For more than a century, pharmaceutical products such as capsules, tablets and injectable medicines have been made in batches, but there's a change coming for the industry. Prompted by the Food and Drug Administration’s (FDA) push for quality by design, pharmaceutical manufacturers are exploring new ways to make drugs, including continuous manufacturing.
To understand the difference, think of baking cookies. In a home kitchen or small bakery, the baker fills a bowl with ingredients and stirs them together. Then the mixture is spooned onto a cookie sheet and slid into the oven. A batch of cookies may be two or three dozen.
On an industrial scale, ingredients are fed into a machine that plops rows of cookie mixture onto a conveyor that moves through an oven and then shuffles baked products into a bin for packaging. The process may occur without human intervention after loading bags of ingredients into the machine. An industrial bakery can produce thousands of cookies per day through continuous manufacturing.
Basically, in batch manufacturing, inputs are added to the beginning of the process, and outputs are removed at the end. In continuous production, input and output occur at the same time.
"It's all about how cost-effective a manufacturer can be. Continuous manufacturing means you run one machine until the material runs out or you make your order quantity, Maryanne Steidinger, head of marketing at Webalo, told Supply Chain Dive. "You aren't as concerned with freshness as you would be with small batches, whereas with a smaller batch, the more personalization you can add to it."
Taking a page from food manufacturing
In 2004, the FDA issued guidance on process analytical technology to improve the quality of medicines. Then in September 2017, the FDA asked the pharmaceutical industry for input on continuous manufacturing. In February 2019, the FDA issued a statement calling for manufacturers to make the switch to help address drug shortages and lower the price of drug products as well as improve quality.
"The industry came together out of the FDA guidance and asked, ‘If we want to do quality by design, what's the best path for us to do that and leverage process-analytical technologies?’" Laks Pernenkil, manufacturing practice leader for life sciences at Deloitte, told Supply Chain Dive.
While researching manufacturing in the pharmaceutical industry, Pernenkil and his clients toured an M&M plant. They looked for similarities to solid oral dosage or tablet production. He also visited an oil and gas refinery and craft brewery to understand process flows comparable to liquid biologics.
Each type of pharmaceutical product requires its own production methods. For oral dosage medicines such as tablets and gels, a close analogy is the food industry. Confectionary makers pump out bite-size morsels by the millions.
One reason behind food’s move to continuous manufacturing is to reduce the possibility of contamination. Food manufacturers use production lines reserved for allergen-free food. A food producer may look for equipment that doesn't run products made with peanuts or carrageenan, or gluten or meat products.
"As companies move away from those ingredients for their own reasons, they are going to be able to make products in facilities that are continuously supporting those 'free from' categories," Suzannah Gerber, a research and outcomes education specialist for the food industry, told Supply Chain Dive.
In the food industry, products often are switched from batch to continuous when a larger brand acquires a smaller company. The large brand is looking for economies of scale and consistent quality, Gerber said.
However, some small food companies failed when they tried to upgrade their production to take on major competitors. Some things get lost in the translation from craft to mass production. "I've watched a lot of companies that were doing just fine bankrupt themselves by trying to scale up to be able to swim with the big boys," Gerber said.
"If there's a problem with the raw materials, by the time you blink, the product is already contaminated."
Manufacturing Practice Leader for Life Sciences, Deloitte
For food production, the fewer ingredients in a product, the more it's suited to continuous production. Breakfast cereal is one example. Also, Gerber sees plant milk production scaling up. "It's boomed recently, and it's a natural fit because it has under three ingredients, and they make the same thing over and over," she said.
Some food products also use a hybrid approach. For a candy such as SweeTarts, the mix is made at one location and shipped in drums to the compacting and packaging line.
"In the pharmaceutical world, the powder could get batched in a scientific laboratory and then sent to the press and pack line," Gerber said. Once the products are packaged, the existing outbound supply chain will most likely remain intact, Pernenkil added.
Managing material quality
Some pharmaceutical products are better suited for continuous manufacturing than others, for example, liquid biologics that use a fermentation process because they offer reduced variations between batches and lower production costs. Some products already use a quasi-continuous approach, such as filling vials or ampules with injectable drugs. There's still batch-style handling at each end of the process, but the middle is a continuous flow.
Few, if any, pharmaceutical products require 'round the clock production. Rare disease drugs may require only a shift or two to satisfy a year's worth of demand, Pernenkil said. Even generic painkiller tablets that are made in the billions change products on the line for different dosages and coatings.
The relatively small production runs for some drugs present a quality control challenge. "In pharma, you have minimal residence times so, if there's a problem with the raw materials, by the time you blink, the product is already contaminated," Pernenkil said. Residence time is the time it takes for a product to move through the manufacturing process. "Whereas in batch,” he said, “you tend to have a little bit more control in the middle stage end and can stop the process, so you don't lose all the material."
Because of the brief residence times, product purity at the source is critical. Sensors can monitor quality on the production line, or manufacturers can use feed-forward control, a process commonly used in petroleum and chemical refining. "You can measure raw material quality upfront and feed it forward in the process and send the information forward if there's an issue in the raw materials," Pernenkil said.
Adopting new recipes
For manufacturers making the switch from batch, they’ll have to implement some changes to operations processes and/or products.
The shift to continuous manufacturing leads to the question of what is a batch, the basic unit by which medicines are monitored and tracked to manage recalls, among other uses. Manufacturers must develop a way to identify lots of products continuously run on the line. It could be by time, such as a shift, or the number of materials used or produced.
"There could be a metric for the expected output from a line with an allowance for items pulled for quality control that could be tied to a manager on the shift," Gerber said.
Switching between materials or colors requires a purging process to remove remnants of the previous product from the machinery, a practice the plastics industry follows as well. Resins are produced in large quantities via continuous manufacturing. But individual products may use a batch approach to create custom colors or other characteristics, Eric Larson, a plastics consultant with Art of Mass Production, told Supply Chain Dive.
"I've watched a lot of companies that were doing just fine bankrupt themselves by trying to scale up to be able to swim with the big boys."
Research and outcomes education specialist for the food industry
Drugs could be made in much larger quantities for longer expiration dates but may need new formulas or packaging.
"They may add stabilizers or other preservatives or do environmental control packaging because it's more advantageous to pump out large quantities of product," Gerber said.
Rather than implement a wholesale change, some pharma manufacturers are designing new products to use continuous manufacturing as part of the research and development process.
"They're using it as another tool to see if they get better quality and have a better understanding of the process, so by the time the drug comes to commercial manufacturing, they already have the continuous system in place," Pernenkil said.
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