Quality by Design Approach to Cycle Development and ... A Quality by Design Approach to Cycle Development and Optimization for Freeze-Dried Parenterals Steven L. Nail, Ph.D. Principal

Presenter

A Quality by Design Approach to Cycle Development and Optimization for Freeze-Dried Parenterals

Steven L. Nail, Ph.D. Principal Scientist BioPharma Solutions September, 2012

Elements of QbD 2

Baxter Confidential © 2010 Baxter International Inc. Baxter is a registered trademark of Baxter International Inc.

Assurance of product quality through design of robust formulations and processes

Scientific understanding of how formulation and processing affect product performance

Ability to effect continuous improvement

Reduced regulatory burden over life of product

However… 3


One of the biggest obstacles to implementation of the QbD regulatory paradigm appears to be lack of understanding by the pharmaceutical industry

This is particularly true for parenteral products when compared to solid oral dosage forms

Key Features of a Quality by Design Approach 4


Application of prior knowledge in establishing an experimental approach

Some type of formalized risk assessment process

Definition of formulation and process design spaces

“Traditional” Approach to Freeze-Dry Cycle Development 5


Largely by trial and error, identify freeze-dry process conditions that produce an acceptable product

Establish “proven acceptable ranges” around process variables such as shelf temperature, chamber pressure, and shelf temperature ramp rates during transitions from one phase of the process to another

The Big Picture


6

Knowledge Space

Design Space

Control Space

QbD Approach to Cycle Development 7


Identify optimal processing conditions based on a thorough understanding of the process, and know where the edges of failure are

Design Space Layout for Primary Drying

Chamber P

Subl

imat

ion

Rat

e

-10 C

0 C

+10 C

+20 C

+30 C Product T -20 C

-25 C

-30 C -35 C

-40 C

Cake Appearance


9

Failure

Cycle Design with Equipment Capability

Chamber P

Subl

imat

ion

Rat

e

-10 C

0 C

+10 C

+20 C

+30 C

-25 C

Freeze Dryer Capability Product T

Cooling or Heating Power

Gas Flow


11

Chamber P

Subl

imat

ion

Rat

e The Optimum Cycle Follows from the Design Space Concept

Acceptable Zone

Optimum

Outline of Steps 12


Characterize the formulation and identify the failure mode

– Eutectic melting (“melt-back”) – Collapse – Powder ejection from the vial? – Others?

Differential Scanning Calorimeter (DSC)

Thermal Transitions in Frozen Systems

Freeze Drying Microscope

Microscope View of Frozen Formulation

Crystallization of Drug During Annealing

Freeze Drying with Retention

Onset of Collapse

Further Collapse

Outline of Steps 21


Based on the above data, run trial lots intended to make the product fail during primary drying

– Confirm the failure mode

Outline of Steps 22


Establish the relationship between the process variables you control (shelf temperature and chamber pressure) and the one you don’t directly control (product temperature)

– Measure the vial heat transfer coefficient, Kv, as a

function of chamber pressure – Measure the resistance of the dried product layer, Rp, to

flow of water vapor

Coupled Heat and Mass Transfer

Equations for Heat and Mass Transfer


24

dq/dt = KvAv (Ts –Tb) dm/dt = Ap (Pi – Pc)/Rp dq/dt = ∆Hs dm/dt

Where, 25


dq/dt = rate of heat transfer Kv = vial heat transfer coefficient Av = cross sectional area of vial (outside) Ts = shelf temperature Tb = temperature of product at bottom of vial dm/dt = mass flow rate of water vapor Ap = cross sectional area of product (inside of vial) Pi = vapor pressure of ice at sublimation front Pc = pressure in the chamber (in Torr) Rp = resistance of dried product layer ∆Hs = heat of sublimation of ice

How to measure sublimation rate? 26


Tunable Diode Laser Absorption Spectroscopy

– TDLAS is a near-IR based instrument that measures the

instantaneous mass flow rate of water vapor from the chamber to the condenser by “looking” through the connecting duct, or spoolpiece, connecting the two

TDLAS Instrumentation

What if you don’t have access to TDLAS? 28


Smart Freeze Dryer software should work

It can be done gravimetrically (but it’s tedious)

Measurement of Kv

Fill the intended vial with the intended volume of water. Note: We use one full tray in the LyoStar Place thermocouples in the bottom center of several vials – minimum of three Carry out the freeze dry cycle at an appropriate shelf temperature and at the low end of the intended pressure range Monitor mass flow rate by TDLAS until it stabilizes, then change to a new pressure set point. Keep repeating until you’ve covered the selected pressure range Calculate Kv at each pressure using the relationship:

Kv = DHs dm/dt/[Av(Ts – Tb)]

Example: Pressure (mT) Kv (joules/hr-cm2- oK) 25 3.58 50 5.25 75 6.11 100 7.24 125 8.20 150 9.01 175 9.75 200 10.31 250 11.21 300 12.07 350 12.92 400 13.77

Measurement of Rp

Fill the intended vial with the correct volume of formulation in the intended vial and run a trial cycle Place thermocouples in at least three vials Monitor mass flow rate by TDLAS Calculate Rp as follows:

Rp = Ap(Pi – Pc)/(dm/dt) where

Pi (in Torr) = 2.698 x 1010exp (-6144.96/Tb)

Mass Flow Rate vs. Time


32

Note: We use a value of Rp near the end of 1° drying. In this example, we use a value of 5.94 Torr-hr-cm2-gm-1

020406080

100120140160

0.00 1.00 2.00 3.00 4.00 5.00 6.00

Time (hrs)

Mas

s Fl

ow R

ate

(g/h

r)

-50-40-30-20-10010203040

Prod

uct T

empe

ratu

re (C

)

Primary Drying for Sodium Ethacrynate

Calculate the Design Space

1. Choose an arbitrary value for Ts and Pc

2. Calculate the corresponding values of Tb and dm/dt

DHs Ap (Pi –Pc) = Kv Av(Ts – Tb) Rp

or,

{DHs Ap[2.698 x 1010exp (-6144.96/Tb) – Pc]}/Rp

= KvAv(Ts – Tb)

Solve this iteratively for Tb

Construct Shelf Temperature and Product Temperature Isotherms

Design Space Calculations (continued)

3. Now calculate the corresponding mass flow rate by

dm/dt = KvAv (Ts – Tb)

4. Now choose a new value of Pc at the same Ts

5. Repeat this process for several values of Pc. The resulting plot of mass flow rate vs. pressure generates one shelf temperature isotherm


6. Choose a new value of Ts and repeat the previous steps. This then generates a set of shelf temperature isotherms. They are non-linear, so several pressure data points are needed for each shelf temperature isotherm

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0 0.1 0.2 0.3 0.4 0.5

Pressure (Torr)

Mas

s Fl

ux (g

/cm

^2hr

)

Ts=0oC Ts=10oC Ts=20oC Ts=30oC Ts=40oC

Shelf Temperature Isotherms


7. Generate the product temperature isotherms by choosing an arbitrary product temperature, Tb,

and a chamber pressure, Pc 8. Calculate the sublimation rate under these

conditions by

dm/dt = Ap[2.698 x 1010exp (-6144.96/Tb) – Pc] Rp

Note: The product temperature isotherms are linear, so only two pressures are needed for each value of Tb

00.050.1

0.150.2

0.250.3

0.350.4

0.45

0 0.1 0.2 0.3 0.4 0.5

Pressure (Torr)

Mas

s Fl

ux (g

m/c

m^2

hr)

0oC 10oC

20oC 30oC 40oC

-10oC

-15oC

-20oC

-25oC

Primary Drying Design Space

Next Step. . . . 39


Add the equipment capability curve – the maximum sublimation rate supported by the equipment as a function of pressure

We do this by ice slab testing

Equipment Capability Curve


40

= Choke Point

Advantages of This Approach 41


It results in a truly optimum cycle – not just a “pretty good” one

It maximizes process/product

understanding with a minimum of experimentation

It facilitates handling of process deviations It’s strongly connected to the QbD philosophy

Documents

Quality by Design Approach to Cycle Development and ... A Quality by Design Approach to Cycle Development and Optimization for Freeze-Dried Parenterals Steven L. Nail, Ph.D. Principal