June 1, 2012
In 2003, BPI’s first year of publication, the Food and Drug Administration released a draft of its updated guidelines on aseptic processing. In it, the agency included the statement, “A well-designed positive pressure isolator, supported by adequate procedures for its maintenance, monitoring, and control offers tangible advantages over classical aseptic processing, including fewer opportunities for microbial contamination during processing” (1).That kind of statement, seemingly approving one technology over another, was unprecedented in an FDA guidance and perhaps an indication of the industry’s future emphasis in aseptic processing. Today, maintaining the sterility and quality of biologic products through aseptic fill and finish operations, whether conducted in isolators or cleanrooms, remains a vital part of the bioprocessing industry.
Advances in barrier isolation, single-use technologies, automation, and packaging moved fill and finish operations in line with the FDA’s quality by design principles and risk management, especially in contamination monitoring and control. In an interview with BPI last year, Ryan Hawkins (vice president of drug product operations at Cook Pharmica) said, “No question that automated inspection provides a more robust and consistent inspection for all drug product defect criteria. I would expect that as container shapes and materials evolve from traditional glass, handling mechanisms will need to adjust to perform the inspections, not scratch material, and transport units effectively” (2).
These vials of lyophilized product in a Seidenader inspection machine appeared on the cover of BPI in November 2011. ()
The Outsourcing Option
Contractual partnerships for final fill and finish operations is a common practice, and several contract organizations tailor their services to the biologics industry (e.g., Althea, Microtest, Cook Pharmica, Vetter). When working with a contract provider, a sponsor company should make sure to discuss certain vital points. That involves detailing the product’s appearance and physical state (whether a liquid or lyophilized solid), packaging and labeling, and how the product will be stored and administered in the clinic. A sponsor should ensure that a batch-record preparation and approval is agreed upon so that the fill schedule is met. (A batch record details all activities associated with filling, including components, volumes, and release assays as well as any buffer preparation and in-process testing required.) Technical considerations include facility design, a CMO’s validation status, and its quality system (3). Elements of Filling
Filling machines come in various configurations and formats, including stainless-steel syringe-type and peristaltic. Several factors influence selection of a filling machine (in addition to footprint, operation, and cost), including a product’s characteristics (solubility, viscosity, and foaming tendency); vial properties; stoppers or other closure components; sealing; validation, cleaning, and sterilization method (4).
Current filling operations occur in barrier isolators (closed or open) or within dedicated modules. Sterilization of aseptic fill isolators continued as a topic of discussion during the past decade. Ten years ago, use of vapor-phase hydrogen peroxide (VPHP) was the prominent method for sterilization of closed barrier isolators for aseptic filling and other operations. The use of chloride dioxide gas, however, was gaining attention and has shown comparable results as an alternative. Chlorine gas is noncorrosive to common industrial construction materials, and it is less expensive (based on efficiency) than other broad-spectrum, high-performance sterilization agents (e.g., VPHP). A challenge with that method, however, is a lack of efficient means of generation (5). One early BPI article describes high-level spore reduction from the use of a prototype chlorine dioxide gas generator to successfully disinfect the interior surfaces of an isolator (6). One of the greatest advantages of VPHP is that when the process is finished, water and oxygen are all that are left. Wintner et al. compared some sterilization methods, including the use of chlorine dioxide gas (5).
A vial’s or syringe’s construction material is also important. Glass, vials, and ampules were traditionally made of USP Type I or II glass. But during the past 10 years, product recalls raised concerns (e.g., Amgen’s Epogen and Procrit recall in 2010) specific to glass delamination and the presence of glass flakes (lamellae) and breakage (7). Some manufacturers have sought alternative materials such as using cyclic olefins for vials and prefilled syringes (8). Changes in component materials and design have helped to make prefilled syringes a fast growing segment of the industry during the past decade (2, 9) and have led to innovations in prefilled designs and mechanisms of action, including microinjection systems (e.g., Soluvia microinjection system, BD).
As in many parts of downstream processing, aseptic filling has benefited from implementation of single-use technologies. Gamma-sterilized disposable bags, transfer sets, connectors, and rapid-transfer ports are commercially available and can be sent to a manufacturers for immediate use in aseptic fluid transfer. Cost comparisons and design optimization studies of such technologies with those of traditional materials show favorable results associated with disposables implementation (10,11,12). Packaging
Packaging has been described as “the first line of defense for all formulated drugs. A good package protects its contents from the outside world and vice versa. The vial, stopper, and seal materials must be fully compatible with a product, whether it is lyophilized or in solution” (13). A product’s primary package must maintain product purity, activity, and shelf life through transportation and storage, especially for parenterals, which are still the delivery mechanism of most biologics.
Strong consideration must be taken to a product’s sensitivity to heat, light, and chemical contaminants as well as any interaction with packaging and/or container–closure components (leachables and extractables) (14). Lyophilized drugs are sensitive to moisture, so an inadequate seal can allow water and other contaminants to enter a package. Some biopharmaceuticals are sensitive to silicone oil (used to lubricate elastomeric stoppers during fill and finish to facilitate insertion of stoppers into vials). It has been associated with inactivation through nucleation of proteins around oil droplets.
An increasing number of companies are using contract providers (e.g., ALLpaQ Packaging Ltd., AAI Pharma) for packaging and clinical packaging services. Key considerations when working with a packaging company include regulatory compliance, level of automation, and flexibility of scale (15).
Anticounterfeiting and security measures have increased during the past decade, especially for products such as pandemic-flu vaccines and high-valued monoclonal antibodies. In 2004, the FDA issued a final rule requiring certain human drug and biological product labels to have bar codes (16). In 2007, Millipore (now EMD Millipore) announced that it had become the first company to embed radiofrequency identification (RFID) tags in its filtration products.
Experts have argued for the investment in anticounterfeiting measures during the past decade (17,–18). Advanced systems include multilayerd authentication codes for each dose and/or vial (e.g., NanoEncryption technology, NanoInk, division of NanoGuardian) and sophisticated track-and-trace networks for supplies and finished products (e.g., Tracelink).
About the Author
Author Details
Maribel Rios is managing editor of BioProcess International; [email protected].
1.) Guidelines for Industry: Sterile Drug Products Produced by Aseptic Processing. Finalized September 2004.
2.) McLeod, LD, SA Montgomery, and C. Scott. 2011. Fill and Finish for Biologics. BioProcess Int. 9:34-46.
3.) Butler, B, J Luczak, and LJ. Schiff. 2003. Outsourced Aseptic Fill/Finish and Stability Programs for Biopharmaceuticals. BioProcess Int. 1:44-50.
4.) Smith, KA 2006. Considerations for Aseptic Filling of Parenterals 4:12-17.
5.) Wintner, B, A Contino, and G. O’Neill. 2005. Chlorine Dioxide, Part 1: A Versatile, High-Value Sterilant for the Biopharmaceutical Industry. BioProcess Int. 3:42-46.
6.) Eylath, A. 2003. Successful Sterilization Using Chlorine Dioxide Gas: Part One: Sanitizing an Aseptic Fill Isolator. BioProcess Int. 1:52-56.
7.) Reynolds, G, and D. Paskiet. 2011. Glass Delamination and Breakage. BioProcess Int. 9:52-57.
8.) Eakins, MN. 2005. New Plastics for Old Vials. BioProcess Int. 3:52-58.
9.) Otto, T. 2007. Wave of the Future: Prefills Emerge As a Major Growth Market. BioProcess Int. 5:24-29.
10.) Zandbergen, JE, and M. Monge. 2006. Disposable Technologies for Aseptic Filling. BioProcess Int. 4:S48-S51.
11.) Paganini, G, and L. Machulez-Hellberg. 2007. Single-Use Technologies Bring Flexibility to Final Filling Operations. BioProcess Int. 5:84-88.
12.) Jenness, E, and V. Gupta. 2011. Implementing a Single-Use Solution for Fill-Finish Manufacturing Operations. BioProcess Int. 9:S22-S26.
13.) DeGrazio, FL. 2006. Parenteral Packaging Concerns for Biotech Drugs: Compatibility is Key. BioProcess Int. 4:12-16.
14.) Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics — Chemistry, Manufacturing, and Controls Documentation. May 1999
15.) DeGrazio, FL. 2010. Increasing Biopharmaceutical Quality Through Packaging Partnerships. BioProcess Int. 8:16-20.
16.) Zordan, SM. 2004. The FDA’s Final Rule on Bar Coding. BioProcess Int. 2:28-30. https://bioprocessintl.com/wp-content/uploads/bpi-content/0210ar04_76754a.pdf
17.) Konski, A. 2008. IP Strategies to Combat Distribution of Counterfeit Drugs. BioProcess Int. 6:2-5.
18.) Dillon, RL, and JF. Noferi. 2008. How to Justify Investment in Anticounterfeiting. BioProcess Int. 6:24-29.
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