Biowaste Management During Biopharmaceutical Plant Start-Up: From Regulatory Guidance to Verified Inactivation Methods - - BioPharm International

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Biowaste Management During Biopharmaceutical Plant Start-Up: From Regulatory Guidance to Verified Inactivation Methods


BioPharm International


Chinese hamster ovary (CHO) cells are one of the most commonly utilized expression systems for the production of biopharmaceutical products, principally because they have been well-characterized and there is a history of regulatory approval for recombinant proteins produced from these cells. Employing recombinant DNA technologies, CHO cells used in the biopharmaceutical industry are genetically manipulated enabling the production of proteins of interest. These cells are classed as genetically modified microorganisms (GMM). Current European Union (EU) legislation requires the biopharmaceutical industry to comply with regulations governing the contained use of GMM (Council Directive 98/81/EC, amending Direc-tive 90/219/EEC).1 In Ireland, the Environmental Protection Agency (EPA) is the competent authority responsible for the implementation of Directive 98/81/EC, transposed into Irish law by the Genetically Modified Organisms (contained use) Regulations, S.I. No. 73 of 2001. The directive covers any activity involving the genetic manipulation, culturing, usage, storage, and destruction of GMM. Under the directive, there is a mandatory requirement for waste-containing Class 2 to 4 GMM to be inactivated prior to discharge. Inactivation of Class 1 GMM is optional but may be stipulated in certain circumstances by the competent authority. Inactivation refers to the destruction of GMM, ensuring that subsequent contact between the GMM and the general public or environment is limited, thereby providing an enhanced level of protection.

GMM inactivation may be achieved by thermal or chemical treatment. Heat treatment is the most common method of inactivating liquid effluent and may involve autoclave decontamination or the use of heat inactivation or "kill" systems.2,3 Chemical treatment involves the addition of a bactericidal agent capable of inactivating the GMM and generally consists of the manual addition of chemicals such as chlorine, caustic solutions, or iodophor compounds.


Figure 1. Wyeth Medica Ireland's New Biopharmaceutical Campus in Dublin, Ireland
In consultation with the EPA, a strategy was established for managing GMM waste during start-up and commercial operations at Wyeth BioPharma's new biopharmaceutical manufacturing facility in Ireland (Figure 1). The EPA required that all GMM waste be inactivated prior to discharge from the facility, including Class 1 organisms. This is a customary approach for most companies in the EU. Verification of cell-inactivation methodology prior to its site-wide implementation was also agreed upon in consultation with the EPA. A routine inactivation strategy based on autoclave inactivation and a heat "kill" system was devised for solid- and large-volume liquid waste, respectively. Cell inactivation based on sodium hypochlorite (NaOCl) addition was planned for routine use in the quality control and development laboratories for small culture volumes. Inactivation by sodium hydroxide (NaOH) addition to large-volume liquid waste was devised for use during the cell culture facility start-up, prior to commissioning and qualification of the "kill" system. It would also be available as a backup for the "kill" system during routine operation.

Literature supporting the effectiveness of heat-inactivation systems for the destruction of mammalian cells is available.4 Although chemical treatment is a classical method of cell inactivation, there is a shortage of published information pertaining to its modes of use and efficacy for CHO cells and other GMM. Bench-scale trials were performed to characterize the chemical-inactivation schemes. This paper outlines the definition and verification of the NaOH- and NaOCl-based processes for inactivation of a CHO cell line producing a recombinant therapeutic protein.

CHEMICAL INACTIVATION STRATEGY

NaOCl is a broad-spectrum antimicrobial agent.5 However, its corrosive nature renders it unsuitable for in situ cell inactivation in stainless-steel stirred tank reactors. NaOH, as a disinfectant and cleaning agent, is compatible with stainless-steel tanks, is effective in dissolving proteins and denaturing nucleic acids, and is widely used in the pharmaceutical industry for cleaning, sanitizing, and system storage.5 As NaOCl and NaOH are sensitive to the chemical environments in which they are used and their activity may be modulated by the presence of large amounts of protein, validation of the inactivation procedures is required to confirm that inactivation is effective and reproducible within normal working conditions at the site.


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