Applying a Stability Budget to Cold Chain Biologics. Rebecca E. Gentile Merck & Co. Inc. June 2015

Transcription

1 Applying a Stability Budget to Cold Chain Biologics Rebecca E. Gentile Merck & Co. Inc. June 2015

2 Overview Define Stability budget PDA Technical Report # 53 What is a stability budget Why set up a stability budget How to apply a stability budget How to establish a stability budget Case Study Regulatory Considerations Summary 2

3 PDA TR# 53: Guidance for Industry: Stability Testing to Support Distribution of New Drug Products The objective of TR# 53 is to describe the stability studies required to determine a stability budget for a drug product. Acknowledgements: Erik J. van Asselt, Rafik Bishara, Maryann Gribbin, Paul Harber, Ian G. King, Arminda O. Montero, Fabian S. de Paoli, Robert Seevers, David Ulrich 3

4 PDA TR# 53: Guidance for Industry: Stability Testing to Support Distribution of New Drug Products A stability budget considers long term, accelerated, and stress temperature exposure, as well as temp. cycling studies to determine the amount of time out of storage ( TOS ) that a drug product may experience without any significant risk to its quality. Other synonymous terms: Time out of Refrigeration TOR Time at Room Temperature TRT 4

5 Why Establish a Stability Budget? Temperature sensitive products may have limited time that they can be exposed to temperature outside label storage conditions and still meet quality attributes through expiry Definition of that exposure time, and distribution of parcels of time to product life cycle steps helps to ensure product won t be exposed to temperatures that exceed acceptable limits The Stability Budget ensures product will meet shelf life specifications given end to end TOS requirements Ensure product retains Quality (safety and efficacy) at time of patient administration 5

6 How to Apply a Stability Budget? The allowable TOS outside Long Term storage conditions must be budgeted among competing needs: Manufacturing Packaging Labeling Global transport End user Tracking and/or control of product exposure is essential at each step of the process and distribution chain Allowable TOS should account for both planned and unplanned excursions 6

7 PDA TR 53: Example Inputs to a Stability Budget Manufacturing Filling and Inspection Shipment Secondary packaging Shipment Warehouse Receive, store, Pack-out Final customer Handling and administration Shipment 3 rd party distributor/ wholesaler Receive, store, pack-out Shipment Excursion Bucket 7

8 How to Establish a Stability Budget? The stability budget may be established with data from Phase III Stability Studies (Formal Stability Studies) Requires LT and accelerated / stress studies, typically 3 lots per study, GMP studies Example stability studies to establish Stability Budget (5 C product) Long term: 5 C for 36 months Accelerated: 25 C for 6 months Shipping: 15 C for 3 months Extreme stress: 40 C 3 months Low Temp stress: 0-2 C or -20 C or lower for 30 days Cycling studies: -20 C for 5 days followed by 5C for 5 days x 4 cycles Sequential TOS study: thermal stress followed by LT storage A word about humidity 8

9 Temperature TOS Sequential Study Example TOS followed by long term storage condition 40 C 25 C 30 days 25 C 3 days 40 C 5 C 35 months 5 C Long term stability testing to confirm specifications are met through product expiry Time 9 36 months

10 Potency Statistical Model Example Requirement for separate release and end expiry specifications to account for LT and accelerated stability losses Manufacturing target Lower Release Limit Variability 25 C loss: 30 days 40 C loss: 3 days 5 C loss: 36 months LT storage Expiry Spec. Clinical effective dose 10 Time Expiry

11 Considerations for Biologics Products to Establish TOS Understand primary stability indicating parameters May be potency, may be other attribute, may be multiple attributes Effect of TOS exposure to aggregation and particulates is of high concern Be sure to measure as part of studies May need to consider combination stability studies: shock, vibration, and temperature stress combined Particularly important to support shipping at wider temperature ranges Consider early in product development address with formulation and image Carry over impact from drug substance Regulatory expectations: real life and simulated shipping studies 11

12 Stability Budget Example Example Product is: Liquid DP Minimal head space two primary stability attributes Do not freeze Stability Budget: 36 month expiry at 5 C (2-8 C) 20 days allowance at 15 C for shipping (0-15 C shipping range) 30 days allowance at 0-2 C for shipping and excursions 2 weeks allowance at 25 C (man/pack/label/end user) 5 days manufacturing 2 days labelling 1 day shipping packout and receipt 3 days end user 3 days remaining for excursions 12

13 Regulatory Considerations TOS Information may be included in product license: The 30 day exposure period at C is comprised of: 7 days allowed for manufacturing and packaging operations, 3 days (72 hours) allowed for the end customer/administration purposes, Remaining 20 days allowed to support unplanned temperature excursions. End user TOS allowance may be added to label: Store refrigerated at 2 to 8 C (36 to 46 F). Do not freeze. Protect from light Product can be out of refrigeration (at temperatures at or below 25 C/77 F), for a total time of not more than 72 hours. 13

14 Summary Stability Budgets may be used as a way to control TOS for temperature sensitive products Maximum TOS supported by long term and accelerated / stress stability data Time allowances are divided among competing needs (i.e. manufacturing, transport, end-user) Design stability studies for temperature sensitive new products to support stability budget Stability Budgets ensure product quality through all phases of the sample life cycle 14