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Manufacture of sterile radiopharmaceuticals labelled with fluorine-18

Interpretation of the PIC/S guide to GMP

11 February 2019

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Quality control


Perform the testing of starting materials and each batch of product manufactured in accordance with any conditions of a Marketing Authorisation (where relevant) and default standards relevant to the material or product. Validate all test methods used in the analysis of starting materials and finished products before use, (Part I, clause 6.15).

All tests for finished products including the test for sterility should be performed as soon as possible (Annex 3.42)

Material Specifications

A specification for the testing requirements for each starting material and finished good should be available and documented in the PQS. The specifications for finished products should include a clear justification for the test regime, particularly where the testing of specified related substances is omitted.

Fluorine-18 based radiopharmaceuticals are allowed to be dispatched before formal completion of all tests; however, the specification should outline the mandatory tests that should be conducted before the product is released for shipment or released for supply (i.e. administration into patients) respectively, (Annex 3.39).

Chemical testing

Perform chemical testing of sterile radiopharmaceuticals labelled with fluorine-18 for each batch manufactured. Testing protocols should normally include:

  • appearance of solution
  • half-life of fluorine-18
  • radioactivity
  • pH
  • radiochemical purity
  • radionuclidic purity
  • stabilising agents
  • residual solvents
  • impurity testing

Sterility testing

Due to the relatively small batch size, of sterile radiopharmaceuticals labelled with fluorine-18, full compliance with the sample number and volume requirements specified in the default standards is not expected. Justify sampling plans and test volumes in accordance with quality risk management principles.

Commence sterility testing of filled containers 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).

Utilising quality risk management and validation principles, it may be possible to justify the accumulation of sterility samples over a period of several working days (up to a week) before shipment for sterility testing. However, sterility testing should be performed as soon as practicable when:

  • any quality issues are identified that indicate any possible impact to product sterility for batches awaiting testing
  • changes to the manufacturing process, materials or environment indicate the need for expedited testing
  • a newly qualified operator has commenced production of product for commercial supply and clinical use

Any delay in sterility testing (following decay of radioactivity) should be supported by appropriate validation to demonstrate that contamination in the product would be detected, i.e. there is no risk of false-negative sterility results following accumulation of samples.

The pooling of sterility samples across multiple batches is not encouraged, but may be permissible where justified by risk assessment. If pooling is conducted, you must fully investigate all batches (and input materials) implicated by a sterility failure.

Endotoxin testing

Perform endotoxin testing on each batch as soon as practicable, unless otherwise justified in accordance with the principles outlined in the sterility testing section and appropriately documented (Annex 1.125-1.127).

Test endotoxin samples from each batch as discrete samples (i.e. not pooled).

Endotoxin samples should be representative of the whole of the batch. Justify sampling plans and test volumes in accordance with quality risk management principles.

Stability testing

Perform stability testing for sterile radiopharmaceuticals labelled with fluorine-18 in accordance with the principles of Part I Clauses 6.26-6.36. Stability data addressing each product, formulation and activity level should be available for each product supplied. Stability testing should represent worst-case conditions, for example, include batches manufactured at the upper activity concentration.

Additional stability is required to support the shelf-life and storage conditions for any additives or stabilisers added to the formulated preparation to assure the chemical and microbiological quality of the finished product.

Environmental monitoring (EM)

Controls in place for microbiological media should include supplier evaluation and the availability of a certificate of analysis (C of A). Verify the suitability of each lot of prepared media before use, either by performing growth promotion testing of each delivery of each lot of media received, or alternatively, by validating the transport system used by qualified pre-prepared media suppliers to ensure that media deliveries are routinely transported under appropriately controlled conditions. Media and their containers (such as agar plates) used in grade A/B areas must be sterile before use.

The identification of all microorganisms in grade A areas should routinely be to species level. Staff performing identification tests should be adequately trained and experienced.

Isolates from Grade B should be identified to at least genus level except when:

  • high individual counts are recovered
  • negative trends indicating a deterioration in environmental control emerge
  • recovery of potentially objectionable organisms

In these cases, additional identification of organisms (at least to species level) should be performed to aid in investigation and rectification of the event.

Typical local isolates should also form part of the validation for cleaning and EM programs. Isolates from the grade A areas upon identification should be verified against the EM validation database to ensure that the currently employed validated decontamination programme remains valid.

Perform reading and incubation of any microbiological plates in a location and in a manner that does not present a risk to manufacturing operations.

Release for supply

Annex 3.2, 3.39 & 3.51 permit sterile radiopharmaceuticals labelled with fluorine-18 to be dispatched to the clinical institute (under quarantine status) before formally recording the conformity of the batch with all QC tests and conditions. These provisions of Annex 3 prevail over Part I, clauses 1.4xv &1.9vii.

The finished product must not be administered to patients until the batch has been conditionally certified (released) for patient administration by the Authorised Person. The Authorised Person performing release for supply can conditionally certify the product for patient use, and then finally certify the product after all the relevant test results are obtained (Annex 3.39).

Procedure for release for supply

Establish a written procedure detailing the assessment of production and analytical data and include an exact and detailed description of the whole release procedure including the responsibilities of the involved personnel and the continuous assessment of the effectiveness of the PQS (Annex 3.2 and 3.51). The written procedure should be followed and compliance demonstrated before the batch is dispatched (Annex 3.43).

The release procedures should clearly outline the production and quality control data that should be reviewed before the product is dispatched (Annex 3.43).

Product distribution to the clinical institute may commence while the product is under quarantine providing:

  • The receiving site has been fully briefed in the shipment and release process and has signed a contract agreeing that they will not administer the product before notification from the manufacturer.
  • Appropriate sampling of the batch has been performed.
  • All checks that are required prior to dispatch have been completed and any results assessed.
  • The product is shipped with documents clearly indicating that the product must not be administered prior to conditional certification by the Authorised Person.

The order for the product (in written format) should be available at the time of performing the final check for product release. It can be an authorised true-copy of the original order. The final product release should include an independent check against the original order and this check should be recorded on the batch record. Any discrepancies should be investigated and appropriate corrective action taken before the product is released for administration to the patient.

This procedure should also describe the measures to be taken if unsatisfactory test results (out-of-specification) are obtained after dispatch and before expiry (Annex 3.45), and the process effectiveness verified. Out-of-specification events should be investigated and documented, including the relevant corrective actions taken and preventative actions put in place to prevent future events.

Procedures should clearly indicate the formalised communication mechanisms for ensuring the customer receives the release for administration for recording in the patient's documentation, and in the case of defective in-expiry product, the formalised notification processes and customer confirmation.

Separate testing and release person

The testing of a batch of radiopharmaceutical should be by a separate individual from the person who manufactured the batch. Likewise, the release for supply should be performed by an Authorised Person who was not involved in the manufacture or testing of the product, (part I, clause 2.5).

However, under exceptional circumstances, this may not always be possible and therefore release procedures should address these situations. When a single person is responsible for testing, release and manufacturing of a batch of a radiopharmaceutical, a review of the testing results and release of that batch by an independent person should be performed at the earliest opportunity, ideally within 24 hours.

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