modes in pharma manufacturing?

There are many examples of varying size and scope, but three examples in particular stand out. Emerson worked with one organization to develop a machine learning system that could detect sensor drift on a temperature sensor for a heat-treat skid. That implementation detected an aberration 60 days in advance, which allowed the organization to save a batch worth over $1 million.

	Another organization used vibration analysis to detect misalignment and bearing failure on a chilled water system pump for a system performing batch experiments that require constant temperature. That system detected a failure 120 days in advance, saving batch experiments that, if lost, could have wasted months of time.

	In one innovative example, a pharmaceutical organization used machine learning to capture knowledge and monitor systems with the objective of minimizing the impact of a potential loss of 25% of the organization’s workforce due to expected retirements. 

	What all successful examples have in common is that decision makers closely examined critical points of failure in the organization and developed solutions that gave the organization the time it needed to react efficiently but thoughtfully, to drive more positive outcomes overall.

Articles

Predictive and prescriptive maintenance improve pharmaceutical manufacturing equipment effectiveness. 

Data Analytics Technologies Help Reduce Equipment Failure

	Pharmaceutical manufacturers must adhere to cGMP no matter what their batch size, but producing small batches in aseptic fill/finish has particular challenges. 

spoke with Robert Popilock, Packaging and Production segment manager for DWK Life Sciences, about some of these challenges and possible solutions using ready-to-use components.

What are some of the considerations and challenges for fill/finish and packaging that are specific to small-batch manufacturing? 

For small batch entities, the most notable considerations are related to capital investment (processing equipment and physical plant space), internal competency development (standards interpretation, process implementation, maintenance, and review), workflow or production capacity (hand filling, semi-automated, or high-speed lines), and meeting regulatory guidelines.

	Common ways to produce an aseptic drug include internal preparation of sterile components or procurement of sterile components. The selection of one method over the other is often based on production run rates, batch frequency, and operational constraints. Small batch entities are typically constrained to plant space, capital investment, and personnel competencies. Small batch processors may be limited in their ability to dedicate space for automated cleanroom operations with high-efficiency particulate air (HEPA) environments. They may also have limited ability to make the capital and process investments to achieve 

<71> (sterility) (1–3) as well as environmental monitoring requirements. Of interest, the capital outlay for equipment to wash, autoclave, and irradiate can exceed $1 million, and required process verifications and content integrity evaluations can be time consuming.

	To overcome these economy-of-scale limitations, small batch manufacturers seek alternatives to in-house processing by procuring or contracting components and processing services or through the use of ready-to-use  components or kits.

	Although the option of procuring components and processing services does allow the small batch operator to select foundational packaging components, such as clear and amber vials, aluminum seals, and stoppers, this option is associated with operational and capital investment challenges. One limiting factor is that the required production demand may be below the minimum order quantity threshold of both the component manufacturer and processing agency. Another challenge is related to the lead time and fulfillment cycle for processing services, which can create forecasting and planning challenges for ad hoc and small batch consumption scenarios.Unplanned demand is typical, as small batch processors desire to minimize on-hand stock of processed products given that the products have a finite shelf life and desire to reduce capital deployed.  Together, such issues have driven interest in ready-to-use (RtU) packaging components.  

	RtU component packs from DWK are available in quantities from 200–230 units and accompanied by a certificate of analysis (CoA) supporting off-the-shelf use. The small quantity packs consisting of clear or amber vials, aluminum seals, lyophilization stoppers, coated stoppers, and straight plus stoppers help to reduce scrap and management of opened sterile inventory and are ideally suited for small batch and compounding entities. RtU configurations consist of inventory-matched vials, stoppers, and seals available in off-the-shelf kitted quantities from 200–1200 units. The kits minimize risks associated with inventory shortages by assuring matched quantities of sterile components being available in a single kit and limit scrap through small batch pack formats.

	As can be seen, small batch manufacturers can match their batch rates, batch frequency, and operational preferences or governances to maximize workflow, investment, and risk. 

What challenges do you see in fill/finish at compounding pharmacies? 

Compound pharmacies create medications tailored to the specific needs of the patient by combining and mixing ingredients, then packaging them for delivery and use. Typically compounding is a small batch or ad hoc [as needed] production scenario. While compounding is becoming increasingly common, there is a large portion of compounders who may struggle to comply with regulations, including the demonstration of consistent production of clean and sterile parenteral packaging components. Despite the fact that there are guidelines for industry and sterile drug products that require conformance to aseptic processing (cGMP) and 

Pharmaceutical Compounding-Sterile Preparations 

(4), ongoing problems have led to intensified efforts by FDA to assure safety of compounded drug products. 

	In addition to regulatory compliance, compounders who use sterile vials and closures are also challenged by physical plant space to host sterile processing equipment, capital investment in expensive washing and sterilization equipment, and analytical capabilities to assure compliance to published standards, along with personnel required to implement, maintain, and audit processes and procedures to assure compliance. Like fill/finish operations, compounders are challenged in coordinating the purchase of raw components and contracting processing services at minimum order quantities. They also face challenges associated with navigating the processor’s schedule and processing backlogs. This makes RtU solutions a viable alternative through off-the-shelf and small pack quantities accompanied with CoA and traceability documentation. 

	The regulatory environment can be quite complex. So much so, that we are seeing a trend in the number of manufacturing projects being outsourced for large batches to contract manufacturing organizations (CMOs). CMOs typically have dedicated staff who perform such compliance activities and are extremely efficient and less prone to complications that may delay production. In the case of small batch manufacturing and compounding entities, however, their volumes don’t align with such outsourcing agencies, so they must rely on their own compliance person. Knowledge of particulate cleaning, final water for injection rinse, total organic carbon levels, depyrogenation, autoclaving, irradiation, surface treatments, sterile bagging methods, CoA handling, and keeping up with compliance standards pose obvious challenges. A common misconception is that RtU components and kits are associated with a cost premium. However, when balancing against non-compliance risks, adding regulatory headcount, and annual training and processor audits, the convenience of filing the CoA becomes desirable.

<788> “Particulate Matter in Injections” (US Pharmacopeial Convention, Rockville, MD, July 1, 2012 ).	

<85> “Bacterial Endotoxins Test” (US Pharmacopeial Convention, Rockville, MD, July 1, 2012 ).	

<71> “Sterility Tests” (US Pharmacopeial Convention, Rockville, MD, July 1, 2012).	

<797> "Pharmaceutical Compounding-Sterile Preparations" (US Pharmacopeial Convention, Rockville, MD, 2008).

Ready-to-use components help compounders and manufacturers of small batches overcome economy-of-scale limitations in aseptic GMP manufacturing.

Challenges for Compound and Small-Batch Aseptic Manufacturing

	Design for reliability (DfR) is a methodology for ensuring that equipment or other assets are built so that they run consistently without unexpected failure, and that they can be accessed and maintained over time. “Asset health accountability drives the creation and execution of a robust reliability framework,” says John Ganaway, Design for Reliability practitioner at Jacobs. Software may assist in DfR, but in reality it is the stakeholders who must “build and execute a reliability framework,” says Ganaway. 

interviewed Ganaway about DfR and its application in pharmaceutical manufacturing.

Design for Reliability (DfR) aims to ensure reliability, maintainability, ergonomics, accessibility, and availability of assets. The concept blends aspects of statistics, probability, and reliability theory, as well as engineering, analysis, and stakeholder engagement. DfR should be  active throughout an asset’s or product’s lifecycle so that users can evaluate and verify that the equipment has been robustly designed, and so that problems caused by any design issues may be predicted before they can affect performance. 

	DfR practices allow equipment systems to meet reliability requirements, while applying the latest methods for risk management and design assessment. Stage gates for equipment concept and design trigger DfR and the application of each element of the method.

What are the main goals of a DfR program?

Its main goals are institutionalized knowledge improvement, continuous improvement, and the elimination of defects at the design stage. Those using the methodology must be able to transform information into knowledge and to integrate what they have learned. They must also be humble enough to ask all stakeholders for their input to improve overall knowledge, including the craftspeople who support equipment maintenance activities.

Can you share example(s) showing how DfR is used in bio/pharma manufacturing? 

Let’s consider the air-handing system used for a seed lab and associated 20-L room. Its design had to ensure that airflow was adequate in order for the facility to meet biozone requirements. When the design review had reached the 30% point, the equipment included six, fan-powered, high-efficiency particulate air filters (HEPAs). 

	All components within a fan-powered HEPA are accessible from the cleanroom side, eliminating the need to access the fan-powered HEPA from above the ceiling. In this case, the project reliability lead, who understood the holistic maintenance strategy for HEPAs throughout the plant, also projected what might happen if the fan failed. If failure occurred, he noted, unfiltered air could easily enter the seed lab. In this case, the HEPA filter would have to be removed from its sealing frame in order for maintenance technicians to access the fan components (e.g., the damper and controller). 

	HEPA filters are not typically changed at regular intervals. Instead, they are usually recertified at a time interval set by the owner. If the fan-powered HEPA filter were to fail, this failure would result in an expensive process interruption. Not only would the filter have to be recertified before being put back into use, the 20-L room would need to be cleaned three times, and the cumulative time required for all of these activities would exceed allowable downtime and compromise the ISO biozone’s cleanliness requirements. 

	Taking these potential risks into account, the filter’s final design was altered so that there was only one fan-powered HEPA, which prevented the loss of ‘fan power filter fan failure’ mode. Additionally, the fan-powered HEPA’s function was changed so that it is now simply a recirculation fan. 

	During the commissioning of this space, tests were run to understand the impact that loss of one fan-powered HEPA would have overall, and whether it was even needed. In this case, the reliability lead’s knowledge of operations, requirements, and potential risk, led to an improved design, highlighting the importance of involving all stakeholders in the DfR process.

How do new technologies such as AI/predictive maintenance aid in DfR? 

System health indicators (SHIs) are crucial. They are based on such process health indicators (PHIs) as pH, conductivity, pressure, temperature, and flow, and then integrated with asset health indicators (AHIs) (e.g., vibration magnitude with frequencies, oil cleanliness such as ISO codes, temperature using thermography, ultrasound using acoustics, current, voltage, and material thickness). With this data, artificial intelligence (AI), using improved data models, can create a method for enunciating defects. Once users are aware of the defects and the probability of their occurring, they can make better design decisions, eliminating those defects at the design stage.

What do you see as the trend for using DfR? 

The concept is now being integrated into capital planning and execution, which is a very positive trend. As the industry gains more experience with DfR and improves the way it handles and analyses data, information will be freed from individual data silos to create new specifications and standards. Although the pharma industry is still at an early stage in its digitization (compared with the steel, petrochemical, and automotive sectors), as competitive factors continue to impact its profit margins, manufacturers will be more interested in reducing total cost of ownership of their equipment and other assets. Creating standard work within the framework of robust maintenance and reliability programs will demystify that point where capital expenditure and operational expenditure intersect.

The goal of Design for Reliability (DfR) is to eliminate defects at the design stage; PharmTech interviews Jacobs about DfR for pharma equipment.

Designing Pharma Equipment for Reliability

Transdermal drug delivery offers benefits such as needle-free delivery and easier self-administration. Microarray patches are one type of transdermal delivery in which a set of microscopic projections (i.e., microneedles) that contain a dry drug are applied to the skin using a bandage-like patch. PATH is a nonprofit, global health organization that has been investigating transdermal drug delivery patches for more than 10 years. In August 2018, the organization launched the Microarray Patch (MAP) Center of Excellence as a four-year initiative to accelerate development, particularly for global health needs, such as vaccines and essential medicines. 

spoke with Darin Zehrung and Courtney Jarrahian, directors of the MAP Center of Excellence, about the initiative and some of the challenges they have identified for transdermal patch manufacturing. Zehrung is global program leader and Jarrahian is a program advisor, both in Medical Devices and Health Technologies at PATH.

Please explain what the Microarray Patch Center of Excellence initiative is and how it was started. What are your current goals?

Microarray patches, or MAPs, are an innovative delivery technology in early-stage development that could be used to administer vaccines and drugs without a needle or a syringe. For the past decade, PATH, in collaboration with developers and global stakeholders, has advanced the design and development of microarray patch technology for a range of public health needs, including measles, HIV, influenza, malaria, neonatal sepsis, and polio (1). We recognized challenges-including siloed information and limited opportunities for platform-wide approaches-that we could address to improve efficiency of product development. As a result, PATH formed the MAP Center of Excellence, with support from UK Department for International Development, to catalyze development of this promising technology.

	Through the Center of Excellence, our aim is to mobilize stakeholders and coordinate a strategic effort to identify and accelerate MAP technology for high-priority health needs in low- and middle-income countries. Currently, we are one year into this four-year initiative. PATH is working with the MAP developer community and global health stakeholder organizations on six functional areas-program needs, product development, manufacturing, regulatory, business strategy, and engagement-that are critical to advance this promising innovation. 

What are some of the key challenges for manufacturing microneedle patches?

Establishing scalable, automated, good manufacturing practice–compliant manufacturing processes for MAPs is a major focus area of this technology class and will be critical for its success. Technologies can be adapted from other fields to address challenges of precise loading of very small quantities of liquid into the MAP projections. Minimizing drying time is necessary to enable high throughput. Developing processes with high production yield and efficiency in use of the drug substance is also important for cost and sustainability, particularly for costly APIs. 

	For delivering drugs that require larger dosages (more than a couple of milligrams), a major challenge is providing sufficient drug loading and release, which can require alternative array designs and larger patch sizes. Under our MAPs for PrEP (pre-exposure prophylaxis) program, funded by the US Agency for International Development and the President’s Emergency Plan for AIDS Relief (PEPFAR), PATH has been working with partners to address this challenge to enable delivery of long-acting antiretrovirals and hormonal contraceptives by MAP.

What are some of the challenges for developing/manufacturing microneedle patches for vaccines in particular?

One key challenge is that vaccines cannot be terminally sterilized. Experts have debated about whether a low-bioburden manufacturing approach will be sufficient from a product quality and risk perspective, or whether vaccine MAPs will have to be produced aseptically, which adds complexity and cost to manufacturing facilities and equipment. In addition, vaccine antigens can lose potency quickly, so formulation optimization to maintain stability is critical, especially if enhanced thermostability is desired.

Have you completed any projects for vaccines patches that have been transferred to commercial use? 

Commercialization is the moonshot. Currently, vaccine MAP development is at preclinical and early clinical stages and no vaccine products have been commercialized yet. However, to build an evidence base to support future commercialization, we’ve completed studies evaluating factors that will influence cost-effectiveness (2) and stakeholder acceptability (3) of seasonal influenza MAPs, for example. Several developers have published Phase I clinical study results for influenza vaccine MAPs (4–6). To advance the development of MAPs for measles-rubella (MR) and inactivated poliovirus vaccine, PATH worked alongside other organizations such as the World Health Organization (WHO) and the Bill & Melinda Gates Foundation to develop target product profiles and cost analysis. In Ghana, PATH conducted a user study of MAP prototypes with healthcare workers, mothers, and children (7). PATH participates in the WHO MR MAP Product Development Working Group. Under the Center of Excellence, we are assessing the feasibility and value proposition of MAPs for other vaccines, including hepatitis B, human papillomavirus, rabies, and vaccines delivered during disease outbreaks.

One of the benefits of patch delivery for vaccines is greater stability for storage and transportation, which reduces the need for a cold chain. Can you share some of your findings from your work in this area? 

If MAPs are sufficiently thermostable to not require storage in the traditional cold chain (in which vaccines must be stored between 2 and 8 °C) for part of their storage life, that could facilitate new delivery strategies that have the potential to increase access to vaccination. This access is especially important in countries where the cold chain infrastructure is weak. WHO’s minimum standard for a vaccine to be eligible for licensure for use in a controlled temperature chain (CTC) is stability for a minimum of three days at a temperature greater than or equal to 40 °C (8). MAPs could simplify storage and transport, and ultimately improve vaccine access. CTC storage won’t be feasible for all vaccine MAPs due to inherent stability limitations of some antigens.

	PATH has developed the Vaccine Technology Impact Assessment (VTIA) model, which compares the total cost of delivery of different vaccine presentations, including the costs of transportation and storage in the cold chain. Our analyses have found that MAPs eligible for CTC storage can reduce vaccine transportation and storage costs. However, the total impact on the cold chain will depend on the storage volume of the MAP compared to the currently used vaccine presentation and the length of time the vaccine can be stored in a CTC. Many vaccines used in low- and middle-income countries are packaged in 10-dose vials, so MAPs are likely to require more storage space on a per-dose basis, particularly those with an integrated applicator device. But compared to the single-dose vials and prefilled syringes commonly used in high-income countries, MAPs could have a packaged volume advantage.

	PATH is also supporting the Vaccine Innovation Prioritization Strategy (VIPS) launched by Gavi, WHO, the Bill & Melinda Gates Foundation, PATH, and UNICEF in 2017. This global initiative aims to drive vaccine product innovation to better meet country needs and to improve immunization coverage and equity. MAPs are among the vaccine product innovations being assessed. Insufficient cold chain capacity has also been identified as a key immunization challenge through VIPS that could be addressed through the use of innovations. 

What are some of the considerations for packaging of patches (in vaccines or otherwise)? Do you have any research projects in this area?

Maintaining low moisture content over the shelf life of the product is generally critical for MAPs, as the microneedles can lose their sharpness and mechanical strength if exposed to moisture. This will require careful consideration of materials and seals for MAP packaging, and potentially incorporation of desiccant into the packaging system. In addition, it is important to consider physical protection of the microstructures if the product is dropped or crushed during storage or prior to use, so a rigid package format may be needed. Human factors design is also a critical consideration, as well-designed packaging can improve usability and prevent some types of user errors. Requirements for labeling, extractables/leachables, and biocompatibility are important as well. PATH is currently reviewing materials and designs for MAP packaging. 

What are the next steps for the Center of Excellence initiative? 

We’re initially focusing on the regulatory and manufacturing pathways for MAP technology as a platform. In partnership with Cardiff University, Wales [UK] we’ve launched an initiative working with industry, regulators, and academia to harmonize MAP definitions, critical quality attributes, and key test methods and will aim to produce a white paper documenting these considerations. We’re assessing manufacturing readiness across the technology class, and we plan to host a workshop in early 2020 to delve into key manufacturing challenges and potential solutions.

	Related to advancing MAPs specifically for global health impact, we’ll be conducting user needs assessments in low-resource countries and using the information to inform target product profiles for prioritized MAP products. User feedback will help ensure that the product meets the needs of health care workers, patients, and health systems to optimize uptake and impact of MAPs in the future.

37 (32) 4427–4434 (2019).
	2. B.Y. Lee et al., 

33 (37) 4727–4736 (2015).
	3. E. Jacoby et al., 

33 (37) 4699–4704 (2015).
	4. S. Hirobe et al., 

57, 50–58 (2015).
	5. N.G. Rouphael et al., 

390 (10095) 649–658 (2017).
	6. G.J.P. Fernando et al., 

36 (26) 3779–3788 (2018).
	7. PATH, “Evaluation of Microarray Patches for Human Factors-Considerations and Program Feasibility” 

(August 2017).
	8. World Health Organization, “

Immunization, Vaccines and Biologicals, Controlled Temperature Chain (CTC)


	Vol. 43, No. 11
	November 2019
	Pages: 48–49, 54

	When referring to this article, please cite it as J. Markarian, “Advancing Transdermal Drug Delivery,” 

PATH’s Microarray Patch Center of Excellence aims to accelerate transdermal patch technology for public health needs.

Advancing Transdermal Drug Delivery

	Digitalization and Industry 4.0 tools are being employed to improve pharmaceutical equipment and systems. An example of this is Optima Packaging’s Comprehensive Scientific Process Engineering (CSPE) approach to project planning for its fill/finish systems, which uses simulation for mock-up, engineering design, and design review to speed the design process. Three-dimensional models can be experienced using virtual reality to collect input from users early in the design process. The company opened a new facility, the CSPE Center, at its Schwaebisch Hall, Germany site in July 2019 that gives the company space to build, test, and commission multi-story, turnkey, fill/finish facilities. 

spoke withJan Deininger, editor at OPTIMA Packaging Group, about the company’s approach to equipment and process design.

What are some of the parameters you might consider in the design phase? 

During the design phase, strength calculations, flow simulations, and determination of the resonance values of individual components support the developers. First, air flow and simulations of vaporized hydrogen peroxide flow support a flow-optimized machine design. In addition, designers use simulation to optimize the line layout, considering factors such as accessibility. Simulation can also be used for preliminary tests, such as setting the stopper. 

	The CSPE approach minimizes the risks associated with large plant construction projects by conducting a thorough analysis even prior to the design stage. If potential risks based on reliable data gained from comparable earlier projects are identified, they can be proactively countered.

What are some best practices you use for factory acceptance testing (FAT) and site acceptance testing (SAT)? 

The CSPE Center is designed so that the entire system-consisting of isolator and filling and closing machine-is brought together in Schwaebisch Hall and can be fully tested and approved on the supplier site under conditions that are as realistic as possible. In the past, in projects without integrated FAT (iFAT), the separately pre-tested plant parts were not combined until they reach the customer’s site. With iFAT, the system components are optimally coordinated as an overall system, which allows reliable performance of qualification work that is similar to the later SAT of the overall system at its destination. The only deviations that might arise later result from special features of the cleanroom environment on the customer’s premises. The systematic exploitation of digital engineering in combination with iFAT significantly reduces the overall project duration. 

	The entire system is tested before it goes to the customer. This means we carry out smoke studies, leak tests, SCADA [supervisory control and data acquisition] tests, and alarm tests. Also included are interface tests and filling tests under production conditions, sometimes with original or placebo product of the customer. Line safety tests and cycle development also take place. In general, everything can be tested that is later required in installation qualification, operational qualification, and even in performance qualification. By doing this, risks of unexpected delays at the customer site can be reduced to a minimum, and the time to market is reduced as well. 

Optima Packaging explains its approach to process design. 