SARQA/DKG Conference 3-4 October 2002 1 SARQA/DKG Conference 3-4 OCTOBER 2002 Annex 13 Update An Industry Perspective Michael J Cooke Director, Global.

SARQA/DKG Conference 3-4 October 2002

1

SARQA/DKG Conference

3-4 OCTOBER 2002

Annex 13 Update

An Industry Perspective

Michael J Cooke

Director, Global GMP QA

AstraZeneca


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Annex 13 Update

• Introduction

• Revision to Annex 13

• Issues and Concerns

• Role of the Qualified Person

• Other Challenges for the CT Directive Implementation


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Annex 13 Update

• Timings

• Draft issued November 2001

• Comments submitted May 2002

• End of Year for Issue ?– As for other guidance documents ?


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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


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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


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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 ?


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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


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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 ?


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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


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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


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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


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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 ?


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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


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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”


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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 ?


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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 …..


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Annex 13 Update


• Difficult to get assurance of GMP compliance ?

• Accept Certificate of Analysis ?

• Testing on import ?

• What would be acceptable in the Application ?


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Annex 13 Update


• Easiest route to source comparator product from EU with a Marketing Authorisation !


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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 ?


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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 ?


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Annex 13 Update

Where does the QPs responsibility end ?

• Expiry date extensions ?

• Re-labelling ?

• Randomisation ?

• Manufacture v Dispensing ?


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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


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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)


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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


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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”


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Annex 13 Update

Other comments –Para 55

• implies destruction at the manufacturing site…


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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


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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


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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 ?


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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 1 SARQA/DKG Conference 3-4 OCTOBER 2002 Annex 13 Update An Industry Perspective Michael J Cooke Director, Global.

Documents

sarqadkg conference

supply slide

audit slide

update imp

register slide

update comparator products

clinical trial slide

update assessment of