PARVEEN BHATARAH CV APPENDIX (PAGES 1- 5)

1. MANAGEMENT EXPERIENCE

Experienced Head of Technical Operations (5 years) and Small Scale Manufacturing & Development Manager (6years)

My departmental responsibilities include R&D, Analytical Development, Production, Warehouse and External Project Departments. Team consist of Organic PhD/Graduate Chemists, including Analytical Chemists, Plant Operators and Warehouse Operators. Responsibilities includes departmental budget & resource control, new project pipeline, in-house /external training to the staff where required and setting departmental and individual KPI’s which measure productivity, profit and quality. This also includes liaising with CMO’s and Lawyers on all aspects of current projects. I had one to one executive management training on a regular basis by Mr Ted Clarke (Executive Business Coach & Managing Director at Fraser Clarke, www.Fraserclarke.com).

2. API DEVELOPMENT TO DRUG SUBSTANCE DMF SUBMISSION AND TECHNOLOGY TRANSFER FOR COMMERCIAL MANUFACTURE

Extensive experience in development, scale-up and production of Drug Substance with successful approval from FDA and MHRA both in-house and at CMO’s.

The main objective is to develop eco-friendly, low cost, high yield & purity routes in shortest possible time. QbD is deep rooted in all my operations where recycling of solvents and un-wanted isomers is routine practice.

Typically synthesis of each API from designated starting materials is adequately established with validation of manufacturing process, appropriate critical /in-process controls for the stages which forms the carbon skeleton of the molecule to ensure both key intermediates and drug substance complies with FDA, MHRA, EMEA, ICH and cGMP standards. This also includes IP (intellectual property) management of respective project patents.

I actively get involved in the whole process from initial literature evaluation, route selection, costing, setting specifications where no EU or US Pharmacopeia specifications are available to manufacture of submission batches. I organise a management of change control meeting to address/initiate the risk assessments, COSHH and hazard evaluation, cleaning requirements, validation requirement (for methods, process and equipments) prior to the manufacture of pilot scale batches for DMF Submission.

I periodically set necessary targets for my External Project team to prepare technology transfer package and execute technology transfer, validation followed by commercial production manufacturing on sites in India, China and Europe in timely fashion to meet dead lines. This includes that QMS is followed by regular QMR and any deviations are tracked by CAPA’s and if required by Change Controls.

I jointly lead any FDA, MHRA or any customer audit at our facility with our Head of QA & Head of Regulatory Affairs. I also assist QA team at CMO’s facility for pre & post preparation during the FDA audit.

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Type of Chemistry/Methods Developed, Scaled-Up And Technology Transferred By Me Or Under My Supervision

Steroid Chemistry which includes API’s with anti-anderogenic /progestational, and anti-gonadotropic properties.

Ergot Derivatives which are dopamine agonist & prolaction inhibitors Tetrahydrocannabinols for nausea, vomiting and anoexia Prostaglandin API’s and related intermediates Thioxanthenes with CNS-activity Hydroxy chloroquine and Mercaptopurines used for rheumatoid arthritis Isomerisation of structural isomers Development of single Stereo-isomer using Chiral derivatising agent Impurity investigation and root cause analysis of drug substance & product Structural characterisation of reference standards & impurities Setting up release specifications for intermediates and API’s based on FMEA

(failure mode effective analysis) using information gained during development Formation of amide bond in highly efficient and stereospecific manner using

PEPTICLEC-TR Preparative HPLC, Flash Column Chromatography and Biotage technology.

Introduced cyclic stills for efficient solvent removal on large scale. Particle size reduction via milling, sieving or as suspension using

Microfluidiser technology All novel product and procedures/technology are protected by Patents. I have

successfully defended the patent claims in the European Court at Munich. Production of drug substances with particular Polymorphic form. Using

appropriate Chemical manufacturing controls (CMC) to ensure the polymorphic purity of the desired drug substance. These CMC’s include validation of solid state 13C NMR, DRIFT, DSC and X-ray methods using various percentage mixtures of different polymorphic form reference standards. In two cases novel methods were developed for the production of particular polymorphic forms (Patent US20070197576 and US7884222).

Responsible Person for Site Environmental Permit And Controlled Drug LicencesSite has environmental permit and maintains ISO14001 equivalent standards supported by SOP’s. This summer I have prepared and submitted MPP (multi-product protocols) variation for the site with successful upgrade of the site permit to MPP status. Site also has Control Drug Schedule 1 and 4 Licence to produce, possess and supply. Schedule 2 Licence to possess and supply.

SOP/ QRA (quality risk assessment) PreparationIn order to maintain H&S, Risk Management/Management of change, compliance with EU/US Pharmacopoeia & Regulatory changes; all necessary SOP’s are regularly up dated/implemented to ensure all products comply with FDA, MHRA, EMEA, ICH and cGMP standards both in-house and manufactured at CMO’s.

Commissioning and Qualification of New cGMP Facility2012 I have successfully commissioned and qualified a new dedicated cGMP building on site for the manufacture of Final stage of the API batches for Type 1B variation under time constrains. 3. FORMULATION DEVELOPMENT OF DRUG SUBSTANCE TO FORM STABLE BULK DRUG PRODUCT (BDP)

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Extensive experience in various formulation development and manufacture of BDP/Pharmaceutical formulations.

In some cases full life cycle of a drug product (Generic/ANDA) from R&D to Market Authorisation was completed. Examples of some of the dosage form formulation development work are detailed below:

i) Ophthalmic Solution Formulation Using Prostaglandin API’s

Following the development of Prostaglandin API’s these Prostaglandins were then successfully formulated to BDP to produce sterile eye drops.In all cases both Drug substance and Drug product manufacturing technology was transferred to CMO’s in Asia/Europe for commercial scale manufacturing under my supervision.

ii) Production Of Unit Dose Sachets-Oral Dry Product For Reconstitution.

An amorphous moisture sensitive Bulk Dry Product (BDP) was developed. The BDP manufacturing technology involved vacuum belt drying, modification of product density by roller compaction and batch identity. Technology was then transferred to a CMO’s facility in Europe; where process was further developed and validated prior to ANDA submission.

Moisture sensitive BDP was successfully transported to US facility for manufacture of the submission batches for two different unit dose sachets. Unit dose sachets were constructed from either of two alternative foil laminates sachet formed from pre-printed laminate material during filling operation at US site. The finished dosage form has now passed the 48 month stability testing.The BDP manufacturing facility has been successfully audited by FDA in June this year for pre-approval inspection of this ANDA. The ANDA application is pending with the FDA.

iii) Development Of Sterile Formulation Of Dry Powder For Oral Use And Inhalation Suspension (0.25mg/2ml And 0.5mg/2ml) For Commercial Use

Very small particle size requirement and instability was an issue for the formulation team. Therefore, stability of BDP was investigated under range of potential sterilisation conditions and under various particle size reduction methods. The successful sterile slurry with desired particle size was developed after evaluating the use of Microfludiser technology (developed novel technology Patent US 7644880). The main methods investigated for sterilisation were dry heat, aqueous steam sterilisation, Gamma radiation and Ethylene Oxide treatment to form the sterile dry powder and inhaler.

iv) Soft Gel Capsule Formulation Of Bulk Drug Product Which Is Sensitive To Light, Temperature And Heat.

I worked with major soft gel capsule manufacturer in Germany on their production facility to advice on the formulation process and handling of sensitive drug product during formulation work up. I was responsible for working with their team to do the modifications to their Becomix formulation vessel and development of the formulation process leading to BDP encapsulation. Finally 400,000 capsules

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of 3 different strengths (2.5mg, 5mg & 10mg) were prepared for ANDA’s submission with successful FDA approval. However, application is still pending subject to DEA approval.

v) Formulation Development Of Air & Moisture Sensitive Steroidal Drug Product

The BDP was showing degradation during stability trials due to air and moisture sensitivity of the drug substance. I worked with BDP manufacturer in Australia to implement necessary critical controls during the manufacture and packing of the BDP. This work is still on going at CMO’s facility using different formulation method.

vi) Formulation Development Of Air & Moisture Sensitive Alkaloid Drug Substance

Light, Air and Moisture sensitivity was a concern, therefore I visited drug product manufacturer in Australia and worked with their micronisation team to develop particle size reduction technology and enabling pilot scale batches for submission with successful FDA approval. The micronisation procedure has now been transferred to European CMO’s by my External project team under my supervision for future commercial manufacture.

vii) Reduction In Fill Volume Of Light, Air & Moisture Sensitive BDP In A Sterile Injections/Ampoules.

A particular CMO has developed three strengths of injectable dosage form (200mg/1ml,100mg/1ml, and 50mg/0.5ml ) using one of our very high cost drug substance. My External Project team worked on their site under my direction to assist the CMO in improving the handling of BDP and hence achieving significant reduction in overage.

4. Maintaining Industry and University Relationship

Experienced in building relationship between University and Pharmaceutical disciplines In 1998 I was acting as an Industrial Supervisor for collaboration between Celltech Chiroscience and The University of Liverpool for an MSc course in Chemical Process. My Student Mr William Heal successfully completed his industrial training and gained the MSc qualification. I have also been working with Imperial College, Queen Mary, Durham and Birmingham University on various projects on an on-going basis.

5. Expert Witness in Court

Experienced in working/preparing solid state patent challenge and court presentation

In June/July 2013 successfully designed the experimental work, directed the team to do supporting laboratory work for patent challenge of Escitalopram, a single enantiomer and finally prepared the expert written witness statement for the presentation of my work in London court.

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I have also successfully defended my patent regarding Cabergoline polymorphism and particular solid state in Amsterdam District court in November 2012 and in June 2014 in Munich European court. 6. Bio-fermentation scale up from R&D to 3m3 at CMO in Europe

Experienced in evaluating CMO’S suitable for technology transfer from laboratory scale to tonne scale production for both non-GMP and GMP

As part of Almac Sciences strategic planning my role/objective was to take Bio-catalysis group to a level that Almac Sciences can offer customer market competitive scale-up option for Bio-fermentations and finally Chemical transformations for non-GMP and GMP manufacturing. In 2014 October I successfully identified two sites in Europe for scale-up for Almac Sciences, did technical audit against ICH Q7. Prepared technology transfer package based on laboratory scale for 20L trial runs on both sites. In February 2015 successfully completed 3m3 batch production on one site and 35kg batch production on the second site. Currently preparing for 10m3 and finally planning to go up to 60m3 run for commercial production.

7. Communication and presentation to DEA (Drug Enforcement Administration), Department of Justice

Experienced in putting facts together for petition to remove Cannabis from Schedule 1

Delta-9-THC is a controlled substance, Schedule I drug. After successful FDA PAI inspection, project could not be launched in USA market as it controlled drug in Schedule I. Petitioned DEA to have marijuana removed from schedule I of the CSA and rescheduled as cannabis in schedule III, IV or V. Therefore, to support the petition worked with Oxford University neurology department and consulted literature to put 8-factor analysis to support the case and presented it to US in 2011.

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