# Presentation: 666713

## “Creating your own SUPAC”

**“****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

**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

**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

**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

**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 guidelines

**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.

- 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

**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

**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

**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

**Product development process and milestones**

**Candidate**

**Selection**

**Process**
**Development**

**Scale up**

**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

**Post**
**Approval**
**changes**

## Ritonavir: HIV protease inhibitor

**Ritonavir: HIV protease inhibitor**

- 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:**_

- 1992
- 1996
- 1998
- 1998 - 1999
- 1999

## High throughput technologies exist, capable of identifying essentially all potential forms. 

**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

**Summary of Ritonavir Crystal Forms**

**Launch in 1996**

**Summer of 1998**

**                                                          ****TransForm 2002 – 6 week effort**

**Launch in 1996**

**Summer of 1998**

**2 g of compound**
**>2,000 crystallization experiments**
**32 combinatorialized solvents**

## Process characterization:

**Process characterization:**

**Region where process is robust**

**Region where process is unstable **

**Region where parameter tracking identifies drift**

## Mass-Spectrometric Residual Gas Analysis

**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

## Process characterization:

** ****Granulation end-points**

**Process characterization:**

## Merck & Co Inc

## Merck & Co Inc

**Power profiles of 65 and 250**
**liter granulators are similar**

## Controlled release formulation: process characterization

**LASER DRILLED APERTURES**

**CORE TABLET**

**IMPERMEABLE COATING**

- Merck & Co Inc

**Controlled release formulation: process characterization**

**GEM tablet**

## Formulations with Small Variations in Amounts of 

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

- Merck & Co Inc

## Varying pulse width and power

- 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    **

**Varying pulse width and power**

- Merck & Co Inc

## % Release at 8 hours vs. Hole Size

**% 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

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

- • 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)**

**% Drug Release**

**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)

**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)**

**% Drug Released**

**223**

**microns**

**326**

**microns**

**385**

**microns**

**432**

**microns**

**456**

**microns**

**501**

**microns**

- Merck & Co Inc

## What has to happen? Pharmaceutical companies

**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**

## 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? Pharmaceutical companies**

## 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**

**  ****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”

**“****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

**Back-up slides**

## Scaling up a suspension formulation

**Scaling up a suspension formulation**

_**Batch size**_

**Biobatch 10 liters**

**Commercial batch 100 liters**

_**Mixing time**_

**30 mins**

**45 mins**

- drug

- excipients

- drug

- excipients

## Suspension formulation preparation 

- Preparation tank

- Filling tank

- Filling points

- Re-circulating filling line

- Pump

**Suspension formulation preparation **
**and filling**

## Site specific stability

**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

**Effect of Removing Polymer & Neutralizing Agent**

- Polymer Removed

- Neutralizing Agent Removed

- Control

- Merck & Co Inc

## Hole size vs drill energy

**Hole size vs drill energy**

- Merck & Co Inc

## Varying Energy

**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/hole

- 166 mJ/hole

- 132 mJ/hole

- 106 mJ/hole

- 145 mJ/hole

- 114 mJ/hole

- 95 mJ/hole

- 84 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

**Varying coat weight**

- 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]

- 13.0 to 14.9 mg

- 15.0 to 16.9 mg

- 9.0 to 12.9 mg

- 17.0 to 18.9 mg

- 19.0 to 20.7 mg

- 20.8 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

## Slide 37