Industry leaders tell us their thoughts on the future of sterile dosage
Q: In 2012 and beyond what specific areas of biopharmaceutical manufacturing should be the focus to improve sterile dosage production?
Craig Mastenbaum Director,
Business Development
OSO BioPharmaceuticals Manufacturing, LLC
Regarding sterile dosage production, the past ten years have seen major advances in a number of areas. This includes cleanroom design and sterile filling equipment. Today, it is much more common to see cleanrooms built utilizing clean build standards, as well as fi lling machines which can check and adjust fill weights automatically. These were great advances forward in the industry. For 2012 and beyond, the focus now must shift to the people in the cleanroom, and specifically how those people are trained.
Training personnel to work in a cleanroom environment involves teaching two separate items simultaneously, aseptic technique and equipment operation. Teaching one without the other will result in an issue for the company. Undoubtedly, aseptic technique takes the longest to learn, as an individual needs to become acquainted with handling themselves and going about their business in a sterile environment, which can be a very un-natural thing. Individuals need to relearn how to hold their hands, how to walk, and not to scratch an itch. Learning how to operate equipment is just as important. As filling machines grow more complex and involve more and more advanced controls, individuals with a propensity for operating CPUs have an advantage, but must still be trained to know all of the workings of the equipment used. Failure to do so would be akin to asking the average person to fl y the space shuttle.
Training programs for aseptic employees vary from company to company. At OsoBio, we use Sterile University to train our personnel. Sterile University is a hands-on classroom environment which contains all of the equipment that an individual would use in the production environment. Individuals must pass an examination prior to being considered fully trained and working in the actual production environment.
Kent Payne, Ph.D.
Vice President & General Manager
Biologics, Catalent Pharma Solutions
The industry should focus on four main opportunities: 1) enhanced delivery and 2) contamination risk mitigation, 3) intervention reduction and 4) API preservation.
It is important to build a formulation that is robust and avoids the need for cold chain management and reduce costs. Focus on development of more sophisticated approaches through molecular modification or enhanced delivery approaches to improve delivery to site of action and/ or half life.
The use of pre-sterilized container components introduced directly at the filling core, are gaining acceptance in an effort to reduce microbial exposure. The industry is turning to “glass free” alternatives as one approach to address particulates and product incompatibility. The use of laminate plastic vials and syringes is one option. Blow/Fill/Seal technology (recognized as an advanced aseptic processing technique) also offers very accurate and cost effectively liquid dosing into a variety of extruded resin based plastics. Single use bag technology has also gained industry credibility to prevent product cross contamination, and reducing the overall cost associated with performing complex and expensive cleaning validation studies.
Less human intervention equals higher sterility assurance. Filling lines in isolators or restricted access barriers (RABs) provide a barrier between product and contamination sources. Application of more automated processes, like Blow/Fill/ Seal (where, after initial set up, few interventions are required from raw material insertion through container formation, filling and closure) provide significant advantages over traditional vial filling processes that inherently have more manual interventions (i.e. manual transfer, depyrogenation tunnels, vial washing, autoclaves).
Finally the growth of Pre-Filled Syringes and other unit dose solutions will continue to off er a lower total overall cost of goods: 1) no over filling of expensive API in vials and 2) deliver the right amount in the right concentration for the patient without reconstitution, extraction and injection.
Thomas Otto
Managing Director
Vetter
Looking at a list of parenteral drugs approved by the FDA in the past three years, it is evident that approximately 30% of them were lyophilized drugs. And because a majority of injectable substances currently in development are complex molecules, this percentage is likely to grow. Due to the reason that such molecules are sensitive to environmental infl uences and other materials, lyophilization can offer suitable protection from these problems.
An important focus for Vetter in aseptic manufacturing both now and in the future will be an emphasis on having the appropriate solutions to lyophilize drug substances. This involves not only production lines, but also the development processes and the best primary packaging. The challenge with lyophilized drugs lies in preparing them for administration, as the drug substance must be dissolved in a diluent prior to use. If the lyophilized substance is in a conventional vial, for example, several steps are necessary. Even for seasoned healthcare professionals, the handling process is not always easy. Such difficulty in handling limits market opportunities. This is especially true in the ever-expanding homecare section. More user-friendly systems are drug-delivery systems that make the dissolution step easier. Presently, the best drug-delivery system is an application in which the lyophilized substance and the diluent are present in a single system. One such example is a dual-chamber system, e.g. a dual-chamber syringe. The aseptically filled freeze-dried drug resides in one chamber, the diluent in the other. Pushing the syringe plunger mixes the two with one stroke.
Since these types of systems demand more complex development and manufacturing processes, it’s not always feasible to utilize them for a new market introduction. In such cases, to optimize time to market, filling in vials as a first step might be the best solution for the approval process. Switching to a dual-chamber system can then be considered within the framework of lifecycle management. This is especially why the know-how and state-of-the-art facilities for various drug-delivery systems are needed both in early development as well as for later commercial manufacturing.
Luis Jimenez, Ph.D.
Assistant Professor, Biology and Horticulture Department
Bergen Community College
The production of sterile dosages in biopharmaceutical manufacturing can be improved by the implementation of analytical technologies that can enhance the quality control analysis and release time of raw materials, intermediates, and finished products. Several studies have demonstrated the applicability of rapid sterility testing by ATP bioluminescence, CO2 production, and fl ow cytometry (1-3). All the methods are equivalent or better than the standard tests. Furthermore, if a microbial cell is present in the sample, detection was shown to be faster allowing the rapid implementation of corrective action.
- Smith, R., Von Tress, M., Tubb, and C., Vanhaecke, E. 2010. Evaluation of the ScanRDI as a rapid alternative to the pharmacopoeial sterility test method: comparison of the limits of detection. PDA J. Pharm. Sci. Technol. 64:356-363.
- Gray, J.C., Staerk, A., Berchtold, M., Hecker, W., Neuhaus, G., and Wirth, A. 2010. Growth-promoting properties of diff erent solid nutrient media evaluated with stressed and unstressed microorganisms: prestudy for the validation of a rapid sterility test. PDA J. Pharm. Sci. Technol. 64: 249-263.
- Jimenez, L., Rana, N., Amaraj, J., Walker, K., and Travers, K. 2012. Validation of the BacT/ALERT® 3D System for Rapid Sterility Testing of Biopharmaceutical Samples. PDA Journal of Pharmaceutical Science and Technology 66: 38-54.