CASE STUDY: Overcoming

Challenges Involved with Removal

of the Expiry Date from

Investigational Drug Product

Steven Yim

Manager, Clinical Research Pharmacy Services

MedImmune, LLC

Case Study Highlights

Initiate the Process

Expiry Date Challenges

Impact of the Challenges

Overcoming the Challenges

Supporting Documentation

Expiry Date Management

Additional Considerations

Where do you start?

ISPE White Paper

– Using An Interactive Voice System or Interactive Web Technology to Manage IMP Retest Dates in Lieu of Placing Retest Dates on IMP labels

EU regulation

– In accordance with the Clinical Trials Directive 2001/20 and GMP Directive 2003/94 and as detailed in Annex 13, Rules Governing Medicinal Products in the European Community, Volume IV, the period of use (use-b date, expiry date or re-test date as applicable), in month/ year format and in a manner that avoids any ambiguity must be provided on the IMP label “unless its absence can be justified, e.g. use of a centralized electronic randomization system”.

Where do you start?

EU regulation (continued)

– Recent EMA publication on the reflection paper on the use of IXRS in clinical trials provides guidance on expiry date usage justification.

Having information of companies that have been able to eliminate the expiry date from their IP by using IXRS technology.

Attended one or more conferences where the topic

was discussed.

What are some of the challenges faced in

Clinical Supplies?

Short expiration or retest dates for new compounds

Increased labeling requirements

Federal, country, regional and site specific

regulations

Non uniformity in regulations (even within the

country)

– Regulations are written as guidance, therefore it’s

open to interpretation.

– Our interpretation of the regulations is not

necessarily the same as that of in-country

regulators

What does this mean to us?

Increased packaging, labeling and over-labeling

costs

Increased risks associated with excessive IP

handling

Limited space on the IP labels

Two inspectors in same country may have a different

interpretation of the regulations

What does this mean to us?

Even if stated in the regulations, some countries may

choose not to accept the regulation and have their

own country specific requirement (i.e. Germany)

We are all navigating uncharted and unfamiliar

waters, leverage off your Regulatory, Quality and QP

expertise and share your experience with others

Where did we go from here?

Reviewed all available information and had many

internal discussions within the clinical supplies group

to better understand what was required

Met with QA, QP and RA (both clinical and CMC) and

presented the idea

The strategy was presented to the CRO, whom did

not have any experience on the subject

We got everyone on the bus and proceeded to

approach each trial systematically

Steps followed

Communication was key

Clearly delineated plan to follow and defined stakeholders.

Defined packaging requirements for trial

– Blinded, Kit configuration, prepared by pharmacists, does not go home with the patient

Approved label text

Leverage your successes and learn from your mistakes.

Use any new information as supporting documentation for the country

Supporting Documentation

Clinical Trial Application Submission

– Include IVRS Justification Document

Based on ISPE White Paper

Justifies the removal of the expiry date from IP label

IVRS Justification Document

– Supporting Documentation defines

Labeling strategy (ensure to have a backup plan)

Label text

Re-stated regulatory guidance (Annex 13)

Described packed stock

Supporting Documentation

(continued)….

Provided IVRS operating principle

Described shipment of packed stock and receipt at

clinical site

Guidance on access to packed stock and handling

at clinical sites

Notification and Management of expiring packed

stock

IVRS Audit and Validation

Use of the IVRS with respect to control of product

quality

Supporting Documentation

(continued)….

IVRS Justification Document

– Highly accepted internally by QA, RA, QP

– Provided for every study

Supporting Documentation

(continued)….

Expiry Date Management

Extensive UAT of IP expiry date in IVRS to ensure

IP can not be shipped or dispensed outside the

approved specifications/parameters

IP manual explanation of expiry date management

process within IVRS

Expiry date printed on IVRS Dispensing/Kit

Assignment notifications

Updated expiry date in the IVRS

– Notified internal teams first as date approaches

Sites, monitors and CRA’s were trained on IP as

well as on use of IVRS

Additional Considerations

Present the idea, even though you know that country

will not accept it or has not accepted it in the past

Regulations change, but documentation is not

necessarily updated at the same rate (Canada

experience)

Challenge the reviewers of your CTA, knowledge is

key

Present your IVRS UAT plan to see if this helps in

getting approval:

– Demonstrate by stress testing the UAT around the

expiry parameters (i.e. shipping, randomizing,

dispensing…etc)

Additional Considerations

Alternative packaging and labeling capabilities like

JIT labeling and packaging

Application of JIT ancillary label with expiry date only

for those countries that require it

Robust distribution instructions and IVRS

configuration

Ensure your IVR vendor has the capability to

configure the IVR to release IP at the lot and country

level

Things to remember

ISPE White paper

Regulations

– US does not require “use by” dates on IP label, but

most other countries do require it.

CRO knowledge or experience on removal of expiry

dates is increasing

Industry & company experience knowledge base is

increasing, therefore, continue to network

Questions