Chapter 11
Start-Up and Validation of Sterile Formulation and Filling Processes for the Manufacture of Parenteral Aluminum Hydroxide-Based Vaccines 1
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Downloaded by GEORGE MASON UNIV on June 15, 2014 | http://pubs.acs.org Publication Date: July 23, 1998 | doi: 10.1021/bk-1998-0698.ch011
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R. A. Ramelmeier , P. M. McHugh , M. S. Rienstra , C. J. Orella , W. L. Stobart , M. W. Henley , and R. D. Sitrin 1
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Merck Research Laboratories and Merck Manufacturing Division, West Point, PA 19486 Merck Research Laboratories, Rahway, NJ 07065-0900 3
The start-up and validation of sterile processes for manufacturing parenteral vaccines involves a considerable effort across many disciplines. Using Merck's Hepatitis A vaccine (VAQTA) as a primary example, the start-up and validation challenges associated with sterile formulation and filling are described. Process robustness was generally determined employing a worst-case analysis of the critical parameters and their effect on the critical quality attributes, which were identified in prior characterization studies. The final validation of the processes was completed during production demonstration lots. The formulation process was validated based on the performance of the first ten consecutive lots, while the formal validation of the dilution and filling steps was based on 3 consecutive lots within the first ten. While manufacturing parenteral formulations, the final sterile steps are particularly critical. Failure at this point results in a considerable loss of invested time and resources. Of utmost importance, however, is the quality of the final product, which is a human injectable. Consequently, the FDA has placed considerable emphasis on process validation for sterile products since the mid 1970's (1,2). Process validation provides higher assurance for batch-to-batch success and greater confidence that the product will meet its pre-determined specifications and quality attributes. When executed properly, validation can benefit a company by assuring a controlled process and a high quality product without significant testing in the long term. According to the Pharmaceutical Manufacturer's Association (PMA), prospective validation (rather than retrospective) must be performed for the validation of sterile processes (3). Routine end-product testing is inadequate because it cannot assure product quality due to limited statistical sampling. This is particularly true for the sterility test where a product batch with a true 1.0% contamination would be 4
Formerly in Bio/Sterile Validation in the Merck Manufacturing Division.
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©1998 American Chemical Society
In Validation of Biopharmaceutical Manufacturing Processes; Kelley, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
145 released eight times out of ten based on the USP sterility sample size of 20 units out of 1000 (3). Many aspects of the manufacturing process require close scrutiny via a welldocumented validation program, including the equipment and control systems, the facility and its environmental conditions, raw materials and quality testing, personnel, and the process itself. This chapter will focus primarily on the sterile formulation and filling processes, their related equipment, and the unique start-up and validation challenges associated with aluminum-based vaccines. The other aspects of validation have been summarized thoroughly elsewhere (4-6).
Downloaded by GEORGE MASON UNIV on June 15, 2014 | http://pubs.acs.org Publication Date: July 23, 1998 | doi: 10.1021/bk-1998-0698.ch011
Background The start-up and validation approaches discussed in this chapter are based on experiences with Merck's aluminum hydroxide-adsorbed vaccines for immunization against Hepatitis A (VAQTA) and Hepatitis B (RECOMBIVAX HB), with major emphasis on VAQTA (7). VAQTA is derived from an attenuated picornavirus that is highly purified, then inactivated in a low concentration of formaldehyde (8). RECOMBIVAX HB is a recombinant surface antigen from yeast (9). Both vaccines possess complex macromolecular structures. The protein antigens are adsorbed to an aluminum-based adjuvant to improve immunological response; these adjuvants possess a long history of safety and efficacy in humans. (10-12). Currently, only the aluminum-based adjuvants have regulatory approval for routine injection into humans. The exact mechanisms for the improved immunological response are not known; a "depot effect" or enhanced recognition due to its large size are believed to play a major role (13). There exist a number of aluminum-based adjuvants (11-14). The adjuvant is created by precipitating aluminum into aluminum hydroxide lattices, which polymerize into higher-ordered structures over time. This polymerization releases hydrogen ions making long-term pH difficult to control (11,12). pH control is an important aspect of the validation effort as will be discussed below. Aluminum-based vaccines present several challenges, making process development, characterization and scale-up particularly difficult. The first is the sterility requirement. Since the product cannot be sterile-filtered after adsorption to aluminum hydroxide, all process steps subsequent to the precipitation step must be carried out under aseptic conditions and preferably in a closed vessel. These formulations generally do not contain preservatives; sterility must rely completely on the sterile process. To decrease risks during sterile processing, a closed system is the preferred route. To attain this added level of assurance, however, a considerable validation effort is required; the closures must be validated using pressure-hold, helium-leak, and/or microbial challenge tests, while the sterilization cycles must be validated using biological indicators. Closed systems can be sterilized and maintained in several ways. For fixed stainless-steel vessels and piping, the technology for SIP (sterilization-inplace) has been well-developed. Sampling and transfer from such systems require special valving configurations to steam-sterilize the connections. For small-scale bottles or stainless-steel cans (
