"If I sent everyone in this class home with the same recipe for cookies, would all the cookies taste the same?” asked solid dose expert, Mike Tousey, during his recent Techceuticals “Manufacturing Process” training course. Knowing my own habit of carelessly mixing ingredients to the point where they actually take flight out of the bowl, I immediately knew the answer here was “no.” The reality is, even if everyone follows the same recipe, variables in environment, ingredients, equipment and skill still exist.
While cookie individuality isn’t always a bad thing, when it comes to solid dose manufacturing, the goal is consistent, reproducible results.
After decades spent perfecting the craft of tablet making, manufactures (and patients) continue to favor the familiar, accessible oral solid dose format. Despite the increasing number of injectable biologics, solid dose products are a proven pharmaceutical market mainstay. According to GoodRx data, the top 10 drugs based on monthly prescription volume in the U.S. are solid dosages. On the innovation front, 2017 saw the percentage of solid dose new molecular entities (NMEs) approved by the U.S. Federal Drug Association jump from 32 to 50 percent.
Success in solid dose manufacturing comes not only in creating and following the “recipe” for the right formulation, process and equipment selection, but in understanding how to make adjustments when variables threaten product quality. It is within these small details that properly trained and experienced operators can make a big difference.
Despite the frequently discussed concept of a fully automated, “hand’s-off” drug manufacturing process, there is still some art left to crafting high-quality tablets.
NOT YOUR PARENTS' BATCH
Prior to 1978, drug product quality and sterility was based solely on finished product testing. Terms such as “validation” and “protocol” didn’t exist until the FDA introduced changes to GMPs. Historically, tablets relied heavily on the specific operators involved in making them, and as such, process adjustments were often made on the equipment present in one particular plant.
This means that for many legacy solid dose products, decades of manufacturing resulted in “know-how” that was plant or operator-related, and documentation associated with development and technology transfer is not robust enough to satisfy current regulations.
“Legacy products are often difficult to validate — because they weren’t designed with validation in mind,” points out Lee Karras, CEO, Halo Pharmaceutical. Halo, a contract development and manufacturing organization, is often tapped by pharma manufacturers looking for someone to step in and “refresh” the process for these older drugs.
Fortunately, the industry has seen significant advancements in areas such as GMP regulations, raw material reliability, analytical tools and equipment automation, all of which have edged the industry closer to a manufacturing process that is less susceptible to human error.
In a recent presentation at INTERPHEX 2018, Dr. Ian Jones, founder, CEO and Chris O’Callaghan, senior product manager, Innopharma Labs, discussed the idea of “intelligent batch manufacturing.” A “smart batch,” said O’Callaghan, involves using algorithms and controls to retrofit existing batch processes. The Dublin-based company’s newly launched advanced manufacturing program lays the groundwork for self-guided coating and granulation processes, using Process Analytical Technology (PAT) to track critical process parameters and the product’s critical quality attributes during manufacturing. Applying PAT concepts to coating helps manufacturers overcome variability and achieve the same coating characteristics every time.
BUT WHAT ABOUT CONTINUOUS MANUFACTURING?
For years, the pharmaceutical industry has been abuzz with the promise offered by continuous manufacturing. In theory, continuous manufacturing would mean an uninterrupted, automated process from powder to finished tablets, resulting in numerous benefits, chief among them less chance for human operator error.
The FDA has sung the praises of the continuous process, encouraging manufacturers to make the switch from batch to continuous, and noting the potential for improvements in speed, flexibility and quality that come with adopting this emerging technology.
“By eliminating breaks between steps and reducing opportunities for human errors during the stops and starts in the batch process, continuous manufacturing is more reliable — and safer,” said Lawrence Yu, deputy director, Office of Pharmaceutical Quality at CDER, in a 2016 blog post announcing the agency’s first approval of a manufacturer’s change in production method from batch to continuous manufacturing.
In fact, many aspects of the solid dose manufacturing process are already considered “semi-continuous” — meaning the specific unit operation is being performed continuously, but only for a discrete time period. Examples include continuous roller compaction, tablet compression and tablet coating. Continuous roller compactors, for example, feed powder into the compaction area and output compacted sheets. These compacted “ribbons” are then milled to produce granules. The granules can then be passed directly from the compactor to a blender, and from there to a tablet press.