Manufacturing Process

Charles M. Ndarathi, D.V.M., Ph.D.

** ******** ****

Louisburg, NC 27549

E-mail: **********@*****.***

Cell: 315-***-****

PROFILE

Scientist with over 10 years of Research and Process development including cGMP manufacturing and Quality Assurance of biologics and recombinant proteins. Extensive experience in drug discovery, protein purification and development of processes for pre-clinical and clinical production, process controls, CAPA development, process optimization, evaluation and improvement to increase product quality and yields, while cutting down production costs. Great experience in bioprocess scale-up, transfers and validation and execution of processes, from lab- scale through pilot and manufacturing scales as well as development of manufacturing scale- down models for troubleshooting full scale manufacturing processes. Dedicated scientist also with significant experience in cell culture, a team player with excellent technical writing, problem- solving and management skills.

AREAS OF EXPERTISE

• Protein Purification

• Column Chromatography

• cGMP Manufacturing and

Contract Manufacturing

• Drug Discovery and

Development (R&D)

• Process Scale-Up and

Optimization

• Ultrafiltration/ Diafiltration

• Pre-Clinical Development

• Process Development

• Process Validation

• MBR’s, SOP’s, Review and

Development

• CAPA Development

• Process Controls

• Cell Culture/Fermentation

• Protein Expression

• Monoclonal Antibodies

• Deviation Mitigation

• IND/BLA Submission

• Technology Transfer

• Troubleshooting/Problem

Solving

• GLP, cGMP, GCP

• Training/Staff Development

CAREER HIGHLIGHTS

Overseeing diverse manufacturing of Biotherapeutic molecules in Third Manufacturing Facilities. Downstream subject matter expert overseeing several projects in the manufacture of recombinant drug substance proteins in contract manufacturing organizations both locally and overseas (Bristol Myers Squibb Company)

Developed robust biopharmaceutical process that increased yields 15% and purity 25% above target (saving over $6.5 million in manufacturing startup costs and several million in running costs) by resolving inherited process bottlenecks and reducing waste. As Lead Scientist for a key plasma-derived product (Alpha 1MP) for chronic emphysema, turned around non-manufacturing compliant process through complex evaluation of chromatographic conditions needed to improve both yield and purity to acceptable levels taking process from bench to clinical scale (100-fold scale-up) and commercial scale (1000-fold scale up). Honored with several on the Spot awards and company’s most prestigious Premier Circle Award. Talecris Biotherapeutics (Formerly Bayer HealthCare, LLC)

Created innovative, scalable biopharmaceutical process for a new product that increased yields two-fold, reduced production time 75%, and enabled production of pre-clinical material for both in vivo and in vitro pharmacology and toxicology studies as project lead for developing purification process for plasma-derived product. Talecris Biotherapeutics (Formerly Bayer HealthCare, LLC) Charles M. Ndarathi, D.V.M., Ph.D. Page 2

Developed a robust new Ultrafiltration/Diafiltration method for HIC flow through that removed the 850mM Ammonium sulfate in the HIC flow through to a mere 0.09mM or 0.9ppm, (product specification is

40ppm) far exceeding expectations. Talecris Biotherapeutics (Formerly Bayer HealthCare, LLC)

Developed chilling process for oxidatively stressed cells that enabled culturing and analysis of inflammatory cytokines for bone marrow reconstitution in treatment of leukemia patients while eliminating effect of Graft vs. Host Disease (GVH). Exposed purified leukocytes harvested from human blood to oxidative stress that killed 99+% within first ten minutes of procedure and grew survivors in in- vitro culture system. Chilling process stopped cell death and allowed growth in cell cultures enabling analysis of intra-cellular inflammatory cytokines and eventually, reconstitution of leukemia patients’ bone marrow, thereby making nearly every person likely bone marrow candidate. Sunnybrook Health Science Center/Vasogen, Inc.

Resolved process challenge and overcame aggregation of protein during elution phase that resulted in increased yields of Troponin I-C worth $250,000+ per purification run while shortening process time 50%. Scaled-up and optimized process for producing recombinant antibody protein for Troponin I-C, a protein released into circulation even in the most mild heart attacks. Antibody is integral component in ER diagnostic kits for myocardial infarction patients. Spectral Diagnostics, Inc.

Developed temperature-sensitive method of albumin polymerization for use in cosmetic industry. Performed studies and established process of converting purified albumin monomers to extensive stable polymers that were found to be superior in anti-aging products compared to monomeric albumin. Intergen Biomanufacturing Corporation (now Serologicals Corporation). EXPERIENCE CHRONICLE

GERSON LERMAN GROUP (GLG- https://glg.it)

An American-based expert network group operating a membership-based platform that provides independent ad-hoc consulting services to business professional] around the world Member and consultant on Biopharmaceutical Process and Manufacturing related issues including start-ups needs and troubleshooting with various GLG clients (Oct 2015- to date) BRISTOL MYERS SQUIBB (www.bms.com) - USA

A global BioPharma company firmly focused on discovering, developing and delivering innovative medicines that help patients prevail over serious diseases

Senior Scientist (Downstream Subject Matter Expert- Biologic Third Party Manufacturing) – Syracuse, NY (Jan 2012 – Mar 2015)

Evaluated in-process performance and process optimization to increase product quality, yield, and throughput while overseeing the manufacture of drug substance in local and international contract manufacturing organizations (CMO’s). Supervised four SME's (1 Ph.D. and 3 M.Sc. Scientists) Some key functions of this position:

Managing downstream processing and manufacture of biologics as subject matter expert Charles M. Ndarathi, D.V.M., Ph.D. Page 3

Reviewing of manufacturing master batch records (MBR’s) and for completeness and thoroughness prior to execution and release of production lots

Interfacing with a multidisciplinary team including Process development, third party manufacturing QA and Manufacturing Operations within BMS internal and Contract Manufacturing Organization (CMO) local and international sites.

Authoring and reviewing of critical regulatory documents, manufacture batch records and other technical reports.

Process review, optimization and process performance evaluation and initiating process Control changes

Ensuring process fit, technical transfer, and validation of downstream process at third party Manufacturing locally and abroad

Review of process deviations in TrackWise and ensuring effective Corrective and Preventive Actions (CAPA) are instituted

Initiating Manufacturing Control Changes in TrackWise System in process optimization

Overseeing manufacturing of drug substance at local and international manufacturing sites including person-in-plant (PIP)

Liaising with internal and external teams to provide technical project leadership and drive process decisions for drug substance manufacturing GRIFOS INC. (Formerly Bayer Healthcare and Talecris (www.talecris.com) - USA Legally independent worldwide company comprising two divisions and operating locations in US: Precision Pharma and Biological Products Employs 2,000 with net revenues of about $2 billion. Senior Process Development Scientist II – Clayton, NC (2003 – 2012) Accepted challenge to optimize performance of manufacturing processes by improving product quality, increasing production capacity, and reducing costs. Tasked to identify and develop new processes for product manufacture, optimize existing processes to increase yields and purity, implement process controls and test methods to assess reliability and reproducibility, and scale-up laboratory research prototypes through pilot production to full-scale manufacture while conforming to all relevant legislation and safety regulations. Directly supervised two.

On a Regular Basis:

• Liaise with research scientists, engineers, technical and commercial staff, manufacturing teams, QA, QC, suppliers, contract manufacturers, customers, and management.

• Devise new processes (or refine existing ones) to optimize manufacturing.

• Hands-on purification at various industrial scales using both non-automated methods and automated FPLC systems (e.g. the AKTA platform), as well as material homogenization, batch purification, precipitation, dialysis, tangential flow filtration etc

• Plan, supervise, and perform process trials in laboratories and pilot plants.

• Scale-up production processes, via plant trials, changing raw materials or components and process parameters to ensure quality maintenance during large-scale production.

• Improve yields by reducing costs.

• Implement process controls and devise test methods to assess production processes.

• Validate new processes; demonstrate improvements, and record/evaluate results.

• Work with product pipelines and manufacturing plants to oversee projects. Charles M. Ndarathi, D.V.M., Ph.D. Page 4

• Troubleshoot production processes and ensure compliance with finished product specifications.

Selected Achievements:

Saved $6.5+ million in manufacturing startup costs by developing robust biopharmaceutical process that increased yields 15% and purity 25% above target. Decreased volumes of buffers and solutions, eliminated some solutions/buffers, reduced concentrations of solutions/buffers, and determined appropriate storage period of starting material, a critical parameter.

Developed scalable biopharmaceutical process for plasma-derived product, doubled yields and reduced production time 75%, enabling production of pre-clinical material for both in vivo and in vitro pharmacology and toxicology studies.

Improved productivity by employing semi-automated AKTA systems to utilize several chromatography ideas regarding charges on protein and resin molecules to determine optimal conditions for removal of contaminant proteins as column wash while captured desired product is recovered by elution.

BAYER HEALTHCARE (BIOLOGICS DIVISION) - USA

Legally independent worldwide company comprising two divisions and operating locations in US: Precision Pharma and Biological Products Employs 2,000 with net revenues of about $2 billion. Senior Research Scientist I – RTP, NC (2000 – 2003)

Developed animal study models for clinical indication evaluation of potential protein products

Performed pharmacology studies for recombinant anti-hemophiliac drug to demonstrate efficacy equivalence with plasma-derived counterpart.

Generated and executed non-clinical pharmacology study protocols

Performed in-house potency and fibrinolysis assays for pre-clinical product development

Reviewed in-house non-clinical and clinical data for source verification and documentation

Researched, developed, optimized and scaled-up processes for purification of protein material

(using AKTA platform) for use in pre-clinical in-vitro and in-vivo testing

Identified contract laboratories and investigators for pre-clinical animal testing

Secured contracts with two outside academic institutions to perform pre-clinical work for new product proof of principle.

Convened in-house meetings, teleconferences, performed patent searches, compiled drug data and information for pre-clinical development

VASOGEN, INC. (www.vasogen.com) - Toronto, Canada

Development-stage company focused on bringing to market portfolio of immune modulation therapies to advance treatment of cardiovascular, autoimmune, and related inflammatory diseases. Employs 70 with net revenues of $24.6 million.

Research Fellow (Contract) (1999)

Contracted as Research Fellow to MD at Sunnybrook Health Science Center and tasked to study mechanisms of reducing/obliterating graft vs. host disease (prevalent in most bone marrow transplant patients) and to help develop optimal conditions for oxidatively-stressed human leukocytes after Charles M. Ndarathi, D.V.M., Ph.D. Page 5

separation from human blood in order to ascertain possible growth in cell cultures after stress. Worked closely with Oncology and Pathology-Hematology departments. Selected Achievement:

Furthered progress toward elimination of Graft vs. Host Disease (GVH) by overcoming major handicap of cells dying after oxidative stress through development of innovative chilling process for oxidatively stressed cells that allowed culturing for intracellular inflammatory cytokines analyses for bone marrow reconstitution in treatment of leukemia patients. SPECTRAL DIAGNOSTICS, INC. (www.spectraldx.com) – Toronto, ON Startup biotech company specializing in developing cardiac care products used as first step in diagnosis of heart attack patients. Test kits in US distributed by Princeton BioMeditech of NJ. Process Development Scientist (Contract) (1998)

Accepted challenge to optimize performance of manufacturing processes by improving product quality, increasing production capacity, and reducing costs. Identified manufacturing bottlenecks in new processes, implemented process controls and test methods for assessing reliability and reproducibility, scaled-up laboratory research prototypes from pilot production to full-scale manufacture, and ensured production safety in compliance with all relevant legislation and safety regulations. Liased with QC, QA, and Discovery group project.

Selected Achievements:

Increased yields of recombinant Troponin I-C by $250,000+ per purification run through process optimization and scale-up. Shortened process time 50% by eliminating unnecessary steps and automating delivery of process purification solutions and buffers.

Enabled QC department to analyze and release product to market by resolving eight- month-old problem of protein aggregation of thawed frozen samples of final product in two days through progressive buffer pH changes and buffer constituents. INTERGEN BIOMANUFACTURING CORPORATION (www.intergenco.com) - Toronto, ON International provider of specialty biological products with locations in US, Canada, and UK. Employs 750 with revenues of $147 million. Currently Serologicals Corporation. Scientist (1997)

Researched polymerization of albumin molecule for cosmetic industry use in anti-aging skin products, solubility of lipid products by thin layer chromatography, and albumin aggregates in final product. Also troubleshot for manufacturing facility. Selected Achievements:

Developed temperature-sensitive method of albumin polymerization for use in cosmetic industry. Performed studies and established process of converting purified albumin monomers to extensive stable polymers (found to be superior in anti-aging products compared to monomeric albumin).

Demonstrated that aggregates in final products of marketed albumin products were, indeed, albumin polymers through electrophoretic analysis of aggregates. Charles M. Ndarathi, D.V.M., Ph.D. Page 6

UNIVERSITY OF NAIROBI (www.uonbi.ac.ke) – Nairobi, Kenya Accredited academic institution of higher learning. Senior Lecturer / Research Scientist / Clinical Veterinarian (1989 – 1996) Taught undergraduate veterinary courses in Immunology, Parasitology, Microbiology, Pathology and Mycology and Principles of Scientific Communication to Post-graduate Students. Performed post mortem diagnoses of large and small animals as well as laboratory diagnostic duties. Supervised laboratory personnel and planned, directed, and monitored daily laboratory operations. Developed research funding in area of immunology and pathology of animal parasites, coordinated departmental graduate research projects, and oversaw two postgraduate students and seven technical staff. Also held part-time teaching positions in Immunology, Human Physiology, Biology and "Frex 1000": A Natural Sciences (Biological and Environmental Sciences) at two local universities.

Selected Achievements:

Isolated and purified antigen successively used in diagnosis of and immunization against Ovine Fascioliasis.

Discovered completely new species of Besnoitia in goats named Besnoitia granulomae.

Successively developed multivariate Bovine Papillomatosis autogenous vaccine used to treat epidemic of papillomatosis in herd of calves.

Recognized as first to demonstrate new outbreak of Infectious Bursal Disease (IBD) (also called Gumboro Disease) and provided advice on control measures. MCGILL UNIVERSITY (www.mcgill.ca) – Montreal, Canada Accredited academic institution of higher learning. Doctoral Student / Research Assistant (1988 – 1989) Studied Immunobiology of Trypanosoma lewisi infections in rats (doctoral project) and investigated role of human colonic mucin glycoproteins in pathogenesis of Entamoeba histolytica infections in humans (Research Assistantship project).

EDUCATION

MCGILL UNIVERSITY – Montreal, Canada

Ph.D. in Immuno-Biology/Biochemistry (1989)

NAIROBI VETERINARY COLLEGE – Nairobi, Kenya

Doctor of Veterinary Medicine (1981)

CL INICAL RESEARCH/REGULATORY AFFAIRS

TRAINING

Charles M. Ndarathi, D.V.M., Ph.D. Page 7

1. Roles and responsibilities of Clinical Research Associates and Coordinator: UNC, Chapel Hill (2003)

2. Foundations of Clinical Research: Center for Clinical Res. Practice, Wellesley, MA (2003) 3. Regulatory Affairs Certificate: California State University/San Diego State University. Topics Included:

i. The Pharmaceutical, Biotechnology and Medical device Industries ii. Introduction to Food and Drug Law

iii. Current Good Manufacturing Practice

AWARDS & COMMENDATIONS

Premier Circle Award in recognition of consistent delivery of quality work in achieving personal, departmental, and organizational goals (2004)

Two “On The Spot” Awards for great achievement in developing a robust process for a new product with increased purity and yields beyond expectations (2001, 2004) Canadian International Development Agency (C.I.D.A.) scholarship to pursue doctoral studies at the Institute of Parasitology, McGill University (1984 – 1989) The Best Paper Presentation -The Canadian Society for Immunology, Calgary Alberta (1987) MEMBERSHIP /CONSULTANCY

Gerson Lerman Group Consulting (GLG): Member and consultant on Biopharmaceutical Process and Manufacturing related issues including start-ups and troubleshooting with various GLG clients (Oct 2015- to date)

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