Production of sterile powders requires specialized expertise and capabilities in sterile crystallization. To meet growing demand for this unique technology, Fareva is doubling its capacity.

Why Sterile Crystallization

The global market for sterile injectable drugs is expanding at a compound annual growth rate of more than 7% from 2016 to 2024 and is expected to reach a value of $657 billion by the end of the forecast period, due to the growing popularity of injectable drugs, including both biologics and small molecule drugs.¹ 

Sterile injectable drug products can be formulated as sterile solutions and suspensions. In the case of sterile suspensions, terminal sterilization of the drug product is usually appropriate. However, in some cases, the active pharmaceutical ingredient (API) is unstable and can degrade from heat, gamma irradiation, or other methods of sterilization. In these cases, sterile crystallization of the API is needed to produce a sterile powder before formulation.

Crystallization Under Aseptic Conditions

Sterile crystallization involves the conversion of non-sterile drug substances to sterile APIs. The non-sterile compound is charged into a non-sterile vessel, and solvent is added to generate a solution. This solution is passed through a through a 0.2-micron sterilizing filter cartridge and collected in a sterilized crystallizer (reactor). Aseptic crystallization is then achieved either by cooling, the addition of a sterile counter-solvent, seeding with sterile crystals, or other appropriate methods. The crystals are collected via sterile filtration and then aseptically dried.

The sterile dry powder APIs can be subjected, if necessary, to aseptic milling/micronization to generate particle size distributions with enhanced physicochemical properties. They can also be mixed with excipients under aseptic conditions to produce long-acting formulations and/or with other APIs to produce combination drugs. The final step is filling into presterilized containers (e.g., vials, bags), which is generally faster and requires less energy than liquid filling, leading to reduced costs. The powder in containers is ultimately packaged with sterile aqueous solutions for reconstitution before administration.

Specialized Expertise

Sterile crystallization is a niche technology, and only a limited number of contract development and manufacturing organizations (CDMOs) have this capability. Because the sterile powders are used to prepare suspensions for injection, ensuring sterility is essential to minimize risk and assure patient safety. Successful aseptic crystallization therefore requires extensive expertise in both crystallization and aseptic manufacturing.

Facilities designed for aseptic crystallization of bulk APIs should have the same design features as facilities used for aseptic liquid drug product manufacturing, including temperature, humidity, and pressure controls. Equipment (sterilizer, dryer, mill/micronizer) must be designed with the need for sterilization in mind. Procedures must be in place for sterilization, as well as validation of sterilization.

Deep knowledge of the crystallization equipment, sterilization processes, and methods for demonstration of sterility are essential to ensure control of microbial contamination. Automation of equipment should be employed as much as possible to minimize operator interaction with the API. Operators must also be highly trained and must recognize the importance of maintaining sterile conditions.

The ideal CDMO will have a long track record of successful regulatory inspections and a history of producing commercial products via sterile crystallization.

Sterile Crystallization at Fareva

Fareva Pharmaceuticals has been performing sterile crystallizations on the laboratory and commercial scales since 1995 and is registered in more than 40 countries around the world. We have nearly 25 years of experience developing and commercializing products across the spectrum of customers from big pharma to smaller specialty companies.

Our sterile crystallization capabilities are located at Fareva’s Valdepharm site in Normandy, France. All of the equipment (crystallizer, filter dryer, milling/micronization, packaging) is housed in a closed system and designed specifically for easy sterilization and drying of the equipment in preparation for use. Once the entire system is steam sterilized and dried, it is placed and maintained under a flow of sterile nitrogen.

Within our R&D lab at Valdepharm, we have small milling/micronization equipment that enables us to simulate conditions in the plant and develop optimized processes that can be readily scaled.

To date, regulatory inspections of our sterile crystallization have been successfully closed without findings

Doubling Capacity

In response to growing demand for our sterile crystallization services, Fareva has invested $17 million in the Valdepharm site to double our capacity for this rare technology. We now have 2500-L and 4000-L crystallizers. The new unit was designed by leveraging our extensive technical, engineering, quality, and regulatory expertise in aseptic crystallization to provide enhanced process controls and to expand our capabilities for milling and packaging.

As such, we have included continuous wet milling capability for particle size reduction in the new unit and added micronization technology for fine particle generation. Seeding under sterile conditions is also possible in the new unit, enabling the production of crystals with specific polymorphic forms. Sterile “wet” nitrogen for drying of sterile powders after crystallization is also available in the new unit for APIs that are stable only under certain relative humidity conditions. A new isolator for packaging has been designed with flexibility in mind, enabling us to offer packaging in multiple formats, such as bags, liners, and pouches.

Overall, we have emphasized the extensive employment of automation and online controls for risk minimization. In addition, the new sterile crystallization unit at Fareva has been designed with the future in mind. It not only enables us to offer the capabilities and technologies customers are demanding today, but will allow us to address future needs, growing with the needs of the industry.

One-Stop Shop for Sterile APIs and Drug Products

Fareva has extensive experience in sterile drug substance and drug product manufacturing. In addition to sterile crystallization, our Valdepharm site offers sterile finished dosage form manufacturing and packaging, including freeze-dried and liquid vials, pre-filled syringes, ampoules, and disposable bags. We are also licensed to handle controlled substances.

These combined capabilities position us as a one-stop shop for sterile production. We have all of the support functions required to ensure maintenance of sterility on site, including a strong quality assurance team and analytical and microbiological laboratories. Importantly, projects are managed by dedicated project teams that support projects from initiation to completion, whether that involves only API production or both API and drug product manufacturing, ensuring seamless progress.

With approvals from EMA, FDA, ANVISA, ANSES, and other regulatory agencies, we are able to submit drug master files (DMFs) in more than 40 different countries in Europe, North and South America, and Asia. With over 20 years of experience bringing products to market, we have the expertise to develop DMFs tailored for each regulatory authority.

Fareva also welcomes customers with special project needs. We are committed to innovation and are willing to invest in new technologies that will help our customers achieve their goals.

References

1. “Sterile Injectable Drugs Market Poised to Reach US$657 Bn through 2024, APAC Expected to Emerge Lucrative.” Persistence Market Research. 23 Jan. 2017. Web.