1
Creating your own SUPAC
Colin R Gardner, Currently CSO, Transform
Pharmaceuticals Inc Lexington, MA,
02421 Formerly VP Global Pharmaceutical RD
Merck Co Inc
May 21 , 2003
www.transformpharma.com
2
Creating your own SUPAC
Facts

• Drugs are materials

• Pharmaceutical production processes are a series
  of unit operations

• They are governed by the same chemical and
• engineering principles that operate in other
• manufacturing processes

• We need to treat them that way

3
Historical timeline
Late 1980s Pre-approval inspections
Mid 1990s SUPAC
Late 1990s Site-specific stability
Late 1990s PQRI
Early 2000s Comparability protocols
4
Historical timeline of regulatory initiatives
Late 1980s Pre-approval inspections
Mid 1990s SUPAC
Late 1990s Site-specific stability
Late 1990s PQRI
Early 2000s PAT
Early 2000s Comparability protocols
5
SUPAC RATIONALE
Pharm Res 10, 314 (1993)

• For years the Agency has had difficulty
  developing a regulatory policy, based on solid
  pharmaceutical principles for scaling-up solid
  oral dosage form batch sizes. The published
  scientific literature does not presently provide
  a sufficiently rich source of data to enable such
  regulatory policy formation.

Additionally, the process should be
controlled by employment of a validation protocol
which defines the critical parameters and also
establishes the acceptance criteria for the
granulation or blend which may include sieve
analysis, flow, density, uniformity,
compressibility, moisture content, etc
These are all phenomenological measurements, not
fundamental process parameters that can be used
to model and predict process performance as
conditions change
6
A look at SUPAC guidelines

• Composition
• Changes defined as minor or major are purely
  arbitrary
• 5 change in filler
• change of more than 20 in particle size of
  excipients,
• 20 in volume of granulating fluid etc.

• Where are the data to support these guidelines?

• Would it be expected that the same criteria would
  apply
• to all formulations and processes?

7
An engineers view

• It has been decades since the chemical
  engineering discipline made the transition from a
  highly descriptive framework of distinct unit
  operations and processes to a generalized body of
  knowledge based on interlocking fundamentals
  (transport phenomena, thermodynamics, kinetics,
  chemistry).

These fundamentals have been quantitatively
developed so as to create powerful predictive
tools that permit us to apply know-how acquired
in one context to any other, as well as to deal
with the broadest range of natural
phenomena. C. Rosas, Chem and Biochem
Engineering, Rutgers University, 1999.
8
SUPAC A different view

• Pharmaceutical product processing has not taken
  advantage of the skills extant in the chemical
  engineering arena and already in widespread use
  in the chemical and other manufacturing
  industries.

Complete characterization of the API, Selection
of appropriate manufacturing processes,
Characterization of each unit operation,
Establishment of scale-up, tech transfer and
validation criteria
These activities would alleviate many of
production problems evident in the industry.
This is not envisioned in the current generalized
SUPAC guidelines.
Create your own SUPAC
9
Comparability protocols

• FDA guidelines available for comment

• Similar in concept to create your own SUPAC

• Successful only if
• pharmaceutical processes are adequately
  developed and
• the influence of fundamental process parameters
  understood and used to define protocols for
  scale-up, technology transfer and raw material,
  formulation and process changes

10
Product development process and milestones
Discovery
Development
Manufacturing
Post Approval changes
Candidate
Process Development
Scale up
Selection

• Properties
• Potency
• Selectivity
• In vivo efficacy

• Form selection
• Salt form
• Polymorph
• Hydrate.

• Excipients
• Physical effects
• Chemical effects
• Process selection
• Granulation
• Direct compression
• Lyo.

• Characterize
• Raw materials
• Unit operations
• Process flow

• Establish criteria
• Tech transfer
• Validation
• Process monitoring

• Equipment
• Qualify
• Process
• Engineering run
• Validation
• Process monitoring

11
Ritonavir HIV protease inhibitor
Case history

• ABT-538 discovered
• Launch of semi-solid capsule/polymorph I
• Polymorph II appears, lt50 solubility
• Product pulled from the market
• Massive effort to reformulate the product
• Reformulated softgel capsule launched

1992 1996 1998 1998 - 1999 1999
12
High throughput technologies exist, capable of
identifying essentially all potential forms.

• Parallel processing of thousands of
  crystallizations
• Comprehensive discovery of solid forms
• polymorphs, salts, hydrates, solvates,
  co-crystals

• Better, more informed choices
• Better products

13
Summary of Ritonavir Crystal Forms
Launch in 1996
Launch in 1996
Summer of 1998
Summer of 1998

TransForm 2002 6 week effort
2 g of compound gt2,000 crystallization
experiments 32 combinatorialized solvents
14
Process characterization
Region where parameter tracking identifies drift
Region where process is robust
Region where process is unstable
15
Mass-Spectrometric Residual Gas Analysis
120
water
100
nitrogen
80
60
40
20
'C
0
-480
240
960
1680
2400
shelf temp
water
-20
nitrogen
shelf temp
temp probe
-40
temp probe
Time (mins)
-60
Merck Co Inc
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Process characterization

• Granulation end-points

17
Merck Co Inc
18
Power profiles of 65 and 250 liter granulators
are similar
Merck Co Inc
19
Controlled release formulation process
characterization
GEM tablet
IMPERMEABLE COATING
LASER DRILLED APERTURES
CORE TABLET
Merck Co Inc
20
Formulations with Small Variations in Amounts of
Polymer (P) Neutralizing Agent (N)
Merck Co Inc
21
Varying pulse width and power
120
100
80
60
40
20
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Time hours

• Changing pulse width and power at constant
  energy results in similar dissolution profiles
• Hence energy/hole used as a process control
  variable

Merck Co Inc
22
Release at 8 hours vs. Hole Size
100
95
90
85
80
75
70
9.0-12.9 mg Coat Weight
65
15.0-16.9 mg
60
20.8-22.9 mg
55
50
300
350
400
450
500
550
600
650
Hole Size micron

• Correlation between hole size and release
  exists which is independent of the coat weight.
  Hole size can be used instead of release to
  determine the driller performance.

Merck Co Inc
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Effect of Number of Holes (Ave. Diam. 485 µm)
100
20 holes
90
30 holes
80
70
40 holes
60
50 holes
Drug Release
50
60 holes
40
70 Holes
30
20
80 Holes
10
88 Holes
0
0
100
200
300
400
500
600
700
800
Time (mins)
Merck Co Inc
Drug release rate increases with number of
holes Rate of increase diminishes as number of
holes increase
24
Effect of Hole Size (80 Holes per Face)
90
80
223
70
microns
326
microns
60
385
microns
50
Drug Released
432
microns
40
456
microns
30
501
microns
20
10
0
0
100
200
300
400
500
600
700
800
Time (mins)
Drug Release Increases with Size of Holes
Diminishing Rate of Increase with Increasing Hole
Size
Merck Co Inc
25
What has to happen? Pharmaceutical companies

• Understand and control raw materials APIs and
  excipients

• Develop and understand the fundamentals of each
  unit
• operation in the process

• Track key critical parameters (including
  in-process controls)
• during development

• Use these parameters to characterize the process

• Use a sub-set to conduct scale-up, technology
  transfer
• and validation

• Define a smaller sub-set to set as regulatory
  specifications

• Define a larger sub-set to be used for trend
  analysis to
• monitor process drifts before they are disastrous

This all makes good business sense since it will
reduce batch failures and simplify changes and
inspections
26
What has to happen? Pharmaceutical companies
In a regulatory submission (NDA, sNDA, ANDA)
Include a well-constructed formulation and
process development report showing the rationale
for the choice of materials, processes and
critical parameters to control the process

• The company would use this document as the basis
  of
• the regulatory specifications for review at the
  FDA central office
• AND
• the validation and change control protocols for
  review at PAI and
• during GMP inspections

It would also be the document to be used in
negotiation of the regulatory pathway for
subsequent composition, process and site changes
27
What has to happen? Regulatory agencies

• Move beyond stability as an indicator of process
  reliability,
• site transfer, and composition and process change

• Apply chemical, material science and engineering
  principles
• to evaluation of new products and post-approval
  changes

• Treat trend parameters differently from
  regulatory
• specifications they indicate drift, not process
  failure

• Provide incentives to encourage companies who
  develop
• and run robust manufacturing processes
• Reduction of prior approval requirements
• Faster and less frequent GMP inspections, etc

28
Creating your own SUPAC
Colin R Gardner, Currently CSO, Transform
Pharmaceuticals Inc Lexington, MA,
02421 Formerly VP Global Pharmaceutical RD
Merck Co Inc
May 21 , 2003
www.transformpharma.com
29
Back-up slides
30
Scaling up a suspension formulation
drug
excipients
drug
excipients
Batch size
Biobatch 10 liters
Commercial batch 100 liters
Mixing time
30 mins
45 mins
31
Suspension formulation preparation and filling
Preparation tank
Re-circulating filling line
Pump
Filling tank
Filling points
32
Site specific stability

• Regulators claimed that moving a process from
  one site to another not within the same campus
  could result in differences in the stability of
  the product variability was a consequence of
  the change of venue

• Proposed running stability at the manufacturing
  site as proof of technology transfer

• Two flaws in the argument
• Stability is not a measure of effective
  technology transfer
• The observed differences were due to inadequate
  process development and poor environmental
  controls

33
Effect of Removing Polymer Neutralizing Agent
Control
Neutralizing Agent Removed
Polymer Removed
Merck Co Inc
34
Hole size vs drill energy
Merck Co Inc
35
Varying Energy
100
Decreasing Energy
90
(General Trend)
80
70
60
50
232 mJ/hole
166 mJ/hole
40
132 mJ/hole
30
106 mJ/hole
145 mJ/hole
20
114 mJ/hole
10
95 mJ/hole
84 mJ/hole
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Time hours

• Decreasing energy / hole at constant coat
  weight results in slight reduction in release rate

Merck Co Inc
36
Varying coat weight
100
90
80
Increasing
70
Coat Wt.
60
Release at
mean hole size
(General Trend)
6 hours
microns
50
13.0 to 14.9 mg
79 (1.0)
525 (10.5)
40
15.0 to 16.9 mg
75 (2.2)
503 (15.1)
30
9.0 to 12.9 mg
75 (3.8)
559 (13.4)
17.0 to 18.9 mg
73 (3.2)
488 (8.5)
20
19.0 to 20.7 mg
72 (0.5)
458 (13.1)
10
20.8 to 22.9 mg
70 (2.2)
457 (10.7)
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Time hours

• Increase in coat weight results in slight
  lowering of the release rate.

Merck Co Inc
37
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