Student INTRA Report

Name

Ian Martin

Student ID

11532343

Degree Programme

Genetics & Cell Biology (GCB)

Faculty

School of Biotechnology

Year

3rd Year Undergraduate

Company

Eli Lilly

Abstract

Eli Lilly is an American pharmaceutical manufacturing company situated near the

scenic seaside town of Kinsale Co.Cork. Today Eli Lilly Kinsale manufactures 9 different

small and large molecule products on its expanding 140 acre parkland site. The company

offers INTRA students relevant lab bench and desktop work experience connected with their

course. One’s role as a Quality Control laboratory (QCL) analyst entailed of performing

experimental analysis in the analytical lab, GMP documentation and project work which

required oral presentation. While chemistry tests conducted were not totally applicable to

DCU’s Genetics and Cell Biology degree, the opportunity to learn and perform these tests

was an awarding and educational experience.

Ultimately these lab bench and desktop skills will compliment one’s biology degree

and benefit future employment. In addition Eli Lilly provided one the chance to visit large

scale manufacturing facilities on site, training in a variety of areas and help in finding

accommodation in Cork. Its internship programme is unique as there are up to 20 other

undergraduate students on site during the summer months. This provides social interaction

and an opportunity to take part in many extracurricular activities provided by the company's

very active sports and social club. One feels fortunate to have experienced industry for the

first time in Eli Lilly and would highly recommend this internship to future DCU students.

Introduction

Purpose of the Job

The primary purpose of an Eli Lilly Quality Control laboratory (QCL) analyst is to

ensure that raw materials used in experimentation and Active Pharmaceutical Ingredients

(API) produced in Eli Lilly Kinsale are safe for patient use and adhere to the guidelines

stipulated by international drug authorities. This fundamental objective is achieved by

carrying out a broad range of analytical tests on Eli Lilly products and examining specific

parameters such as particle size, potency and water content to confirm products are fit for

purpose. One’s specific lab purpose was to carry out a qualitative IR analysis of API and

determine if any notable impurities were detectable in each drug batch. Additional objectives

connected with one’s placement in QCL included:

Improving and addressing safety practices in the lab.

Implementing efficient management and archiving of documents.

Enhancing handling and disposal of reagents and samples.

Company History Structure

Eli Lilly is an American pharmaceutical company founded in Indianapolis in 1876 by

civil war veteran Colonel Eli Lilly. From its modest beginnings over 100 years ago in a small

pharmacy in downtown Indianapolis, Eli Lilly Company has grown to become the 10th

largest

pharmaceutical company in the world employing 38,0000 employees globally. Eli Lilly sells

its wide-range of pharma products to 140 countries and generates revenues of over $20

billion dollars a year.

Eli Lilly’s Irish manufacturing facility is located at the periphery of the picturesque

and historical seaside town of Kinsale. Operations in Eli Lilly’s Cork branch commenced in

1981 and the site now occupies 140 acres of land with a workforce over 600 employees. The

focus of the Kinsale facility is to develop, manufacture and finally supply a variety of

medicines found in Eli Lilly’s extensive portfolio. The site utilizes a wide array of chemical

and biological processes to provide a selection of API that can be shipped to finishing plants

where they are converted to tablets, capsules or injectables, depending on the drug's approved

dosage form.

Small & Large Molecule Operations

Kinsale has played a central role in the commercialization of small molecule APIs

throughout its 30 year history. Today the site endeavours to be one of the most important

suppliers of API for newly launched Lilly medicines. In conjugation with chemical product

development Kinsale continues to be instrumental in late phase product optimization, which

includes technical transfers, scale-ups and clinical trial API manufacture.

Kinsale Eli Lilly has been constantly evolving throughout its existence and current

manufacturing operations are aligning with the dynamic environment of the

biopharmaceutical industry. In 2006 Lilly announced that the Kinsale would become a hub

for production and supply of API for new bio pharma products. This transition from small to

large molecule has allowed the site to diversify into new biotechnology fields to produce

innovative monoclonal antibody therapies.

A new state of the art 240,000 square foot Bio-pharma facility is currently being built

on the existing Kinsale site. The new IE43 building will cost in the region of €330 million

when complete and will require an additional 300 employees when fully operational in 2017.

The new unit will focus on providing new biopharmaceutical therapeutic treatments for

cancer and diabetic patients.

Basic Overview of Small Molecule Processes

Small molecules API are manmade chemical entities derived from synthetic reactions that

result in new therapeutic molecules. The basic overview of small molecule production can be

broken into 4 stages:

Reactions

Purification

Isolation

Analysis

Reactions: Solvents and reagents are added in distinctive product specific manner to

synthesise API molecules.

Purification: During this refinement stage, the desired API is separated from impurities such

as intermediates and residual solvents which are by-products of chemical synthesis.

Isolation: Isolation is the final stage of the purification process whereby the target API is

totally segregated. Drying, filtration and centrifugation are some of the most used techniques

to separate out desired API.

Analysis: The last part of small molecule production consists of examining the various

parameters of the manufactured molecule to ensure that it conforms to FDA standards. This

stage of the process is the responsibility of the Quality Control department and is where one

performed their duties on placement.

Duties performed

Duties executed in QCL included:

SOP training

Reading and electronically signing off of Standard Operational Procedures SOPs.

Safety Data Trending

Evaluating safety observations in the Bio, Micro and Analytical labs.

Final Product Campaign Review

Forming reagent/equipment lists for final products testing.

Lab maintenance

Restocking Personal Protective Equipment and cleaning of the lab.

Documentation & Archiving

Archiving Equipment files, storing Control Charts and implementing a T Card system.

Reagent Check

Reviewing expiry dates and disposing of expired reagents.

Waste Deposal

Clearing of waste materials from the lab.

Debagging

Transferring API from secondary containment for lab use.

API IR Analysis

Performing Infrared Spectra Analysis on API molecules.

SOP Training

Prior to carrying out any laboratory activities or partake in any documentation

practices, Lilly Kinsale employees are required to acquaint themselves with all relevant Lilly

methods connected with their work. This familiarization process involved the reading of an

encyclopaedia of Standard Operational Procedures (SOP). During the first week of one’s

placement there were over 100 hundred SOPs to be completed before certain tasks could be

carried out. One appreciates that by reading these documents a greater understanding of

operations at Lilly were attained and thus improved overall performance.

Safety Trending

It is a mandatory requirement of all Lilly employees to abide by the Kinsale’s site

health and safety practices in order to maintain a safe work place. Lilly‘s commitment to

safety is best illustrated by its interactive B-SAFE software which encourages employees to

be proactive in recording positive and negative safety observations. It was ones’ duty to

categorise these entries and evaluate if any trends were apparent. The findings were then used

to drive discussion at safety committee meetings and resolve safety issues.

Product/Intermediate Campaign Inventory

Kinsale Lilly products are produced and rolled out in a coordinated campaign

strategy. QCL testing is directed by campaign production scheduling and deadlines must be

met so batches can be released. Protocols from every campaign were reviewed and the

necessary reagents needed for testing were displayed in a Microsoft spreadsheet which was

freely available to the QCL staff. As a result of one’s documentation QCL staff could easily

review and checklist inventory required for experimentation.

Lab Maintenance

PPE

The QCL department in ELI Lilly is run 24 hours a day resulting in lab consumables

such as nitrile gloves and lab coats being continually used. The availability of these items is

important as all testing performed by lab analysts require specific protective apparel in order

to safeguard them from potential contamination and mutagenic chemicals. For this reason it

was one’s task to check that consumables were routinely restocked and obtainable for over 20

analysts working in this busy lab. Specifically this required one to monitor lab equipment on

a daily a basis and visit the store room to replenish supplies that were low or out of stock.

Waste Disposal

The disposal of contaminated materials was a fundamental job carried out on

placement and involved organizing a spectrum of waste into specific disposal units. Non-

toxic waste material such as nitrile gloves were disposed of in regular plastic bin bags.

Contaminated material which accumulated in the fume hoods were placed into protocol bags

and then placed in blue drums also. Glassware and various sharps such as needles were

placed into specialised non-resalable yellow plastic boxes. Solvent glassware was directly

dumped into a glass recycling units and similarly mixed dry materials such as cardboard were

also recycled.

Documentation & Archiving

Control Charts

One of the key tasks allocated to oneself during placement involved the archiving of

lab control charts into electronic form. Laboratory control charts are used to graphically

monitor patterns of analysis for short and long-term QC processes. The purpose of scanning

these important charts was to avert the potential loss of the chart and make the document

more available to staff.

Equipment Folders

The QCL houses 100’s of analytical instruments that require continual maintenance

and monitoring. Records of out of use instruments were archived or disposed of in

accordance to SOPs.

T Card System

The QCL department contains notebooks which hold the results all tests carried out in

the lab. These notebooks are routinely passed from analyst to analyst during documentation

procedures including 2nd

person verification. It is vital that notebooks can be quickly accessed

to facilitate such review processes and are readily available during audits. It was one’s duty to

implement a simple T-Card system in order to track down the whereabouts of each notebook.

A department coloured T-card was placed inside every notebook and a noticeboard

displaying every analyst name was erected. If an analyst was in the procession of a particular

notebook it is their responsibility to indicate this on the noticeboard by placing the relevant

T-Card by their name.

Reagent Check & Reagent List

The QCL laboratories contain a broad variety of analytical reagents which are needed

for the analytical assays carried out in the lab. For these tests to satisfy criteria stipulated in

lab protocols it is critical that all reagents to be used are in date. The regular assessment of

reagent and solvents expiration dates was a responsibility one undertook during placement.

Reagents were checked for expiration by referring to their supplier’s website and inputting

details batch details connected with that reagent. A reagent list was also compiled for entire

analytical lab.

Disposal/Transfer Procedures of various Chemicals

An allotted lab duty that one carried out was the safe disposal and transfer chemicals

in accordance to particular SOPs. This task allowed one to identify the various safety hazards

associated with materials such as oxidizing materials and organic solvents.

Debagging

Before any analytical tests were conducted on production samples, one had to transfer

batch samples from secondary containment into suitable bottles as detailed by specific SOPs.

The transfer of batch samples from secondary containment to final testing vessels was an

important step in the QCL lab as it was is the first time a sample from a particular batch

entered the lab for testing. For this reason it is imperative that the debagging procedure was

correctly performed as the identity of the sample cannot be questioned due to improper

handling and labelling.

Infrared Spectrometry

Infrared Spectrometric testing was one’s allocated test in QCL. The purpose of the analysis

was to perform a quick qualitative investigation of what functional groups and impurities

were found in given API molecule. The underlying principle behind the technique is that

specific bands of infrared light interact with molecules to give off detectable vibrations of

atoms. Based on specific bond vibrations and rotational frequencies one can determine

functional groups within a molecule by evaluating an IR spectrum of these energy profiles

over a given wavelength range. The basic method consists of Potassium Bromide being

combined with the powdered API. This mixture is then compressed into a fragile thin disk

and placed into an IR instrument where various waves of light are directed at the sample. One

was also trained on a handheld variant of this technique RAMAN Spectra analysis.

IR Analysis was a highpoint of placement as it was first time that one had carried out a

scientific experiment that had significance in the real world outside the college .As one

performed IR spectra analysis one appreciated that knowledge gained about GDP, health

safety and other training molecules were of relevance when performing this task

Knowledge Gained

Good Document Practice (GDP)

One of the biggest learning outcomes working in QCL was implementing Good

Document Practices (GDP) in accordance with guidelines set out by regulatory authorities. In

a Good Manufacturing Pratice (GMP) Environment it is fundamental that documentation

meets certain requirements to ensure product quality and safety. One has learnt that

documentation provides a detailed account of when, where, who, why and how tasks inside

and outside the lab were completed. This documentation process provides conclusive

evidence that tasks were completed as they should be.

A useful aspect of GDP that will benefit one in the future is the proper maintenance of a lab

notebook. Expiry dates of reagents, days tests are run, temperatures of solutions, weights of

materials and sample identification codes are some of the key details that must be recorded in

a lab notebook. A notebook with accurate descriptions of observations provides clear and

concise data that can be reviewed and understood in the future if required. Correcting

inscribed mistakes in documentation was a time consuming, difficult and at times frustrating

experience but one’s neatness and note taking has improved immensely.

One understands the standard of documentation within a company such as Eli Lilly

can directly influence the level of success in manufacturing quality products and audit

reviews. One gained an appreciation how second person verification which is the review of

GDP documents by fellow analysts is vital to ensure official papers are documented properly

.Ultimately GDP practice has entered a new era in Eli Lilly whereby paper documentation is

now being replaced by electronic records. One understands that electronic capturing data on

an analytical instrumentation and connecting wirelessly to computers will become the new

norm in industry and is the future of GDP.

Computer Systems

QCL uses computer systems Smartlab, Darwin, and Empower to coordinate

experiments, document results and manage samples in the lab. The collective term for the 3

systems is LIMS (Laboratory Information Management Systems) and they play an imperative

role in providing transparent audit trails and improving operational efficiency in QCL.

Darwin

Darwin enables the safe management of data connected with received batch samples in the

lab by providing an electronic audit trail. Darwin ensures tests conducted in the lab comply

with regulations and internal quality standards of Eli Lilly.

It contains a reservoir of information about samples including:

• QCL sample registry

• Trending details about stability samples.

• Test methods and specifications.

• Result entry management

One experienced first-hand the usefulness of Darwin when debagging API products. Using

the unique bar code labels placed on the outside of each debagged sample one observed the

tracking capabilities of such software when scanning and registering these samples into the

lab. Once logged onto the Darwin system one could monitor the status of the sample and

location where the sample is stored. This monitoring capacity was useful when disposing of

analytical and reference samples because one could whether determine if all testing had been

completed lab.

Smartlab & Balance Calibration

Smartlab is a fully validated computer system that has a range of abilities including:

• Inputting and storing experimental data.

• Monitoring overall experimental progress of batches.

• Accessing the limit criteria of experiments.

• Facilitating wireless connectivity with instruments.

• Providing transparent audit trails.

The basic purpose of Smart lab is to reduce documentation errors and better facilitate

regulatory audits. It diminishes the need for paper as samples are tracked and documented

throughout the analysis process. The audits trails produced in Smart lab allow one to view,

calculations and supporting data of each analysis of samples. Smart lab accommodates faster

2nd Person verification processes by containing built in limits. These parameters allow the

software to identify tests that are outside specification limits for an experiment.

A good example which illustrates the practicality of Smartlab is its use regarding

capturing and calibration of balances. As eluded to previously GDP is entering a new period

where wireless electronic documentation between computer systems and lab equipment will

be industry standard. Balances can connect wirelessly to smartlab when capturing data and

weights of samples used for testing. Furthermore daily calibrations are also stored in this

manner using Smart lab. Ultimately this method further enhances the validity of testing and

transparency when subject to audits.

Empower

Empower is a software that allows users to control chromatography instruments and

process data. While one did not directly use this software one must acknowledge the

convenience of this software when running samples. One example of its usefulness is that

Empower allows analysts to program chromatography runs overnight so results can be

integrated and interpreted the next day thus saving time and money.

Teamwork Communication and Time Management

Not only did one learn numerous lab techniques but working in the QCL department allowed

the acquisition of teamwork, communication and time management skills. One now

understands that having these abilities is vital in any working environment and will be of

benefit in one’s future career.

Teamwork

Many hands make light work is an expression that could be defined by the teamwork

that is evident in QCL labs. API Batch authorization requires a range of analyses to be

conducted on each sample. By delegating work these tests can be carried out in the most

efficient and effective manner thus streamlining the QCL assessment process. In addition one

of the advantages of working in a team is its capacity to solve problems. If an issue did arise,

one could consult with a collection of other analysts and overcome the problem in the best

manner.

Communication

One improved their communication skills by continually reporting to team leaders,

collaborating with supervisors and interacting with analysts in the QCL department. The

ability to: speak appropriately with a wide variety of people whilst maintaining good eye

contact, demonstrate a varied vocabulary and tailor your language to your audience, listen

effectively, present your ideas appropriately, write clearly and concisely and work well in a

group are good communication skills one acquired inside and outside the lab.

A basic area of communication that one assimilated beneficial experience was

presentation making. Attending weekly and monthly meetings allowed one to watch senior

analysts talk about their work in a professional manner and answer questions in an

informative concise style. One also received presentation training in which the elements that

make an engaging and memorable presentation were taught. Presentations were always

something that one was reluctant to perform before the placement commenced however

having delivered presentations to various department forums, one now enjoys conveying

presentations to large audience

Time Management

A central skill one acquired was how to plan your day and identity tasks that need to

be completed. This was a major learning experience during placement and one’s ability to

prioritise jobs definitely aided completion of tasks. A significant lesson one learnt is the

ability sometimes to say “no” when you have already a considerable amount of work to do.

While being enthusiastic and helpful is a great characteristic to have, it’s better to complete

important tasks correctly and on time than rushing through minor work that will hinder more

imperative tasks.

Safety Training

Safety is of utmost importance to Eli Lilly, therefore it is mandatory that every Lilly

employee is trained correctly so they can carry out their work in the safest manner. The

mandatory training that one received included:

• Manual Handling & Ergonomics

• Fire Safety Training

• Eye Protection and Treatment (Diphoterine) Training

• Evacuation Training

Manual Handling & Ergonomics:

Training consisted of a practical session teaching the proper handling of heavy

equipment. The training conducted demonstrated the consequences of wrongly lifting large

objects and one learnt of the various injuries that can result of mishandling.

Fire Safety Training

One was informed during fire safety training that different types of fire require

different types of actions to extinguish them. Ultimately one learned by eliminating the

parameters of the fire triangle as depicted in figure a fire can be stopped.

Eye Protection Training

As part of eye protection safety one learnt that in the event of chemical exposure to

the eye Diphoterine is an adequate eye decontamination solution .Diphoterine is hypertonic,

polyvalent, amphoteric compound which neutralises approximately 600 chemicals.

Diphoterine can prevent eye/skin burns following chemical splashes and results in nearly

immediate pain relief.

Evacuation Training

In the evident of an unlikely accident occurring on site one was educated on how to

respond to an emergency situation. Eli Lilly employ a practice of Shelter in Place if a harmful

chemical is emitted into external environment .One is recommended to stay indoors in order

to separate individuals from the hazardous outdoor gases.

pH Calibration Training

The pH calibration practice employed in Lilly ensures that the tuning of a respective

meter is at an optimal setting to produce a more accurate and efficient reading when

measuring the pH of a solution. An interesting observation one learnt about the calibration

process was that temperature is a critical parameter that has to be monitored during the entire

pH meter standardization procedure. Throughout the pH measurement of buffers and

solutions temperature is recorded simultaneous using a temperature probe. One learnt that the

purpose of this practice was that temperature can adversely reduce the accuracy and speed of

response of a pH electrode.

Shadowing

During placement one had the opportunity to shadow a range of chemistry set ups in

the analytical lab. One gained theoretical and practical knowledge connected with each

instrument by observing and questioning analysts during experimentation. The chance to

witness these experiments was seized upon because many of the experiments in the lab were

not touched upon during one’s biology degree. Thus one has gained a great insight of how to

operate the following instruments:

• Chromatography (HPLC & GC)

• ICP Spectrophotometer Operation demonstration

• Scanning Electron Microscope (SEM)

• NMR Operation demonstration

• Particle Size analysis demonstration

• Water (Analysis Karl Fischer Water Titration LOD)

Chromatography

High Performance Liquid Chromatography HPLC

HPLC is the most common experimental technique utilised in the analytical lab and

was among a few tests that one that had some previous college exposure. The most beneficial

outcome following shadowing of the HPLC was how to troubleshoot problems. What do you

do if ghost peaks appear? How to eliminate bubbles in the system? What to do if pressure is

building the instrument? How can you avoid leaks? These are just some of the issues one

encountered during observing the running of a HPLC instrument. Touching upon these topics

is the definition of what hands on experience is about because no textbook can communicate

years of practical knowledge acquired by analysts in the lab. Its HPLC tips and tricks like

washing a column after use to prevent future problems that have deepened one’s knowledge

from a practical perspective the use of this typical industry instrument.

Gas Chromatography (GC)

Similarly just like HPLC above, GC analysis was among a few experiments that one

had encountered briefly during college practical sessions. The main take home point after

shadowing many GC experiements is the importance of using clean glassware. GC analysis is

a highly sensitive method and picks up any unwanted contaminants resting on glassware.

Under supervision one was shown how to properly clean glassware using detergent

formulations stipulated in SOPS. During this cleaning procedure one acquired the ability of

using a simple bulb pipette.

Inductively Coupled Plasma (ICP) Spectrophotometer

ICP Spectrometry was one of the many instruments that one had no previous

knowledge of before entering Eli Lilly. The purpose of the instrument is to measure trace

metal elements in a variety of drug preparations. The basic concept underpinning the method

is that superheated plasma, which is at a temperature of 10,000K, vaporises samples until

they radiate excited atoms and ions. These emitted energized photons and electrons create

detectable electromagnetic wavelengths that are characteristic of particular trace elements.

One recognizes from a learning perspective the use of such an instrument is important to

detect toxic heavy metals that are potentially detrimental to patient safety.

Scanning Electron Microscope SEM

SEM analysis employed by QCL examines the crystal structure and conformation of

intermediate and final drug products. The high resolution 200,000 magnification of the

microscope enables users, to determine if unwanted crystalline clumping has occurred during

production crystallisation processes . This capacity to visualise materials that are as small as

2um in size allows a microscope operator the opportunity to detect any visible impurities or

foreign material in a given sample. From a practical perspective one was intrigued to see

microscope manipulation was joystick controlled. One had only encountered simple light

microscopes during college so observing careful microscope handling using a joystick device

was an educational experience.

Nuclear Magnetic Resonance NMR

The most complicated instrument that one was exposed to in the lab was the Nuclear

Magnetic Resonance (NMR) spectrometer. In the most simplistic of terms this instrument

measures electromagnetic radiation emitted by nuclei spinning in the presence of a given

magnetic field. This analytical technique is used for product identification testing to ensure

that the content, purity and molecular structure of given API meet quality assurance

standards. From a biology viewpoint one appreciates the use of the instrument to quantitate

protein feed components and metabolites in mammalian cell culture. This type of testing is

known as large molecule fermentanomics quantization and was a feature of the instrument

one found hugely engaging.

X-Ray Diffractometry

One now understands the significance of crystallographic analysis in regards

accessing the molecular bonds within drug products. The structure of given molecule must be

the correct configuration to interact properly with its cellular target. This can be achieved by

examining the geometry of bonds within an API using an X-Ray Diffractometer .After

shadowing an analyst using this instrument one has acquired the theoretical background of

how the instrument operates. A narrow X-Ray beam emitted from a source copper is directed

at a drug sample. This radiated X-Ray beam produces a characteristic wavelength which

scatters once it interacts with the crystalline structure of a given sample. The X-Ray energy

resulting from this diffraction process can be measured using a scintillation counter.

Particle Size Analysis

The need for particle size analysis during pharmaceutical manufactory is of upmost

importance because it ensures milling processes during production are effective. Small

molecules need to be of the correct size to cross membranes in order to interact with

intracellular targets. Particle size analysis allows users to evaluate if wet and dry samples

measuring 10 nanometers to 5 millimeters are of the correct size. The central idea behind this

form of analysis is that a particle will scatter light from a laser at particular angles. In theory

larger particles will scatter at small angles and smaller particles scatter at wide angles. One is

now aware of how the instrument operates and significance of particle size in relation to

bioavailability.

Karl Fischer Titration

The Karl Fischer titration method is one of the most common experiments carried out

on a daily basis in the QCL labs in Lilly. The main objective of a Karl Fischer instrument is

measure the water content found in an intermediate or API. The basis of this technique is that

samples are heated by the oven and carrier gas facilitates the transfer of released water

vapour into the KF titration cell. One found out that in industry if a product had more than

likely low moisture content this is the preferred method of analysis.

Loss on Drying (LOD)

Another test which evaluates moisture levels is LOD testing. This is a crude

alternative to Karl Fischer titration and also evaluates alcoholscontent. Loss on Drying

compares the weight of a product before and after it is dried. This difference in weight is

taken as the percentage of moisture in the product. One was trained on this method.

Large Molecule Production and Testing

During the latter weeks of placement one was fortunate to gain exposure of large

molecule production and testing. One received a tour of the IE42 facility where

Ramucirumab and other therapeutic monoclonal antibodies are manufactured. During the

following section one will discuss briefly large scale bioprocessing which can be broken into

upstream and downstream practices.

Upstream (Cell Culturing)

Upstream bioprocessing starts by thawing genetically engineered cells, which carry

DNA sequences of therapeutic proteins. Once cells are defrosted from a frozen state they are

cultured in large bioreactors over a period of weeks. During this culturing process product

producing cells are gradually scaled up in larger vessels and are regularly inoculated with

larger quantities of media. The final stage of the upstream processing involves high speed

centrifugation and filtration separating unwanted cell matter from the therapeutic proteins

that have been secreted in solution.

Downstream (Cell Purification)

The aim of the downstream process is to purify the clarified protein solution to a

degree which is compliant with product quality standards and ensure the correct

concentration of therapeutic proteins is obtained. In addition any non-infectious viral

components which accumulate during the culturing process are removed. The initial

purification consists of column chromatography whereby the protein solution is passed

through a filter resin. This step is followed by virus inactivation which is carried out by

filtering viral particles using a fine mesh. The final stages of the purification consists of is

ultra-filtration which concentrates proteins into its final formulation.

Observing the upstream and downstream bioprocessing of IE42 was a major highlight

of ones time in Eli Lilly. It was a unique experience to see large scale ups of some the basic

procedures that one had encountered in college labs. From observing the bioprocessing one

has gained a greater knowledge and a new appreciation of column chromatography and

engineering surrounding bioreactors. Another important learning outcome was the

importance of maintaining a sterile environment when growing and purifying cells. Cell

culture conditions used during upstream bioprocessing provide an optimal environment for

opportunistic bacteria to flourish. Likewise the transfer of sample from purifying step also

presents risks to contamination. For these reasons strict gowning procedures and regular filter

inspections are performed to eliminate potential contamination.

Bio-Assays

One learnt of the significance and usefulness of bioassays when accessing the toxicity

of therapeutic antibodies. It is a requirement before a chemical compound receives FDA

approval that it must be thoroughly tested on laboratory cell lines before human use. For

bioassays to provide information about the activity of therapeutic antibodies cells which are

subjected to drug products are engineered to have receptors that only stimulated by these

ligands. If receptors transduce a signal the cell will elicit a detectable response which will

provide information to a user. The intensity of the signal can be varied by using various doses

of the ligand and this can provide information about the potency of a particular molecule.

Cell Culturing

The main skill that one obtained during Bio-assaying was how to correctly manage

and maintain a healthy cell line over a long period. Sub-culturing (Passaging) which is the

transfer of cells from a pre-existing vessel to another new container is needed to maintain a

large number of healthy cells. Under supervision one practiced the correct aseptic techniques

used for passaging cells and how to set up a fume hood to minimise contamination. One was

given the opportunity to monitor a PIG cell line by visually inspecting cells on a daily basis

with a microscope. This allowed one to acquire an ability to evaluate cell viability by

checking cell confluence and morphology.

Antibody Characterisation

One obtained a greater knowledge of antibody characterisation by shadowing a

variety of complex experiments. Analyses such as mass and florescence spectrometry allow

analysts to examine in detail the complex protein structures of antibodies for

commercialisation and investigative purposes. These characterisation techniques can be

divided into two categories: (a) primary structure characterisation and (b) biophysical

classification of secondary, tertiary and quaternary structures of antibodies. It was fascinating

seeing how state of the art confidential instruments manipulate antibodies by unfolding their

protein structure, disturbing intramolecular bonds, cleaving polysaccharide side chains and

splitting peptide grouping to decipher the composition of these intricate molecules.

Gel Electrophoresis

Gel electrophoresis analysis shadowing was one the most applicable assays in regards

to ones Genetics and Cell biology degree. One had some previous exposure to typical SDS –

Gel electrophoresis but one was delighted to oversee the use of Capillary Electrophoresis

which is steadily becoming the new industry norm. This more innovative variant of gel

electrophoresis is replacing SDS analysis because it resolves proteins more efficiently. It is

also safer and quicker than the previous method. The fundamental difference in this method

is that protein separation occurs in a narrow voltage controlled nanofluidic capillary..

QPCR

Real-Time PCR which is also known as quantitative polymerase chain reaction (qPCR) is

gene analysis technique that measures the amount DNA produced during gene amplification

.Its purpose in Eli Lilly is to detect any viral pathogens following upstream processing. This

was one of the most thought stimulating experiments in QCL as this technique featured

heavily one’s Genetics and Cell Biology degree. A clever tip that one acquired during

observation was contamination prevention. PCR in general is a highly sensitive technique so

maintaining sterility is a pivotal practice. By adding the constituents of the PCR test in

separate UV fume hoods one reduces the chance of contaminating

Self-Reflection

Theory -v- Practice

The skills and concepts developed in DCU during one’s Genetics and Cell Biology

(GCB) degree were advantageous in the workplace. While the degree programme is primarily

biology orientated, one discovered that the fundamental chemistry techniques that were

acquired during first year were relevant and helpful .Simple skills such as making up

solutions, ph metering and weighing accurately samples are pivotal techniques any scientist

must be able to carry out in an efficient and accurate manner. While on the surface these

techniques appear very simplistic when working in a GMP lab accuracy is essential and even

these techniques cannot be overlooked.

The latter years of one’s degree are more specialized to GCB and are principally

biology based. For this reason before starting the placement at Lilly one knew that it would

be difficult to grasp and understand the more advanced chemistry experiments. The only

experiments in Lilly Analytical QCL that overlapped with one’s degree were HPLC and GC.

These setups were central to many of the tests conducted in the Lilly QCL lab and having a

rudimentary understanding of chromatography was of an advantage. During my final weeks

of placement one encountered and shadowed more relevant experiments such as qPCR,

ELISA and large molecule production.

One thinks this particular placement would be more tailored towards a DCU

chemistry student. However while one considers that a chemistry student would be perhaps a

more suitable candidate, one firmly believes that there is no such thing as the perfect

placement. Students should be open-minded when encountering an area that may not be

totally well-matched to their degree and the onus should not be totally on the employer to

adapt work to adjust to your needs as a student. By being motivated, productive, positive and

having a general interest about your work, one can benefit a unique appreciation and insight

of entirely new areas in an industrial setting. Furthermore in an economy and environment

were jobs are hard sought the ability to adapt to work environments which are not suited to

you will become an ever more critical skill.

While one’s degree programme did not touch on many of the experiments carried out

in the QCL lab this has been an awarding work placement and great overall learning

experience. One has acquired an understanding of a variety of sophisticated chemistry tests

which will definitely stand to oneself going forward when pursuing a future career. It is one

thing learning about concepts in textbooks and testing your knowledge in exams but true

learning is attained by implementing models efficiently in real life practice in the lab.

Interacting with chemists who are patient and are experts in their field allowed one to acquire

new skills first hand that will no doubt complement the biology skills ascertained in

university.

Your first day on the INTRA job

One’s first day on site at Lilly comprised of several introductory talks designed to familiarize

new undergraduate starters with the general layout and safety procedures of the Kinsale site.

Whether working in a lab or walking between the buildings, safety of Eli Lilly employees is

paramount. We were shown how to respond to an accident and the correct use of a fire

extinguisher among other safety topics. The orientation was scheduled over two days and the

second day consisted of more specific safety practices and work conduct on site. Overall

one’s first days in Lilly were an enjoyable and educational experience.

Being expected to undertake a completely new area of knowledge

or a complex task

DCU’s Genetics and Cell Biology degree programme did not touch on many of the

experiments or chemistry concepts carried out in the QCL analytical. For this reason the vast

majority of the work undertaken was completely new. Approaching work in which one

doesn’t have previous experience or knowledge was a daunting task before starting in Eli

Lilly. However one is an extremely motivated individual and relishes any challenge that is

presented to them. By being enthusiastic and applying yourself to your work one was able to

overcome this information gap.

Finding yourself with nothing to do

A key skill that one established during work placement was becoming proactive.

While supervisors did there upmost to keep you occupied, there were times that one had

nothing to do. It’s during these periods that showing a bit of initiative and asking for more

work or carrying menial tasks is important. One quickly discovered that executing small tasks

that seem insignificant can actually be of a huge benefit. The QCL lab is an extremely busy

section of the Lilly and all analysts working very hard to meet demanding daily deadlines. By

carrying small tasks, one can alleviate some pressure from some of the analysts. It was vital

that one recognised that they were a part of a team and by doing minor tasks one can help

fellow team members work in a more efficient manner.

Realising that you have made a mistake

Perhaps the biggest learning outcome one gained working in the strict environment of

QCL is that mistakes happen no matter how careful you approach your work. The stringent

standards set out by drug authorities such as FDA are in place to ensure the safety of

pharmaceutical products. At the start one was afraid of making even the smallest mistake as

an error in documentation or deviation from procedure would let down the QCL team and

hold up work in the lab. One is a perfectionist at heart and takes tremendous pride in their

work but despite one’s best efforts mistakes were made. The best advice received while in Eli

Lilly was do not let the mistake define you instead learn from it and set the bar higher.

Admitting to a mistake and overcoming hurdles is something that one will definitely take

away from this placement and will be apply it to all areas of life.

Self-Development Plan

This Lilly placement has reinvigorated one’s enthusiasm for science. One truly

understands the role the pharmaceutical industry plays in treating illnesses. It was for this

reason why one studied science because not only does it satisfy your curiosity of how things

work but also it has the capacity to help improve millions of lives simultaneously. By

working in small molecule an appreciation of chemistry was gained in which one had

previously limited exposure to. One believes biopharma products are truly the future of

medicine but acknowledges that small molecule formulations will continue to play a central

role in medicinal treatments. Overall this placement has opened one’s eyes to working in the

pharmaceutical industry.

Eli Lilly promotes a balanced lifestyle and one has engaged in several social and sports

events outside the lab. One understands final year in college is of upmost significance but it is

imperative that it does not take over one’s life. By keeping fit and maintaining an active

social life the demands of final year can be reduced.

Self- Evaluation of Performance

One performed to the best of their abilities and represented DCU well. One’s

expectations of the work placement at Eli Lilly were surpassed considerably as the Internship

programme immerses students into the real inner workings of a lab. QCL was a demanding

environment to work with continuous testing and stringent documentation practices that need

to be abided by. However one feels that they carried some productive tasks that helped the

QCL team and reciprocally benefited one’s learning experience.

While one did try their best in all aspects of placement, there were areas that could

most definitely improved upon including gaining a better eye for detail when reviewing lab

practices and dealing with blunders when they sometimes occur. Ultimately this unique

experience in Cork has been a test and has allowed one to learn a lot inside and outside the

lab. One has matured as a person and feels more confident as result of working in QCL.

While this work placement was not entirely relevant to my course one made the most of it

and it has been a truly awarding experience.

Conclusion

Without a moment of hesitation one has been fortunate enough to have attained and

experienced the most sought after undergraduate scientific internships in Ireland. Upon

reflection one feels lucky to have been able to take their first steps in their science career in

one of the biggest pharmaceutical companies in the world. Ultimately one would highly

recommend Eli Lilly’s undergraduate internship to any DCU student. The pleasant and

relaxing atmosphere in Eli Lilly allows students to smoothly transition from college lecture

hall to analytical laboratory. During the six months in Eli Lilly one has truthfully experienced

the inner workings of huge pharmaceutical company from how pharmaceutical drugs are

produced in large scale, tested in accordance to FDA guidelines and marketed across the

globe.

One received a great deal of training on safety practices, experimental analysis and

employee conduct which gave assurance when completing tasks in areas not encountered

before. This placement immerses students in the day to day running of QCL and permits

students to get involved in a variety of desktop and lab bench projects that can be only

experienced in an industrial setting. This internship has allowed one to attain a wealth of

practical and theoretical scientific knowledge that will compliment one’s biology degree and

will no doubt be of enormous benefit when conducting analysis and seeking future

employment.

One now recognizes to be a good scientist not only takes proficient laboratory skills

but also social skills. From approachable team leaders to patient analysts the entire staff strive

to ensure each student has an enjoyable educational experience by offering advice on lab

projects and personal challenges in industry. In addition the opportunity to share your

internship experience with 20 other undergraduate students from a range of disciplines was

an unparalleled experience. This allowed one to learn from each other’s involvements, share

everyday experiences and partake in countless social activities outside work. Having a

miniature student community within Eli Lilly allowed one to mingle with people from

colleges all over Ireland and ultimately this contributed to a desired balanced lifestyle after

working hours. During one’s six month placement friendships have been forged that will

extend for a long time after internship.

In conclusion in Eli Lilly employees and students work hand in hand with the

common to purpose of manufacturing drugs that help people. This ethos of helping people is

the cornerstone of the work conducted in Eli Lilly and one’s passion in life. Science

especially pharmaceutical science affords individuals the opportunity to improve the quality

of health of millions of patients by producing safe and quality products. Not only has this

internship been a defining educational and social experience but one senses for the first time

they contributed to a process that endeavours to save lives.