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Radiopharmacy · QC

Radiopharmaceutical Quality Control

Snapshot

Before release, every radiopharmaceutical is checked for radiochemical purity (the fraction of activity in the desired chemical form — by chromatography), radionuclidic purity (correct isotope; e.g. ⁹⁹Mo breakthrough), chemical purity (e.g. aluminium), plus apyrogenicity (endotoxin), pH and, for particulates, particle size; sterility testing of short-lived products is completed after release.

QC protects the patient from impurities that degrade images (biodistribution errors) or cause harm. Some tests are performed on every batch, others periodically.

RCPChromatography
Radionuclidic⁹⁹Mo/isotope
Sterile & pyrogen-freeEndotoxin (LAL)
Reference values
  • Radionuclidic purity = fraction of activity that is the desired nuclide; radiochemical purity = fraction in the desired chemical form; chemical purity concerns non-radioactive species (e.g. aluminium).
  • ⁹⁹Mo breakthrough limit: 0.15 µCi/mCi ⁹⁹ᵐTc at administration (USP/NRC), measured through a lead pot that passes only the 740/778-keV photons; Ph. Eur. 0.1%.
  • Aluminium limit: 10 µg/mL of eluate (USP); 5 µg/mL (Ph. Eur.).
  • Sterilising filtration uses a validated 0.22-µm (0.2-µm) membrane with an integrity (bubble-point or pressure-hold) test after use; 0.45-µm filters are not sterilising grade.
  • Sterility test: fluid thioglycollate medium at 30–35 °C and soya-bean casein digest medium at 20–25 °C for 14 days.
  • Endotoxin limit for radiopharmaceuticals 175/V EU per mL (V = maximum dose volume); general parenteral limit 5.0 EU/kg, intrathecal 0.2 EU/kg.
  • Ideal product pH is 7.4 (tolerated range about 2–9 thanks to blood buffering); pertechnetate eluate pH 4.5–7.5 (USP).
  • Dose calibrator: AAPM Report 181 action level ±5% for constancy, accuracy and linearity (older US NRC guidance allowed ±10%); see counting statistics and the dose calibrator.
Worked example

Radiochemical purity by two-strip ITLC

Given. ⁹⁹ᵐTc-MDP. Strip 1 (ITLC-SG, acetone): solvent front (free TcO₄⁻) 3,500 cpm, origin 38,000 cpm. Strip 2 (ITLC-SG, saline): origin (hydrolysed-reduced Tc) 1,200 cpm, front 40,300 cpm.

  1. Free pertechnetate = 3,500 / 41,500 = 8.4%.
  2. Hydrolysed-reduced ⁹⁹ᵐTc = 1,200 / 41,500 = 2.9%.
  3. RCP = 100 − 8.4 − 2.9 = 88.7%.

Answer. RCP ≈ 89% — below the >95% expected for MDP, so the preparation should not be released; free pertechnetate is the main impurity (look for oxidation or too little tin).

Worked example

Endotoxin limit for an FDG dose

Given. Endotoxin limit 175/V EU/mL; maximum dose volume V = 10 mL; patient 70 kg; general limit 5 EU/kg.

  1. Limit = 175/10 = 17.5 EU/mL.
  2. A full 10-mL dose at the limit contains 175 EU.
  3. 175 EU / 70 kg = 2.5 EU/kg.

Answer. 17.5 EU/mL; even a full dose at the limit gives 2.5 EU/kg, within the 5 EU/kg threshold for pyrogenic reactions.

Schematic of two chromatography strips: in acetone free pertechnetate moves to the solvent front while bound and hydrolysed-reduced technetium stay at the origin; in saline bound agent and free pertechnetate move while hydrolysed-reduced technetium stays; a box gives the formula radiochemical purity equals 100 minus percent free minus percent hydrolysed.
Figure. Two-strip instant thin-layer chromatography for a soluble ⁹⁹ᵐTc agent such as MDP: acetone moves only free pertechnetate, saline leaves only hydrolysed-reduced Tc at the origin, and radiochemical purity is 100% minus both impurities (after Saha, Fundamentals of Nuclear Pharmacy).

Purity tests

  • Radiochemical purity by ITLC or paper chromatography separates free pertechnetate and hydrolysed-reduced ⁹⁹ᵐTc from the labelled complex; acceptance is usually >90–95% (>80% for exametazime).
  • Radionuclidic purity: ⁹⁹Mo breakthrough (USP/NRC ≤0.15 kBq/MBq at administration; Ph. Eur. ≤0.1%) and the correct photopeak or half-life.
  • Chemical purity: aluminium in generator eluate (≤10 µg/mL USP, ≤5 µg/mL Ph. Eur.); for PET products, residual solvents and phase-transfer catalyst (Kryptofix 2.2.2).

Biological & physical

  • Sterility (14-day culture) and bacterial endotoxins (LAL test); sterility results for short-lived products are only available after release.
  • pH and appearance (clarity, colour, visible particles).
  • Particle size and number for ⁹⁹ᵐTc-MAA and particle size for colloids.

Pitfalls

  • Low radiochemical purity gives abnormal biodistribution and non-diagnostic scans.
  • Skipping the ⁹⁹Mo breakthrough check can give excess patient dose.
  • Endotoxin or sterility failures risk pyrogenic reactions and infection; a sterile product can still be pyrogenic.
In the clinic — why the physics matters
  • Poor radiochemical purity gives high soft-tissue and blood background and unnecessary dose — so kits are tested by ITLC, at least for each new batch and per local risk assessment.
  • Free ⁹⁹ᵐTcO₄⁻ shows thyroid, stomach and salivary uptake; hydrolysed-reduced ⁹⁹ᵐTc shows liver and spleen uptake — each impurity has a recognisable pattern.
  • A product can be sterile yet pyrogenic — endotoxin survives normal sterilisation — so endotoxin testing is separate (critical for intrathecal agents).
  • Aluminium above the limit flocculates sulfur colloid (lung uptake) and agglutinates red cells.
Radiopharmaceutical QC tests (Saha / USP / Ph. Eur.)
TestMethodAcceptance
⁹⁹Mo breakthrough740/778-keV assay through lead pot≤0.15 µCi/mCi at administration (USP); ≤0.1% (Ph. Eur.)
Aluminiumcolorimetric strip vs standard≤10 µg/mL (USP); ≤5 µg/mL (Ph. Eur.)
Radiochemical purityITLC (acetone + saline) or HPLCtypically ≥90–95%
pHpH meter or validated paper4.5–7.5 eluate (USP)
Sterilitythioglycollate / soya-bean casein, 14 dno growth
Bacterial endotoxinsLAL gel clot or kinetic chromogenic175/V EU/mL; ≤5 EU/kg (0.2 intrathecal)
Filter integritybubble point / pressure hold≥ manufacturer's specification
Common pitfalls & misconceptions
  • Do not confuse the three purities — ⁹⁹Mo is radionuclidic, free TcO₄⁻ is radiochemical, aluminium is chemical.
  • A single acetone strip is not the RCP — its origin holds both bound and hydrolysed-reduced Tc; two solvent systems are needed.
  • Sterile ≠ apyrogenic — sterilisation does not destroy heat-stable endotoxin.
  • A 0.45-µm membrane is not a sterilising filter — sterile filtration needs a validated 0.22-µm filter and a passed integrity test.
In depth
  • Two-strip ITLC logic: in acetone (or methyl ethyl ketone) only free pertechnetate migrates; in saline, pertechnetate and soluble complexes migrate and only hydrolysed-reduced ⁹⁹ᵐTc stays at the origin; RCP = 100% − %free − %hydrolysed-reduced. For MAA and colloids the product itself stays at the origin, so filtration or other methods are used instead.
  • For ⁹⁹ᵐTc-MAA, Ph. Eur. tests radiochemical purity by filtration (≥90% of radioactivity retained on a 3-µm polycarbonate membrane) and particle size by microscopy (≥90% of particles 10–100 µm, none >150 µm).
  • Sterility results for short-lived products arrive after administration. EANM cGRPP recommends in-house sterility testing only for products with half-lives over 7 h; otherwise samples are allowed to decay and are sent to an external laboratory, and operators are qualified by media-fill simulations.
  • Endotoxin testing: the traditional LAL gel-clot test takes about 1 h and the kinetic chromogenic test about 15 min, so a pre-release endotoxin result is feasible for cyclotron products and is recommended, particularly when reusable equipment or resin purification is involved.
  • The membrane-filter integrity test is the practical pre-release evidence of sterility: a filter that holds its bubble-point pressure after use has not been breached. It is not in the BP or USP FDG monographs but is expected by US FDA PET guidance and by EANM cGRPP.
  • Analytical methods for in-house products must be validated unless taken directly from the Ph. Eur. monograph; the EANM guideline adapts ICH validation parameters (specificity, linearity, accuracy, precision, range, limits of detection and quantification) to radio-HPLC, radio-TLC and gamma spectrometry.
  • For licensed kits, the SmPC quality-control test should be done at least for each new kit batch; for very short-lived products made several times a day (e.g. ¹³N-ammonia), full testing of the first and last batch can suffice once the process is validated.
  • Retention samples of unlicensed in-house preparations should be kept for at least 1 month after testing is complete or after expiry, whichever is longer.

Sources: Saha, Fundamentals of Nuclear Pharmacy, 7th ed. (2018), Ch. 8 · Jensen et al. 2022 (Molecules 27:3997) · Gillings et al. 2021 (PMID 33580358) · Gillings et al. 2020 (PMID 32052212) · Yu 2006 (PMID 21614337)

Sources

  1. Saha GB. Fundamentals of Nuclear Pharmacy. 7th ed. Cham: Springer; 2018.
  2. Gillings N, Hjelstuen O, Ballinger J, et al. Guideline on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals. EJNMMI Radiopharm Chem. 2021;6:8.
  3. Gillings N, Todde S, Behe M, et al. EANM guideline on the validation of analytical methods for radiopharmaceuticals. EJNMMI Radiopharm Chem. 2020;5:7.
  4. Gillings N, Hjelstuen O, Behe M, et al. EANM guideline on quality risk management for radiopharmaceuticals. Eur J Nucl Med Mol Imaging. 2022;49:3353–64.
  5. Jensen SB, et al. Issues with the European Pharmacopoeia quality control method for ⁹⁹ᵐTc-labelled macroaggregated albumin. Molecules. 2022;27:3997.
  6. Yu S. Review of ¹⁸F-FDG synthesis and quality control. Biomed Imaging Interv J. 2006;2:e57.
  7. European Pharmacopoeia. General chapters 2.6.1 (Sterility) and 2.6.14 (Bacterial endotoxins); general monograph Radiopharmaceutical preparations. Strasbourg: EDQM (current edition).
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