Vinod Vilivalam, Senior Director, Marketing and Lloyd Waxman, Principal Chemist from West Pharmaceutical Services share insights on new containment systems for cell therapy products and the benefits they offer to meet the pharma industry’s need for scale and integrity
Research has shown that some injectable drug vial systems can effectively be utilised to freeze, store and ship cryopreserved living cell products in a format that enables large-scale manufacturing and fill-finish operations, in addition to providing caregivers and patients with a system that is easy to handlei. This finding comes at a time when manufacturers are beginning to realise that the current blood-banking bag technology may not work on the scale they will require, as therapeutic cell products reach later stages of clinical trials.
Blood bags are sufficient for small-scale processes that generate tens of product doses per lot. However, commercial-scale sizes of hundreds to thousands of living cell doses per lot will be required to supply a commercial-scale cellular product, a volume that may preclude the use of bags. Thus, more consideration is being placed on manufacturing processes that are capable of producing commercial – scale quantities of living cell productsii.
With the emergence of cellular therapy as a more widely used clinical practice, improved containers and closure systems for effective, safe use and cell preservation are required. While still effective for some indications, there has been more focus on the shortcomings of cryopreserved bag storage. A study by Khuu et al investigated a series of catastrophic bag failures first noticed in 2001iii. In that study, high rates of bag failure were associated with four specific bag lots made from poly (ethylene co-vinyl acetate). While no serious adverse patient effects occurred, extensive bag failures led to microbial contamination of the cell product, along with increased product preparation time, antibiotic use and resource expenditure to replace products.
Pharma-grade vials provide ease of delivery by caregivers. They also leverage the pharma manufacturing infrastructure. Importantly, there are established standards in sizes, quality and regulatory attributes that can be capitalised upon in order to facilitate uptake into the rapidly developing cell therapy industry.
The ideal vial-based container system should be suited for packaging, storing and transporting cell therapy products at low temperatures and meet pharma quality requirements to maintain cell viability over its intended shelf life. Polypropylene is a plastic resin that has been used for decades in various packaging applications, including bottles, pouches, tubes and containers. However, these plastic resins have made minimal headway in the area of parenteral vials and prefillable syringes owing to various quality attributesiv.
Recent availability of newer plastic resinsv with key features such as glass-like clarity, lower potential for extractables, allowing for various modes of sterilisation, very low moisture permeability, biocompatibility and lower particulates – has enabled the use of these superior plastics for pharmaceutical and biopharmaceutical drug delivery applications. However, the use of vials has not yet been translated to cell-based biologic products, due in part to the lack of data on the ability of cells to be successfully cryopreserved and stored while maintaining viability and important functionalities relevant to therapies over a reasonable shelf life (e.g., six months).
In a recent study,i the suitability of a commercially available vial, West’s Daikyo Crystal Zenith, consisting of cyclic olefin polymer resin, was evaluated for low-temperature and cryopreserved storage of cell systems. These vials are currently being used to package and deliver pharma drugs in global markets, and are in development for biologic drugs, such as peptides, proteins and monoclonal antibodies vi, vii, viii. Being nonpolar, this particular vial has low moisture absorption and excellent drainability, which prevents water and liquid drug preparations from adhering to the vial surface. It is compatible with a wide range of pHs (2–12) and solvents, such as alcohols, ketones and dimethyl sulfoxide. It also has excellent thermal characteristics and can withstand cryogenic temperatures as well as sterilisation by autoclaving. Compared with polypropylene, it also has lower gas and moisture permeabilityix. Furthermore, the pharma industry is already accustomed to the filling of various – sized vials with drug and biologic products on a large automated scale, which is not available for bags.
From a mechanical standpoint, the Crystal Zenith vials exhibited excellent durability. No study vial exhibited gross breakage or cracking after a frozen drop test, which involves freezing 60 per cent full vials, dropping them at a height of one meter at a 15o angle to the lab floor, thawing them, and visually inspecting them. Slight damage occurred occasionally to the flip-off caps, but this did not compromise the closure integrity as demonstrated by the post-thaw dye and microbial immersion studies performed following typical transportation methods. These results, combined with the fact that none of the cell cultures became contaminated, provide good evidence that in any standard clinical application, vials provide robust container closure maintenance.
Overall, this initial proof-of-concept study indicated that the vials are highly suitable for cold and cryogenic storage of biological cells, and provide a suitable container system for clinical and commercial cell therapy products. The vials were easy to freeze and more convenient to use as compared with bags, as they could be adapted to existing storage configurations. From a practical standpoint, these vials are designed with standard dimensions (13 and 20 mm openings) that are capable of fitting into traditional pharma manufacturing filling lines.
Compliance with compendial requirements for containers and closures used in packaging systems for cellular therapy applications should be evaluated based on the final use of the product. However, based on recent research, Crystal Zenith vials may be the ideal replacement for bags as cellular therapies scale up in use and production for today’s clinical pathways.
i. Woods E, Aniruddha B, Goebel WS, Nase, R, Vilivalam, V: Container system for enabling commercial production of cryopreserved cell therapy products. Regen.Med. 5(4), 659-667(2010).
ii. Kirouac DC, Zandstra PW: The systematic production of cells for cell therapies. Cell Stem Cell 3, 369–381 (2008).
iii. Khuu HM, Cowley H, David-Ocampo V et al.: Catastrophic failures of freezing bags for cellular therapy products: description, cause, and consequences. Cytotherapy 4(6), 539–549 (2002).
iv. Akers MJ, Nail SL, Saffell-Clemmer W: Top ten topics in parenteral science and technology. PDA J. Sci. Technol. 61(5), 337–361 (2007).
v. Eakins MN: New plastics for old vials. Bioprocess Int. 3(6), 52–58 (2005).
vi. Esfandiary R, Joshi SB, Vilivalam V, Middaugh CR: Characterization of protein aggregation and adsorption on prefillable syringe surfaces. Presented at: AAPS National Biotechnology Conference. Toronto, Canada, 22–25 June 2008.
vii. Waxman L, Vilivalam V: Development of analytical techniques to determine protein adsorption on sterilized parenteral packaging containers and stoppers. Presented at: AAPS National Biotechnology Conference. Seattle, WA, USA, 21–24 June 2009.
viii. Qadry SS, Roshdy TH, Char H, Del Terzo S, Tarantino R, Moschera J: Evaluation of CZ-resin vials for packaging protein-based parenteral formulations. Int. J. Pharm. 252, 207–212 (2003).
ix. Daikyo Resin CZ Technical Report, West Pharmaceutical Services (2002) www.westpharma.com/ap/en/products/ Pages/ CrystalZenithRU.aspx.