“Creating your own SUPAC” Colin R Gardner, Currently: CSO, Transform Pharmaceuticals Inc Lexington, MA, 02421 Formerly: VP Global Pharmaceutical R&D Merck.

“Creating your own SUPAC”

Colin R Gardner,

Currently: CSO, Transform Pharmaceuticals Inc

Lexington, MA, 02421

Formerly: VP Global Pharmaceutical R&D

Merck & Co Inc

www.transformpharma.com

May 21 , 2003

Creating your own SUPAC

Facts:

• Pharmaceutical production processes are a series of unit operations

• Drugs are materials

• 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 1980’s: Pre-approval inspections

Mid 1990’s: SUPAC

Early 2000’s: Comparability protocols

Late 1990’s: Site-specific stability

Late 1990’s: PQRI

Historical timeline of regulatory initiatives

Late 1980’s: Pre-approval inspections

Mid 1990’s: SUPAC

Early 2000’s: Comparability protocols

Late 1990’s: Site-specific stability

Late 1990’s: PQRI

Early 2000’s: PAT

SUPAC RATIONALE

“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

Pharm Res 10, 314 (1993)

A look at SUPAC guidelinesComposition• 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.

•Would it be expected that the same criteria would apply

to all formulations and processes?

•Where are the data to support these guidelines?

An engineer’s 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.

“Create your own SUPAC”

Complete characterization of the API,

Selection of appropriate manufacturing processes,

Characterization of each unit operation,

Establishment of scale-up, tech transfer and validation criteria

This is not envisioned in the current generalized SUPAC guidelines.

These activities would alleviate many of production problems

evident in the industry.

Comparability protocols

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

• FDA guidelines available for comment

• Similar in concept to “create your own SUPAC”

Product development process and milestones

Candidate

Selection

Form

Selection

ProcessDevelopment Scale up

Technology

TransferComposition

& Process

Discovery Development Manufacturing

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

PostApprovalchanges

Ritonavir: HIV protease inhibitor

ONH

HN

NH

N

CH3

O

OHO

CH3H3C

O

N

SS

NH3C

H3C

ABT-538 discovered Launch of semi-solid capsule/polymorph I Polymorph II appears, <50% solubility

Product pulled from the market Massive effort to reformulate the product Reformulated softgel capsule launched

Case history:

199219961998

1998 - 19991999

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

Summer of 1998

TransForm 2002 – 6 week effort

Launch in 1996

Summer of 1998

TransForm 2002 – 6 week effort

Morissette et al. PNAS 100, (2003).

2 g of compound

>2,000 crystallization experiments

32 combinatorialized solvents

Process characterization:

Region where process is robust

Region where process is unstable

Region where parameter tracking identifies drift

Mass-Spectrometric Residual Gas Analysis

-60

-40

-20

0

20

40

60

80

100

120

-480 240 960 1680 2400

Time (mins)

'C

%

water

nitrogen

shelf temp

temp probe

water

nitrogen

shelf temp

temp probe

Merck & Co Inc

• Granulation end-points

Process characterization:

Normalized Power and Slope: 10 L and 65 L Mixers

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0 0.2 0.4 0.6 0.8 1 1.2Normalized Water

Norm

alize

d Pow

er

0

0.005

0.01

0.015

0.02

0.025

0.03

0.035

Norm

alize

d Sl

ope (

/sec)

65 L

10 L

65 L slope

10 L slope

Pow er

Pow er

Power profiles of 10 and 65 liter granulators are similar

Merck & Co Inc

Normalized Power and Slope: 65 L and 250 L Mixers

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0 0.5 1Normalized Water

Nor

mal

ized

Pow

er

0

0.005

0.01

0.015

0.02

0.025

0.03

Nor

mal

ized

Slop

e (/s

ec)

250 L Power

65 L Power

250 L Slope

65 L Slope

Power profiles of 65 and 250liter granulators are similar

Merck & Co Inc

LASER DRILLED APERTURES

CORE TABLET

IMPERMEABLE COATING

Merck & Co Inc

Controlled release formulation: process characterization

GEM tablet

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0

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

% D

rug

Re

lea

se

d

Control

- 10% P / -10% N

- 10% P / +10% N

+ 10% P / - 10% N

+ 10% P / +10% N

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

Merck & Co Inc

0

20

40

60

80

100

120

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

% Release at6 hours

mean hole size[microns]

76 (2.0) 512 (13.4)75 (2.2) 503 (15.1)74 (1.1) 510 (9.3)

435 usec, 380 J/sec650 usec, 255 J/sec825 usec, 201 J/sec

Varying pulse width and power

Merck & Co Inc

% Release at 8 hours vs. Hole Size

50

55

60

65

70

75

80

85

90

95

100

300 350 400 450 500 550 600 650

Hole Size [micron]

9.0-12.9 mg Coat Weight

15.0-16.9 mg

20.8-22.9 mg

• 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

• Drug release rate increases with number of holes • Rate of increase diminishes as number of holes increase

Effect of Number of Holes (Ave. Diam. 485 µm)

0

10

20

30

40

50

60

70

80

90

100

0 100 200 300 400 500 600 700 800

Time (mins)

% D

rug

Rel

ease

20 holes

30 holes

40 holes

50 holes

60 holes

70 Holes

80 Holes

88 Holes

Merck & Co Inc

Effect of Hole Size (80 Holes per Face)

• Drug Release Increases with Size of Holes• Diminishing Rate of Increase with Increasing Hole Size

0

10

20

30

40

50

60

70

80

90

0 100 200 300 400 500 600 700 800

Time (mins)

% D

rug

Rel

ease

d

223microns

326microns

385microns

432microns

456microns

501microns

Merck & Co Inc

What has to happen? Pharmaceutical companies

Understand and control raw materials – API’s 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

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 sitechanges

What has to happen? Pharmaceutical companies

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

Provide incentives to encourage companies who develop and run robust manufacturing processes

• Reduction of prior approval requirements• Faster and less frequent GMP inspections, etc

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

What has to happen? Regulatory agencies

“Creating your own SUPAC”

Colin R Gardner,

Currently: CSO, Transform Pharmaceuticals Inc

Lexington, MA, 02421

Formerly: VP Global Pharmaceutical R&D

Merck & Co Inc

www.transformpharma.com

May 21 , 2003

Back-up slides

Scaling up a suspension formulation

Batch size Biobatch 10 liters

Commercial batch 100 liters

Mixing time

30 mins

45 mins

drug excipients drug excipients

Preparation tank

Filling tank

Filling points

Re-circulating filling line

Pump

Suspension formulation preparation and filling

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 transferTwo 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

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14

Time (hrs)

% D

rug

Re

lea

se

d

Polymer Removed

Neutralizing Agent Removed

Control

Merck & Co Inc

Hole size vs drill energy

Merck & Co Inc

Varying Energy

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Time [hours]

232 mJ/hole166 mJ/hole132 mJ/hole106 mJ/hole145 mJ/hole114 mJ/hole95 mJ/hole84 mJ/hole

Decreasing Energy(General Trend)

• Decreasing energy / hole at constant coat weight results in slight reduction in release rate Merck & Co Inc

Varying coat weight

0102030405060708090

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13Time [hours]

13.0 to 14.9 mg15.0 to 16.9 mg9.0 to 12.9 mg17.0 to 18.9 mg19.0 to 20.7 mg20.8 to 22.9 mg

% Release at 6 hours

mean hole size [microns]

79 (1.0) 525 (10.5)75 (2.2) 503 (15.1)75 (3.8) 559 (13.4)73 (3.2) 488 (8.5)72 (0.5) 458 (13.1)70 (2.2) 457 (10.7)

Increasing Coat Wt.

(General Trend)

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

Merck & Co Inc