Services
Custom Ligand/Adsorbent Development Programs
In addition to our range of standard adsorbent products, PBL also offers a custom ligand/adsorbent development service. Because of the enormous diversity of biomolecules, and the similarly large diversity of PBL’s ligand libraries, the most practical solution to identifying an appropriate Mimetic Ligand™ for a specific application (purification or removal) is to design or select a ligand against the biomolecule of interest. PBL offers a comprehensive Custom Ligand/Adsorbent Development Program to provide users with a fully validated affinity adsorbent and associated information required for operation in a downstream process. Selection of an optimal affinity ligand/affinity adsorbent enables high yields of highly purified protein with a minimum number of process steps.
PBL is able to develop Mimetic Ligand™ adsorbents tailored to suit almost any target biomolecule by use of Intelligent Combinatorial Chemistry® ("ICC") which comprises automated synthesis and screening of ligand libraries against the target biomolecule of interest. These programmes are conducted by PBL in-house and we work closely with the sponsor throughout. A typical ligand discovery/adsorbent development programme consists of three distinct stages and five key activities:
Custom Phases
At the beginning of a programme a list of the attributes and properties that are required of the affinity adsorbent are identified and agreed with the sponsor. These criteria serve as the basis for assessing the performance of a programme in achieving the desired objectives/performance at each stage of the programme and also serve as a list of critical performance parameters for the final adsorbent product.
A full ligand/adsorbent discovery program comprises the following components or phases:
Ligand discovery
Ligand Discovery
Both rational design and combinatorial chemistry approaches (ICC) are used to identify ligands suitable for use in adsorbent development. PBL's Chemical Combinatorial Libraries® are screened against the actual material to be purified using automated screening techniques. This ensures the ligand selected is able to bind and purify the target in the presence of the impurities expected to be present. Screening is performed with ligands bonded to a hydrophilic chromatographic solid phase, normally agarose beads (Purabead®), to ensure binding of the target protein is by interaction with the immobilised ligand and not the underlying support matrix. High-throughput assays are implemented to enable identification and quantification of both the target biomolecule and impurities. This information is used to identify Mimetic Ligands™ which are selective for the target protein. Based on information obtained from initial screening rounds, additional ligand libraries might be constructed and screened to facilitate the development and optimisation of ligands possessing the desired properties and capable of achieving target specifications. On completion of Ligand Discovery activities a report is issued and samples of adsorbent are provided to the sponsor for use in small-scale laboratory evaluations.
Adsorbent Development
Specific binding ligands identified during the discovery stage are further developed and, if necessary, studies performed to identify the most appropriate method of ligand attachment to support particles to provide an affinity adsorbent which meets the defined specifications. Factors such as ligand density and the requirement for a spacer linkage are also investigated at this point. The Adsorbent Development phase also includes the development of a defined manufacturing method for the adsorbent, including procedures for washing the adsorbent to remove any soluble components which remain following ligand attachment.
PBL's Purabead® support matrix (rigid near-monodisperse agarose beads) are used for the construction of the affinity adsorbent. A single ligand structure is selected for scale-up. Small adsorbent batches (up to 1 litre) are produced as a part of the Adsorbent Development phase and made available to the sponsor for laboratory-scale processing. On conclusion of the Adsorbent Development phase, written methods describing the manufacture of the affinity adsorbent (including raw materials, in-process and finished product controls) are produced in readiness for transfer to PBL's manufacturing facility located on the Isle of Man, British Isles.
Chromatography Development
Conducted in parallel with Adsorbent Development, Chromatography Development work is conducted to determine optimal conditions for using the identified adsorbent. Included in the Chromatography Development phase are investigations into loading, washing, elution, sanitization and regeneration procedures. The objective for this phase is achievement of the process performance criteria identified in the target specifications. An extensive adsorbent re-use study can be performed as part of this work.
Validation & Scale-Up
Procedures for manufacture of the affinity adsorbent are transferred to PBL's Isle of Man production facility. One or more trial lots (technology transfer batches) are made at small scale prior to validation of the manufacturing process at the desired process scale (up to 275 litre single batches). Manufactured batches are tested for conformance with the defined performance specifications. A validation plan and associated summary report are produced as a part of this activity which includes an assessment of the ability of the identified process to deliver a reproducible adsorbent product which meets target specifications. Validation batches are available to the sponsor for use in pilot-scale or process scale manufacture. Given the large batch sizes that can be accommodated during process validation, the cost of an adsorbent development programme can be off-set against the volume and value of adsorbent produced during process validation (which can be used for cGMP manufacture of biopharmaceuticals).
Regulatory Package
An extensive supporting package of information is developed and provided to the sponsor to assist with implementation of the adsorbent in regulated manufacturing processes and registration of the purification process. The Regulatory Package includes information derived from ligand leakage studies, adsorbent stability trials and, if required, toxicology studies.
Quality Systems
PBL is ISO 9001 accredited. All work performed as part of custom ligand / adsorbent development programs follow GLP/cGMP principles, and completed adsorbents are manufactured under controlled environment (clean room) conditions. PBL welcomes audits of its manufacturing and research & development facilities by potential sponsors and clients.
Partial Programmes/Contract Manufacture
Owing to their modular structure, Custom Ligand/Adsorbent Development Programmes can be conducted with time intervals between the completion of one phase and commencement of the next. This flexibility can be useful in situations where the target biomolecule is in early-stage clinical development and positive results from Phase I or Phase II clinical trials are required before committing to investment in large scale manufacture. In such situations the Custom Ligand/Adsorbent Development Programme can be paused on completion of Ligand Discovery or the Adsorbent Development phases pending a decision on future adsorbent manufacture and scale-up. In situations where you may have developed your own affinity adsorbent material but lack the ability to manufacture process-scale quantities, or perhaps you may be seeking to outsource the manufacture of an adsorbent developed in-house, PBL would be pleased to discuss your requirements.
If you require further information or indeed wish to make an enquiry about our Custom Ligand/Adsorbent Development Programs then please contact us at sales@prometicbiosciences.com