Cold Chain and Biologic Product Quality A Reviewer’s Perspective

1. Cold Chain and Biologic Product QualityA Reviewer’s Perspective Nancy Green April 8, 2010

2. What if your refrigerator was warmer than normal? What if your shipment was left on the tarmac at Pearson? What if the purification process was delayed by the long weekend? Are you confident that a vial of Drug Product will be safe and potent when you need it?

3. Where is Cold Chain Important? • Everywhere! • Home • Clinic, hospital or pharmacy • Wholesaler • Manufacturing sites • In transit

4. Drug Substance Drug Product Biologics Manufacturing is Complex

5. Biologic Product Quality • An ongoing activity: • Process Design • In-Process Controls during manufacturing • Hold time and specifications for key intermediates • Hold time and specifications for Drug Substance • Hold time and specifications for Drug Product • Initial and on-going Stability Studies

6. How do you decide on cold chain parameters? • The conditions of the stability studies define the acceptable cold chain conditions • We are most used to thinking about the Drug Product storage and expiration dating but there are many other cold chain points in the life of a biologic

7. When is Material Held? • Harvest media is often pooled and stored before purification (days to weeks) • Loads and Eluates from protein purification columns may be stored before the next step (days to weeks) • Drug Substance is often stored for long periods of time before manufacture into Drug Product (weeks to years) • Drug Product is held up until its expiry date (years) • Any material may be transported from one site to another (hours to days)

8. Drug Substance Drug Product When is Material Held? Months to years Days to weeks Days to weeks Weeks to years Years

9. Many issues are considered when establishing hold time conditions • What are the Critical Quality Attributes of the material at this stage? • What temperature is optimal to maintain the CQA? • What hold time is optimal to maintain the CQA? • What container closure system is optimal? • What is my next manufacturing step or use? • How does the optimal situation mesh with productivity in the facility?

10. Control of Storage Areas The temperature range and set point used in a storage area should mimic those used in stability studies and in the temperature mapping study Temp Range Set point 8 Set point 5

11. Control of Storage Areas • Storage area temperature should be controlled, monitored and documented • Constant active control, monitoring, documenting (e.g. cold room/freezer in the manufacturing facility or at wholesaler) • Active control with periodic monitoring and documenting (e.g. refrigerator/freezer in hospital, clinic, pharmacy, home) • Passive control with post-transport monitoring and documenting (e.g. shipping configuration with thermologgers)

12. What if you have a temperature excursion? • Get your documentation of the event organized • Determine if you have data to cover the excursion • Document the scientific rationale to reject the material or to justify using the material in spite of the excursion • Consider setting up a stability study with the material to get more data for future events • Ask BGTD for assistance