The challenge:Can you validate my cGMP process and get my

product to market faster at a lower cost?

How we said yes:Albemarle has extensive expertise in the Design of

Experiments (DoE) approach—the modern

alternative to single-variable experimentation. In

our research facilities, DoE is used to conduct

process optimization in a rapid, responsive fashion,

while supporting efforts for cGMP process

validation. (The DoE approach can also be applied

to non-GMP process development.) In our

experience, DoE is an excellent course for

facilitating reduced costs and time to market.

Current Trends in ICH GuidelinesAlbemarle's DoE methods fully support the FDA

ICH Quality by Design (QbD) initiative. FDA

publications that have had an impact on our work:

• PAT — A Framework for Innovative Pharmaceutical

Development, Manufacturing, and Quality Assurance

(Final) Sept. 2004

• ICH Q7 — Good Manufacturing Practice Guidance for

Active Pharmaceutical Ingredients (Final) August 2001

• ICH Q8 (R2) — Pharmaceutical Development

(Final) Nov. 2009

• ICH Q9 — Quality risk management (Final) June 2006

• ICH Q10 — Quality systems (Final) April 2009

• Process Validation: General Principles and

Practices (Final) Jan 2011Fine Chemistry Services

Case Study E: Process optimization using Design of Experiments

OFAT v. DoE Approaches

OFAT(One Factor At a Time)

Central composite DoE

Single variable experimentation results in limited

ability to rapidly investigate process design space

Our approach for this particular client included:

STEP 1: Conducting a thorough quality risk review of the

process as per the FDA's Q9 approach to risk analysis:

• Identified relevant Critical Quality Attributes (CQAs);

• Initiated a 3-factor, 21-experiment central composite

DoE to understand the relative impacts of the putative

Critical Process Parameters (CPPs); and

• Performed the DoE on one of Albemarle's parallel

reactor systems, drastically shortening the amount of

time required to complete the study.

Factor Y Factor Y

Factor X Factor X

Factor ZFactor Z

Source: Owen, M. R.; et.al. Org.ProcessRes.Dev. (2001), 5, 308-323

The information presented herein is believed to be accurate and reliable, but is presented without guarantee or responsibility on the part of Albemarle Corporation. It is the responsibility of the user to comply with all applicable laws and regulations and to provide for a safe workplace. The user should consider any information contained herein, including information about any health or safety hazards, only as a guide, and should take those precautions that are necessary or prudent to instruct employees and to develop work practice procedures in order to promote a safe work environment. Further, nothing contained herein shall be taken as an inducement or recommendation to manufacture or use any of the herein described materials or processes in violation of existing or future patents.

Find out how we say yes to hundreds of fine chemistry projects annually.

Albemarle is experienced and equipped to provide custom manufacturing for customers worldwide.

To experience the difference of a committed fine chemistry partner, contact your Albemarle Representative.

www.albemarle.com

A M E R I C A S

Fine Chemistry Services

Tel: +1 225 388 7402

ALBSales@albemarle.com

E U RO PE , M I D D L E E A ST, A F R I C A

EMA Fine Chemistry Services

Tel: +32 10 48 1711

EMASales@albemarle.com

FCS-0011 (01/11)

The yes formula direct customer benefits:• The Albemarle DoE determined that performing

the reaction at a higher concentration could save

time and money.

• A distillation step was removed.

• The process was improved when relative Green

Metrics were analyzed.

• The customer gained a better understanding

of the process.

• The Albemarle DoE facilitated the process validation

according to the FDA's guidance on the topic (Quality

by Design). As a result:

> Our team has firm grasp on the process

design space.

> We have the confidence to operate this

process, which is characterized by very

high raw material input costs.

> We minimized the risk of encountering a

quality-related incident due to the DoE work.

> Albemarle has created value by applying

“big pharma” industry and FDA-endorsed

best practices for process optimization and

subsequent validation.

STEP 2: Three factors were tested in the context of the

DoE. The process was a bimolecular reaction (A + B > C):

• Relative amount of input B

• Reaction concentration

• Reaction temperature

STEP 3: Three responses were tested in each of the 21

parallel experiments:

• Amount of isomer of C found

• Overall conversion to C

• Product purity assay

STEP 4: The DoE results were verified on 2-L equipment,

then the information was explicitly applied to validations

at 1,000- and 4,000-gallon scale.