Creating your own SUPAC

Colin R Gardner,
Currently: CSO, Transform Pharmaceuticals Inc
Lexington, MA, 02421

Formerly: VP Global Pharmaceutical R&D

Merck & Co Inc

May 21 , 2003
www.transformpharma.com
 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

 Historical timeline
Late 1980s: Pre-approval inspections

Mid 1990s: SUPAC

Late 1990s: Site-specific stability

Late 1990s: PQRI

Early 2000s: Comparability protocols

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

 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
 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?
 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.
 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

 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
 Product development process and milestones

Discovery Development Manufacturing

Candidate Form Composition Process Technology Post

Selection Selection Development Scale up Transfer Approval
& Process
changes

Properties: Form Excipients: Characterize: Establish criteria: Equipment:

selection: Qualify
Potency Physical Raw materials Tech transfer
Salt form effects
Selectivity Unit operations Validation Process:
Polymorph Chemical
In vivo Process flow Process monitoring Engineering run
effects
efficacy Hydrate.
Validation
Process
selection: Process monitoring
Granulation
Direct
compression
Lyo.
 Ritonavir: HIV protease inhibitor

H3C CH3
O O

H
H3C N N
N N N O
H H

CH3 O OH
H3C S S

Case history:
1992 ABT-538 discovered
1996 Launch of semi-solid capsule/polymorph I
1998 Polymorph II appears, <50% solubility
Product pulled from the market
1998 - 1999 Massive effort to reformulate the product
1999 Reformulated softgel capsule launched
 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
 Summary of Ritonavir Crystal Forms

IV

mp 122 C mp 125 C mp 80 C mp 97 C mp 116 C

Launch in 1996
Launch in 1996
Summer of 1998
Summer of 1998 Morissette et al. PNAS 100, (2003).
TransForm 2002 6 week effort
TransForm 2002 6 week effort

2 g of compound
>2,000 crystallization experiments
32 combinatorialized solvents
 Process characterization:
Region where parameter tracking Region where process is robust
identifies drift

Region where process is unstable

 Mass-Spectrometric Residual Gas Analysis
120

water
100
nitrogen
80

60
%

40

20

0
-480 240 shelf temp 960 1680 2400 water
-20
'C

nitrogen
shelf temp
-40 temp probe
Time (mins) temp probe
-60

Merck & Co Inc

 Process characterization:

Granulation end-points
 Normalized Power and Slope: 10 L and 65 L Mixers
65 L Pow er
2 0.035 10 L Pow er
1.8 65 L slope
0.03
1.6 10 L slope
1.4 0.025
1.2
NormalizedPower

0.02

Normalized
Slope (/sec)
1
0.8 0.015
0.6 0.01
0.4
0.005
0.2
0 0 Power profiles of 10 and 65
0 0.2 0.4 0.6 0.8 1 1.2 liter granulators are similar
Normalized Water
Merck & Co Inc
 Normalized Power and Slope: 65 L and 250 L Mixers
2 0.03
250 L Power
1.8 65 L Power
0.025 250 L Slope
1.6
65 L Slope
1.4
0.02
Normalized Power

1.2

Normalized
Slope (/sec)
1 0.015
0.8
0.01
0.6
0.4
0.005
0.2
0 0
Power profiles of 65 and 250
0 0.5 1 liter granulators are similar
Normalized Water

Merck & Co Inc

Controlled release formulation: process characterization

GEM tablet

IMPERMEABLE COATING

LASER DRILLED
APERTURES

CORE TABLET

Merck & Co Inc

Formulations with Small Variations in Amounts of
Polymer (P) & Neutralizing Agent (N)
100.0

90.0

80.0

70.0
% Drug Released

60.0

50.0
Control
40.0
- 10% P / -10% N
30.0 - 10% P / +10% N

20.0 + 10% P / - 10% N

+ 10% P / +10% N
10.0

0.0
0 2 4 6 8 10 12 14
Time (hrs)

Merck & Co Inc

 Varying pulse width and power
120

100

80

60
% Release at mean hole size
40
6 hours [microns]
435 usec, 380 J/sec 76 (2.0) 512 (13.4)
20 650 usec, 255 J/sec 75 (2.2) 503 (15.1)
825 usec, 201 J/sec 74 (1.1) 510 (9.3)
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
 % 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
 Effect of Number of Holes (Ave. Diam. 485 m)
100

20 holes
90

80 30 holes

70
40 holes
% Drug Release

60
50 holes
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
 Effect of Hole Size (80 Holes per Face)
90

80
223
70 microns
326
% Drug Released

60 microns
385
50 microns
432
40 microns
456
30 microns
501
20 microns

10

0
0 100 200 300 400 500 600 700 800
Time (mins)

Drug Release Increases with Size of Holes Merck & Co Inc

Diminishing Rate of Increase with Increasing Hole Size
 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
 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
 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
 Creating your own SUPAC
Colin R Gardner,
Currently: CSO, Transform Pharmaceuticals Inc
Lexington, MA, 02421

Formerly: VP Global Pharmaceutical R&D

Merck & Co Inc

May 21 , 2003
www.transformpharma.com
Back-up slides
 Scaling up a suspension formulation
drug excipients drug excipients

Batch size Biobatch Commercial

10 liters batch 100 liters

Mixing 30 45
time mins mins
Suspension formulation preparation
and filling

Preparation tank

Re-circulating filling line

Pump
Filling tank

Filling points
 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
Effect of Removing Polymer & Neutralizing Agent

100

90 Control
80

70

60
% Drug Released

50

40
Neutralizing Agent Removed
30

20

10 Polymer Removed
0
0 2 4 6 8 10 12 14
Time (hrs)

Merck & Co Inc

 Hole size vs drill energy

Merck & Co Inc

 Varying Energy
100 Decreasing Energy
90 (General Trend)

80
70
60
50 232 mJ/hole
40 166 mJ/hole
132 mJ/hole
30 106 mJ/hole
20 145 mJ/hole
114 mJ/hole
10 95 mJ/hole
0 84 mJ/hole
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
 Varying coat weight
100
90
80
70 Increasing
Coat Wt.
60 (General Trend) % Release at mean hole size
50 6 hours [microns]
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)
20 17.0 to 18.9 mg 73 (3.2) 488 (8.5)
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