Challenges of Multilayer Compression for Combination Products

1
Challenges of Multi-layer Compression for
Combination Products

• Russell Plank
• Merck Co.
• West Point, PA
• AAPS Workshop on Fixed Dose Combination Products
• September 13, 2006

2
Outline

• Introduction
• Multi-layer compression basics
• Formulation challenges
• Interfacial adhesion
• Process challenges
• Weight control
• Final Thoughts

3
Introduction

• Multi-layer compression is becoming more
  prevalent across the pharmaceutical industry as
  the number of FDCs increases
• Advantages include
• Extension of a conventional technology
• Potential use of single entity feed granules
• Separation of incompatible components
• Ability to combine different release rates
• Disadvantages include a number of formulation
  process challenges to be discussed today

4
Multi-layer Compression Basics

• Presses can be designed specifically for
  multi-layer compression or a standard
  double-sided press can be converted for
  multi-layers

5
Multi-layer Compression Basics

• Two features in particular stand out from single
  layer compression
• New Quality Attribute Interlayer Adhesion
• Insufficient adhesion could lead to
  delamination, defined as a clean separation of
  the layers along the interface
• New Process Parameter Tamping Force
• If too high of a tamping force is used, the
  layers will not adhere
• If too low of a tamping force is used, blending
  of the layers or an uneven interface may occur

6
Formulation Challenges

• Achieving suitable interfacial adhesion
• Highly dependant on feed material properties
• Particle size morphology
• Extent of lubrication
• Compaction properties
• Strongly tied to process parameters
• Tamping, pre, and main compression forces
• Press speed
• Image tool design
• Influenced by environmental conditions
• Moisture content at time of compression
• Storage conditions following compression

7
Formulation Challenges, cont.

• Minimizing tablet size
• Multi-layer tablets tend to be larger than
  normal
• Common trait of many FDCs
• Can be exaggerated for multi-layer tablets due
  to need to operate within a reasonable ratio of
  layer masses
• Avoiding interactions between the layers
• Release properties can be influenced among
  layers
• Multi-layer release rates cannot always be
  easily matched to single entity release rates
• Problems are more likely to be encountered for
  modified release compounds

8
Routes of Delamination

• Following compression, delamination can be caused
  by
• Physical stresses associated with tablet
  handling
• Bulk distribution
• Packaging lines
• Pharmacist consumer handling
• Differential swelling and/or contraction between
  layers upon changes to environmental conditions
• Storage in the primary package
• After removal from the primary package

9
In-situ Monitoring of Adhesion

• Critical tamping force
• Defined as the highest tamping force at which
  all tablets are adhered at the time of
  compression
• Provides an indirect measure of adhesion
• Aids in assessing process robustness (i.e.
  higher critical tamping force equals a more
  robust operating space)
• Procedure for determining critical tamping force
• Increase tamping force until gross signs of
  delamination
• Decrease tamping force incrementally while press
  is running and collect tablets at various forces
  after press stabilization
• Gently agitate to induce delamination of weakly
  adhered tablets
• Critical tamping force is recorded when zero
  delamination is observed

10
Critical Tamping Force Example
Birringer N., Shoemaker S., Gilman C., Haynes M.,
Plank R. Measurement and Optimization of Layer
Adhesion in Bi-layer Tablets American Association
of Pharmaceutical Scientists Annual Meeting,
Nashville, 2005
11
Critical Tamping Force Example, cont.
Birringer N., Shoemaker S., Gilman C., Haynes M.,
Plank R. Measurement and Optimization of Layer
Adhesion in Bi-layer Tablets American Association
of Pharmaceutical Scientists Annual Meeting,
Nashville, 2005
12
Ex-situ Monitoring of Adhesion

• Options for evaluating the two main routes of
  delamination include
• Tablet exposure to physical stresses
• Uniaxial or shear force tests
• Bulk distribution and packaging studies
• Consumer handling tests (bottle agitation,
  deblistering, etc.)
• Tablet exposure to environmental stresses
• Moisture and temperature differential testing
• Kinetic evaluation

13
Ex-situ Monitoring of Adhesion, cont.

Birringer N., Shoemaker S., Gilman C., Haynes M.,
Plank R. Measurement and Optimization of Layer
Adhesion in Bi-layer Tablets American Association
of Pharmaceutical Scientists Annual Meeting,
Nashville, 2005
14
Process Challenges

• Weight Control
• Inability to measure individual layer masses of
  intact multi-layer tablets leads to weight
  monitoring challenges
• Weight control is less straightforward compared
  to single layer compression
• High signal-to-noise associated with low tamping
  force
• Variability of layer 1 mass influences control
  over layer 2
• Cross-Contamination
• Possibility exists for cross-contamination of
  feed materials during compression
• Risk is partially minimized by eliminating feed
  recirculation of one or both feed materials
• Press vacuum locations/settings are very
  important

15
Process Challenges, cont.

• Yield and Productivity
• Multi-layer compression yield and productivity
  are notably lower relative to single layer
  compression
• One tablet per press revolution
• Lower press speeds
• Sampling losses
• More sources for feed powder loss
• Scale-up
• Multi-layer tablet scale-up is not
  straightforward
• Limited ability to leverage compaction
  simulators and small scale presses
• Performance is sensitive to press set-up and
  mechanical subtleties

16
Bi-layer Weight Control Options

• Layer 1
• Different presses have different mechanisms for
  obtaining a sample of layer 1 in the absence of
  layer 2
• Eject the tamped layer 1 compact prior to fill
  of layer 2
• Cut off layer 2 feed
• Increase tamping force to induce delamination
  upon ejection
• Layer 2
• Determine layer 2 mass via subtraction of layer
  1 mass from total bi-layer tablet mass
• Reliability decreases as layer-to-layer mass
  ratio increases and as feed material flow
  properties worsen

17
Final Thoughts

• Multi-layer compression is an attractive option
  for formulating fixed dose combinations but the
  technology is not without its challenges
• Areas of focus during development should include
• Maximizing interfacial adhesion
• Understanding delamination propensity
• Optimizing a weight control strategy
• Proactive planning around the known formulation
  and process risks can increase chances for
  successful development and commercialization

18

Acknowledgments

• Nick Birringer
• Chris Gilman
• Matt Haynes
• Scott Shoemaker
• Jim Zega