1

Antony Pham / Gitte Albert

Århus / November 2016

Dansk Selskab For GCP

BASIC HANDLING OF

CLINICAL TRIAL SUPPLY

GITTE ALBERT

(Cand.Pharm.)

ga@altrapharma.com

Latest Position:

Director IMP, FERRING Pharmaceuticals A/S

2

ALTRAPHARMA APSONY PHAM (Cand. Pharm)

ANTONY PHAM(Cand.Pharm.)

antony.pham@impinsight.com

Latest Position: Principal IRT Manager, LEO Pharma A/S

IMP INSIGHT APSONY PHAM (Cand. Pharm)

AGENDA

3

LABELLING

PACKAGING

STORAGE AND DISTRIBUTION

• GENERAL REQUIREMENTS (DOCUMENTATION)

• DIRECT TO PATIENT SHIPMENT• RECALL PROCEDURES• TEMPERATURE SENSITIVE PRODUCTS

(COLD CHAIN)• DESTRUCTION OF IMP

NEW EU REGULATION

• RE-LABELING

• RECALL PROCEDURES

IRT SYSTEMS

4

LABELLINGANNEX 13 RULES

IMP LABELLING – VOLUME 4 ANNEX 13 REQUIREMENTS

5

Annex 13 Label Requirements

Name, address and telephone #

Dosage form, adminstration route, quantity of dosage unit, name/identifier and strenght

Batch and or code number

Protocol ID

Subject # or kit # and if relevant the visit #

Direction for use, or reference

Name of investigator

”For clinical trial use only”

Storage conditions

Expiry /use-by / re-test date

”Keep out of reach of children”

NAME OF INVESTIGATOR MAY BE LEFT OUT IF AVAILABLE ELSEWHERE E.G. ON PATIENT CARD

IMP LABELLING – Volume 4 ANNEX 13 REQUIREMENTS

6

TRANSLATE TEXT

TO LANGUAGE OF

THE COUNTRY

WHERE THE IMP IS

USED

SYMBOLS AND

PICTOGRAMS +

WARNINGS AND

HANDLOING

INSTRUCTIONS

ARE ALLOWED

IMPLEMENT

COUNTRY

SPECIFIC LABEL

REQUIRMENTS

WHEN ORIGINAL

PACKAGING (APPROVED

COMPARATOR) THEN

ALLOW ID OF TRIAL

SITE, INVESTIGATOR

AND TRIAL SUBJECT

COLOR CODING

MAY ENHANCE

PATIENT AND SITE

COMPLIANCE

USE A LABEL

INTENDED FOR

THE APPLICATION

TEMPERATURE

BASIC ANNEX 13 LABEL ON OUTER PACKAGING

7

Protocol ID: Test ABC123

For Clinical Trial Use Only

This box contains: 30 tablets for oral useTake 1 tablet after breakfast with waterStore between 15℃ - 30 ℃

Keep out of reach of childrenKit no.: A0001Expiry date: 31 Jan 2019Batch no.: Y1234

Patient no.: ___04____

Sponsor: IMP Insight ApS, Rosenborggade 3, P: +45 60 19 84 64

EXECPTION RULES

8

WHEN LEAVE OUT REMEMBER TO

LEAFLET OR PATIENT CARD HAVE THE ADDRESS AND PHONE NUMBER LISTED

ADDRESS AND PHONE NUMBER ON THE OUTER PACKAGING

INSTRUCT PATIENTS TO KEEP LEEFLET OR CARD IN THEIR POSSESSION AT ALL TIMES

OUTER AND IMMEDIATE PACKAGING ARE KEPT TOGETHER

ADDRESS AND PHONE NUMBER ON THE IMMEDIATE PACKAGING

ORAL SOLID DOSE FORM ROUTE OF ADMINISTRATION ON IMMEDIATE PACKAGING

BLISTER AND SMALL UNITS ROUTE OF ADMINISTRATION (FOR ORAL SOLID DOSE FORMS) AND DOSAGE FORMS AND QUANTITY OF DOSAGE UNIT

REMEMBER THAT THE OUTER PACKAGING MUST CONTAIN ALL ANNEX 13 REQUIRMENTS.

BLISTER OR SMALL UNIT LABEL (IMMEDIATE PACKAGING)

9

Protocol ID: Test ABC123

Kit no.: A0001

Patient no.: ___04____

Sponsor: IMP Insight ApS

PROCESS FOR RELABELLING AT INVESTIGATOR SITE (EXTENSION OF EXPIRY DATE)

10

START

STEP 1

CLINICAL SITE

PREPARE

RELABELING

PLAN (TO

BE APPROVED

BY QP)

STEP 4

SPONSOR + CLINICAL SITE

ARCHIVE

EXECTUED

BATCH RECORD

(+UPDATE IRT)

STEP 3

CLINICAL SITE

RE-LABEL +

COMPLETE

BATCH RECORD

STEP 2

SPONSOR / CMO

PRINT

EXPIRY DATE

LABELS +

RELABELING

BATCH RECORD

- SPONSOR IS RESP. FOR THE ACTIVITY AND THE DEVELOPMENT OF SOP (+ TRAINING OF SITE STAFF)- QP DOES NOT NEED TO RELEASE AGAIN (APPROVE BEFORE THE PROCESS)- NOTIFY COMPETENT AUTHORITY- PEFORM ON PACKAGING SITE OR ON CLINICAL SITE (UNDERSUPERVSION OF SITE PHARMACIST)- MAY BE PERFORMED BY TRAINED MONITOR (AND CHECKED BY SECOND PERSON) – GMP

PROCESS FOR RELABELLING AT INVESTIGATOR SITE (EXTENSION OF EXPIRY DATE) CONT.

11

ADDITIONAL LABEL SHOULD STATE

NEW USE-BY-DATE / RE-TEST DATE

AND THE SAME BATCH NO. (STRIKE –

OUT “OLD” EXP. DATE)

BATCH NO: Y1234NEW EXPIRY DATE: 30 APR 2020

12

PACKAGING

13

• Space at

site

• Expiration

date of all

products

being

packaged

together.

• Keep the

IMP flexible

• No kits are

pre-

assigned to

subjects

• If possible,

keep the

different

types

separate.

• Minimize

the

packaging

materials.

PACKAGING AND LABELING CONSIDERATIONS

14

Leave room on the

labels for additional

label (if possible)- Useful when changing use-by-date

Use labels suitable for

the intended

temperature range

and use- Freeze / Thaw; Twisting bottle etc.

Avoid to pack

scheduled drug in the

same dispensing kit

as unscheduled- Limited space at site

Use color and

pictograms - Will enhance site and

patient compliance in dosing

Avoid single panel

labels (if possible)- Ensure the greatest

flexibility

Be careful for varied

retest dates- Potential un-blinding if only replacing kits for a

single arm

SOME CONSIDERATIONS

PACKAGING AND LABELING

PACKAGING – REFERENCE AND RETENTION SAMPLES

• ANNEX 13 PARAGRAPH 12: SPECIFY NUBER OF UNITS TO BE PACKAGED PRIOR TO START OF PACKAGING OPERATION INCL UNITS FOR QUALITY CONTROL AND RENTENTION SAMPLES

• REFERENCE SAMPLES (STORE FOR ANALYSIS PURPOSE): SAMPLE OF BATCH OF A STARTING MATERAL, PACKAGING MATERIALS AND/OR PRODUCT CONTAINED IN ITS PRIMARY PACKAGING.

• RETENTION SAMPLES: PACKAGED UNITS FROM A BATCH OF FINISHED PRODUCT. TAKE OUT FROM EACH PACKAGING RUN

15

• BEST PRACTICE: KEEP SAMPLES FOR AT LEAST 2 YEARS AFTER COMPLETION OF STUDY• DEFINE STORAGE OF SAMPLES IN A TECHNICAL AGREEMENT (ENSURE ACCESS BY COMPETENT

AUTHORITIES AT ALL TIME• REFERENCE SAMPLING: AT LEAST 2X FULL ANALYTICAL CONTROL IN ACCORDANCE WITH

SUBMITTED IMP DOSSIER• BEST PRACTICE: RETENTION SAMPLING: 2-3 SAMPLES PER PACK RUN

16

STORAGE

REQUIRED DOCUMENTATION FOR STORAGE AT SITE

17

DOCUMENTATION DESCRIPTION TO BE VERIFIED / APPROVED BY

REMARKS

SITE INVENTORY LOG ALL RECEIVALS AND SHIPMENTS

MONITOR AND INVESTIGATOR OR DELIGATED IMP RESP.

DATE AND SIGN FOR EACH ACTIVTY

DRUG DISPENSING AND ACCOUNTABILITY LOG

ACCOUNTABILITY ON PATIENT LEVEL

MONITOR AND INVESTIGATOR

RETURN OF IMP FROM PATIENT TO BE INCLUDED

TEMPERATURE LOG LOG WHEN THE TEMPERATURE HAS BEEN READ OUT

MONITOR NOT NEEDED IF USING A FULL AUTOMATIC TEMP SYSTEM

- IF IRT: CONSIDER TO LEAVE OUT THE SITE INVENTORY LOG.

STORAGE AT CLINICAL SITE – REQUIREMENTS

18

SECURE ACCESS

TEMPERATURE CONTROL AND MONITOR

STORE CONTROLLED SUBSTANCE AND NARCOTICS IN A LOCKED COMPARTMENT (SAFE)

LOG MOVEMENTS

USE DEDICATED QUARANTINE AREA FOR OUT OF SPECS

TRAIN STAFF

• STORAGE CONDITION SHOULD BE IN COMPLIANCE WITH THE LABELING

• TEMPERATURE DATA SHOULD BE AVAILABLE FOR REVIEW BY MONITOR

• READ THE LOGGER AT PREDETERMINED INTERVALS (DEFINED IN E.G. PHARMACY MANUAL OR SITE SOP)

• KEEP TEMPERATURE DATA / READOUTS IN THE SITE MASTER FILE

• LOG SHEET / TEMPERATURE LOG SCHEME

TEMPERATURE DEVIATIONS

19

SITE RESP. SITE RESP. SPONSORSITE /

SPONSOR

PLACE IMP IN A

QUARANTINED

AREA

FORWARD TEMP

READOUT AND

SIGNED

DELIVERY NOTE

TO SPONSOR

QP EVALUATES

AGAINST

STABILITY DATA

IF OK – CRA WILL

INFORM SITE

(IF NOT OK –

NEW

MEDICATION TO

BE ORDERED

AND AFFECTED

IMP TO BE

RETURNED)

FILE COPY OF

DEVIATION

REPORT IN SITE

MASTER FILE

(SPONSOR TO

INVESTIGATE

DEVIATION)

“RELEASE” IMP

AND PLACE IN

STORAGE.

IF IRT: CRA WILL

NEED TO

RELEASE IN THE

SYSTEM

SITE / SPONSOR

IF TEMP DATA MISSING:

- CONTACT COURIER (CHANCE THAT THEY HAVE LOG IN THE TRUCK)

- IF “STABLE” IMP – USE WEATHER FORECAST

- IF NOT – REORDER NEW IMP TO SITE

20

DISTRIBUTION

ENSURE KITS ARE

“SHIPPED” IN IRT• In order for the site to

acknowledge drug receipt

ENSURE THAT TEAM

IS READY• QA is informed, to quickly

resolve any temperature deviation

• Local CRA is informed etc.

ASK FOR THE AWB NUMBER• Track and Trace

• Check that the AWB number is uploaded in systems

• Review/Check completed shipment documents (incl. invoices, certificate etc.)

ACTIVITIES TO KEEP IN MIND FOR THE

INITIAL SHIPMENT TO SITE

ENSURE THAT APPROVALS

ARE IN PLACE • QP Cert.• Submission of paperwork to custom

• Regulatory Green Light (EC and approved submission)

PROCESS FOR RECEIPT OF IMP

22

PLACE IMP IN

CORRECT STORAGE

CONDITION

STOP

DATA LOGGER +

CHECK CONTENT

AGAINST DELIVERY

NOTE

READ

DATA LOGGER

(USB) + COMPLETE

DELIVERY NOTE

IF IRT: CONFIRM

SHIPMENT AND

UPLOAD

TEMPERATURE

READOUT

FORWARD

DELIVERY NOTE

AND READOUT TO

DEPOT*

ARCHIVE SHIPMENT

DOCUMENTS IN SITE

FILE

1 2 3 4 5

TIP TO SPONSOR: COLLABORATE WITH CMO /

DEPOT TO FIND THE MOST SUITABLE SHIPPER

BOX AND CONSIDER TO HAVE SEVERAL SIZES TO

PICK FROM

DIRECT TO PATIENT SHIPMENTS

23

WHEN TO USE?REQUIRMENTS

• OBTAIN REGULATORY (DURING CTA SUBMISSION), ETHICS COMMITTEE APPROVAL

• INCLUDE IN INFORM CONSENT

• COMPLIANCE WITH GCP

• CAREFUL ON PATIENT CONFIDENTIAL INFORMATION

CONSIDER TO BENIFITS

• VISITS WITHOUT MEDICAL ASSESMENT (ONLY DRUG DISPENSING)

• PATIENTS LIVING IN REMOTE LOCATION

• COLD CHAIN PRODUCTS

• LOW ”RISK” SAFETY IMP

• CAREFUL WITH CONTROLLED DRUG

• USE ”PREMIUM” COURIER

• USE CENTRAL DATABASE – MAKES IT EASIER FOR BOOKING THE SHIPMENT

• FOLLOW UP BY PHONE / OR ENCOURAGE PATIENT TO CONTACT SITE

• REDUCED NUMBER OF VISITS (AND TRAVELS)

• CONTROL OF THE TEMPERATURE DURING TRANSPORT

• TAKES OUT THE TRANSPORTATION BURDEN FOR PATIENTS

DIRECT TO PATIENT SHIPMENT – (SITE TO PATIENT) – PROCESS

24

SITE TO UPLOAD

PATIENT

INFORMATION

(NAME AND

ADDRESS) TO

BOOKING SYSTEM

SITE TO BOOK

SHIPMENT TO

PATIENT

COURIER TO RETURN

SIGNED DELIVERY /

DISPATCH NOTE AND

LOGGER READOUT

TO SITE

SITE TO ARCHIVE THE

SIGNED DELIVERY

NOTE AND LOGGER

READOUT IN SITE

FILE

STEP 1 STEP 2 STEP 3 STEP 4 STEP 5

PICK UP AT SITE AND

FORWARD TO

PATIENT HOME

(TEMPERATURE

CONTROLLED)

OTHER OPTION:

-DIRECTLY FROM DEPOT TO PATIENT

RECALL OF STUDY DRUG

25

ANNEX 13 REQUIREMENTS

• PROCEDURES FOR RETRIEVING INVESTIGATIONAL MEDICINAL PRODUCTS AND DOCUMENTING THIS RETRIEVAL SHOULD BE AGREED BY THE SPONSOR, IN COLLABORATION WITH THE MANUFACTURER OR IMPORTER WHERE DIFFERENT. THE INVESTIGATOR AND MONITOR NEED TO UNDERSTAND THEIR OBLIGATIONS UNDER THE RETRIEVAL PROCEDURE.

• THE SPONSOR SHOULD ENSURE THAT THE SUPPLIER OF ANY COMPARATOR OR OTHER MEDICATION TO BE USED IN A CLINICAL TRIAL HAS A SYSTEM FOR COMMUNICATING TO THE SPONSOR THE NEED TO RECALL ANY PRODUCT SUPPLIED.

RECALL OF STUDY DRUG – PROCESS AT CLINICAL SITE

26

RECALL ACCOUNT RETURNQUARANTINE

“FOLLOW

PROCEDURE

PROVIDED BY

SPONSOR”

ACCOUNT /

RECONCILE

AFFECTED

STUDY DRUG (BY

COMPLETING

“IMP DRUG

RETURN FORM /

LOG)”

AND

A “PRODUCT

RECALL FORM”

(VERIFY THAT

ALL AFFECTED

KITS ARE HAVE

BEEN RETURNED

AND NO KITS

ARE HELD AT

SITE)

RETURN

AFFECTED

STUDY DRUG IN

ACCORDANCE

WITH AGREED

SPONSOR

REQUIREMENT

(E.G.

TEMPERATURE

MONITORED)

QUARANTINE

AFFECTED

STUDY DRUG BY

PLACING THE

KITS IN A

“QUARANTINE”

AREA.

IF IRT, PLACE

KITS IN

QUARANTINE

THE RECALL REPORT (SPONSORS RESPONSIBILITY)

27

• PRODUCT NAME, STRENGTH, MANUFACTURER, ADMINISTRATION FORM, PACK SIZE, TYPE OF PACKAGING, EXPIRY DATE, BATCH NUMBER(S) AND OTHER INFORMATION AS DEEMED NECESSARY.

• DETAILS OF DEFECT (IF ANY) – ROOT CAUSE AND CAPA ANALYSIS

• WHICH BATCH HAS BEEN PACKED TO THE PATIENT

• WHICH PRODUCTS/BATCHES HAVE BEEN USED IN WHICH STUDY (PROTOCOL NUMBER), COUNTRIES AND SITES

• DECRIBE THE ACTION TAKEN (AND VERIFY THAT ALL AFFECTED KITS HAVE BEEN RETURNED FROM TRIAL SITE)

• INCLUDE AN OVERALL RECONILCATION

• LIST THE PEOPLE / DEPARTMENT / SITES THAT HAVE BEEN NOTIFIED

• IF APPLICABLE, INCLUDE DESTRUCTION CERTIFCATE

• STATE THE CONCLUSION OF THE RECALL (FORMAL CLOSURE)

REPORT THE FOLLOWING:

TIP TO SPONSOR:

PERFORM FREQUENT MOCK RECALLS AND TRAIN PROCEDURE (HOW TO “Q” AFFECTED KITS)

DECRIBE PROCEDURES FOR ALL SCENARIOS (E.G. SPONSOR CMO WAREHOUSE PHARMACY PI PATIENT)

RECALL ID – TRACEABILITY

28

KIT IDENTIFIERS

• PRODUCT NAME• BATCH NUMBER• KIT NUMBER• PACKAGING NO.

“BUILD INTO”

KIT NO. FORMAT

• IF OPEN-LABEL:• PROTOCOL ID• PRODUCT

NAME• VISIT NUMBER

(IF VARIATION IN VISIT)

• IF BLINDED:• PROTOCOL ID

TIP TO SPONSOR:KEEP THE FORMAT

“DIFFERENT” FROM OTHER NUMBERS SUCH AS

SUBJECT, RANDOMISATION, SITE ETC.

IRT

29

BALANCED

CONTROLLED

RANDOMIZATION

DRUG NOT LINKED TO

PATIENT BEFORE

DISPENSATION

PRODUCT

POOLING

KNOW WHEN DRUG ARE

ASSIGNED TO PATIENT

VISIBILITY

END-TO-END DRUG

ACCOUNTABLITY

INVENTORY

MANAGEMENT

DRUG ACCOUNTABILITY AND RECONCILATION

30

INVESTIGATORSPONSOR

• DEMONSTRATE THAT STUDY DRUG HAVE BEEN PROPERLY CONTROLLED THROUGHOUT THE CTS CHAIN:

• INITIAL SUPPLY TO SITE• DISPENSING AT THE SITE AND

RETURN TO SITE• DEFINE THE LEVEL OF RECONCILIATION

(E.G. TABLET LEVEL)

TIPS:

• DOCUMENT DRUG DISPOSITION• USE DRUG ACCOUNTABILITY AND

DISPENSING LOGS• ACCOUNT IN THE SAME LEVEL OF

RECONCILIATION AS THE SPONSOR

• IRT SYSTEM CAN SHOW FINAL DISPOSITION OF MATERIALS

• DETAILED THE PROCESS IN A IMP HANDLING GUIDE

• TRAIN MONITOR PROPERLY FROM THE START

• ICH GCP guidelines section 4.6, 5.14, 5.18.4

• Annex 13 Outlines guidance on returns, reconciliation adn destruction

SITE LEVEL INVENTORY LOG – EXAMPLE

31

AMOUNT OF KITSRECEIVED

AMOUNT OF KITS DISPENSED AMOUNT OF KITSRETURNED/ DESTROYED

STUDY DRUG IDENTIFICATIONBATCH # /KIT #

CURRENT STOCK LEVEL IMP RESPONSIBLE(DATE AND INITIALS)

COMMENTS

10 5 5 B1234 5 23 OCT 2016 / AP N/A

30 15 14 B1234 20 27 OCT 2016 / AP 1 KIT WAS ACCIDENTALLY DESTROYED

DRUG RECONCILIATION STATEMENT (TO BE COMPLETED BY INVESTIGATOR OR IMP RESPONSIBLE)I CAN CONFIRM THAT ALL STUDY DRUG ABOVE HAS BEEN FINALLY RECONCILED AND ACCOUNTED FOR

NAME: GITTE ALBERT SIGNATURE: GA DATE: 03 NOV 2016

TOTAL AMOUNT OF KITS RECEIVED: 40 TOTAL AMOUNT OF KITS DISPENSED: 20 TOTAL AMOUNT OF KITS RETURNED/DESTROYED: 19

SPONSOR NAME IMP INSIGHT APS PROTOCOL ID ABC123 PAGE NO. PAGE 1 OF 1

PI NAME GITTE ALBERT SITE NUMBER 12 COUNTRY DENMARK

IMP DISPENSING AND ACCOUNTABILITY LOG – EXAMPLE

32

SPONSOR NAME IMP INSIGHT APS PROTOCOL ID ABC123 PAGE NO. PAGE 1 OF 1

PI NAME GITTE ALBERT SITE NUMBER 12 COUNTRY DENMARK

PATIENT # 1201

VISIT # DISPENSED BY AND DATE STUDY DRUG IDENTIFICATIONBATCH # /KIT #

NUMBER OF UNITS DISPENSED(TABLETS)

DATE RETURNED TO SITE

NUMBER OF UNITS

RETURNED

VERIFIED BY(IMP RESP.)

CHECKED BY(CRA)

1 23 OCT 2016 B1234 25 01 NOV 2016 0 AP/ 01 NOV2016

MT/01 DEC2016

2 01 NOV 2016 B1234 25 7 NOV 2016 0 AP / 01 NOV 2016

MT/01 DEC2016

DRUG RECONCILIATION STATEMENT (TO BE COMPLETED BY INVESTIGATOR OR IMP RESPONSIBLE)I confirm that all the investigational product for this subject has been finally reconciled and accounted for:

NAME: GITTE ALBERT SIGNATURE: GA DATE: 03 NOV 2016

FROM DIRECTIVE TO REGULATION

33

COMES INTO FORCE

2001/20/EC

SINGLE PORTAL

EU PORTAL

GO-LIVE

NEW EU CLINICAL

TRIAL REGULATIVE

CTR EU No.

536/2014(PUBLISHED IN MAY

2014)

PHASED OUT

2001/20/EC

NO LONGER

APPLICABLE

MAY 2004 SEP 2018 OCTOBER 2021OCTOBER 2018

34

What is coming with regards to

CTR EU No. 536/2014

Centralized/ Single

Application Process – EU

Portal AMP willreplaceNIMP

Reporting of Trial

Progress

Simple Reporting of

SUSARs

HarmonizedConduct of

TrialsBinding for all

MemberStates

Clinical Data Transperancy(EU Database)

http://ec.europa.eu/health/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf

LINK:

Co-Sponsorship

35

DEFINTION“AMPs are related to

the design of a clinical trial, but are

not considered as Investigational

Medicinal Product (IMP), e.g.

background medication, rescue

medication, diagnostics etc.”

Not concomitant medication.

“AMP” Replaces “NIMP”

• PROVIDE RATIONALE FOR USE OF AMP

IN PROTOCOL

AND

• AUTHORIZATION STATUS

36

• STANDARDIZED

LABEL CONTENT

• NO ADDITIONAL

LABEL TO

AUTHORIZED AMP

COMMERCIAL

LABEL NEEDED

• LABELING OF

UNAUTHORIZED

AMPs ARE ALMOST

IDENTICAL TO

UNAUTHORIZED

IMPs

Labeling Requirements for IMP/AMP

(Chapter X and ANNEX 6)

37

Re-test or Expiry date Labeling of

IMP/AMP (ANNEX 6)

• Expiry date / Re-test on all inner containers

(immediate / primary pack)

• Without exception! (NO IRT…)

OBS. When updating Expiry / re-test date

Current “Annex 13” provisions allows for omitting “Retest/Expiry date” on outer and inner package, because it could be controlled more safely by an electronic information system e.g. IRT system.

THANK YOU

38