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Biomedical subjects

A S Lubiniecki

Publications and source records attributed to A S Lubiniecki.

At least 19 recordsLinked to original sources
PubMed2003

Validation of fermentation processes.

The ability to prepare consistent biopharmaceutical products depends extensively on possession of banked and characterized cell substrates and on development of production processes which can be validated. While the attributes that define cell characterization have been extensively detailed by ICH and the regulatory agencies in the past decade, little has been specified regarding process validation for biological processes. The extent to which validation concepts can be applied to biological processes varies depending on the nature of the process, the nature of the product, and the level of knowledge regarding the relationship between process parameters and product quality. Expectations concerning the rigour of the validation programme should be adjusted accordingly. There is no single approach that is appropriate for all processes and products. At a minimum, there should be an attempt to define which process parameters are critical, and to focus the attention of validation efforts on these parameters.

Biotechnology↗
PubMed2001

Recent trends in cell substrate considerations for continuous cell lines.

Product development activity in the past five to ten years has reconstituted a version of an old debate on the safety assessment of biological products, namely whether the use of some types of continuous cell lines (CCLs) is appropriate in the preparation of some types of biological products. Since 1987, dozens of purified recombinant DNA products derived from CCLs have been developed and have received regulatory approval. In addition, several live attenuated and inactivated viral vaccines manufactured in CCLs were approved after thorough review of product safety and manufacturing issues. The current discussion revolves around the potential use of CCLs (human or not) to prepare purified protein subunit vaccines, such as for HIV, and the use of human CCLs to prepare purified protein products.

Animals↗
PubMed1999

Elimination of serum from cell culture medium.

Growth of continuous cell lines for preparing biopharmaceuticals in the absence of animal serum has been attempted by many organizations to improve process and product quality, prevent exposure to adventitious agents, and reduce costs. Literature surveys suggest that substantial academic studies on serum-free medium have been pursued for many decades, with varying levels of success for different cell types and cell lines in terms of achieving cell growth while retaining cell function. Industrial research proceeded for at least three decades. Recent work with CHO cells and with some hybridomas has been successful in providing the basis for serially propagating cells on a large scale in suspension in the total absence of serum, while preserving the ability to prepare biopharmaceuticals. In some cases, this can be achieved not only without serum, but also without the use of other animal-derived proteins.

Animals↗
PubMed1997

Raw material considerations.

Raw materials (RM) testing and control strategy form a major part of the foundation of a well-characterized protein (WCP) or biopharmaceutical. Raw materials may be present in the final vial as excipients or may have product contact earlier in processing. Manufacturers of WCPs should use a scientific approach to set acceptance criteria and test methods for bulk raw materials which are not present in dosage forms in substantial amounts. These methods and standards should enable the procurement of specified RMs which enable the reliable preparation of a product which consistently meets its quality attributes. Manufacturers of WCPs must use available pharmacopoeial standards for excipients and bulk process RMs which cannot be substantially removed during purification or other processing steps. Manufacturers should support efforts to harmonize pharmacopoeial standards for excipients.

Biopharmaceutics↗
PubMed1996

Current issues in viral assays and viral clearance evaluation.

Viral contaminants are less amenable then chemical contaminants to analytical detection due to the lower sensitivity, specificity and precision of existing assays. In combination with the potential for biological amplification of viral contaminants in cell substrates or product recipients these analytical limitations lead directly to potential risk of virus infection of product recipients. While less than perfect, a broad spectrum of assays is available to characterize cell banks for the presence of adventitious and endogenous agents. Each product lot can be tested by an appropriate subset of assays for selected viruses of concern. Engineering and procedural controls over facilities, equipment and operations are necessary to minimize the possibility of viral contamination. Processes can be designed to include unit operations to remove or inactivate specific viruses of potential concern; the efficacy of these measures can be evaluated. While each of these measures has value, each also has limitations. None is solely adequate by itself to the task of preventing potential exposure to viral contaminants in product recipients. Biopharmaceuticals (purified characterizable macromolecules) are prepared by using a combination of such preventive measures. Specific measures will vary from product to product, depending on the nature and origin of the cell substrate, cell bank characterization results, raw materials used, physicochemical properties of the biopharmaceutical, effectiveness of assays, available facilities, and the agents of concern. Thus, flexibility in approach is necessary, resulting in different combinations of measures for each set of circumstances. So far, this approach has been successful in preventing viral infection in large populations treated to date with cell culture-derived biopharmaceuticals. Current issues for discussion include appropriate assays for adventitious and endogenous agents, appropriateness of current control systems and the scientific basis for standards.

Biological Products↗
PubMed1994

Purified protein products of rDNA technology expressed in animal cell culture.

During the past 7 years, 14 versions of 7 rDNA proteins have been licensed which are derived from animal cell culture expression systems. These medically useful products have included hormones, coagulation factors, enzymes and a vaccine. Aspects of the molecular complexity, manufacture, control and utilization of these products are discussed. In contrast to previous generations of biological production technology, the technology for production of rDNA-derived proteins in animal cells appears to be safe.

Animals↗
PubMed1992

Effects of fermentation on product consistency.

A variety of different fermentation processes has been successfully employed to produce consistent protein-based biopharmaceuticals from genetically engineered animal cells. Chinese hamster ovary (CHO) cells were genetically modified to produce recombinant human soluble CD4, tissue plasminogen activator (tPA) or erythropoietin (EPO). Soluble CD4 was collected from extended perfused fermentations of several months' duration, during which some quantitative loss of DNA copy level, mRNA expression level, and fermentation titer were observed. In one extended run, a novel contaminant appeared in intermediates purified from later harvests. However, in all cases, the final soluble CD4 product was consistent in terms of purity and potency. Evaluation of genetic stability for tPA examined both biological traits at the cellular level as well as potency, purity and structure of product derived from cells at various levels of in vitro age; no significant cell age effects were observed. Similarly, evaluation of the EPO product showed that genetically-determined and process-determined traits such as potency, tryptic peptide mapping, and sialylation were consistent from lot to lot. These data exemplified how process design, process validation, and in-process and quality control assays can be used effectively to ensure the consistency of recombinant products derived from cell culture fermentations.

Animals↗
PubMed1990

Process validation for cell culture-derived pharmaceutical proteins.

Principles of process validation are extremely powerful tools in assurance of product quality. They are especially useful for reducing those risks not easily measured routinely during production. When combined with effective process and facility design principles, characterization of cell banks and products, appropriate lot release tests, and adherence to cGMP, safe cell culture biologicals can be prepared in a reliable manner.

Animals↗
PubMed1990

Continuous cell substrate considerations.

The debate over the potential risk of tumorigenicity attributable to the use of CCL substrates for biologicals production has continued for over 30 years and may continue for some time to come. Manufacturers and regulatory agencies are developing scientifically based guidelines for such products. It is currently possible to follow these guidelines to prepare recombinant biologicals and monoclonal antibodies in CCLs which do not pose unreasonable risks. This chapter has attempted to describe the scientific tools available to evaluate the putative risk of tumorigenicity due to potential virus DNA and protein contaminants. No theoretical or experimental basis exists to hypothesize that residual cellular protein might present a significant risk of tumorigenicity. The tools are certainly adequate for characterization of putative risks due to viruses and DNA but are not sufficiently powerful by themselves to assure product safety. The subsequent chapter on process validation describes how adequate assurances of safety ultimately can be obtained for products of CCLs against theoretical risks of tumorigenicity due to putative viruses and DNA. In addition to these safeguards, no evidence of tumorigenicity has been found in human or livestock animal recipients of the products prepared in CCL substrates. Many patients have received inoculations of tissue plasminogen activator, erythropoeitin, factor VIII, soluble CD4, GM-CSF, hepatitis B surface antigen vaccine, and various monoclonal antibodies and other recombinant products of continuous cell lines in clinical trials. For tissue plasminogen activator, large doses of 100 mg per patient or more have been used. At the time of writing over 10 kg of CHO-derived tissue plasminogen activator has been sold since late 1987 for administration to over 100,000 human patients. For recombinant factor VIII, erythropoeitin, and soluble CD4 proteins, chronic administration has been employed. Millions have received polio and rabies vaccines prepared in continuous Vero cells. In addition to this human experience, livestock animals have received annual inoculations of foot-and-mouth virus vaccine prepared in BHK-21 (a highly tumorigenic CCL) for up to 14 years without effect (69). No effects have been reported which might be attributed to oncogenic factors. Thus, scientific tools of characterization and principles of process validation are available to protect patients from putative risks of tumorigenicity associated with products prepared in CCLs. Increasing clinical experience also supports this conclusion.

Animals↗