Transcript SARQA/DKG 3-4 OCTOBER 2002

SARQA/DKG Conference
3-4 OCTOBER 2002
Annex 13 Update
An Industry Perspective
Michael J Cooke
Director, Global GMP QA
AstraZeneca
SARQA/DKG Conference 3-4
October 2002
1
Annex 13 Update
•
•
•
•
•
Introduction
Revision to Annex 13
Issues and Concerns
Role of the Qualified Person
Other Challenges for the CT Directive
Implementation
SARQA/DKG Conference 3-4
October 2002
2
Annex 13 Update
•
•
•
•
Timings
Draft issued November 2001
Comments submitted May 2002
End of Year for Issue ?
– As for other guidance documents ?
SARQA/DKG Conference 3-4
October 2002
3
Annex 13 Update
Proposed Changes :
• Some are welcome !
• Removal of the 25% rule for dating of
comparator products
• Removal of requirement to retain
unused product until after finalisation
of the clinical trial
SARQA/DKG Conference 3-4
October 2002
4
Annex 13 Update
(1) Product Specification File (para 11)
• Specifications, analytical methods
• Manufacturing methods
• In process testing and methods
• Relevant clinical protocols and
randomisation codes, as appropriate
• Stability data and Storage and shipment
conditions
SARQA/DKG Conference 3-4
October 2002
5
Annex 13 Update
(1) Product Specification File (cont)
• Relevant Technical agreements with contract
givers
• Single File
• “Approved” and referenced on the Order
(para 10)
• How to ensure its up to date ?
• How will the Qualified Person be kept up to
date with PSF ?
SARQA/DKG Conference 3-4
October 2002
6
Annex 13 Update
(2) Labelling Requirements (para 29)
(a) Name, address, telephone number
– inflexible supply for multi-national
trials
– Suggest name only
(b) As written, implies name/identifier
of the product for blinded trials
SARQA/DKG Conference 3-4
October 2002
7
Annex 13 Update
(2) Labelling Requirements (cont)
(d) Trial subject identification number
on label
– May be added at time of dispensing to
retain flexibility of supply
– Expectation for inspections ?
SARQA/DKG Conference 3-4
October 2002
8
Annex 13 Update
j) “Use by” date
• Product may require re-labelling (36)
– Should be at manufacturing site
– Alternatively, at investigator’s site by trial
pharmacist or maybe by trial monitor
• Option to allow sponsor to provide this
information to investigator
SARQA/DKG Conference 3-4
October 2002
9
Annex 13 Update
(2) Labelling Requirements (cont)
• Small label
– Legibility and impact may be affected
• Some information may be added at time of
dispensing (subject/investigator
identification
– Provides flexibility in supply
SARQA/DKG Conference 3-4
October 2002
10
Annex 13 Update
(3) Role of the Qualified Person and
Assessment of Batches
• Article 13 of Directive 2001/20/EC requires
that the Authorisation holder must have a
QP at his disposal
• Allows for “transitional arrangements”
– Grandfather clause
SARQA/DKG Conference 3-4
October 2002
11
Annex 13 Update
Transitional Arrangements
• “person engaged in activities as the QP for
IMP…shall continue the activities in the
Member State concerned” (Article 13.5)
• Acceptable to other Member States ?
– Movement of IMPs with EU ?
SARQA/DKG Conference 3-4
October 2002
12
Annex 13 Update
IMP Manufactured within EU
• 91/356/EEC (GMP)
• Product Specification File
• Article 9(2) [Authorisation to conduct the
trial]
• Certify in Register
SARQA/DKG Conference 3-4
October 2002
13
Annex 13 Update
IMP Manufactured in a Third Country
• GMP equivalent to 91/356EEC
• Absence of MRA, QP must determine the
equivalency
• 42.c i) “normally by participation in audit”
SARQA/DKG Conference 3-4
October 2002
14
Annex 13 Update
Multi national organisations
• Frequent transfers between sites
• Same Corporate standards, possibly same
QA and function management
• Audit by QP not necessary ?
• How to justify to inspector ?
SARQA/DKG Conference 3-4
October 2002
15
Annex 13 Update
Comparator Products from Third Country
• Requires, for each production batch,
documentation is obtained to show
equivalent GMP….
• Otherwise ensure each batch has undergone
all relevant tests …..
SARQA/DKG Conference 3-4
October 2002
16
Annex 13 Update
•
•
•
•
Comparator Products from Third Country
Difficult to get assurance of GMP
compliance ?
Accept Certificate of Analysis ?
Testing on import ?
What would be acceptable in the
Application ?
SARQA/DKG Conference 3-4
October 2002
17
Annex 13 Update
Comparator Products from Third Country
• Easiest route to source comparator product
from EU with a Marketing Authorisation !
SARQA/DKG Conference 3-4
October 2002
18
Annex 13 Update
Assessment of batches may include : (para 43)
• Currently documents listed include many
that will not be referenced routinely ?
• Covered by Reference to the Product
Specification File ?
SARQA/DKG Conference 3-4
October 2002
19
Annex 13 Update
Assessment of batches may include : (cont)
• Where relevant, results of tests or analysis
after importation ?
– Why test at all ?
– Commercial product requirements ?
• Audit reports of the manufacturer ?
• Stability reports ?
SARQA/DKG Conference 3-4
October 2002
20
Annex 13 Update
Where does the QPs responsibility end ?
•
•
•
•
Expiry date extensions ?
Re-labelling ?
Randomisation ?
Manufacture v Dispensing ?
SARQA/DKG Conference 3-4
October 2002
21
Annex 13 Update
Other comments - Para (6)
• Not clear whether the QP’s responsibility to fulfil
“these requirements” relates to all requirements of
the annex or just to the training of these.
• Broad knowledge of “clinical trial processes”
does not include manufacture of supplies
SARQA/DKG Conference 3-4
October 2002
22
Annex 13 Update
Other comments – Batch release of Products
• Table 1
– Confusing, “before “ and “after” clinical trial
processing
– (e) implies testing in EU is required for IMPs and
comparators from outside of EU
– Contrary to Directive 13.3 (b) and (c ) which requires
the QP to confirm testing has been carried out
– No mention of testing in 42c) (i)
SARQA/DKG Conference 3-4
October 2002
23
Annex 13 Update
Other Comments –Para 47
• Requirement for de-coding documents to be
accessible before shipped to investigator
site –restrictive
• Propose “before dispensed” at …site
SARQA/DKG Conference 3-4
October 2002
24
Annex 13 Update
Other comments – Para 51
• Requirement for Investigator to understand
the procedures for retrieving IMPs - not
appropriate or necessary
• Propose .. “investigator and monitor need to
understand their obligations under the
retrieval procedure”
SARQA/DKG Conference 3-4
October 2002
25
Annex 13 Update
Other comments –Para 55
• implies destruction at the manufacturing
site…
SARQA/DKG Conference 3-4
October 2002
26
Annex 13 Update
Summary
• Few changes in proposed draft are
welcomed but ….
• Further amendments/deletions necessary to
simplify, clarify and ensure appropriate
level of control
SARQA/DKG Conference 3-4
October 2002
27
Annex 13 and GCP Directive
91/356/EEC current draft revision
• Added “importer” after “manufacturer”
without adequate attention to the impact of
the meaning
• Further amendments to simplify and clarify
SARQA/DKG Conference 3-4
October 2002
28
Annex 13 and GCP Directive
Requirements for Authorization referred to in
Article 13, Directive 2001/20EC
• Information should “high level”, not
detailed
– Minimise bureaucracy ?
• Should not be more demanding than for
commercial products
– Proof of legal status ?
SARQA/DKG Conference 3-4
October 2002
29
Annex 13 and GCP Directive
Requirements for Authorization referred to in
Article 13, Directive 2001/20EC
• Alternative approach ?
• information complied similar to “Plant
Master File” presented to local inspectors
• Mutual recognition of inspections if IMP
manufactures
SARQA/DKG Conference 3-4
October 2002
30