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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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Sampling and management of starting materials

Radioactive starting material

Reference samples of radioactive starting materials, are not required (part I, clause 1.9viii).

The radioactive starting material fluorine-18 (18F), does not need to be sampled or tested by the dosage form manufacturer before use where the quality, radioactive properties and identity are examined during the testing of the finished product (part I clauses 1.9ii and 5.30).

Where fluorine-18 (18F) is supplied as an API to third parties, the material does not need to be sampled and tested by the API manufacturer for compliance with Default Standards before use where the quality, radioactive properties and identity are examined during the testing of the finished product (part I clauses 1.9ii and 5.30).

You are not expected to perform sampling or testing of radioactive materials where there is a radiological hazard to operators(s) that cannot be effectively controlled to acceptable levels.

Non-radioactive starting materials

Retain reference samples of non-radioactive starting materials and packaging materials in accordance with Annex 19 - Reference and retention samples, to permit future examination of the material if necessary.

Reference samples of gases, solvents or water used during production are not expected (Annex 3.49).

Sample every container of non-radioactive starting materials on receipt. Reduced sampling is only permitted in cases where the supplier has undergone a detailed qualification and evaluation, and the sampling procedure validated (refer Annex 8.2-8.3).

Non-radioactive starting materials should meet the requirements of relevant monographs in the default standards e.g. British Pharmacopoeia, European Pharmacopeia or United States Pharmacopoeia, and testing on each delivery of each lot received for compliance with the pharmacopoeia is required. Perform identity testing on each container sampled. Other tests may be performed on composite samples where scientifically justified.

Any reduction in testing must be fully justified in accordance with QRM principles and considering the results of the assessment and qualification of the supplier, and supply history, (Annex 8.3)

The sampling of gases purchased from commercial sources and used during production is not expected, and the approval for use of these gases may be performed based on supplier approval and certificates of analysis.

Stabilising solutions or additives

Manufacture any stabilisers used in the production of sterile products in accordance with GMP requirements, e.g. sodium thiosulphate.

H218O starting materials

Source the H218O used in the production of 18F from a suitably qualified supplier. Assess each lot received for compliance with a defined specification; certificates of analysis should be available for each lot used.

Synthesis kits

Reference samples are not required for commercial synthesis kits and their accompanying reagents manufactured in accordance with GMP, e.g. peptide precursors and solvents (part I, clause 1.9viii).

Synthesis kits and reagents 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 8.3).

Sampling areas for starting materials

A separate sampling area is not usually required for radiopharmaceutical starting materials. However, where sampling is performed and materials are exposed to the environment, conduct sampling in such a way as to prevent contamination or cross-contamination of the material and environment (part I, clause 3.22).

Qualification of suppliers

All suppliers of starting materials (including packaging materials) should be qualified under the manufacturer's Pharmaceutical Quality System (PQS) and in accordance with Quality Risk Management Principles. Take account of the following when validating starting materials (Annex 8.3):

  • manufacturer and supplier understanding of GMP requirements of the pharmaceutical industry
  • Quality Assurance system of the manufacturer
  • manufacturing conditions
  • nature of the starting material and the medicinal products in which it will be used

Clean areas

Clean room and clean air device design

Carry out the manufacture of sterile products in clean areas. There are four grades of clean area, A, B, C and D, classified according to required environmental characteristics of the area (Annex 1.3, 1.4 & 1.19). Air supplied to clean rooms or clean air devices should be passed through filters of an appropriate efficiency.


'Hot-cells' used for the production of sterile radiopharmaceuticals labelled with fluorine-18 should be carefully designed and located so that:

  • the required air quality for the respective zones can be achieved in accordance with Annex 1.3 & 1.17
  • the risk of contamination from the environment of aseptically manufactured products is effectively minimised

For hot-cell systems that are built or upgraded after 1 January 2019, the following grade requirements should be met.

Grade Examples of operations for manufacture of sterile radiopharmaceuticals labelled with fluorine-18
A Aseptic preparation and filling
B Background or adjacent environment for the grade A zone, e.g. transfer hatch between grade C and grade A environments

Preparation of solutions prior to sterile filtration, e.g. synthesis

Fully closed and automated operations

A hot-cell with a Grade C internal environment will be suitable when closed and automated systems (for example chemical synthesis, purification, on-line sterile filtration) are used. Hot-cells are required to meet a high degree of air cleanliness, with filtered feed air when closed. Carry out aseptic activities in a Grade A area (Annex 3.27).

Hot-cells used for aseptic processing should normally be equipped with integrated transfer systems that allow multiple decontamination steps via areas of increasing cleanliness in accordance with Annex 1.1, 1.31 & 1.33, requirements, e.g. materials are transferred from grade D → grade C → grade B → grade A.

Facilities seeking TGA licensing or licenced manufacturers upgrading their facilities after 1 January 2019 would be expected to design and implement equipment meeting the full requirements of Annex 1. i.e. Grade A/D interfaces would not be permitted.

Existing manufacturing facilities licensed by the TGA before 1 Jan 2019

For existing manufacturing facilities licensed by the TGA before 1 January 2019, 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 1.21). However, additional controls regarding the management of the grade D/A interface should be implemented and their effectiveness monitored, such as (but not limited to):

  • Detailed in-operation and at-rest classification data demonstrating the appropriateness of the operations and manipulations at the A/D interface.
  • Comprehensive In-operation and at-rest air-flow visualisation studies to clearly indicate and demonstrate the impact of the grade D air on the critical operation and cleanliness of the grade A zone is negated.
  • In-operation and at-rest recovery studies to assess the required recovery time for the cleanliness of the grade A zone.
  • Validated decontamination processes for the transfer of all materials from the grade D zone into the grade A zone. Ongoing routine environmental monitoring of the effectiveness of the decontamination processes employed both viable and non viable.
  • Validated cleaning processes using a cleaning agent(s) with broad-spectrum activity. Consider the possibility of spore-forming isolates being present that may contaminate the grade A zone during set-up.
  • Comprehensive environmental and personnel monitoring of the grade A, B, C and D environments where applicable during critical operations, e.g. equipment transfer and set-up, based on a risk assessment of the operations and qualification data (Annex 1.8). Reviewing any organisms isolated from the grade A environment and identifying to species level and maintaining a database of organisms to verify existing disinfectant regimes are effective in rendering the organisms(s) non-viable. On-going trend analysis to be performed on all operators to verify consistency with strict environmental monitoring limits, and appropriate procedures in place regarding exclusion where demonstrated non-compliance is observed.
  • Ensuring operators wear gowns, facemasks, goggles and gloves that provide protection to the grade A environment and decontaminated equipment during critical operations, e.g. equipment transfer and set-up.
  • Initial and on-going process simulations (media fills) including worst case manufacturing operations for all operators performing sterile manufacture.


Classify clean areas under both in-operation and at-rest conditions in accordance with EN ISO 14644-1. Detailed environmental characteristics can be found in Annex 1.4-1.5 of PIC/S Guide to GMP.

Monitoring of clean air device and clean rooms

Monitor clean areas under both in-operation and at-rest conditions in accordance with EN ISO 14644-2. Detailed environmental characteristics can be found in Annex 1.8-1.20 of PIC/S Guide to GMP. Follow Quality Risk Management principles when determining the ongoing environment monitoring programme; justify the selection of sampling locations, frequencies and methods based on risk to product quality (Annex 1.8).

Commence monitoring of the Grade A zone for both non-viables and viables at the start of each work session (during set-up) and where possible continue for the full duration of the session. Monitor and trend viable results.

During release of products manufactured in that session, consider:

  • non-viable results for the session,
  • the impact of any historical out of specifications or out of trends for viable results in determining whether the manufacturing environment is in control, any subsequent impact on product quality and if any corrective action needs to be taken.

Perform the environmental monitoring of lower grade areas in accordance with Annex 1 requirements.

If continuous monitoring cannot be achieved, e.g. due to the presence of radiological hazards, provide a full and comprehensive risk based justification of the processes employed in relation to environmental monitoring (Annex 1.9).

You need to set appropriate alert and action limits for the environmental results of particulate and microbiological monitoring, in alignment with Annex 1. If these limits are exceeded, operating procedures should prescribe corrective action.

Perform environmental monitoring whenever possible.

You are not expected to perform environmental monitoring where there is a radiological hazard to operator(s) that cannot be effectively controlled to acceptable levels.

Entry to clean areas

Access to clean manufacturing areas should be via a separate gowning area and restricted to authorised personnel (Annex 3.18). High standards of personal hygiene and cleanliness are essential.

Personnel, equipment and materials should enter clean areas through appropriately designed, controlled and operated airlocks. All items transferred into clean areas should be suitably cleaned, decontaminated and sanitised in order to prevent contamination of the grade into which the item is transferred. Decontamination and sanitisation processes should include the use of a sporicidal agent and should be validated for effectiveness, (Annex 1.61, 1.62, 1.64, 1.76, & 1.81).

Further guidance relating to the transfer of items into aseptic areas may be found in the TGA's guidelines for compounded medicines and good manufacturing practice (GMP).


Clothing and its quality should be appropriate for the process and the grade of the working area. Wear clothing in a way to protect the product from contamination (Annex 1.42). A description of clothing required for each grade can be found in Annex 1.43.

Choose clothing to match the grade in which it is used, e.g. low-linting sterilised gowns and gloves are required for personnel entering the grade A/B areas of the facility.

Provide and record training in appropriate gowning processes. For aseptic areas, operators should undergo an initial qualification, and the operator's ability to correctly gown should be assessed periodically. Monitoring of the gown surfaces and gloves worn in grade A and B areas should be performed frequently, e.g. each session, in accordance with risk management principles, (Annex 1.8). Operator gowning qualifications should include all set up processes related to the manufacturing operations for grade A. Operators who do not demonstrate compliance with the environmental monitoring limits should be excluded from aseptic operations until such time they have demonstrated consistent reproducible consistency.

Aseptic processing

Process simulation should cover all parts of the aseptic process, including all aseptic manipulations and should be supported by valid process simulation studies. This is normally achieved by substituting the aseptically produced product with a sterile nutrient medium (media fill) (Annex 1.66).

Perform process simulation tests for aseptically produced sterile products as part of initial validation and repeated at 6 monthly intervals. They should be representative of the batch sizes manufactured.

Perform operator process simulation test twice per year for every operator involved in aseptic manipulations. A risk assessment reviewing the potential impact of operators on product sterility can be used to determine the number of operator process simulation tests performed by each operator; however, operators must participate in at least one operator process simulation test annually.

Process simulation tests using a nutrient medium (media fills) are required unless media in the appropriate container size are not available. In that case process simulation tests using sterile water for injection BP or saline for injection BP 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 1.66).

Bioburden monitoring

Where synthesis kits are used and filter sterilisation is in line, the requirement to monitor the pre-sterilisation bioburden of the radioactive solution during routine production is waived due to the radiological hazard of collecting and analysing active samples, (Annex 1.80).

However, manufacturers should implement procedures to control the pre-sterilisation bioburden and this should be monitored by alternative means. For example:

  • monitoring of the bioburden and endotoxin levels in a flush sample from the transfer lines between the cyclotron and synthesis units
  • monitoring of the bioburden and endotoxin levels in a flush sample from the transfer lines between the synthesis units and grade A dispensing units
  • monitoring the bioburden of any non-sterile additives, e.g. stabilising solutions.

The results of bioburden monitoring should be reviewed against working levels on contamination immediately before sterilisation. These levels should be defined and related to the efficiency of the method to be used. Organisms isolated should be identified to species level and data collected verified against the current disinfectant regimes to ensure the currently employed and validated disinfectant processes remain valid.

You are not expected to sample radioactive products for pre-sterilisation bioburden where there is a radiological hazard to operators(s) that cannot be effectively controlled to acceptable levels.

Sterilising filtration

Sterilisation processes should be validated (Annex 1.83) and in particular, data to demonstrate the ability of the sterilising filter to sterilise the specific product formulation should be available prior to product release.

Sterilising filter validation should include data to meet the requirements of Annex 1.110 - 115, and include:

  • Data to demonstrate the bacterial retention capabilities of the filter assembly;
  • Data to demonstrate the compatibility of the product-contact parts of the filter to ensure that the filter does not affect the solution and s;
  • Data to establish the integrity testing values used to demonstrate filter integrity.

Additional guidance regarding the validation of sterilising filters may be found in ISO 13408 2:2018 Aseptic Processing of Healthcare Products - Part 2: Sterilising filtration.

Filter integrity testing

Confirm the post-use integrity of the sterilising filter using a validated filter integrity test, as soon as practicable. Typically this is performed the next working day, when radiation levels have decayed sufficiently to render the filter safe to handle (Annex 1.113). However, advancements in radiopharmaceutical manufacturing equipment technology can now provide filter integrity test results prior to administration into patient(s), and should be performed if the capability exists within the manufacturers organisational infrastructure.

  • Accumulating used sterilising filters over a period of several working days to test for filter integrity in one session is not acceptable.

Filter integrity test data should be recorded and retained with the batch record.

Finished product

Crimping vial caps

It is not recommended to crimp outside of the dispensing hot-cell where filling has taken place, due to the radiation risk involved (Annex 1.119). If vial crimping is required, the equipment used to crimp vial caps should be designed to avoid the generation of non-viable particulates.

Visual inspection

Visually inspect, to a practical level, filled containers of parenteral products individually for extraneous contamination or other defects (Annex 1.124), for example focusing on external contamination and gross defects which may be supported by post decay examination.

Validate the inspection process through operator training and check the performance of the inspection equipment and operators at defined intervals. Record results of the validation and routine inspection results.

Operators performing visual inspection of filled containers should pass regular eye-sight examinations, and wear corrective lenses where required, (Annex 1.124). Retain records of eye-sight examinations.

You are not expected to perform visual inspection of filled containers where there is a radiological hazard to operator(s) that cannot be effectively controlled to acceptable levels.

Product yield

There are various measurements of product yield, and some variation in the product yield in terms of radioactivity is acknowledged.

It is important that manufacturers define which yield calculations are an indicator of product quality; normally the monitoring of synthesis yield is expected as a minimum. Synthesis yield may be calculated as follows:

% Synthesis yield = (Activity of product at end of synthesis / Activity delivered to synthesis unit)

Document and trend yield results and investigate any significant deviation from the expected yield, as this may be indicative of a process issue that may impact product quality. (Part I, clause 5.39).

A variation in yield need not necessarily affect a decision to release the product if the finished product complies with specifications.

Rejected and waste materials

Clearly mark and store rejected materials, rejected product and waste from the manufacturing process in a safe manner until the radioactivity has decayed to a safe level (part I clause 5.61). A hot-cell used specifically for storing decaying rejected materials, product rejected prior to release and waste materials should be clearly labelled as such.

Finished product retention samples

Retain retention samples from each batch of product in accordance with Annex 19 requirements. The volume of the retained sample should be sufficient to permit repeat testing of samples in case of complaint or quality incident.

Container integrity

Due to the radiological hazard associated with sterile radiopharmaceuticals labelled with fluorine-18, batch specific testing for container-closure integrity is not expected. However, validation to support the integrity of the container-closure system should be performed to verify its ability to maintain the quality of the finished drug product and sterility over the expiry period. (Annex 1.117).

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