Guide to interpretation of the Code of GMP for the manufacture of 18-Fludeoxyglucose injections

Version 2.1, July 2013

17 December 2013

Introduction

Preamble

The purpose of this document is to clarify the Code of GMP (PIC/S Guide to GMP for Medicinal Products PE-009-8 -15 January 2009, Part I and Annexes) requirements for industrial manufacture of the positron emission tomography (PET) radiopharmaceutical, Fludeoxyglucose [18F] Injection (18F-FDG Injection). As the Code of GMP is only applicable to industrial manufacture, this document is only applicable to licensable manufacturing environments.

This document has initially been developed in relation to the Australian Code of GMP for Medicinal Products (2002), following discussions with the Australian and New Zealand Association of Physicians in Nuclear Medicine (ANZAPNM), the Australian and New Zealand Society of Nuclear Medicine (ANZSNM), manufacturers and users of 18F-FDG Injection. After adoption of the PIC/S Guide to GMP for Medicinal Products PE-009-8 -15 January 2009 as the Code of GMP, this document was amended accordingly following discussions with manufacturers of 18F-FDG Injection.

Interpretation of the basic GMP requirements

Where a clause number or an Annex is not listed, there is no specific interpretation provided for manufacture of 18F-FDG Injection.

Interpretation

Clause(s) Page Interpretation
Chapter 1 - Principle 1 The first sentence to mean - " … comply with the requirements of the marketing authorisation unless exempted under the Therapeutic Goods Act 1989, in which case default standards apply …. ".
1.1vii, 1.3vii 2, 4 Annex 3, clause 8 allows radiopharmaceuticals to be dispatched before the conformity of the batch with all QC tests and conditions is formally recorded. This clause should be read in conjunction with Annex 3, clause 10, which requires a documented procedure to describe the measures to be taken for stopping the use of defective radiopharmaceuticals.
1.3ii 3 The radioactive starting material Fluorine-18 (18F) need not be tested as its radioactive properties can be examined during the testing of the finished product. Non-radioactive starting materials should be tested on receipt, although reduced testing is permitted in cases where the supplier has been qualified and the sampling procedure validated (refer Annex 8, clauses 2 & 3).
1.3viii 4 Reference samples of radioactive starting materials and materials supplied as commercial synthesis kits manufactured under GMP are not required.
2.3, 2.7 7-8 The testing and release of a batch of 18F-FDG Injection should be by a separate individual from the person who manufactured the batch. However, it is acknowledged that under certain circumstances this may not always be possible. The circumstances under which a single person may be responsible for testing/release and manufacturing of a batch of 18F-FDG Injection should be identified and documented. In that case, an independent person who is trained and qualified should review the testing results and release of that batch at the earliest opportunity.
3.22 13 A separate sampling area is not always required.
4.14(d), 5.39 17 It is acknowledged that there may be some variation in the product yield in terms of radioactivity. This variation need not necessarily affect a decision to release the product if the finished product complies with specifications. However, the minimum acceptance criteria for radioactivity yield should be documented. Failure to meet minimum acceptance criteria should be investigated and documented.
5.30 25 The radioactive starting material Fluorine-18 (18F) need not be tested for identity as its radioactive identity can be examined during the testing of the finished product. Every container of non-radioactive starting materials should be tested for identity on receipt, although reduced sampling is permitted where a validated sampling procedure is used (refer Annex 8, clauses 2 & 3).
5.58 27 Annex 3, clause 8 allows a batch to be dispatched before the conformity of the batch with all QC tests and conditions is formally recorded.
5.61 28 Rejected materials, rejected product and waste from the manufacturing process should be stored in a safe manner until the radioactivity has decayed to a safe level. This might necessitate storage of decaying rejected materials, product rejected prior to release and waste in a clearly segregated and labelled area of a hot cell that is being used for production of another batch of 18F-FDG Injection.
Annex 1
Principle
1 The application of Annex 1 to the manufacture of 18F-FDG Injection should give appropriate consideration to the unique risk profile this product, based on its short half life and small batch size.
Annex 1.9 3 If continuous monitoring cannot be achieved, the manufacturer must provide a risk based justification of the applied process.
Annex 1.21 5 The use of a laminar flow hot cell that provides Grade A conditions located in a Grade D room for aseptic processing steps is acceptable.
Annex 1.66 11 Media fills are required unless media in the appropriate container size are not available. In that case mock fills using Water for Injection or Saline for Injection are an acceptable alternative to media fills provided the entire contents of each filled vial are tested for sterility by a validated membrane filtration method.
Annex 1.80 12 Where synthesis kits are used and filter sterilisation is in line, the requirement to monitor the presterilisation bioburden is waived.
Annex 1.113 16 A post-use filter integrity test should be performed the next working day when radiation levels have decayed sufficiently to render the filter safe to handle. It is not acceptable to accumulate filters over a period of several working days to test for filter integrity in one session.
Annex 1.119 17 Due to the radiation risk involved it is not recommended to crimp outside of the dispensing hot cell where filling has taken place.
Annex 1.124 17 Visual inspection should be performed to a practical level, for example focusing on external contamination and gross defects which may be supported by post decay examination.
Annex 1.125 17 Sterility testing of filled containers should commence as soon as practicable after radiation levels have decayed sufficiently to render the product safe to handle, preferably the next working day, unless otherwise justified and documented.
Annex 1.125-1.127 53 Endotoxin testing should be performed for each batch with test results available at the time of completion of the sterility test, unless otherwise justified and documented.
Annex 8.3 52 Synthesis kits supplied directly from a supplier in the supplier's sealed containers and supplied with a certificate of analysis are exempt from sampling and identification testing where the supplier is an approved supplier under the quality system of the finished product manufacturer.
Annex 13 67 This Annex is applicable to manufacture of 18F-FDG Injection where the product is intended for use as an investigational medicinal product.
Annex 19 100 This Annex is applicable with reference to the interpretation of clause 1.3viii indicated above.

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Version history

Version Description of change Author Effective date
V1.0 Original publication Office of Manufacturing Quality 1 December 2009
V2.0

Alignment with new Code of GMP: PIC/S Guide to GMP for Medicinal Products PE009-8 - 15 January 2009

General revision of interpretations

Office of Manufacturing Quality 1 June 2011
V2.1 Template update Office of Manufacturing Quality 1 July 2013