An Introduction to Process and Cleaning Validation in the Biologics Industry

Michelle Lombardo, Scientist II MS&T-FLS Presentation for Center for Excellence in Education, Bite of Science-Frederick 02Nov17

Who is Michelle Lombardo?

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My Career Path

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2001 1997 2017

2016 2013

2008

2002

2003

AstraZeneca

Biologics Manufacturing Center in Frederick

• Largest biologics manufacturing facility in

AstraZeneca

• Manufacture medicines for the treatment of

cancer, respiratory and autoimmune conditions

• Careers:

• Manufacturing, Quality Assurance, Quality Control,

Science & Technology, Facilities & Engineering,

Supply Chain

• Global, science-led biopharmaceutical company

• Develops, manufactures and markets medicines to prevent or treat illness

We push the boundaries of science to deliver life-changing medicines 4

Campus Orientation

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Building 636

Occupied

Sq. ft. 134,200

Use of

Space

Manufacturing Science &

Technology space includes

reserve multi-product bulk

manufacturing capacity

4 x 2.5KL bioreactors

Building 660

Occupied Sq. ft. 60,000

Use of Space

laboratories and

administrative

functions

Building 633

Occupied Sq. ft. 367,100

Use of Space

bulk cell culture production

suites, laboratories,

warehouse, and administrative

space

4 x 15K L bioreactors

Building 630

Occupied Sq.

ft. 50,000

Use of Space

Distributed Material Ctr.

Finished Product Storage

(-40°)

Two Types of Medicines: Small Molecules and Biologics

Small Molecules Biologics (Large Molecules)

• Can be 150 kDa

• Produced by living cells

• Example: Durvalumab

(monoclonal antibody)

• Low molecular weight (< 900 Da)

• Synthesized through chemical

reactions

• Example: Aspirin C9H8O4

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Small Molecule Drug Compared to Biologic

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Aspirin (acetylsalicylic acid)

180 Daltons

Human IgG1

(e.g. palivizumab (Synagis ®)

~150,000 Daltons

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Biologics Process Flow

www.bioprocessintl.com

Many different roles in pharma and biotech

companies are needed to develop drugs

Research &

Development

Manufacturing

& Operations

Quality MS&T

Facilities &

Engineering

Finance,

Human Resources,

SHE

Supply Chain

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DELIVERS EFFICIENT BIOPROCESSES Research &

Development MS&T

Manufacturing Sciences &

Technology Supports ongoing manufacturing operations

and leads cell culture process monitoring,

troubleshooting and optimization for

products manufactured on site

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MS&T Career Ladder

Manufacturing Technology Associate I

Manufacturing Technology Associate II

Associate Scientist II / Associate Engineer II*

Scientist I**

Scientist II

Senior Scientist

Manager

Senior Manager

Associate Director

Director

Senior Director

Vice President

Principle Scientist

Fellow

Senior Fellow

Distinguished Fellow

Technical Ladder Managerial Ladder

Associate Scientist I / Associate Engineer I*

*Associate Scientist or Engineer

title is based on college major

** No title distinction between

Scientist or Engineer title since

both disciplines must be

understood at this level and above.

Job Scope for MS&T Scientist

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Project Management

•Plans, designs, and executes multiple simultaneous projects that are complex and technically demanding within a specific area/field.

• Initiates, implements, plans, directs, and executes investigations to resolve deviations, understand process trends, and/or improve process performance.

•Typically conducts more than one significant project at a time.

•Responsible for meeting project goals within time and budget constraints.

Manufacturing Support

•Responsible for balancing day-to-day technical support for manufacturing and longer term projects and investigations.

•Develops investigation findings and makes recommendations.

•Makes detailed observations, analyzes data, and interprets results.

•Utilizes forward-looking perspective to contribute to “go/no go” decisions.

Industry Knowledge

•Effectively presents results at internal meetings and external scientific meetings.

•Responsible for maintaining technical expertise on an entire section of the manufacturing process (either upstream or downstream).

•May make recommendations on outside technologies for company to pursue.

Leadership

•Works under general supervision of higher-level scientist or manager.

•May supervise lower-level scientists and associates

A Day in the Life

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What is Validation?

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Validation is the process of establishing documentary evidence demonstrating that a procedure, process, or activity carried

out in testing and then production maintains the desired level of compliance at all stages.

• In the pharmaceutical industry, it is very important that in addition to final testing and compliance of products, it is also assured

that the process will consistently produce the expected results.

• Validation is a requirement of food, drug and pharmaceutical regulating agencies such as the US FDA.

• Since a wide variety of procedures, processes, and activities need to be validated, the field of validation is divided into a number

of subsections.

IVT Network

What is Cleaning Validation?

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The process of providing

“Documented evidence that the

cleaning methods employed within

a facility consistently controls

potential carryover of product,

cleaning agents and extraneous

material into subsequent product to

a level which is below

predetermined acceptance criteria”.

CIP Supply

PG

CIP Return

CIP Return Pump

Background of Clean-In-Place (CIP)

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Up to the 1940s, closed systems were disassembled and

cleaned manually • Brushes, buckets, hoses

• Staff entered large vessels to clean the interior.

• CIP originated as a manual practice in the dairy industry.

• Basis of CIP technology is largely derived empirically; “rules of

thumb” from early dairy applications.

• Basic “Law” of CIP: “If you can get it wet, you can get it clean.” Dale

Seiberling

• In early 1980’s, CIP entered BioPharm Industry

• The advent of automated/ semi-automated CIP was a boon to

industries that needed frequent internal cleaning of their equipment

– Pharmaceutical, Food & Beverage, Cosmetics

Process Flow for Bringing in New Soilants

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FactoryTalk

1 2 3 4

Fundamental Design of CIP: Cleaning Process

Rinse, Clean, Rinse, Verify

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Dirty Equipment Removal of most

of product Removal of any

remaining residual

Cleaning agents/

residuals Removed

Initial water rinse

(cold) Cleaning agents Final WFI rinse

(hot) Swab worst-case

locations

Cleanliness

verified

What is Process Validation?

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Process Validation – Elements of Evaluation

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Population Doubling Level

www.what-when-how.com, GE Healthcare, bioMerieux, Grainger

What is Continued Process Verification (CPV)?

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Developed by Walter Shewhart (Bell Labs ~1924)

W. Edwards Deming- became the foremost

champion and proponent of

Shewhart's work.

“You can’t manage what you don’t measure” – W. Edwards Deming

Process Capability

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www.qualitytrainingportal.com

HOW CAN YOU PREPARE FOR A CAREER IN THIS

INDUSTRY?

Sciences

• Chemistry

• Physics

• Biology

Communications

Economics

Engineering

Intellectual Property Law

Computer Sciences

Math & Statistics

Technical Writing

POSSIBLE SUBJECTS TO

STUDY IN SCHOOL PRACTICAL EXPERIENCE

Internships

Job shadowing

Presentations

Science camps

Science clubs

Science fairs

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WHAT TRAITS AND SKILLS HELP PEOPLE SUCCEED?

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Creativity

Curiosity

Honesty

Persistence

Accept advice

Be a gracious winner/ loser

Check your work

Follow rules

Learn from mistakes

Teamwork

Respect for others

Practice Good Communication

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References

MedImmune Annual Report 2005

www.FDA.gov

Marketing Research Bureau

PALL

www.statisticsviews.com

Pharmaceutical Online

VWR

www.bioprocessintl.com

IVT Network

Acknowledgements

Center for Excellence in Education

Scott Rosenthal

Michelle Michael

Edward Wyman