Bioprocessing Facilities: New Technologies are driving a Deeper Understanding of the Entire Process

Tom Piombino

While most architecture in the world is devoted to creating environments for human occupancy, who is tasked with designing facilities that manufacture drug products to occupy humans?

If you have been immersed in the business and/or science of developing a new drug for the last 20 years and are fortunate enough to be thinking about a manufacturing facility for your new Phase III blockbuster biotherapeutic, trying to navigate the sea of starting point options may be your next big life challenge. Depending on the size of your organization, your experience and perhaps your geographical location, you may or may not have access to the resources needed to kick this effort off. As you embark on finding a firm to guide you through the process and design your facility, you might hear confusing terms like Lab Planners, AE (big A, little e or big E little a), healthcare/institutional architects, EPC, EPCM, EPCMV, Design Assist, Design Build, ……and the list goes on. All these terms may be relevant to your quest at some point, but if you really need to build an FDA compliant bioprocessing facility, there is a term that you may want to focus on first, Process Architect. Not the type that designs IT infrastructure or commercial office complexes or stadiums, but one with the highly specialized skills and experience required to design a facility to make drug products that are safe for one of the most intricate and sensitive communities in the world, the human body.

Billions of dollars are spent each year to research and develop new and improved therapies meant to defend, mend and extend human life. Once your therapy advances to a stage that inspires commercial development and investment, it’s critical that the facility where that therapy will be manufactured be designed to mirror the level of sophistication of its final human host. Therein lies the role of the Process Architect and “their process” to extract, understand and organize the volumes of requirements into a compliant matrix of logical compartments that emulate regulations, unit operations, safety and efficiency. A qualified Process Architect applies the appropriate regulatory requirements, engineering data points and process information available to make sense of your process, architecturally and operationally.

In the recent years, the art of bioprocess facility design and the experience that was needed to understand its many fundamentals was thrown against a wall and smashed into hundreds of small parts. To make the change even more profound, the parts move and more often than not, get replaced by many other parts that must be received, stored, cleaned, serialized and organized to avoid confusion and cross contamination. Flow through the corridors of a highly utilized facility has become a congested super highway of materials that were once hidden in “the process” and are now ushered by human hands to their interim destinations. The process architects for the next generation of manufacturing facilities will need to breathe in these new operating dynamics in order to engineer solutions that integrate hybridized platform bioprocesses and reduce the boundaries of clean travel. They will need to understand more than architecture and the published regulations; they will become experts on the technologies themselves.

At INTERPHEX 2015, the subject matter experts and process architects at IPS will again be organizing technology tours to assist you with where to start your project. They will provide introductions to the many new technologies in bioprocess that are shaping future manufacturing environments for drugs that will occupy humans.

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The Flexible Filling Line: The Crossover Vehicle for Aseptic Manufacturing

Paul Valerio, IPS-Integrated Project Services

People want it all, don’t they?  The type of cars many drive is one indicator.  Crossover vehicles have become a very popular vehicle segment.  They offer: practicality while still maintaining a cool factor; spaciousness with decent fuel efficiency; and car-like handling with the safety of all wheel drive for slippery conditions.  In much the same way, parenteral manufacturers are seeking availability of filling lines to do the equivalent of the routine drive to work, as well as the weekend camping outing on the unpaved road.

Flexibility has become a strong business driver, especially for clinical and small scale operations.  Having the ability to fill vials for liquid or lyophilized products, as well as filling syringes and cartridges all on one line, enables clinical operations to support product pipelines and contract manufacturers to handle whatever small manufacturing requests may come their way.

As we saw during the IPS Interphex tours in 2014, equipment vendors in recent years have made significant progress in developing their designs for flexible filling lines.  It is an exciting time when some of the first lines are being validated.  Increases in orders and inquiries for new lines are proof that flexible configurations will become more of a standard offering and are here to stay.

Flexibility is a good thing but we know that, like the crossover vehicle, a flexible filling line may not offer sports car performance or the ability to plow through a foot of snow with confidence.  Some important points to understand when considering a facility with flexible technology include:

  • Most designs today are using nested, pre-sterilized components in tubs. Vial suppliers have started offering the most common vial sizes but are still catching up with the full size range.
  • It is not feasible to perform 100% check weighing on systems that maintain vials in the nested format, similar to syringes.
  • Designs with most flexibility usually end up bigger and more expensive.

As with any solution, it is important to understand the benefits and challenges of flexible filling technology.  The good news is that several quality vendors offer sound solutions.

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Serialization: Don’t Wait Until the Last Minute

By Kevin Swartz and Tina Gushue, IPS-Integrated Project Services

A reminder to pharma manufacturers, the Drug Supply Chain Security Act (DSCSA) deadlines are quickly approaching. Have you planned for the implementation of Transaction Documents for your packaged products and how to introduce them into your supply chain? Have you developed a strategy for implementing packaging serialized data and infrastructure?

With the coming New Year, the Drug Supply Chain Security Act (DSCSA) requires Transaction Information, Transaction History and a Transaction Statement be forwarded to your distributors with the finished packaged product. Most wholesalers have specific requirements for how to do this. Have you spoken with them? Do the right people in your organization know the requirements?

We’re only a few months out. Documents should be going through your quality departments and vetted out with dry runs to ensure you’re not only compliant, but well versed in the process.

Once you’ve got the Transaction Documents squared away, it’s time to create a strategy to implement serialization into your packaging lines by November 2017. This may seem far away; however don’t underestimate the amount of time required to develop and execute a solid, well-thought plan. There are many steps that need to be taken before these systems can go live.

First, put together an internal team that understands your corporate culture and processes to learn about the requirements for DSCSA compliance. Then, contact and interview serialization solution vendors. These include machine level printing and vision up through line control, plant data management and enterprise systems to communicate with your ERP system. Once you’ve got a solid understanding of vendor requirements for time and cost, put together your budget and capital requests quickly. As you know, the approval phase of these budgets takes time (sometimes significant time) away from your implementation and troubleshooting. Also note that it’s critical to pick the right partner-vendors. Remember thousands of other companies are speaking with those vendors too. As the deadline approaches, your first choice(s) may have lead times that exceed your timeline and costs that exceed your budget.

As you learn more about what is required from a compliance level and from a resource and education level, you may decide that 100% internal resources for the project are not available. We all have other daily responsibilities.

Now that you’ve been reminded, let’s get started!

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Manual Cleaning in an OSD Facility – Will it ever go away??

By Michael Vileikis

Manually executed cleaning techniques and procedures have been utilized to wash small change parts and equipment since the inception of oral solid dosage manufacturing. As processes, procedures and perceptions have matured the apparent risks associated with manual cleaning have become a frequently discussed topic throughout the pharmaceutical industry.

Why haven’t companies completely transitioned to automated parts washing? Capital cost is a consideration that limits some companies from an upgrade to a cabinet style parts washer. Along with the cost of the equipment and the facility modifications, specific washing racks must be designed and maintained for each set of designated components. Another consideration is that cleaning validations must be performed as new products and materials are introduced into the facility. And after your capital investment and your time and effort to complete a cleaning validation, there is still a manual element of loading the washer, which can be considered a risk.

There are many challenges and risks associated with manual cleaning, including but not limited to: Cross Contamination, Consistency, Quality and Material Handling. Consistency, or the ability to demonstrate control of your cleaning procedure, is the largest challenge associated with a manual cleaning operation.

To ensure a repeatable washing operation, all potential operators must be trained to execute the same scrubbing patterns, soap/detergent application, cleaning procedures and drying procedures. They must consistently execute required soaking or rinsing for a designated length of time, and under the same temperature of water. Also, all operators need to be trained and continually monitored to identify “visually clean” surfaces accurately.

In addition to the inherent variability in human performance, the risk of cross-contamination during manual cleaning is highly dependent on the suitability and effectiveness of the room design and material handling methods employed. Operators must physically segregate soiled components from areas in the room used for cleaning and drying to ensure that clean, dry materials will not be contaminated by dirty equipment. Manual cleaning operations in multiproduct facilities should be performed in segregated washing paths to prevent mix-up and product-to-product carry over.

A trend is emerging in the industry showing movement towards semi-automated cleaning methods. This is mainly driven by the demands of cleaning potent compounds. The total elimination of manual cleaning is not anticipated in the near future. If implemented correctly, manual cleaning can be effective and repeatable. To provide their operators with the best chance to succeed, organizations must develop sound procedures, define cleaning goals, train personnel, optimize wash room design and select proper material handling methods.

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Rapid Microbiology Methods (RMM), an alternative for traditional microbiology?

By Vilma Bonilla, MMC, President-BPTS Learning Center

Much has been published about the limitations of traditional microbiological culture-plate methods and the need of rapid methods to solve these limitations.

Traditional methods tend to be labor-intensive and take several days to obtain results. As per FDA, Rapid Methods are methods designed to provide performance equivalent to the traditional testing methods while providing results in significantly less time. Manufacturers should show that an alternative method will provide assurances of the safety, purity, potency and effectiveness of the product equal to or greater than the assurances provided by the method specified in 21 CFR Parts.

RMM include identification, qualitative and quantitative methods. Identification methods provide the name or species of the microorganism in a sample. Qualitative methods provide a presence or absence result in a sample. Quantitative methods provide a numerical result (number of microbes present in the sample.) Common technologies used in RMM include nucleic-acid-based detection, which uses DNA or RNA targets; antibody-based detection; biochemical and enzymatic detection methods, among others. Some of the benefits of RMM are shorter production cycles and shorter release time of finished products to market; also, reduction of inventory requirements, among others.

Comparison of both methods:

TRADITIONAL METHODS RAPID MICROBIOLOGY METHODS (PAT-PROCESS ANALYTICAL TECHNOLOGY)
Microorganisms growth in media.

Cultures are visually check for microorganisms.

Microbes can only been seen when growth reaches a high number of colony-forming unit.

Use markers that can be detected by an instrument.

Many instruments detect those markers even at a low number of colony-forming units which reduces time for detection

It is slow, labor-intensive, and subjective It is easier to use and provide a much faster time to result. Are sensitive and objective in detecting bacteria and fungi compared with the traditional methods

BPTS Learning Center will be providing one-hour conference and demonstration on “Advanced Methods for Detection and Identification of Microorganisms in Controlled Environments?

Traditional and RMM methods will be compared using Genotypic Identification Method-Micro SEQ Microbial Identification System for detection and identification of a fungi. It will be held Th (4:30pm-5:30pm); Fr (3:30pm-4:30pm) @ Booth 1231. Spaces are limited.

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Part Four – Container Integrity Testing – Capping, Residual Seal Force & Laser Diffraction| Whitehouse Laboratories

PartFour_Thumbnail(1)Part Four – Container Integrity Testing – Capping, Residual Seal Force & Laser Diffraction | Whitehouse Laboratories

Author: Brian Mulhall – Managing Partner, Director of Container Testing

In part four of this series on CCIT, two commonly used methods – Residual Seal Force and Laser Diffraction – will be reviewed.

Parenteral Vial Capping and Residual Seal Force Testing

Residual seal force testing of parenteral vials is often performed in conjunction with helium leak testing or vacuum decay testing. Residual seal force is not a leak test, but is an indirect measure of the compressive force exerted by the stopper on the vial’s land surface. A slow, constant rate of strain is applied to the top of a capped vial and the resistance to compression is monitored and reported. The appropriate amount of compressive force is required to ensure a quality seal. Vials capped at an insufficient force may leak from the sealing surface. On the other hand, vials capped at an excessive force may experience cracking and bulging, also risking the integrity of the closure system. When used in conjunction with leak test methods such as helium mass spectrometry or vacuum decay, an optimal range of residual seal force values may be determined that correlate to a reduced risk of leakage resulting from improper capping force.

This type of testing is of value to clients aiming to establish optimal sealing parameters or those who wish to implement a sampling procedure during product production.

Laser-Based Headspace Analysis

Gas headspace analysis via laser-based analysis techniques provides a quantitative, nondestructive measure of oxygen content, nitrogen content, water vapor content, or low internal pressure in a nonporous, rigid or non-rigid package headspace.

A near-infrared diode laser light is passed through the gas headspace region of the sealed package. Light absorption, measured using frequency-modulated spectroscopy, is indicative of gas concentration and pressure. Gas headspace analysis, as a function of time, provides a quantitative measure of the total leakage rate of the test sample.

This technology is especially applicable when verifying the integrity of packages that must maintain a specific gas headspace content such as low oxygen, low water vapor, and/or low pressure. For testing, packages only need be either transparent or semi-transparent material, either amber or colorless; test samples require a minimum headspace volume and headspace path length. Vials, syringes, cartridges and bottles are all amenable to this approach.

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Part Three – Container Integrity Testing – Helium & Mass Extraction| Whitehouse Laboratories

PartThree_Thumbnail(1)Part Three – Container Integrity Testing – Helium & Mass Extraction | Whitehouse Laboratories

Author: Brian Mulhall – Managing Partner, Director of Container Testing

In part three of this series on CCIT, two commonly used methods – Helium and Mass Extraction – will be reviewed.

Helium Mass Spectrometry

Helium mass spectrometry, based upon ASTM F 2391-05 “Standard Test Method for Measuring Package and Seal Integrity Using Helium as the Tracer Gas” is applicable to non-porous packaging such as vials, syringes, and cartridges. Even flexible packages can be tested by helium mass spectrometry using appropriate test fixture.

Helium-filled samples are placed in a test chamber, where a vacuum is created by the instrument’s internal pumps. Leaking samples allow helium to escape, enter the test system, and be detected by an analyzer cell. The stream of helium ions hitting the analyzer cell target is proportional to the partial pressure inside a sample. From this, a specific leak rate can be calculated and reported to the user. Results can be reported quantitatively (as a leak rate), or qualitatively (Pass or Fail) if method development is performed.

This type of testing may be of interest to clients looking to accurately assess the performance of an established package or analyze the effect of processing variables, such as capping force, closure materials, etc., on the performance of a package system.

Mass Extraction

Mass extraction leak detection operates by drawing vacuum on a sample enclosed in a chamber. Once vacuum is established, the instrument monitors the amount of airflow required to sustain a specific vacuum level. The amount of flow required to keep the vacuum steady is equal to the amount of flow escaping from leaks in sample under testing. Specific test parameters must be set after adequate method development. Results are reported quantitatively, as flow rates, as well as qualitatively (Pass or Fail) according to acceptance criteria established in method development.

Mass extraction testing is applicable to any package containing headspace, including parenteral vial packages, screw-capped bottles, and flexible bags or pouches. In some cases, liquid-packages can also be leak tested by this approach if the product formulation poses no threat of clogging leak paths.

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