Real-Time Release Testing for Dissolution Has Arrived

Lonna Gordon
Senior Engineer
IPS-Integrated Project Services, LLC

In October of 2011 in a presentation on real-time release testing (RTRT)[1], the FDA gave an example of how a multivariate model could create a surrogate for dissolution testing of tablets.  This example has been repeated in nearly all FDA presentations on RTRT and continuous manufacturing for OSD since.

As the pharmaceutical industry seeks to improve efficiency and decrease work-in-progress (WIP), RTRT is an important way to do so. Currently, tablets must undergo a rigorous series of end-product tests when they come off the press to prove that they have the correct ingredients in the correct ratios and will perform as expected in the patient. Eliminating these tests would mean tablets could go directly from the coater to the packaging line without delay. This would reduce WIP, storage, and production time.

There are a number of end-product tests that could be eliminated by on-line process analytical technology (PAT) measurements. The fact that the FDA chose to emphasize dissolution testing is an interesting one.

Dissolution testing is not an industry favorite. It takes a long time, it doesn’t always correlate to in-vivo dissolution[2], and some testing apparatus have been accused of unreliable and inconsistent results[3]. If there’s a list of tests that QC labs would like to replace, dissolution would be near the top.

Dissolution describes how long it takes a tablet to dissolve in an in-vitro bath, as a way of predicting its in-vivo release profile. The dissolution test is heavily dependent on hydrodynamics, and performance varies between testing apparatus. A testing method and parameters must therefore be selected first and then a product profile created. API properties such as pKa, stability, solubility as a function of pH, particle size, and polymorphism are evaluated as part of the profile development.

Although the FDA has been pushing modeling for dissolution for close to a decade, reality has lagged. In order to access RTRT for dissolution, the most important properties need to be linked to process or product characteristics that can be measured on-line, in-line, or at-line using available PAT. There are many variables that could contribute to the rate of dissolution, some easier to measure than others. The sheer complexity of study required has dragged out the timeline for meaningful results. Meanwhile, leaders in continuous manufacturing have busied themselves with the many far more fascinating (and less frustrating) challenges inherent in breaking ground in a new field.

This is why it was big news when Doug Hausner, Associate Director of the Rutgers Center for Structured Organic Particulate Systems (C-SOPS), announced in 2017 that they had developed a dissolution model for Janssen’s Prezista, being produced by continuous OSD manufacturing in Gurabo, Puerto Rico. The post-approval change request was filed with the FDA to great anticipation. It was approved a few months ago, making Prezista the first product that can be released without end-product testing for ID, assay, and dissolution. This was one small step for Prezista, one giant proof-of-concept for the industry.

Around the same time, the FDA released a draft guidance entitled “Quality Considerations for Continuous Manufacturing,[4]” a non-binding compilation of the FDA’s thoughts on quality control for continuous OSD. Once again, “a multivariate model to predict dissolution” was cited as a real-time release benefit of a robust PAT model.

But this time, it was less a statement of potential, and more a statement of reality.

 

[1] “Regulatory Perspective on Real Time Release Testing,” Moore, Christine M. V. 27 Oct 2011.

[2] “Moving Toward Real Time Release Testing,” Shanely, Agnes. Pharmaceutical Technology. 02 July 2017

[3] “Hydrodynamics-Induced Variability in the USP Apparatus II Dissolution Test,” Baxter JL, Kukura J, Muzzio FJ. International Journal of Pharmaceutics. 23 March 2005.

[4] “Quality Considerations for Continuous Manufacturing: Guidance for Industry,” February 2019.

Pharma 4.0 – Part 2, the Double-Edged Data Sword

By:  John Niziolek
Associate Director, CSV
IPS-Integrated Project Services, LLC

This post is the second of a three part series exploring Pharma 4.0, its beneficial impact to organizations, and the additional steps necessary to maintain compliance with the new technologies.

One of the key benefits of implementing Pharma 4.0 technologies into your manufacturing process is the abundant volumes of data that can be potentially produced. With this newly created data about your process, you may have the ability to predict mechanical breakdown, more closely monitor product quality, and potentially have insight into areas where optimization can occur.

As you may have guessed from the title of this post, there are also several potential items to note regarding additional responsibilities and precautions you should take with your newly generated manufacturing data.

1. Completeness and accuracy of data – The data generated should be concise and self-explanatory. You should determine if the new data objects generated can be understood independently of other related data.
2. Increased overhead cost – While the cost of data storage has decreased dramatically over the last five years, one should consider the impact to budget as well as staff resources required to implement and maintain additional storage capacity.
3. Security – For the most part, as long as one follows their current organizational IT security best practices, there should be little to no concern attributed to the increase in the volume of data. Take precaution when leveraging IIoT (Industrial Internet of Things) technologies. There have been several high profile malicious attacks on organizations implementing IIoT systems and technologies; it would be wise to educate and empower your support organization.

In summary one should embrace the opportunities provided by your newly generated process data, when wielded properly it can empower your organization, provide insight into new aspects of your business, and even decrease your overall spend.

In our final post we will summarize the impact Pharma 4.0 technologies will have on the future of manufacturing and how it will change the way we work.

Lab 4.0 for CROs – Operations and Supply Chain Management Perspective

By: Komal Hatti, NCARB, LEED AP
SME R&D, Sr. Process Architect
IPS-Integrated Project Services, LLC

The advancements in data analytics and ever-increasing competitive forces are driving more laboratories than ever before to adopt lean and Industry 4.0 principles. Once considered luxury items, they are quickly becoming a necessity for the process-driven labs owned by Clinical Research Organizations (CROs). CRO labs align with a more traditional manufacturing operation in their need for highly efficient operation and cost-competitive environment; they are at a point where the benefits of Lab 4.0 cannot be ignored.

As we enter the fourth phase of the Industrial Revolution, CRO labs will undoubtedly be the early adopters of smart lab technology solutions that integrate all instruments, samples, reagents, consumables and researchers under a single server and technology platform. In order to create an effective 4.0 platform, labs need to create a framework by which the lab operations teams can effectively evaluate resource utilization, and customize the lab management server to eliminate waste to the greatest extent possible.

This framework for analysis, synthesis, and design must be developed using operations and supply chain management (OSCM) principles. To ensure success, we need to follow these guiding principles:

• Data-driven view of the firm’s business;
• A strategy that is consistent with the operations-related priorities of the firm; and
• A comprehensive and long-term approach to 4.0 implementation.

Tactical and operational steps in implementing Lab 4.0 follow lean principles, utilize Internet of Things, and use modern data analytics to develop an optimal performance model that maximizes profitability by minimizing waste. CROs must be patient as this process is complex and tedious. A hasty implementation without an underpinning of the OSCM principles will lead to disappointment and capital loss.

“Top Ten” CGMP Compliance Implications for Cell Therapy / ATMPs

As new medicines and treatments continue to evolve, so do the challenges with their production. Cell therapy facilities present many unique challenges from the intricacies of patient-specific autologous therapies to numerous high-risk manual aseptic manipulations during the processing.

The “Top Ten List” of compliance concerns for cell therapy facilities are:

#10     Application of the FDA’s Aseptic Processing Guideline and EU Annex 1 requirements, that were primarily developed for large-scale fill/finish facilities to cell therapy facilities

#9       Facility airlock requirements and compliance driven flows: unidirectional vs. bidirectional

#8       Containment and segregation of viral vector areas and suites

#7       Transitioning and transforming from laboratory & development to commercial; Scaling-up not just scaling-out

#6       Quality Management System (QMS) development for start-ups and QMS adaptation to cell therapy operations for Big Pharma

#5       Labeling, batch records, and traceability from patient back to patient

#4       Large volumes of material transfers from unclassified → CNC → Grade D → Grade C (ISO 8) → Grade B (ISO 7) → Grade A (ISO 5) without introducing contamination

#3       Concurrent processing of multiple batches in the same room; multiple biosafety cabinets, multiple autologous batches in same incubator, etc.

#2       Equipment design (incubators, centrifuges, etc.) not conducive for Grade B and the ability to clean and sanitize

#1       Numerous open and manual aseptic manipulations

 

With the multitude of compliance and process challenges, cell therapy facilities of the future must resolve several underlying issues and drive progress in the following areas:

• Separate people from product:
  • Develop processes with limited manual manipulations
  • Design for less handling of materials and product
  • Utilize isolation technology as adapted to cell therapy processes
  • Implement greater use of available automation
• Close the process to the greatest extent possible and utilize the latest available technologies
• Scale-up to commercial manufacturing vs. duplicating laboratory scale in greater quantities
• Design robust facilities that can be easily cleaned, sanitized and operated in a state of control
• Challenge vendors to develop “built-for-purpose” CGMP equipment and automation / software
• Establish a robust Electronic Batch Record (EBR) system, bar coding, and/or labeling system to prevent possibilities of mix-up

 

 

Pharma 4.0 – Will you embrace it?

By:  John Lyons
Senior Process Engineer
IPS-Integrated Project Services, LLC

I’ve been wondering what to think of Pharma 4.0.

Is it a buzzword to help push new, but not much improved, equipment and systems into the industry?

Or is it more substantial?

Ultimately, I think the moniker and what it represents carries significant weight as it places what is possible to the forefront of our industry in an unprecedented manner. An industry which is not particularly known for pushing the cutting edge of manufacturing technology. While many fields stretched the limits of what we defined as Industry 3.0 to something closer to Industry 3.9, there are still many operations living in regulatory contentment and technological antiquity.

As a computer engineer by schooling, Pharma 4.0 is exciting not only for its raw technology, but also the opportunity to provide a completely new framework for how we approach manufacturing design and implementation. Change in a regulated environment will not be quick but as in life, is inevitable.

The question to each of us now is – Will you embrace it? A strategic review of opportunities presented by Pharma 4.0 technologies against existing values and objectives guiding today’s business can create an exciting vision for the future. This will ultimately lead to better service and care to patients by invigorating teams that both execute projects and run facilities.

Pharma 4.0 – Welcome to a Smarter Way of Manufacturing

By:  John Niziolek
Associate Director, CSV
IPS-Integrated Project Services, LLC

This post is the first of a three part series exploring Pharma 4.0, its beneficial impact to organizations and the additional steps necessary to maintain compliance with the new technologies.

Through evolution, creation, or by chance, the human race has become the dominate species on this planet. Our intellect is what has allowed our species to advance, innovate, and master the Earth in many capacities. With each generation, advances in technologies have allowed for longer and healthier lives, more abundant food sources, and the ability to explore the depths of space.

In more recent times, the technologies which have impacted us the greatest can be categorized into four industrial phases:

• Steam Power (Industry 1.0)
• Electricity (Industry 2.0)
• Computers & Automation (Industry 3.0)
• The Internet (Industry 4.0)

In the life sciences manufacturing process, Industry 4.0 (or more specifically Pharma 4.0) is in a period of rapid growth and adoption.

Pharma 4.0 can be defined as the integration of technologies into the manufacturing process, systems, and platforms to allow for intelligent, data-driven decisions to occur. Pharma 4.0 is focused on the data in, around, and resulting from the manufacturing process.

Advances in sensor technologies which allow for the capturing of more precise data, speed of data acquisition, and advanced data analytic practices allow organizations to leverage both real-time and trend data to reduce production costs, increase product quality, and equipment reliability.

Life sciences organizations that implement these smart technologies have the potential ability to gain better control over resources, make more rapid and accurate decisions, and ultimately have better ability to develop and maintain a higher quality of product for their patients.

In our next post we will discuss the impact implementation of Pharma 4.0 technologies has on the organization specifically in regard to the abundant data produced and maintaining its integrity.

Setting a Standard

By: Nikki Withers

In contrast to food and beverage packaging, pharmaceutical packaging must, in many cases, be child resistant yet present no difficulty for its intended users – often elderly adults – to open and use properly. In the European Pharmaceutical Review’s Packaging In-Depth Focus, Stephen Wilkins, Chairman of the Child-Safe Packaging Group, discusses the standards that govern child-safe packaging, as well as the importance of ‘ease of opening’ for elderly adults. He shares details of the rigorous testing processes – where both children and adults are subjected to panel testing – and advises how the standards can be used not only for design, but as a competitive advantage tool.

There is also an article written by Andrew Meyers, Global Director of Cold Chain Consultants Ltd, who provides examples from the field – when I spoke to him, he was travelling through North India. He discusses the decision-making process for cold-chain packaging companies and advises how to ensure your product is transported throughout the supply chain correctly.

Also in the latest issue, Torgny Rundlöf and team, from the Swedish Medical Products Agency, have looked at the use of matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) for the identification of peptides and proteins in suspected illegal medicinal products, while Juan Antonio Vizcaíno from the European Bioinformatics Institute and Wellcome Trust Genome Campus discusses how open data policies in proteomics are starting to revolutionise the field in the context of mass spectrometry.

If, like me, you are curious about blockchain, I spoke to Bob Celeste, founder of the Centre for Supply Chain Studies, last month who has been exploring the potential use of blockchain technology to address the data-sharing requirements of the DSCSA. His team has tested several models to demonstrate the potential viability of various blockchain solutions for the pharma supply chain.

This edition also includes articles on aseptic containment, legal advice on licensing negotiations and an In-Depth Focus article from near-infrared spectroscopy pioneer Emil W. Ciurczak.

To find out more, please click here.

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.

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.

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.

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.