Overview of Aseptic Fill/Finish Manufacturing
Overview of Aseptic Fill/Finish Manufacturing
Douglas Stockdale, President, Stockdale Associates, Inc.
American Pharmaceutical Review
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Editorial note: This article was written prior to the new FDA Guidance for Aseptic Processing being published. The second part of this article to be published in the near future will reflect the new Guidance recommendations.
Provide an overview of the critical manufacturing process, aseptic fill/finish production of sterile products.
This article is the first of a two part series to provide a broad overview of the aseptic fill/finish manufacturing process. This first article will discuss the background of aseptic products and the operational requirements of the aseptic operation. This will include the personnel, cleanroom, preparations, and the fill/finish process equipment and a brief discussion of the sterile lyophilzation requirements. The second article will discuss the global regulatory and compliance requirements and will include the process validation of an aseptic manufacturing operation.
Aseptic filling of sterile drugs, also know as sterile filling, still remains one of the most critical processes in biopharmaceutical manufacturing. This is due to its highly technique driven processes and the potential safety impact to the end user, usually an already compromised patient. There are only indirect safeguards for the sterility of the filled drug after it is stoppered and capped in the cleanroom.
Unlike terminal sterilized filled drugs, the stability of the aseptic filled drugs will be affected by steam autoclave, dry heat ovens, Ethylene Oxide, and irradiation, either Cobalt 60 Gamma or E Beam. Thus the need to utilize an aseptic process to fill certain biologicals, pharmaceuticals and biotechnology drugs.
The history of aseptic fill/finish processing is relatively recent with the sterility requirements for injectables being established in the 1920s and large scale biological manufacturing of blood and plasma products during WWII. Plasma products did have, and some products still use, a post-fill pasteurization process of low heat treatment of 60?C for 10 hours. Pasteurization does not provide sterility, but can reduce the contamination of fungi. Anti-fungicidal reagents were also added to parenteral drugs to help mitigate the contamination that was occurring with early aseptic processing.
Then in an effort to help improve consistency in aseptic processing, the Parenteral Drug Association (PDA) published its Aseptic Validation Technical Report in 1981 . This was followed by the Food & Drug Administration (FDA) in 1987 with its Aseptic Processing Guidelines . The International Society of Pharmaceutical Engineering (ISPE) published its Sterile Facilities as part of their Guidelines Series in 1999 . Recently, the FDA published its Concept Paper: Aseptic Guidelines in 2003 .
Aseptic filling is an aseptic process that requires the close coordination and complex interaction between personnel, sterilized product, the fill/finish equipment system, cleanroom and support facilities, and sterilized filling components.
There is also the perception issue for aseptic fill/finish, which is another reason for the many safeguards that I will discuss shortly, since micro contamination is not readily visible. Micro contamination is very small, and the surfaces that look clean and sterile may in fact not be. Thus the aseptic fill/finish processes are highly dependent on technique, detailed procedures, equipment and controls.
As with our industry, there are many global regulatory requirements for aseptic/sterile fill/finish manufacturing. Although each country or geography has its regulatory guidance, we have not yet achieved full harmonization. Most of these are listed in this article's appendix, and I will be only briefly discussing the current FDA 1987 Guidance. This FDA Guidance provides a couple of nice definitions for us.
"In aseptic processing, the drug product, container and closure are subjected to sterilization processes separately and then brought together. Because there is no further processing to sterilize the product after it is in its final container, it is critical to the maintenance of product sterility that containers be filled and closed in an environment of extremely high quality."
We also have written in the Code of Federal Regulation (CFR), section 21 CFR 211.113 (b) that states
"Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization processes."
Another section, 21 CFR 211.167 (a) states
"For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be appropriate laboratory testing to determine conformance to such requirements. The test procedure shall be in writing and shall be followed."
Currently, the FDA has been expressing a number of concerns about aseptic manufacturing, citing all drugs recalled due to non-sterility over the last 10 years were produced by aseptic processing (Spring 2002). If you drill down in these recalls, you will find that there are a few companies who have multiple recalls, and that there are a lot of "documentation" recalls. These are situations in which the documentation or procedures had omissions and errors and as a result a recall was initiated. The consensus within our industry is that, in fact, we have been getting much better with our aseptic filling processes