Sepha – Rottendorf Pharma Collaboration

A complete end-to-end solution

Rottendorf Pharma has been manufacturing oral solid dosage forms for the global pharmaceutical industry for more than 90 years. With state-ofthe-art facilities featuring best-in-class equipment and technologies, the company produces multiple originator and generic drug products for big, small, virtual, and global pharmaceutical and biotechnology companies. Sepha’s technical specialists worked with Tina Sonsalla, an expert in formulation development at Rottendorf, and Dr. Judith Uhlenbrock, Rottendorf’s Senior Project Manager for Formulation Development.

“We work with organisations from big pharma to start-up companies with smaller internal development capabilities” says Dr. Uhlenbrock, a specialist in pharmaceutical technology who has worked at Rottendorf for almost eight years. “We operate to strict Good Manufacturing Practice (GMP) and Quality by Design (QbD) standards, and all of our machines in the development department can be used for GMP manufacturing,” adds Tina Sonsalla, a process engineer by training with responsibility for optimising processes at Rottendorf. “As well as using our equipment for routine manufacturing, we can oversee the entire process including data management and product testing.”

A growing need for small batch packaging

The number of registered clinical trials has increased significantly: in November 2022, there were over 434,000 clinical studies registered globally, a significant increase from 2000 when just 2,119 were registered [1]. In recent years, Rottendorf has experienced increasing demand for small batch blister packaging of tablets and capsule formats.

Dr. Uhlenbrock comments, “As well as the considerable growth in clinical trials, the focus has shifted to rare disease and personalised medicine, with orphan drugs, biotechnology and gene therapies attracting attention. Blister packaging requirements are becoming more complex as a result. Small batch runs are needed for drug stability testing and we’re seeing an increase in their demand for use in clinical trials.”

Traditionally, manufacturers have been forced either to divert large-scale production lines to the production of small batches of blister packed capsules and tablets, or have been unable to offer this function at all, as taking down a full scale production line is prohibitively demanding in terms of time and resource.

What was missing in the industry is a standalone, low volume machine that offers the familiar functionality of a large-scale production system, with digital reporting and full audit trail generation, plus the flexibility to switch between different batch production runs quickly and easily, and, critically, in full compliance with 21 CFR Part 11 and GMP.

“At the drug development stage, our customers need to be able to produce small quantities of the product in the format that will ultimately be on the market,” explains Dr. Uhlenbrock. “However, blister packaging facilities are intended to pack a single product at scale, meaning producing small batches is inefficient and expensive. We were therefore looking for a machine that could handle very small batches, without the need to decommission a larger, full packaging line.”

After extensive market research, Rottendorf partnered with Sepha to develop a new technology, which Sepha describes as an intelligent evolution of its existing EZ Blister machine. “Rottendorf Pharma approached us about our EZ Blister, which is used to create small batches of blister packs as proof of concept for the customer or end user, but requested some new specifications,” says Claire Miskelly, Head of Sales at Sepha. The key change was that the Rottendorf team needed the new machine to be 21 CFR Part 11-compliant. “Although many of our leak detection machines are 21 CFR Part 11-compliant, we hadn’t considered it yet for our line of blister packaging machines. The EZ Blister was predominantly used in an R&D setting – so this was a major new product development,” says Claire.

“The new machine needed not only to be used for small-run production of drugs for development purposes, but also for clinical packaging,” says Dr. Uhlenbrock. This meant that all GMP requirements needed to be fulfilled. “Compliance was the major challenge we had to overcome, because most of the smaller machines on the market are used purely for development purposes.”

A collaborative approach

Sepha sought to share its knowledge and capabilities with Rottendorf in this development. Claire Miskelly explains: “We suggested a collaboration where Sepha and Rottendorf Pharma work side-by-side to build a new machine based on the original Sepha EZ Blister. There were clear benefits on both sides: Rottendorf Pharma would own the world’s first customised small batch 21 CFR Part 11-compliant blister pack machine for tablets and capsules built to its exact specification, and Sepha would benefit from the learnings of the collaboration, where valuable customer input was given first hand in a collaborative and transparent environment, throughout the entire product development process.”

The collaborative approach saw great success. “We started from the base of our EZ Blister machine and then listened to Rottendorf’s requirements,” Claire says. “Open communication was an essential part of the process. We encouraged Rottendorf to tell us what worked and what didn’t, what was going well and, more importantly, what didn’t work. Everyone was clear on the direction the project needed to go in – and that was key to its success.”

Dr. Uhlenbrock agrees: “One of the reasons we chose to work with Sepha was because of the level of communication from the very beginning – the team’s response time, their obvious knowledge and experience, and their professionalism,” she says. “We had a lot of meetings with Sepha’s engineers, technical group and sales contacts, which allowed us to build the machine step by step. It was a real partnership.”

Partnership breeds new success

The EZ Blister+ was the result of this collaboration. The new, small batch, 21 CFR Part 11-compliant machine uses forming, sealing and cutting techniques to produce blister packs that are of large-line quality and meet current GMP standards at a rate of approximately 100 cycles per hour. Highly customisable, it offers both cold forming and thermoforming capabilities, knurled or flat heat-sealing plates, and optional perforated cutting tools. It provides a much-needed alternative to using high-speed lines at prohibitive cost and has had a big impact on Rottendorf’s production.

“Previously, we couldn’t create blister packaging in our development department. When small batches were required, we had no choice but to put them on the fully automatic blister line,” says Dr. Uhlenbrock. Not only was this costly and inefficient, but it also slowed down the potential to bring other products to market. “Formerly, at the beginning of development, our customers would have to commission tooling that would be redundant if the product did not pass clinical trials. The EZ Blister+ offers us minimal set up time and costs, and the ability to switch small batches in and out, giving us far more control and a fast turnaround.”

Rottendorf finds the user interface very intuitive. “The machine is quick and easy to set up with no need for specialist engineering support,” says Dr. Uhlenbrock. “Furthermore, once the project ended, Sepha stayed engaged with regular meetings to make sure the machine was optimised and running as we wanted it to – the team was very willing to continue to support us.”

Creating an audit trail

The key requirement was that the blister pack machine would both meet GMP guidelines and offer 21 CFR Part 11-compliance. This code of regulations governs electronic record maintenance, specifically requiring that systems have secure user access and user identification, the capability to store audit trail data, and the ability to assign electronic signatures. This is to prevent unauthorised access and protect against accidental deletion – ultimately allowing manufacturers to market products that can be fully audited, even at trial stage, to ensure testing for packaging stability and compliance – and patient safety.

Dr. Uhlenbrock and Tina Sonsalla are clear that Sepha has delivered on this challenge. “The machine has a database which stores every step of the packaging process and transfers it to our secure server,” says Tina Sonsalla. “You can see the audit trail – every adjustment in temperature and every change to the formulation of a batch is tracked, for example, making the production process easily reproducible, which is critical at the point of scale-up.”

She says this has given them essential levels of security. “Access rights are predefined, so, for example, the operator can’t perform any kind of calibration – it has to be done by a second independent person. Nothing can be changed by accident, which is an important requirement of 21 CFR Part 11-compliance.”

Sepha developed a new touchscreen to make sure the machine was easy to use. “Our previous model didn’t have a human machine interface (HMI) touchscreen; it was a programmable logic controller (PLC) based system, not an industrial personal computer (IPC) control system, so one of our major challenges was adapting that so it was easy to use,” says Claire. “The new HMI is intuitive, cuts out a few steps for Rottendorf, and allows them to meet the standards they need.”

The new system is now in use at Rottendorf and is already having an impact. “We have used it several times for different customers, to manufacture AluAlu blisters or polyvinyl chloride (PVC)-Alu blisters,” says Dr. Uhlenbrock. “Our blister packaged drug products are being used as part of stability studies and blister foil screening studies to help identify the correct blister materials for the drug product, and the familiar format sets out to support patient compliance in clinical studies. These drugs have already been given to patients and we are waiting for results.”

Expanding future responsibilities

The EZ Blister+ has the potential to revolutionise small scale tablet and capsule blister packaging. Rottendorf can now offer faster, more flexible, and simpler production, which has allowed the company to expand its offering to clients, as well as strengthen collaborations with existing customers. “It is a business development opportunity for us, giving us the chance to work with customers we couldn’t have supported in the past,” says Tina Sonsalla.

Working to create the EZ Blister+ was a true partnership that allowed Rottendorf to meet strict GMP and 21 CFR Part 11-compliance, whilst saving costs and unlocking new possibilities. This could be valuable for other companies too, Claire believes: “Other CDMOs could benefit from a 21 CFR Part 11-compliant technology like this. We’ve seen how successful the collaboration with Rottendorf has been – and they now have the opportunity to work with larger pharma organisations as a result. It could definitely be seen as an investment in the company’s future.”

For Sepha, it also opens the door to other collaborations. Claire adds, “We would be delighted to work with any company who has a strategic need that one of our machines can meet, either by customising one of our existing products or, as in this case, launching a full new product development project. Combining the different knowledge pools of two companies in this way can lead to some exciting new product breakthroughs, as we’ve seen. Having a beta tester throughout the development always helps, and our partner gets the product built to the specification they need – it’s a win-win.”

At the heart of this development was what the Rottendorf team describe as a great collaboration. Dr. Uhlenbrock concludes: “I would definitely recommend Sepha as a supplier, not only because of their development of the machine, but because of their customer support. Having regular contact with the Sepha team has been absolutely crucial to the success of the project. As a result of the partnership, we have a new machine that precisely meets our specification, allows us to take on a greater breadth of project work with no need to halt other production runs, and continues to operate in full 21 CFR Part 11-compliance.”

More information about the EZ Blister+ is available via the links below, or contact Sepha to discuss your requirements in more detail.

• Discover the Sepha EZ Blister+
• Watch EZ Blister+ video

References
[1] Total number of registered clinical studies worldwide since 2000, Statista (as of November 2022).
https://www.statista.com/statistics/732997/number-of-registered-clinical-studies-worldwide/

About Rottendorf Pharma

Rottendorf Pharma invests in state-of-the-art facilities, featuring best-in-class equipment and technologies, and is staffed with over 1,100 experienced, skilled workers, including many formulation scientists. In our German facilities, compliant with GMP, FDA, ANVISA, and others, the originator and generic drug products are manufactured, packaged, and developed. Clients choose Rottendorf Pharma for our broad range of expertise, global regulatory capabilities, commitment to quality, state-of-the-art facilities, and exceptional customer service. Rottendorf Pharma was recognized with five CMO Leadership Awards in 2015 for excellence in regulatory capabilities, quality, innovation and productivity.