Development and

Scale up in API
Manufacture (Part1)
Tuesday 22nd September 2009

Dr. Claire Mc Donnell, D.I.T.

1
 Contents
 Terminology
 Development Stages
– Chemical Development
– Process Development and Support
 Costing
 Scale-up
 Case Study – Process Development for Labetalol
Manufacture
 Summary
 Bibliography 2
 Background
“drug” – a compound that interacts with a
biological molecule, triggering a physiological
effect.
Drugs (active pharmaceutical ingredients) can be classified
into 4 groups depending on their origin;
1) Natural products
2) Fermentation products
3) Semisynthetics – substances produced by partial synthesis
4) Completely synthetic products
Will cover synthetic aspects of pharmaceutical production
processes.
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 Background
 Average cost of developing a drug was $500 million in 1999 and
takes 12-25 years usually.
 The chances of a candidate drug that is identified becoming
approved is approximately 1 in 10,000. (For every 10,000 trial
compounds, 20 reach trials on animals, 10 reach clinical trials on
humans and 1 gets FDA approval)
 Discovery stage (research labs) involves preparation of potential
drug compound on 10 mg to 10 g scale. Toxicology tests are carried
out on this material. If these are successful, greater quantities of the
compound will be required for clinical trials .
 At this stage, development work begins.
- Immediate goal – to produce clinical trial material.
- Longer term goal – to develop a commercially viable scaled-up
validated process.
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 Terminology
 Development– covers all work between research and
production (e.g. analytical, chemical, formulation)
and continues when production begins.
 Scale-up – process of going from laboratory
preparation to whatever scale of manufacture is
required to satisfy the market demand (usually 1,000
to 50,000 L range)
 Technology Transfer
- Transfer between manufacturing sites
- Transfer within a manufacturing site
(Partnerships for collaborative R&D)
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 What is Development?
 Broad range - between research and production -
and overlaps with both
 In API (Active Pharmaceutical Ingredient)
manufacture, begins when active substance is
identified and activity demonstrated and more active
substance is required.
 Once a process that works on plant scale is
produced and is validated, development work still
continues to improve cost, efficiency, quality and
environmental impact and to deal with changing
circumstances (vendors, equipment, new regulations
(FDA 21 CFR part 11, Risk-Based Approach etc))
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 Development Stages
1) Chemical Development
Begins when activity of potential API is
demonstrated and more active substance is
required (for clinical trials).
 Process research;
– New synthetic routes (literature survey)
– Some initial optimisation
– Yield improvements
– Possibly scale-up to large lab equipment / kilo lab
(up to about 20 L)
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 Development Stages cont’d
 2) Process Development
- Optimisation (change conditions and parameters)
- Minor change of route / intermediate
- Cheaper / more efficient reagents (new to market)
- Environmentally-friendly reagents and effluent
considerations
- Yield / concentration improvement
- Statistical methods
(e.g. Experimental Design; want maximum amount of
unbiased information about factors affecting a process from as
few observations as possible. Caution - “Facts are stubborn
things. Statistics are more pliable”) 8
 Development Stages cont’d
 ProcessDevelopment cont’d
- SCALE-UP (Kilo Lab, Pilot plant trials)
- Transfer to Manufacturing

Parallel synthesis reactor block

- for optimisation of conditions

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 Development Stages cont’d
 3) Process Support
- Further optimisation (continuous improvement)
- Fine-tuning of yield and throughput
- Cost reduction
- Troubleshooting (reworks, reprocessing,
deviations)
- New vendor approval (use tests)
- Waste minimisation (recycling)

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 What is the Ideal?

“The ideal chemical process is that which a

one-armed operator can perform by pouring
the reactants into a bath tub and collecting
pure product from the drain hole”
- Sir John Cornforth

- (from Foreword by K. Barry Sharpless to Practical Process Research

and Development, N.G. Anderson, Academic Press, London, 2000.)

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 What is the (More Realistic) Ideal
for Scale-Up of a Process?
- No batch failures in pilot plant or on full-
scale
- No long increases in time required for any
particular stages
-Use of existing multipurpose plant
equipment

(Principles of Process Scale-Up, Lecture, Dr. Leen

Schellekens, Mettler Toledo, UCD Engineering
Building, 19th Oct 2004.)
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 Main Issues During Scale Up and
Development
ECONOMICS

ENVIRON-
SAFETY
MENT

SCALE UP

QUALITY HEALTH

(Communication and teamwork between departments.

Role of process technology) 13
 1) Chemical Development
 Selection of Synthetic Route
- GET THE BEST ROUTE FROM THE
BEGINNING - Difficult to change later
- Route should be short, efficient, robust and give a
high yield prior to scale-up
- Discovery route often not the best. Expedient not
optimal. (raw materials may not be available in bulk,
process may not be efficient and may be safety hazards on
large scale)
- Compare like with like during selection (Same level
of optimisation and same scale. Are products of same
purity obtained? What is the cost comparison?)
- Main constraint is TIME 14
 Chemical Development
 Selection of Synthetic Route cont’d
- Shortest route usually best (less effluent, shorter lead
time, short plant occupation, less analytical work)
- A convergent synthesis will be cheaper than a
divergent (linear) one with the same number of steps
- Literature not always correct and perseverance with
a reaction is required
- Better to try routes with high chance of success but
those which offer significant benefits should be
attempted even if little precedent
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 Chemical Development

In Convergent Synthesis, sections of the target molecule are prepared and joined
together to form the target molecule. A better yield than a linear synthesis with
the same number of steps will be obtained. The advantage is significant if the
subroutes converge close to the end of the synthesis.
(page 489, “Medicinal Chemistry, An Introduction”, G. Thomas).
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 2) Process Development
 Optimisation of Synthetic Route – Once Selected
- Work up very important
- Can steps easily be combined (telescoping)?
- Need excellent process control and understanding of
process limits (“stress” the reaction – higher
temperature, longer reaction time, less efficient
mixing). “Critical” steps / parameters (Quality)
- Good analytical methods (standards)
- Isolate and characterise by-products
- A very innocuous process change can often have a
significant influence
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 Costing of Processes
- Must be a standard costing procedure
- Should be dated and updated
- Assumptions should be stated
` - May be several factors leading to variation – scale,
plant configuration etc.
- Compare like with like and be conservative
- Carried out by independent person
- Want to be able to see which factors increase cost
significantly and why
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 Scale-up
 Planning for Scale-up
- Decide on process
- Decide on batch size (not too large an increase)
- Order raw materials (allow for 10% lower yield)
- Carry out safety tests (Exotherms, HAZOP – hazard
and operability studies)
- Discuss the process and plant requirements with
production manager/engineer (materials of
construction). Existing multipurpose plant usually.
- Prepare safety data sheets and discuss handling of
hazardous reagents or intermediates
- Ensure analytical procedures, equipment and staff are
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available
 Scale-up
 Planning for Scale-up cont’d
- Write out detailed procedure (assume nothing);
o Cleaning check and preparative work
o Charging and weighing
o Temperature and time limits
o Sampling (in-process checks)
o Transfers
o Work-up and isolation
o Drying and effluent disposal/treatment
Make allowance for delays / problems (rework
procedures, identify suitable “hold points”)
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 Scale-up
 Planning for Scale-up cont’d
 -Leave space in procedure to record data and observations
-Highlight safety procedures and steps to take if spillage
occurs
- Provide training

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 Scale-up
 Significant Differences Between Lab and Plant
- Heat transfer
- Agitation (frothing)
- Mass transfer (affects kinetics)
- Visibility – of reactions, separations, for cleanliness checks
- Separation (stirring, not shaking)
- Time (slower additon rates and heating/cooling times,
longer work up)
- Hazards (Toxic, Exotherm and Electrostatic)
- Off-gas treatment
- Safe and efficient sampling techniques needed (Process
Analytical Technology - Real time reaction monitoring; FT-IR,
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Particle size -FBRM)
 Scale-up
 Process Development Taking Account of Differences
Between Lab and Plant Equipment
-Use safety data already produced to help characterise
reaction
-Study effect of scale-dependent factors (mixing, mass
transfer and heat transfer) at lab scale
-Plan a logical set of experiments in time-frame available
-Mimic plant conditions; slower addition of reagents,
slower rate of heat increase and decrease and mixing, lab
system should be baffled if reactors are (no vortex)
-Obtain mass and heat transfer data for reactor type,
agitator type and solvents to be used.
-Use simulation software to predict effects of mass and
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heat transfer and mixing changes on scale-up.
 Scale-up - Crystallisation
 Crystallisation often causes problems
 Fine control required
 Changes in crystal habit (external structure) may affect
ease of isolation, washing and drying.
 Changes in crystal form (polymorphism – internal
arrangement of atoms different) affect solubility,
dissolution rate, ease of isolation and drying. Affects
formulation.
 Very common problem – impacts on drug activity
 (FBRM, Raman, PVM real time monitoring)
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 Scale-up - Troubleshooting
 Plan schedule to accommodate delays on first
batches
 Develop contingency plan for incomplete reactions
 If problem occurs, establish whether is physical
(physical manipulations of the processing) or
chemical (process inputs)
 Examine processing steps that occurred just before
problem was noted and work backwards
 Address operations that are simplest to change first

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 Case study; Process Development
for Labetalol Production at Schering
Plough Ltd., Rathdrum
BACKGROUND
 Labetalol – antihypertensive, 30,000 Kg p.a.
produced by Schering-Plough.
 First 2 steps in Rathdrum, Co. Wicklow. Final step
(hydrogenation) in U.S. or Puerto Rico.

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 Labetalol Manufacturing Process
 Mono-pot reaction in jacketed, glass-lined 10,000
L reactor.
 Addition of liquid reagents and jacket temperature
computer controlled. Solid reagents charged
manually via handhole.
 Phase separation using sight-glass.
 Solid product from second step isolated by
centrifugation.
 Product tested to determine if recrystallisation
necessary.
 When required purity achieved, product is dried
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 Labetalol Process – Step 1
CONH2 CONH2
HO HO
Br2
CH3 CH2Br

O O
5-ASA 5-Br-ASA

Main impurities:

CONH2 CONH2 CONH2

HO HO HO

CH3 CHBr2 CH2Br

Br
O O O
~ 5% ~ 2% ~ 1%
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 Labetalol Process – Step 1, Process
Development
 Solvent system modified to isopropanol / ethyl
acetate containing hydrogen bromide from
methanol / ethyl acetate to reduce formation of
third impurity. Original process used chloroform.
 Concentration was increased threefold increasing
throughput and reducing solvent waste.

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 Labetalol Process – Step 2

CONH2 CONH2
HO O HO
CH2Ph
CH2Ph
CH2Br + H N CH2 N
CH2Ph CH2Ph
O O
Dibenzylamine
5-Br-ASA LBH-B/C

+
Br
HO

propylene bromohydrin

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 Labetalol Process – Step 2, Process
Development
 Large excess of dibenzylamine used to ensure reaction
driven to completion (cheap reagent and easily washed
out)
 Propylene oxide added as it reacts with HBr side-
product as it’s produced. Presence of HBr would
neutralise dibenzylamine and no reaction to give product
would occur. Propylene bromohydrin side-product
easily washed out.
 Use gentle reflux to ensure propylene oxide doesn’t
escape
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 Summary
 Stages of development are Chemical Development,
Process Development and Process Support
 Development essential before scale-up and
validation – get process right first
 Time constraints a major factor
 Have process in control (”critical” parameters)
 Consider differences between lab and plant scale.
Try to mimic plant conditions in lab to anticipate
effects when scale up.
 Prepare process description carefully for scale-up
 Development always on-going
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 Bibliography
 Chemical Development and Scale-Up in the Fine
Chemical Industry, Course Notes from Trevor Laird,
Scientific Update, 2000.
 Process Development: Physicochemical Concepts, J.
Atherton and K. Carpenter, Oxford Primer Series, 1999.
 Process Development – Fine Chemicals fron Grams to
Kilograms, S. Lee and G. Robinson, Oxford Primer
Series, 1995.
 Practical Process Research and Development, N.G.
Anderson, Academic Press, London, 2000.
 Pilot Plants and Scale-Up of Chemical Processes II,
W. Hoyle ed, Royal Society of Chemistry, 1999.
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 Bibliography cont’d
 Principles of Process Scale-Up, Lecture, Dr. Leen
Schellekens, Mettler Toledo, UCD Engineering Building, 19th
Oct 2004.
 Scale Up and Transfer with Manufacturing, Michael J.
Valazza, Contract Pharma, Dec 1999.
(http://www.contractpharma.com/dec992.htm)
FURTHER READING:
 Organic Process Research and Development, Journal (Amer
Chem Soc / RSC). In DIT Kevin St.
 Pharmaceutical Technology Europe, Journal (Advanstar
Publishing) - Accessible electronically on DIT library
catalogue http://library.dit.ie/ or subscribe to for free at
http://www.ptemag.com/pharmtecheurope/
 Comprehensive Organic Transformations, R.C. Larock, Wiley
(1999) 34