Filling technology development

Because pharmaceutical filling fills the gap between bulk manufacturers and distributors, every aspect of the drug supply chain influences the process of loading medicines into marketable containers. Whether the drug is in the form of a single dose or multiple doses, or whether the drug is intended for one patient or several patients. These all determine whether the pharmaceutical filling line is to be formulated as milliliters or liters, whether it is a single tablet or many capsules.

Increased speed and cost savings are mentioned repeatedly in the filling area, including reasonable inventory and timely manufacturing, and even pharmacology, pharmacokinetics and the chemical structure of the active ingredients all influence the filling of the drug.

Packaging should be consistent with filling and keeping pace, but packaging and filling are often difficult to coordinate. Howard Thau, president of Westwood said, “You will be amazed at the process we have in the last moment. The packaging designed by creative designers cannot be filled, or the cost of filling the packaging is too expensive to The price of labor exceeds the drug itself."

The desire for greater safety, consistency, and convenience - often leading to increased costs - is driving single-serve packaging, especially prefilled syringes and blister packs. The single-dose package is like a metered-type inhaler and a drip bottle, and presents unique problems in the filling of liquids and solid dosage forms. "It is often more expensive to make a single-dose package on a per-dose basis," Thau commented.

In some high-value drugs, single-dose syringes are indeed more cost-effective than multiple doses, said Jeff Turns, Vetter’s senior vice president.

Jeff Turns also explained: “15%-20% of the solution in each multi-dose vial is wasted, and these may be worth hundreds of thousands of dollars, which is more expensive than 5-10 bottles of drugs.” plus coordination Sex, in the long run, if you reduce the cost of expensive inventory, you can save the entire health care costs. Turns mentioned figures by West
Fred McMillan of Pharmaceuticals confirmed that, according to him, “The medicine bottles that are injected are usually filled with 10%-20% to make up for the waste.”

These innovative packaging, driven by the simplicity and precision of pharmaceuticals, require corresponding innovative filling methods. Marian Robinson, Baxa’s vice president, added: “Prefilled syringes are not just for injections. The syringes are also entering the field of oral medicine.”

Aseptic filling rules

Manufacturers of tablets and capsules may disagree with this, but the most value-added filling operation so far is aseptic liquid filling because of the complexity of the operation technique and the dire consequences of failure.

Maintaining a clinical drug filling operation is expensive and requires special technology from time to time. If this part is not required for their aseptic filling, some large pharmaceutical companies tend to outsource the aseptic filling produced for clinical and developmental operations.
Sterile liquids are filled with two trends: sterilisation and final disinfection, but the complex pharmaceutical structure and molecular formula are slowly disfavoring final sterilization. "In these days, fewer and fewer drugs use this approach and no biotech products use this approach." Afton
Tom Thorpe, president of Scientific, said that he added that another reason for outsourcing is because R&D and manufacturing are not always well-coordinated among research-driven companies.

Aseptic filling requires special and specialized techniques, which are usually represented by professional filling. "Good design, good rules, good practice and training are all at the core," Thorpe said.

Because it is impossible to prove the sterility of the product without destroying the product, the filling producer relies on a good record and simulation tests on the processing of the medicine bottle and the injection bottle in the microorganism growth environment. Even so, some systematic or non-systematic errors can still happen quietly. Therefore, in the training, the operator of the filling line has to go through various interference factors, such as picking up cork or broken bottles from parts of the machine that are relatively difficult to reach, starting or stopping a production line, and repairing machine failures. These should be rehearsed and practiced repeatedly until workers perfect their technology, Thorpe said.

As a small-scale commercial product and clinical trial drug supplier, Afton understands its position in the market, Thorpe said, “Let a large-scale filler manufacturer go to a small business It's a difficult thing because both large and small operations and costs are very different and it's not economical for customers and producers.” Because one size does not fit all needs, Afton’s customers generally Emergency processing requirements for small biotech companies, universities, government agencies, or large companies, as well as small batches of clinical trial medications.

Sterility technology

Some of the new exciting techniques for aseptic filling include blow-moulded closures (for large bottles) and molded closures (suitable for single or multiple doses). Both are extrusions of polyethylene into a mold and then aseptically filled to complete the final product.

When an ampoule is aseptically filled, it is usually necessary to have a separate zone or a class 100 clean room, and any choice must be fully integrated with the sterile production and storage of the vials. Bottle caps, spacers and seals must be processed independently and stored separately. “It's just a million dollars worth of cleaning equipment and it takes a long verification cycle.” Dey
Ray Joske, LP's senior vice president, pointed out that "since each vial undergoes several operations, the classification processing area (or isolation) tends to become larger."

Bottle blowing or forming seals greatly reduce the complexity of aseptic packaging, but manufacturers are still a bit scared about pushing the product to extrusion temperature. In the United States, this filling is limited to ophthalmic and respiratory products. Joske thinks this is a sad one. In Europe, it is common for filling companies to produce home injectables and more general ophthalmic and pulmonary treatments. There are also some European packaging companies that use barriers to apply their innovations to multi-dose packaging.

Anke Henke believes that the United States lags behind Europe in terms of inertness and familiarity with glass containers in terms of new plastic innovations. But sooner or later there will be a breakthrough in polymer containers. "Compared with glass, plastic has many advantages, including easier processing and transportation, and less damage." Although Henke admits that some of the very sensitive drugs cannot be bottled and filled, she still feels that the technology is canceled. The use of protein and other unstable products is a mistake. Because the blowing process is very fast, the medicine is heated instantaneously and cools quickly. "The product can be quickly frozen after leaving the mold," she said.

Observation of freeze-drying technology

If necessity is the source of invention, freeze-drying has created more filling innovations than other dosage forms. This processing gives the peptide product and protein product more stability and shelf life. Lyophilization began around the 1970s and the 1980s, when pharmaceutical products were mostly small molecules and simple molecular formulas. Today, many biotech products begin to be produced, and the star of freeze-drying technology begins to rise.

The downside is that lyophilized vials take a lot of time between sterilization and final packaging. In contrast, aseptic filling vials of liquid dosage forms are still sufficient for capping as long as they are in the classified area or in the isolation area. The complete freeze-dried formulation needs to be kept in a clean environment for several hours, sometimes several days. Obviously those areas are forbidden to contact those who have not taken protective measures, and they must be meticulous in maintaining sterility. Monitoring and verifying this level of cleanliness is very expensive.

Fifteen years ago, a standard freeze-drying line produced 50,000 to 60,000 10-ml vials costing one million dollars. Today, 100,000 freeze-drying lines are not unusual, and their cost has risen to two million dollars. The added features of these new added costs include higher throughput, automated delivery and loading, and of course automatic filling.

If lyophilization can have so many benefits, why is it not used more? Mainly because of the cost. "The freeze-drying process is so much more expensive than ready-to-use liquid filling," Ed Lyophilization Technology president Ed
Trappler said that prior to the implementation of the lyophilization project, Trappler was convinced that investors knew what was going to happen. "The cycle of freeze-drying can be as long as 13 days, and if the equipment fails during this time, then the entire batch of products must be Retirement. Plus capital investment is also high, "all of these also affect the cost of each dose.

Segregation area - is it future?

Pharmaceutical engineers like to argue about the advantages of isolated areas and clean rooms, but the isolation area has already won the frontier of aseptic filling. It is even said that the isolation zone represents the future of aseptic filling.

Forward-looking manufacturers install the quarantine area on a new filling line instead of installing a clean room. The advantage of the quarantine zone is that it is easier to maintain a categorized level of space, a lower cleaning burden, and a much lower operating cost. Operators are also happy (without wearing protective gowns and no claustrophobia). And optimized protection for operators and protection of drugs.

The competition in the filling machine market requires continuous innovation. More and more customers now require the installation of an isolation zone, although the isolation zone requires more installation and verification costs than a clean room. And although the FDA has not yet clearly recognized it, they have shown interest in this view and provided a gentle boost to this trend.