For decades, pharmaceutical firms have manufactured their products in batches. In batch manufacturing, a “batch” is a specific quantity of a drug produced through a multi-step process.
While batch production is a tested manufacturing method, the motion between steps can be slow and inefficient.
To streamline production, manufacturers have begun to apply continuous manufacturing technologies to the pharmaceutical production process.
If batch production involves the sequential processing and testing of material across multiple discrete stages (and potentially facilities), continuous manufacturing combines the full manufacturing stream into a single, fully integrated flow. This “continuous” production eliminates built-in production gaps and can shorten manufacturing times from months to days.
While adoption of continuous manufacturing has been slow, the FDA supports increased implementation of continuous manufacturing technologies. Continuous manufacturing seems poised to play a major role in the coming years, as the number of continuous production facilities under review has quadrupled in the last half-decade.
In this post, we’ll look at the ins and outs of continuous manufacturing. We’ll cover the definition, history, benefits, and challenges of continuous production for pharmaceutical manufacturers.
From Batch to Continuous Production
The widespread support for continuous manufacturing comes from inefficiencies that naturally result from batch processes.
Let’s look at a few.
Long Hold Times
Batch manufacturing occurs across multiple stages. Between each stage, materials are sent to a quality lab for testing. The bulk of the work-in-progress is stored until quality is confirmed, and then materials are moved to the next stage. These “hold times” add up, and contribute to lengthy manufacturing cycles.
Supply Chain Complications
At times, this involves shipment to a new facility. If there are any supply chain disruptions or if specified holding conditions aren’t met, material can degrade and compromise a batch. Supply chain disruptions—especially multinational pharmaceutical supply chains--have led to an increase in drug recalls in recent years.
Because batches move sequentially, each step must be fully complete before the next can begin. If the full manufacturing stream contains 6 or 7 steps, the waiting times can add up. This can lead to low utilization levels and complicated process scheduling.
Batch production is the industry standard and the inefficiencies are well known. As are the advantages (low set-up costs, easier adjustments, deep industry expertise, and best-practices). Nevertheless, enduring problems with production times, human error, and supply chain contingencies have made continuous processes an appealing alternative to regulators and manufacturers alike.
Continuous Manufacturing Defined
Continuous manufacturing is a method for manufacturing pharmaceutical products from end-to-end on a single, uninterrupted production line.
Where batch manufacturing requires transporting, testing, and re-feeding materials from one process to the next, continuous processes execute all testing, feeding, and processing inline. Sophisticated process analytical technologies ensure quality in-process.
History of Continuous Production
Though new to pharmaceutical manufacturing, continuous manufacturing isn’t new.
In fact, continuous processes have been the norm in some industries for nearly a century. Continuous production has a long history in iron production, where facilities can run uninterrupted for years. It’s also the norm in the petrochemical industry, as well as some food and beverage processes.
Here are examples of continuous manufacturing industries and products:
- Oil Refining
- Metal smelting
- Some foods and beverages, like peanut butter
The turn to continuous manufacturing in the pharmaceutical industry has gained momentum over the last decade. Manufacturing technology matured enough to accommodate the complex manufacturing techniques used in pharmaceutical production. Sensors and analytical technology matured enough to bring quality control in-line. And the regulatory and economic environment encouraged manufacturers to pursue innovation. The FDA quickly recognized the potential of continuous manufacturing to improve quality, meet demand, and improve service to patients, and they’ve consistently voiced their support.
In 2015, Vertex Pharmaceuticals became the first firm to secure FDA approval for a drug manufactured on a continuous line. In the next three years, Janssen, Eli Lilly, and Pfizer each received approval for continuously manufactured products.
Continuous manufacturing helps firms eliminate hold times, utilize the full capacity of their manufacturing lines, and bring quality testing inline.
Continuous manufacturing can also help manufacturers react more quickly to changes in demand. A continuous line can process higher and lower quantities of a drug as needed, it allows manufacturers to respond more rapidly to changing markets.
It also enables recipes not possible using traditional batch methods.
In short, the benefits of continuous manufacturing are:
- Improved utilization
- Flexible batch sizes
- Simplified scaling
- Greater control over critical process parameters
- Less energy consumption
- Better adherence to schedules
Continuous Manufacturing Challenges
Continuous manufacturing processes have their fair share of challenges.
For one, changeovers on continuous manufacturing lines are complicated and can take over a week to perform. Continuous manufacturing systems have thousands of parts that need to be cleaned, changed out, and verified. Changeovers are a highly manual process (one made easier by digital SOPs), and they can be time-consuming for even skilled operators.
As one expert put it:
“Whether frequent changeovers can be performed efficiently to enable short duration runs and small batches is still an open question. While the desired goal is to be able to changeover in less than a day, current lines can take a week or more for changeover due to the extensive time for disassembling, cleaning, and reassembling.”
Operating continuous manufacturing equipment requires extensive training. The complexity of the equipment and the risk of mistakes means that everyone involved needs sufficient exposure and understanding of the system to ensure proper usage.
While there are clear manufacturing benefits to continuous manufacturing systems, the economics of the pharmaceutical industry has presented a challenge. Between expenditures for new equipment, abandoning existing capacity, and projections for lifetime profitability of a given therapy, manufacturers are always concerned with the returns on any investment in continuous manufacturing technology.
Even if adoption rates are low, the benefits of continuous manufacturing for the pharmaceutical industry are clear. As advanced manufacturing becomes the norm in life sciences manufacturing, expect to see broader adoption of continuous production.
Improve quality and simplify compliance with Tulip's Frontline Operations Platform
See how a system of apps can capture real-time data and digitize workflows with a free trial of Tulip.