Ask the Expert

Ask the Expert:  I am building out a WFI system where I will need approximately 6 ambient use points.  Three of which will need to pull 2000-3000 liters for media/buffer production.  What would be your suggestion as to handle this?

 By: Brian White
Director, Process Engineering
IPS- Integrated Project Services, LLC

As a general rule, Bioprocess facilities have much greater need for Ambient WFI (AWFI) than for Hot (HWFI).  Consequently, these facilities have some of the greatest justifications for considering some sort of ambient WFI system.

From a capital cost standpoint each POU cooler is going to add roughly $50K to the cost of your capital project.  On a current project we are adding a couple of $35,000 package coolers to deliver 3.5-gpm of ambient WFI for formulation and cleaning applications.  The heat exchanger may only be 30% of that cost, but the valves, instrumentation and controls add up quickly.  Include the cost of installation and utility piping to and from use-points in the plant and you can quickly get to $50K before you’ve added the soft cost to qualify them.  Simply putting in sub-loops to reduce the number of exchangers can produce significant capital cost savings and potentially reduce system complexity.

Operations costs for those exchangers will also be significant if you are cooling hot WFI on demand for every application.  The table below looks at the high level energy cost associated with cooling a 1000-liter batch of WFI from 80°C to 25°C for a generic application (media, buffer, etc.).  If you increase the flow, the instantaneous demand goes up dramatically and you quickly find yourself adding capital for additional cooling capacity to support these users.

Batch Volume 264 gallons 1000 Liters
Flow 3.5 gpm 13 lpm
Time 75 minutes 75 minutes
Temperature In 176 Tin °F 80 Tin °C
Temperature Out 77 Tout °F 25 Tout °C
Heat Load Instantaneous 0.24 Ton chilled
Heat Load Batch 0.30 Ton chilled

From a capital cost stand point one can quickly justify an ambient loop, employing a chase-the-tail configuration.  The utility loads will still be roughly the same, but system complexity and corresponding system cost will be reduced.  Alternately, you could consider an ambient storage and distribution loop.

Several years ago I was involved in a project for a bioprocess facility that installed and qualified an ambient WFI system with 2,500-gallon reservoir and 100-gpm distribution loop.  The system would operate all week tempered to 25°C.  Then on the weekend, the system would heat up to 80°C for sanitization, and then be cooled back down before return to service.  Heat-up took less than an hour, but cooldown could take up to 6-hours.  The biggest advantage to this approach is the sanitization loads all hit the plant utilities during off-peak time.  Capital costs were reduced, not only by not having to install point-of-use coolers throughout the plant, but also by eliminating chiller tonnage and boiler horsepower to support the heating and cooling loads associated with maintaining a hot loop.

We’ve had other clients employ Ozone sanitization for WFI storage and distribution, and thereby, maintaining a persistent sanitization of the contents of the storage reservoir and enjoying the significant energy savings of an ambient loop.

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New Semi-Automatic Case Packers Fill a Void

By: Kevin Swartz
SME Packaging, Sr. Process Engineer
IPS- Integrated Project Services, LLC

How do you case pack when your pharma packaging line has a rate above 150 cartons per minute but less than 1 case per minute? A few years ago, you’d put a few operators after the cartoner and manually erect, load, tape and palletize the cases. The cost of a fully automatic case packer couldn’t be justified and if your lot sizes were small, the changeover time of a semi-automatic system wasn’t worth the effort.

Then came serialization! Or actually, aggregation. Now you need to know which carton went into which case. A camera system needs to read all carton layers in the case to verify and aggregate the contents. Now, more people aren’t enough. You need multiple cameras because multiple cases would be loaded at the same time to keep up with the line. Those cameras and aggregation kiosks start getting expensive. So now, you look to the fully automatic case packer. It does the job: erects, loads, aggregates and closes the case automatically. But it doesn’t come close to fitting on your existing line.

The semi-automatic systems of old aren’t much better. They’re not as large, but the loading is usually still manual and hence can’t keep up because of the cycle time of camera verification. The operator can’t get into a rhythm and any scanning hiccup requires the case to be put aside to be dealt with later or by other operators.

But recently, more hybrid semi-automatic case packers have come on the market. These machines require the operator to fold a case and place it into the machine. The cartons arrive from upstream and are serialized, stacked, loaded layer-by-layer, and aggregated. The operator then gives the case a little push through the tape machine and manually places the aggregated case label onto the case before manually stacking it onto the pallet.

These are a lower cost than multiple manual aggregation kiosks and require few operators (usually only 1). And the best part about them for everyone with an existing line is… they are small! Not kiosk small, but certainly half the size of an automated case packer and probably about the same size as your packing table from a few years ago.

This is a great solution that fills a void. Major manufacturers along with small, privately owned OEMs have nice selections of these semi-automatic case packers with various features and configurations depending on your needs. You no longer have to throw people and money at this problem in order to only get a mediocre solution to mid-speed lines.

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Corima RTU Containers Filling & Stoppering FSP 05

Machine model FSP 05 has been developed to meet the increasing production requirements of products classified as pre-filled syringes. This filling and stoppering machine for syringes in nest is a modular machine, as well as compact and flexible, able to work to required productive speed, up to 12.000 pieces/h. The machine offers also great precision with dosing operations, and a full protection of syringes, essential when sterile products are involved.
FSP05
The machine is modular so that it can be equipped with 2 to 5 filling/stoppering stations, making it suitable both for low and high speed. These features can be modified also with further transformations.

The machine is easily integrated in various possible layouts and material flows thanks to the special design of the work areas. Special attention has been paid to designing the moving components, preferring the use of rotary drive shafts or linear drive shafts with open wheel, which are indispensable techniques to ensure machine cleanliness and to integrate RABS or isolators.

Excellent machine ergonomics and arrangement of the controls for easy integration of the material dispensing, infeed or handling systems, in total compliance with the strictest of directives concerning the assembly of parts in direct and/or indirect contact with the product.

FSP 05 guarantees maximum protection of the syringes, which must not be damaged in any way during filling. In fact, the FSP 05 machine avails of exclusive systems during syringe handling, filling and stoppering phases, which optimise centring, thus safeguarding the syringe tubes against the risk of breakage or damage.

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Powder Transfer for Biotech

By: Lonna Gordon
Process Engineering
IPS- Integrated Project Services, LLC

Solids transfer is typically considered a problem reserved for the oral-solid dosage (OSD) community, where the powder is the main product bulk; however, it comes up with reasonable frequency in the biotechnology world as well. Applications range from adding salts to a sterile media tank, dry media preparation, pH adjustment after filtration processes, as well as addition of precipitation salts to a tank. This article will survey the basics of closed powder transfer for the biotech professional.

The primary assumption we will make is that the powder or salt is pre-weighed and measured into a powder transfer container. If the solids must be metered into the process, this level of complexity is beyond the scope of this piece.  The second assumption is that closed-transfer is desired for protection of the product. Our third assumption is that powder quantities are too large to use a single-use bag and manual lifting as the transfer method. Larger quantities will be moved through the facility in drums or Intermediate Bulk Carrier, and demand more specialized equipment for successful transfer into the processing vessel.

In order to ensure that the transfer is fully enclosed, the primary connection between the powder-supply container and the receiving process vessel will be through an SIP capable split-butterfly valve (SBV). Most commonly used for powder transfer applications in OSD facilities, this specialized valve allows two separate vessels to create a clean, closed transfer connection. However, there are only a few SBVs that can be equipped with a sprayball. This a detail to consider when selecting a valve.

There are two ways to transfer the powder from the container to the vessel: gravity feed and vacuum transfer. Gravity feed involves positioning the entire container above the vessel, opening the connection between them, and allowing the solids to pour down into the vessel. With vacuum transfer, the drums or IBC can be located at any level relative to the tank. The powder is moved via negative pressure to a receiver mounted on the vessel, where it is then dropped into the vessel through the connecting valve.

Both options allow for the powder container to be located either in the processing suite with the vessel or in a separate room.

Gravity Feed – In-Room Transfer

A hoist is used to lift the drum or IBC above the tank and slew or invert it into position. It mates with the SBV. The hoist can be permanently fixed in the room, or it can be a mobile unit that carries the drum into the room and is stored elsewhere at all other times.  The elevation available in the room is the limiting factor when using this method.

Gravity Feed – Second-Floor or Mezzanine Transfer:

The drum or IBC can also be lifted to a second floor or mezzanine using an elevator and docked to a transfer chute that connects to the vessel below. If a completely separate second-story space is used for docking, it can be a lower classification than the vessel’s processing suite. This is due to the connection to the chute will be totally enclosed, and there will be no contact between the contents of the IBC and the surrounding environment. There are some cleaning considerations for the chute; it will require a sprayball cap to wash it in place before removal for cleaning. Additionally, there must be space available for utilization on multiple floors.

Vacuum Transfer:

Vacuum transfer can occur from almost any space adjacent to the receiving vessel – the same room, the next room, the floor above, or the floor below. For IBCs, an adapter on the outlet of the IBC allows the powder to be pulled through a transfer hose to a receiver at the top of the tank. The transfer is completely enclosed and therefore, the IBC can be stationed in a room of any classification.

Drums, on the other hand, typically require an operator to manipulate a wand in the drum to ensure full powder transfer. This process is not completely enclosed and should take place in a space with a classification that matches that of the receiving vessel. There may be some fully closed, more customized options available for drums as well.

IPS image

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2018’s Leading Industry Challenges: Tomorrow’s Biggest Opportunities?

By Meg Snyder, Attendee Acquisition Manager – INTERPHEX, Reed Exhibitions

Whether you work in pharma, biopharma, biotech, or any other sector of the industry, one trend is clear—change. The industry continues to learn and grow, pursuing better, improved, and more sustainable solutions.

Consolidation Reigns Supreme

In 2018, consolidation continues to maintain prominence in the outsourcing space, according to Mark Quick, Executive Vice President – Corporate Development, Recipharm. “The largest CDMOs hold just 2-4 percent of the market and the top ten CMOs represent less than 30 percent,” he added. “With many consolidation opportunities still available, buying expertise remains an attractive prospect for a CDMO with sufficient financial resources.”

Although consolidation as a trend isn’t new to the industry, it’s seeing continued growth as companies are “realizing the time, cost, and efficiency benefits of reducing the number of outsourcing partners they engage with and accessing a full-service offering,” Quick explained.

“Weak players will slowly leave the market, creating supply issues for their customers who will need to find a reliable CDMO partner to ensure continuous business,” Quick continued. “We also expect demand for contract manufacturing to increase as drugs become more complex and pharma businesses look to reduce their in-house costs and resources.”

As a CDMO with a global presence, Recipharm has also experienced the rippling waves of serialization initiatives on multiple shores.

“Clearly, serialization is also a major industry development that is set to shape the sector over the coming months,” Quick said. “Contract manufacturers are facing the introduction of the European Falsified Medicines Directive (FMD) in February 2019 and are at different stages of their preparations. Those that fail to prepare risk loss of business, as they will no longer be able to supply products to this important market. We anticipate that pharmaceutical companies will increasingly make their outsourcing decisions based on whether their CMO has the necessary capabilities to comply with the FMD.”

According to Quick, Recipharm expects that more than 80 percent of the company’s production will require serialization. As a result, they are implementing new systems and processes across around 75 production lines. However, with the CDMO’s proactive approach to implementing a solution, including a dedicated taskforce and a serialization program in place, they are well on their way to being in compliance on a global scale.

Meanwhile, the next deadline for the Drug Supply Chain Security Act (DSCSA) in the US is November 27, 2018, where repackagers must have serialized product. In addition, due to the FDA’s extended deadline, manufacturers will also have to have serialized product by November of this year.

Rise in Manufacturing Demands

In addition to consolidation, the demand for the manufacture of highly-potent active pharmaceutical ingredients (HPAPIs) has seen an influx, said Chris Rombach, President, ChargePoint Technology Inc., which has been fueled by the growth of the biotech and oncology markets.

“As these markets flourish, huge implications have been felt throughout the supply chain, particularly by manufacturers,” Rombach continued. “In addition, we continue to see the diversification of the companies we serve.  Companies are increasingly operating on a global scale and are wanting to coordinate across different sites.”

With so many companies operating across multiple sites and outsourcing services, standardizing and organizing internal processes has become even more important.

“[T]here is a rise in ‘virtual’ companies that rely on outsourcing, collaborations, and contract manufacturing for their production,” said Rombach. “The result of this is there are increasing numbers of stakeholders and decision-makers involved in the projects and therefore being able to bring everything together is more complex today than in the past.”

Although the boom in biotech has been an ongoing industry trend, the containment sector is “expected to continue this rapid growth alongside it,” Rombach said, adding that 2018 appears to be a turning point.

“Finding the best containment strategy has always been important for high potency manufacturers, with operator safety and product quality at the forefront of their priorities,” said Rombach. “However, the growing need for advanced control strategies to improve efficiencies and handle ever-more complex products has led to the adoption of more innovative solutions.”

Increasing Output

According to Parrish Galliher, Chief Technology Officer – Upstream, Bioprocess, GE Healthcare Life Sciences, there have been a number of continued trends in 2018:

  1. Single-use, upstream continuous perfusion systems and continuous DSP
  2. High speed, at-line, on-the-floor QC assays for real-time release
  3. Commercial licensure of additional SU facilities (now at four worldwide)
  4. High productivity/output biomanufacturing

“[N]othing happens rapidly in this industry. It gets tested in the lab first and then takes years to be used in clinical manufacturing and eventually validated for commercial manufacturing,” Galliher said. “The exception is upstream continuous perfusion—this is an old technique used by 19 commercial biologics on the market.”

There have, however, been new trends developing over the past three years, Galliher added. There has been a rapid growth of SU manufacturing in non-US and non-EU territories. In addition, optimizing brioprocess, process understanding, and digital information support has also taken a turn due to digital technology and IoT (the Internet of Things).

Biologics & Biosimilars See a Global Boom

HighTech Business Decisions – Biopharmaceutical Contract Manufacturing states that “the biologics market is expected to grow by 7-9 percent by 2022 and is projected to reach $3.8bn,” Quick said.

Biosimilars entered the US market for the first time in 2015 with US FDA’s approval of Sandoz’s Zarxio (the biosimilar to Amgen’s Neupogen [filgrastim]).

In 2015, the US FDA approved one biosimilar. That number increased to three in 2016 and then to five approved biosimilars in 2017.

More biosimilars have been approved each year in not just the US, but around the world, Galliher added.

“The technically-challenging nature of biologic drug development and manufacturing will certainly help to fuel the outsourcing sector,” said Quick. “Demand for outsourced services is growing in areas, including lyophilization and sterile liquid fill and finish operations, as each requires significant investments and expertise.”

Addressing Industry Challenges

“Rising prices across the globe will always add an element of pressure to our industry,” said Rombach.

But price tags on treatments aren’t the only challenge facing the industry today.

According to Galliher, “hiring enough talent to keep up with growth rates” continues to be a challenge for the industry as a whole, along with “developing technology and expertise to support the development and manufacturing of new drug modalities” and “expanding and enhancing our supply chain to enable digital and IoT capabilities for biopharma.”

For 39 years, INTERPHEX has been the premier pharmaceutical, biotechnology, and medical device development and manufacturing event, taking place in New York and bringing more than 10,500 global industry professionals and 650+ suppliers from across the industry.

By bringing together thousands of industry professionals, assisting in the facilitation of the launches of new technologies, products, and services at the show, and providing opportunities for industry experts to share knowledge, INTERPHEX has assisted the industry in tackling these challenges head-on for nearly four decades.

“As always, we are very much looking forward to meeting with our industry peers to talk about the current industry trends and focus,” said Rombach. “The Technical Conference sessions are always a highlight for us and we are looking forward to seeing advancements being made across the industry.”

Register today and join thousands of industry professionals at the Javits Center in New York City on April 17-19, 2018!

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Manufacturing Facilities: Delivering the Right Tool

By: Erich Bozenhardt
Process Manager
IPS-Integrated Project Services, LLC

Every project manager can tell you that there are only three project drivers: schedule, cost, and quality. We see these factors in every day in tasks we do, and in everything we purchase. The operating companies are also under the same pressure on the delivery of their products: get treatments to patients faster, lower the cost, and answering the question: why can’t our medicine be defect or side effect free.  As an industry, we are answering with a deeper understanding of the science of medicine and better tools to deliver medicine. A manufacturing facility, its technology, compliance, flexibility, and the capabilities are the enabling tools for production.

We need to design before we build

In every application of pharmaceutical technology a design of what we are to build is necessary to provide specifications of construction, construction methodology a fidelity of design and technology (i.e. fit for use), compliance to FDA and EU regulations, and a basis for commissioning and validation.

Our industry uses the following methods and delivery tools:

  • Conceptual Design – This 1 percent of the total facility cost is the key to all designs. This provides the agreement of how we translate the technology into a constructed entity. This level of design provides the process, architectural, HVAC, utility, and facility bases. Typically, depending on the technology, greater depth is provided in the unique technology area.
  • Preliminary Engineering – This engineering stage takes the conceptual design and creates functional documents for each aspect. This stage of engineering can be attenuated if the process technology can be configured from vendor equipment and if the facility can be built with a “building block” concept.
  • Detailed Design – This design stage provides detailed drawings and construction instructions. This level is required on each design discipline if and only if it is being built from scratch.

Clearly, “buy” not “build” can accelerate the design phase

Building Trade-Offs?

  • Schedule

-Minor renovations might be quicker with gypsum board, but particles and an affinity for mold put that construction material at risk and reduces quality.

-Modular wall systems are quick within an existing space and don’t lose speed with scale, walkable ceilings allow more parallel construction activities, and eliminate the need for detailed design.

-Modular pre-built clean rooms and support systems are the quickest for large scopes

  • Cost

While in some lower cost labor markets the use of gypsum board and on-site assembled AHUs may appear to be lower in costs, the adjustments, designs and commissioning exercises add to the costs. Secondly, the labor markets within the biotech business have been increasing and the labor advantage over modular has nearly disappeared.

  • Quality

-modular panels provided a robust easily cleaned solution and a long-term quality finish

– Pre-configured and pretested AHUs in modular systems provide a unique opportunity for precision and reduce installation/balancing/commissioning time.

How to Build?

Design/Bid/Build is the traditional method of building in the US. A firm is contracted to produce a design then the design is bid and a different firm is selected to build. This method is believed to yield the lowest price and philosophy of enforcing checks and balances.

The more modern Design/Build finds synergy of firms that offer design and construction management to reduce cost and schedule. From a contracting standpoint, it provides simplicity and clarity to owners as there is one responsible party for the whole project.

Design/Assist is a method where the designing firm lays the groundwork and then engages the contractors who will be executing the work to provide assistance in completing the design. This method allows the contractors to provide input into the design to facilitate installation and prevent iterations on construction documents yielding a lower cost and quicker schedule. The general consensus is by having a constructability focus to the design the project can be done for less time and money without comprising quality.

So Where Does This Leave Us With Finding The Right Balance?

For small-scale renovations, it makes sense to match existing materials but caution is required for the HVAC system and its extension. Many of these smaller projects can benefit from a Design/Build approach.

For larger scopes of renovation, modular panels allow for reasonable construction schedules and the flexibility to work with spaces of existing complex geometry. For new projects and major renovations that work within a large shell space, modular clean rooms and modular systems can provide both schedule and cost reduction due to the total reduction of labor time in the field (balanced via off-site fabrication).

Some vendors have taken modularization to the next level with pre-engineered solutions that incorporate process equipment based on common process platforms to further reduce cost and schedule.

There is a place in the industry for various delivery methods and the key is matching the method to your project.

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Leapfrog – an Opportunity for Sterile Product Manufacturers with Aging Facilities to Reduce Risk and Become More Profitable

By: Paul Valerio
Director of Technology
IPS-Integrated Project Services, LLC

Aging facilities in pharmaceutical manufacturing are a topic of much concerned discussion in the industry and in world healthcare circles, especially where sterile products are produced. Facility conditions and obsolete technologies pose risks to product quality and, therefore, supply of medicines to patients. Facility finishes, aging water systems, manual cleaning methods, and presence of gowned personnel in the aseptic environment performing open process manipulations all contribute to process risks.

Deteriorating and dated systems are not the only factors working against aging facilities. The world outside those old walls is changing and moving forward. New knowledge and advances in process technology and facility design have improved greatly in the industry compared to the basis against which older facilities were designed. These advances then raise the bar for regulators’ expectation of quality. They observe older construction methods being replaced with sealed modular wall systems that are more cleanable and less susceptible to environmental risks such as mold. Automation of processes is taking over manual steps in areas such as cleaning of vessels and parts, bio-decontamination of equipment, and automated loading of freeze dryers. Operations with fully gowned personnel performing aseptic manipulations adjacent to open sterile product in traditional Grade A clean rooms are replaced with those utilizing barrier systems. Isolator systems, in particular, are becoming simpler and more compact. Regulators expecting these advances in newer facilities organically raises the pressure on manufacturers operating aging facilities to replace or upgrade.

The improvements mentioned above for facility and process design represent advances in protecting sterile products, and they are good for business from a compliance standpoint. Advances in process technology also present opportunities for better profitability due to increased capability. New systems offer higher throughput and product yield through features like 100% in-process checking (IPC) and advanced dosing to utilize every drop of bulk product. Market trends toward specialized products have inspired creation of a new range of technologies capable of providing flexibility to fill numerous components in one suite, including vials, syringes and cartridges.

A compliant facility design coupled with advanced process technology creates capability to run efficiently with fewer process risks and deviations. That’s good business.

So, what does all this serious stuff have to do with Leapfrog? One form of “leapfrogging” in business is to profoundly advance in capability by taking advantage of progress already made by others. In recent years, impressive progress has been made in robust fill-finish process technologies in terms of performance and compactness. The ratio of opportunity to risk is more favorable than ever for manufacturers looking to progress their aging sterile product facility. Robust systems are available to enable just about any product portfolio, offering new business opportunities and multiple paths to return on investment.

Opportunity awaits, yet it is not so simple to seize it. Many organizations are so focused on making their older facilities function well that there is little time to keep up with current technology. Once organizations decide to pursue upgrade or replacement of aging sterile product facilities, simply transferring old processes to new equipment might provide just a fraction of the potential gain. Perhaps the greatest challenge in looking outside those old walls is grasping what new technologies are available and how to apply them. Creating the most successful future possible involves product portfolio strategy and research in several areas, one of them being currently available and emerging process technologies. Internal research and leveraging support from qualified process solution providers and design firms will help lead to a much needed leap ahead.

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