Smoothing the path to isolator adoption for aseptic filling
Data from surveys presented at the March 2018 ISPE Aseptic Conference and PDA Annual Meeting provides important insights into aseptic filling methods, present and future. The insights? Many companies are running very old aseptic filling systems. Regulatory guidelines may prevent companies from using such systems in the near future. Pharma companies state that the cost and complexity of replacing the existing systems with conventional RABS and isolator-based filling systems are significant obstacles to doing so. Vanrx suggests that these obstacles can be avoided by adopting fully robotic gloveless isolators, which avoid the cost and complexity of conventional isolator technologies.
Vanrx attended the ISPE Aseptic Conference and PDA Annual Meeting, both of which took place in March 2018. One presentation from each conference struck us as important, not only for aseptic filling, but for the broader state of manufacturing injectables.
Charlotte Enghave Fruergaard of NNE presented an extensive survey of aseptic manufacturing facilities called “Survey on Aging Facilities” at ISPE Aseptic. Guenther Gapp’s presentation covered “Points to Consider in Isolator Technology” at the PDA Annual Meeting, on behalf of the PDA Task Force Group.
These presentations reviewed pharmaceutical companies’ current aseptic filling operations and their future intentions, especially as it pertained to the adoption of isolators.
Aseptic filling machines are the centrepiece production systems in making injectable medicines. Therefore, these are crucial issues if companies are to continue supplying the market in the needed quantities and bring new drug products to market. The survey reviews the types of filling lines currently being run by respondents, the technology they intended to use in the future, and the perceived obstacles of implementing these new technologies.
What is the problem?
“At the yearly ISPE Aseptic Conference the following question is always asked. ‘How many in the audience have isolators? How many have RABS? And how many have conventional cleanrooms?’ Normally, we see an even ratio between the three, which means a lot of facilities still use conventional cleanrooms,” says Charlotte.
“The ISPE survey on aging facilities was created to determine if this was the real picture and to assist the industry in how to improve these facilities. The regulators are pushing more and more for barrier technology and the industry needs to respond to this,” she adds.
Ms. Fruergaard’s survey data showed that 47 of the 80 filling lines (52%) are 11-plus years old, and 18 of these are more than 20 years old. More than 20 (24%) of the respondents said they had received regulatory observations directly related to fill/finish operations using traditional technology, defined as lines with limited protection. This data covers vial, syringe, cartridge and ampoule filling lines.
Mr. Gapp’s data provides more colour by reviewing the technologies being used for aseptic filling, including barrier systems. Here are some highlights:
- Conventional filling is being used by 48% of survey respondents
- Manual filling is being used by 14% of survey respondents
- Semi-automated filling is used by 20% of respondents.
- Restricted access barrier systems were the most popular barrier system (43%), while closed isolators (27%) and open isolators (18%) were also used.
Regulators see these methods as a problem based on the observations, and there is a significant number of companies running open aseptic filling operations in Grade A space. If a company were to build a new facility today, these production models would not even be considered.
Further data from Ms. Fruergaard’s presentation suggests that there is considerable angst about moving to isolator systems based on the perceived difficulty and cost of doing so.
Why are pharmaceutical companies not acting on these problems?
Note that Vanrx does not categorize its products as “conventional” isolators. Vanrx Workcells differ significantly in both our gloveless robotic isolator technology (no glove ports, airflow, environmental monitoring, decontamination) and the filling and closing process. We will explain below how our systems help overcome the problems described by the survey respondents.
Companies are being pressed by regulators to implement isolator-based containment but Ms. Fruergaard’s presentation revealed that the following factors were obstacles to switching over. The survey results show that the companies believe that isolator-based filling systems:
- Will not meet requirements for flexibility;
- Are not a budgetary priority, or capital investment costs are considered prohibitive;
- Will take too much time and resources to implement and validate;
- Will be disruptive to needed drug supplies.
Let’s break down these comments one-by-one with respect to conventional open or closed isolators.
- Will not meet requirements for flexibility.
At Vanrx we see companies really struggling with the issue of flexibility. It’s a topic we cover in-depth in our latest infographic.
More than 70 of the 82 respondents in Ms. Fruergaard’s presentation represented multi-product facilities. Their struggle lies in how to build facilities and design processes for multi-product portfolios, where each drug has a different delivery format. Vanrx would argue that an ecosystem of upstream production technologies is available (single-use bioreactors, new chromatography and harvesting technologies, etc.). Meanwhile, the incumbent downstream technology providers have taken only a half-step toward flexibility by adapting conventional technologies that employ modular designs. Modularity does not equal flexibility.
How Vanrx solves the flexibility problem:
Vanrx’s founders led the manufacturing operations of a pioneering biotech company prior to founding Vanrx. They experienced the need for flexibility first-hand. Flexibility has two dimensions: operational and strategic. In day-to-day operations, Vanrx Aseptic Filling Workcells enable rapid changeover between formats. Strategically, Workcells can be built and installed faster than conventional systems. Flexibility is built in, with the ability to produce vials, syringes or cartridges, and rapidly add on new formats or sizes when needed.
2. Are not a budgetary priority, or capital investment costs are considered prohibitive.
Having your facility shut down by regulators, or having the launch of a new drug blocked by manufacturing issues will affect your budget. Conventional isolator technologies can be expensive. Companies are stuck between a rock and a hard place.
How Vanrx solves the cost problem:
Despite being new technology, Vanrx aseptic filling machines are cost-effective, including lower facilities requirements. They require only one operator, less cleanroom space at a lower classification (Grade C / D, depending on the regulator), and fewer supporting utilities. By using pre-sterilized nested containers and closures, companies don’t incur the costs of a washer and depyrogenation tunnel.
3. Will take too much time and resources to implement and validate.
This is a legitimate complaint. If you order a system and are quoted a 15-month lead time, followed by a complex installation process it will be 2-3 years before you’re validated and running.
How Vanrx solves the time problem:
Every Vanrx Workcell is the same. These are standard machines that can be built, installed and validated in 15 months or less. This also means that adding capacity, or extending production to global sites, is a repeatable and scalable process. The production process can be developed on the Microcell for preclinical and clinical supplies, and scaled to the SA25 for late clinical and commercial production.
4. Will be disruptive to needed drug supplies.
This is the biggest challenge. A growing drug shortage list in the U.S. and elsewhere coincides with aging production facilities. Companies have to make choices that minimize disruption. Detailed scheduling can help a facility cut away from the old system only when the new one is validated.
How Vanrx solves the disruption problem:
The small footprint, low infrastructure, and fast timelines of the Vanrx Workcells support many different conventional and innovative strategies for adding capacity while maintaining production of existing drug products. One of our customers is making the jump from a traditional facility (open filling in Class A) to a Vanrx SA25 Aseptic Filling Workcell. They saw tremendous value in leaping over conventional RABS and isolators to a gloveless robotic system. The company intends to cut over to the new system when it is fully validated, with a detailed plan in place to handle regulatory filings.
Read about Patheon’s experience with Vanrx
Patheon implemented a Vanrx SA25 Aseptic Filling Workcell at a U.S. production facility. Read their case study about the experience. It shows how to adopt new technology and establish validated flexible filling capacity quickly.