Using partition designs to enhance purification process understanding

Pieracci, John; Perry, Leonard A.; Conley, Lynn

doi:10.1002/bit.22866

Cited by 14 publications

(7 citation statements)

References 80 publications

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“…The need for increased process knowledge, not only on new biopharmaceutical processes but also on existing processes, promotes the application of scale‐down models for rapid acquisition of relevant data. Scale‐down models, used in combination with a design of experiments approach, allow the development of cause and effect models on input and process parameters, their interactions and influence on product attributes, either as single unit operations or as consecutive units using for instance partition designs (Perry et al, 2007; Pieracci et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Scale‐down of the inactivated polio vaccine production process

Thomassen

Oever

Vinke

et al. 2012

Biotech & Bioengineering

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The anticipated increase in the demand for inactivated polio vaccines resulting from the success in the polio eradication program requires an increase in production capacity and cost price reduction of the current inactivated polio vaccine production processes. Improvement of existing production processes is necessary as the initial process development has been done decades ago. An up-to-date lab-scale version encompassing the legacy inactivated polio vaccine production process was set-up. This lab-scale version should be representative of the large scale, meaning a scale-down model, to allow experiments for process optimization that can be readily applied. Initially the separate unit operations were scaled-down at setpoint. Subsequently, the unit operations were applied successively in a comparative manner to large-scale manufacturing. This allows the assessment of the effects of changes in one unit operation to the consecutive units at small-scale. Challenges in translating large-scale operations to lab-scale are discussed, and the concessions that needed to be made are described. The current scale-down model for cell and virus culture (2.3-L) presents a feasible model with its production scale counterpart (750-L) when operated at setpoint. Also, the current scale-down models for the DSP unit operations clarification, concentration, size exclusion chromatography, ion exchange chromatography, and inactivation are in agreement with the manufacturing scale. The small-scale units can be used separately, as well as sequentially, to study variations and critical product quality attributes in the production process. Finally, it is shown that the scale-down unit operations can be used consecutively to prepare trivalent vaccine at lab-scale with comparable characteristics to the product produced at manufacturing scale.

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Section: Introductionmentioning

confidence: 99%

Scale‐down of the inactivated polio vaccine production process

Thomassen

Oever

Vinke

et al. 2012

Biotech & Bioengineering

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“…Affinity chromatography (a single step purification step) was applied for the purification of monoclonal antibodies [31]. The application of partition designs to a monoclonal antibody purification process was reported [32]. Affinity tags are highly efficient tools for protein purification [33].…”

Section: A Purification and Downstream Processing Strategiesmentioning

confidence: 99%

Exploiting the Power of Stereochemistry in Drugs: An Overview of Racemic and Enantiopure Drugs

Sekhon¹

2013

J. Mod. Med. Chem.

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Stereochemistry is one of the essential dimensions in pharmacology as it dictates how enantiomers interact with biological systems. Chirality is very important in drug design. Enantiomers of the same chiral drug can have different pharmacodynamic and/or pharmacokinetic properties. In this context, replacing some existing racemates with single isomers has resulted in improved safety and/or efficacy profile of various racemates. Single enantiomer drug use can potentially lead to simpler and more selective pharmacologic profiles, improved therapeutic indices, simpler pharmacokinetics due to different rates of metabolism of the different enantiomers, decreased drug interactions, and drug companies are increasingly using chiral switching as a marketing strategy. Additionally, due to different pharmacological activity, enantiomers of chiral drugs can differ in toxicity. However, unpredicted toxicity has been reported in some chiral switching cases which has resulted the withdrawal of the enantiomer from the market or a halt in its development. In view of above, before switching to single enantiomer drugs, prescribers should look for evidence from well-conducted clinical trials to prove that the chiral switch is cost-effective and improves the outcomes for patients rather than patents. The U.S. Food and Drug Administration (FDA) have allowed single enantiomers of generic drugs to be patented and marketed under different name. FDA regulations require that all chiral bioactive drug molecules must be isolated and tested for the efficacy and safety, and have to be as pure as possible containing a single pure enantiomer.

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“…So far, few contributions consider interactions across unit operations for process optimization purposes [17]. Especially the application of partition designs for the assessment of parameters across unit operations to build predictive models across entire processes is noteworthy [18]. However, to our knowledge, there is no easy and comprehensive strategy published so far which is applicable to be applied within the QbD context.…”

Section: Parameter Interactionsmentioning

confidence: 99%

An Integrated Downstream Process Development Strategy along QbD Principles

et al. 2014

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The development, optimization, and analysis of downstream processes are challenged by a high number of potentially critical process parameters that need to be investigated using lab-scale experiments. These process parameters are spread across multiple unit operations and potentially show interactions across unit operations. In this contribution, we present a novel strategy for bioprocess development that considers the risk of parameter interactions across unit operations for efficient experimental design. A novel risk assessment tool (interaction matrix) is introduced to the Quality by Design (QbD) workflow. Using this tool, the risk of interaction across unit operations is rated. Subsequently, a design of experiments (DoE) across unit operations is conducted that has the power to reveal multivariate interdependencies. The power of the presented strategy is demonstrated for protein isolation steps of an inclusion body process, focusing on the quality attribute inclusion body purity. The concentration of Triton X-100 in the course of inclusion body (IB) purification was shown to interact with the g-number of the subsequent centrifugation step. The presented strategy targets a holistic view on the process and allows handling of a high number of experimental parameters across unit operations using minimal experimental effort. It is generically applicable for process development along QbD principles.

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Using partition designs to enhance purification process understanding

Cited by 14 publications

References 80 publications

Scale‐down of the inactivated polio vaccine production process

Scale‐down of the inactivated polio vaccine production process

Exploiting the Power of Stereochemistry in Drugs: An Overview of Racemic and Enantiopure Drugs

An Integrated Downstream Process Development Strategy along QbD Principles

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