• Development
• Production
• Purification
• Biopharmaceutical Quality Operations

• Optimization of expression of recombinant proteins
• Cell Banking and optimization of growth conditions
• Bulk manufacture of monoclonal antibodies
• Fermentation for production of recombinant proteins and natural products
• Development and execution of purification protocols
• Aseptic processing and filling operations

Capabilities

The YalePharma has the capacity to develop processes and to produce proteins and other bilogical materials following cGMPs in both mammalian cells and microbial systems.

The YalePharma provides cGMP documentation for Chemistry, Manufacturing and Control (CMC) sections for incorporation in INDs. Cost accounting of projects allows fair recovery of costs from users, and aids cost control measures. Projects have been supported by funds from several sources.

The facility can provide support for translation from basic research to production of clinical materials.

Three types of services for production exist:

• Small quantities of material in support of basic/discovery research from novel cDNA's which code for interesting new proteins that may be implicated in disease processes. These quantities of protein would also support testing in small animal models.

• Larger quantities of well characterized material for preclinical testing in animal models. This activity supports evaluations of efficacy and toxicity in appropriate animal models of disease.

• Clinical-grade material to support final preclinical work, IND submission, and Phase I and II clinical trials.
  

Development

The development group deals with incoming projects at initial stages including evaluation of recombinant constructors, yield, efficiency, and characterization of products. This group also focuses on process development after initial evaluation for supporting cGMP production in YalePharma.

This laboratory has the capacity to construct recombinant bacterial strains and cell lines. Both eukaryotic and prokaryotic systems are employed to generate high expression clones which are selected, evaluated and stored under cGMP conditions as Master Cell Banks. The scientific staff has expertise in a variety of fermentation processes including bacterial, yeast, fungi, insect and mammalian cell culture. Process optimization is the primary focus of the group.

The laboratory currently has 2,000 square feet of laboratory space equipped with PCR, Gel documentation system, column chromatography system, preparative HPLC, environmental shakers, several 20L scale fermentors both researches and process development. 7.5L scale stir tank bioreactors and 80L scale fermentors are in the process of being set up. This group is using and developing novel technologies for the general improvement of yield, efficiency, and quality of biological products. This group can also supply preclinical material for proof of principle in suitable quantities to support studies in animal models, while it's developing optimal, safe, cost effective, scalable, and reliable process for fermentation, recovery, purification, and formulation of the protein.


Production

The Production group focuses on implementation of highly efficient bioreactor production utilizing mammalian and microbial fermentation pilot plants with capacity for product recovery. Bacterial fermentation production and recovery capacity consists of two 30-gallon-300 gallon fermentors and one 3,000 gallon fermentor. Recovery equipment, well-matched to fermentor output, includes a variety of solid/liquid separators, and extraction tanks. The bacterial fermentation plant has recently undergone extensive renovation consistent with current industry standards for producing clinical materials for pre-pivotal studies (Phases I and II). A number of methods are available for concentrating and recovering crude, partially pure and highly pure materials derived from fermentation broths and other suitable starting materials. A new cGMP fermentation plant, presently under construction, will have 100L and 1,000L fermentors as well as down stream processing equipment. A separate facility is utilized for product purification, formulation and filling.

Mammalian cell culture production is currently performed utilizing Cellex's Maximizer and Cellex Xcell hollow fiber bioreactors. Initial working cell banks are expanded in roller bottles to inoculate hollow fiber bioreactors. Capabilities for implementation of stir tank technology are being refined.

Purification

The production of biologics poses special challenges, including stability and aggregate formation. These product characteristics receive considerable attention from YPRI scientists. Formulation expertise is applied for preparation of product in final container in a form that is stable and appropriate for the intended use. This group can study new formulation and delivery technologies to increase the potency and specificity of the drug.


Biopharmaceutical Quality Operations

Biopharmaceutical Quality Operations (BQO) ensures compliance and conformance with appropriate Current Good Manufacturing Practice (cGMP) regulations through the following units:

• BQO Quality Control Laboratory provides reliable, cost-effective and high quality product characterization and pharmaceutical development testing services, which include method development/validation, formulation development, stability evaluation, and process development/validation services.

• The Quality Audit group identifies, qualifies and maintains surveillance of in-house and outsourced repository, testing, shipping, process development, and production activities.

• The Documentation Group manages Standard Operating Procedures and Instructional Worksheets for GMP production. This group also coordinates complete development of Chemical, Manufacturing, and Control (CMC) sections for Investigational New Drug Applications (INDs) and prepares Drug Master Files (DMF).

• Validation Engineering provides utility design review and validation, process equipment design review and validation, automation validation, cleaning validation, calibration and maitenance of equipment, revalidation program, and change control program.