Summary Basis of Decision for GalliaPharm

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.

Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for GalliaPharm is located below.

Recent Activity for GalliaPharm

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for GalliaPharm, a product which contains the medicinal ingredient gallium (68Ga) chloride. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Updated: 2024-11-20

Drug Identification Number (DIN):

DIN 02503603- 1.85 GBq, gallium (⁶⁸Ga) chloride generator, solution

Activity/Submission Type, Control Number	Date Submitted	Decision and Date	Summary of Activities
Drug product (DIN 02503603) market notification	Not applicable	Date of first sale 2023-07-10	The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 227804	2019-05-15	Issued NOC 2019-05-15	NOC issued for New Drug Submission.

Summary Basis of Decision (SBD) for GalliaPharm

Date SBD issued: 2020-11-25

The following information relates to the New Drug Submission for GalliaPharm.

Gallium (⁶⁸Ga) chloride generator

Drug Identification Number (DIN):

DIN 02503603 - 1.85 GBq, solution

Eckert & Ziegler Radiopharma GmbH

New Drug Submission Control Number: 227804

On August 19, 2020, Health Canada issued a Notice of Compliance (NOC) to Eckert & Ziegler Radiopharma GmbH for the diagnostic radiopharmaceutical GalliaPharm.

The market authorization was based on the quality (chemistry and manufacturing) information and minimal clinical and non‑clinical data submitted. Based on Health Canada's review, the gallium (⁶⁸Ga) chloride eluate produced by the GalliaPharm generator is considered to be acceptable for use in the in vitro labelling of specific carrier molecules developed and approved for radiolabelling with such solution to be used for positron emission tomography (PET) imaging. The gallium (⁶⁸Ga) chloride eluate from the GalliaPharm generator is not intended for direct use in patients.

1 What was approved?

GalliaPharm, a radionuclide generator, produces gallium (⁶⁸Ga) chloride eluate which is authorized for the in vitro labelling of specific carrier molecules developed and approved for radiolabelling with such solution to be used for positron emission tomography (PET) imaging. The gallium (⁶⁸Ga) chloride eluate from the GalliaPharm generator is not intended for direct use in patients.

The use of ⁶⁸Ga‑labelled drug products is contraindicated in patients who are hypersensitive to this substance or any ingredient in the formulation, including any non‑medicinal ingredient.

GalliaPharm was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the use of this product.

GalliaPharm (available in activities of 0.74 GBq, 1.11 GBq, 1.48 GBq, and 1.85 GBq gallium [⁶⁸Ga] chloride, drug not to be administered directly) is a generator which produces a gallium (⁶⁸Ga) chloride eluate. The GalliaPharm generator features a titanium dioxide column to which the parent nuclide, germanium 68 (⁶⁸Ge), is fixed. Germanium 68 decays to the daughter nuclide, gallium 68 (⁶⁸Ga), which is eluted with sterile ultrapure hydrochloric acid as gallium (⁶⁸Ga) chloride. The column is enclosed in a stainless steel case, which has two handles and an inlet and outlet port. The solution for elution is attached to the inlet port, and the eluate can either be collected at the outlet port or inserted directly into a synthesis apparatus. Sterile ultrapure hydrochloric acid (0.1 mol/L) is supplied with the generator, along with various accessories including a vented spike, a Male Luer union and adapters, tubing and fingertight fittings of various sizes, and a stopcock manifold.

For more information, refer to the Quality (Chemistry and Manufacturing), Non‑clinical, and Clinical Basis for Decision sections.

Additional information may be found in the GalliaPharm Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was GalliaPharm approved?

Health Canada considers that the gallium 68 (⁶⁸Ga) chloride eluate produced by the GalliaPharm generator is acceptable for use in the in vitro labelling of specific carrier molecules developed and approved for radiolabelling with such solution to be used for positron emission tomography (PET) imaging. The gallium (⁶⁸Ga) chloride eluate from the GalliaPharm generator is not intended for direct use in patients.

Positron emission tomography is a nuclear imaging tool used to observe the metabolic function of various organs and tissues, enabling the diagnosis and evaluation of a wide range of diseases. Imaging is possible through the detection of signals emitted by a radiopharmaceutical introduced into the patient's body, which consists of a ligand labelled with a radioactive isotope. Radiopharmaceutical development often exploits the tendency of a particular element or its ligand to accumulate in regions with high metabolic or chemical activity, which often correspond to diseased areas of the body.

GalliaPharm is a radionuclide generator in which the radioactive isotope ⁶⁸Ga is generated from the decaying radioactive isotope germanium 68 (⁶⁸Ge). The gallium (⁶⁸Ga) chloride eluate produced in the generator may be used for in vitro radiolabelling. The resulting ⁶⁸Ga‑labelled drug product is a radiopharmaceutical, and may be used for diagnostic imaging in a PET scan.

The gallium (⁶⁸Ga) chloride eluate produced in the generator is not intended for direct administration to patients. Due to the nature of the product, the gallium (⁶⁸Ga) chloride eluate does not have a stand alone clinical indication. Therefore, clinical and non‑clinical data were minimal, with quality data constituting the majority of the submitted and reviewed material.

The risks associated with exposure to unbound radionuclides are very low, as the complex formed by ⁶⁸Ga and dodecane tetraacetic acid (DOTA; a commonly used chelator for binding radiometals to biomolecules) is irreversible. The administration of ⁶⁸Ga‑DOTA‑conjugated peptides is therefore not expected to result in a clinically relevant amount of unbound radionuclides. In the event of accidental injection with the eluate or unexpected high levels of unbound ⁶⁸Ga in the ⁶⁸Ga‑labelled drug product, radiation dose estimates based on non‑clinical data have been included in the labelling for the generator. Due to the short physical half‑life of ⁶⁸Ga, no specific action is required. However, the use of any radiopharmaceutical carries the inherent risk of exposure to radiation. The Serious Warnings and Precautions box in the GalliaPharm Product Monograph therefore includes an instruction that radiopharmaceuticals should only be handled by healthcare professionals who are qualified in the use of radioactive prescribed substances in humans. Special warnings and precautions for the use of ⁶⁸Ga‑labelled medicinal products may be found in the Product Monograph or Package Insert of the medicinal product to be radiolabelled.

The Risk Management Plan (RMP) provided for this submission was minimal, as GalliaPharm does not have a clinical indication. Additionally, the gallium (⁶⁸Ga) chloride eluate produced by the generator is not intended for direct administration to patients. At the time of issuance of the Notice of Compliance, there were no RMP‑related issues that would preclude the authorization of GalliaPharm.

The submitted labels meet the necessary regulatory labelling, plain language and design element requirements.

A Look‑alike Sound‑alike brand name assessment was performed and the proposed name GalliaPharm was accepted.

GalliaPharm is considered acceptable for its intended use based on the data reviewed. Appropriate warnings and precautions are in place in the GalliaPharm Product Monograph to ensure safe use of the product.

This New Drug Submission complies with the requirements of section C.08.002 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Quality (Chemistry and Manufacturing), Non‑clinical, and Clinical Basis for Decision sections.

3 What steps led to the approval of GalliaPharm?

Submission Milestones: GalliaPharm

Submission Milestone	Date
Submission filed	2019-05-15
Screening
Screening Deficiency Notice issued	2019-08-12
Response filed	2019-09-11
Screening Acceptance Letter issued	2019-10-25
Review
Clinical Evaluation complete	2020-07-28
Quality Evaluation complete	2020-08-06
Labelling Review complete, including Look-alike Sound-alike brand name assessment	2020-08-14
Review of Risk Management Plan pending as of	2020-08-19
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate	2020-08-19

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post‑market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken place for GalliaPharm?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for GalliaPharm is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
See the Patent Register for patents associated with medicinal ingredients, if applicable.
See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.

7 What was the scientific rationale for Health Canada's decision?

7.1 Quality Basis for Decision

Characterization of the Drug Substance

The gallium 68 (⁶⁸Ga) chloride solution is considered to be the drug substance. The parent nuclide, germanium 68 (⁶⁸Ge), decays in the generator to produce the ⁶⁸Ga radioactive isotope found in the eluate. Analytical methods used to evaluate parameters including the specific activity, identity, radionuclidic purity, and concentration activity of the germanium (⁶⁸Ge) chloride solution were all validated. The batch analysis data reflected consistency in the manufacturing process, and demonstrated that the drug substance met the relevant specifications.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

Drug Substance: Gallium (⁶⁸Ga) chloride solution

The gallium (⁶⁸Ga) chloride solution is considered to be the drug substance. In the GalliaPharm generator, ⁶⁸Ge decays to produce the ⁶⁸Ga radioactive isotope, which is found in the eluate.

Manufacturing of the germanium (⁶⁸Ge) chloride solution occurs through a process in which a target (gallium or a gallium/nickel alloy) is irradiated by a proton beam. The target is left to rest for a period of time to allow unwanted, short‑lived radionuclides to decay. The produced ⁶⁸Ge is then separated from macro quantities of stable gallium, nickel, or copper and long‑lived radionuclide by‑products. The separation of ⁶⁸Ge involves dissolution of the irradiated material, evaporation or filtration of the solution, adjustment of its concentration with hydrochloric acid, selective organic solvent extraction of ⁶⁸Ge, and re‑extraction of ⁶⁸Ge into water.

Drug Product: GalliaPharm generator

The radionuclide generator, GalliaPharm, is considered to be the drug product. It consists of a titanium dioxide column with adsorbed ⁶⁸Ge. The ⁶⁸Ge decays to its daughter nuclide ⁶⁸Ga, which is eluted in sterile ultrapure 0.1 mol/L hydrochloric acid to produce the gallium (⁶⁸Ga) chloride eluate.

The generator is manufactured under aseptic conditions. A pre‑assembled and sterilized titanium dioxide column is loaded with germanium (⁶⁸Ge) chloride solution. The column is embedded in a lead shield, and the column and shield are enclosed in a stainless steel case. Other components of the container closure system are also assembled aseptically. A set of accessories for elution is provided with the generator, to connect the generator to the container of hydrochloric acid and to collect the eluate produced from the generator.

Control of the Drug Substance and Drug Product

The control strategies for the germanium (⁶⁸Ge) chloride solution (parent nuclide solution of the active substance) and the GalliaPharm generator were all reviewed and validated. Each of these met the relevant acceptance criteria for in‑process controls and release testing. Batch analysis data were reviewed, and demonstrated consistency and reproducibility with respect to the established manufacturing processes and controls.

Stability of the Drug Substance and Drug Product

It is recommended that the germanium (⁶⁸Ge) chloride solution (the parent nuclide solution of the drug substance) be used within 3 months after delivery, based on the physical half‑life of ⁶⁸Ge. Other than the physical half‑life, no other instabilities are expected. There are no organic components that are susceptible to degradation, and microbiological contaminations are not expected as the drug substance is dissolved in sterile ultrapure 1.0 mol/L hydrochloric acid. The influence of ionising radiation on the container closure is negligible, as only short‑term storage (typically less than 3 months) is applied. A shelf life of 3 months was determined to be acceptable for the drug substance.

Stability tests of the GalliaPharm generator were designed to simulate real‑time, intermediate, and accelerated conditions, and assessed variables including chemical and radiochemical purity, γ‑emitting impurities, content of ⁶⁸Ga in the eluate, and sterility of the eluate. The generator must be stored at 15°C to 25°C. A shelf life of 12 months after the calibration date was determined to be acceptable based on the stability data reviewed. The shelf life of the sterile ultrapure 0.1 mol/L hydrochloric acid (used for elution) is 18 months. It is recommended that the eluate produced from the generator be used immediately after elution.

Facilities and Equipment

Good Manufacturing Practices (GMP) certificates were granted by the competent authority of Germany to the facilities responsible for manufacturing and sterility testing of the generator. A compliant rating was issued by Health Canada to the facility responsible for importing the generator following a GMP inspection.

Adventitious Agents Safety Evaluation

The gallium (⁶⁸Ga) chloride eluted from the GalliaPharm generator met specifications for sterility and bacterial endotoxin levels defined in a European Pharmacopeia monograph.

A microbiological challenge study was conducted according to guidelines in the European Pharmacopeia. No growth was observed in eluates from generators in which the columns had been loaded with microorganisms. The results demonstrated that the environment inside the generator (acidic pH and gamma radiation) does not promote microbial growth.

7.2 Non-Clinical Basis for Decision

The gallium (⁶⁸Ga) chloride eluted from the generator is not intended for direct administration to patients. The toxicological properties of the carrier molecule labelled with the eluate will depend on the nature of properties of the final radiolabelled drug product.

The sponsor submitted reports from a study conducted to estimate human radiation dosimetry in case of accidental injection, and to determine the potential of germanium 68 (⁶⁸Ge) breakthrough from the generator. This study characterized the absorption, distribution and elimination of ⁶⁸Ge and ⁶⁸Ga radionuclides following the intravenous injection of eluate into healthy Sprague‑Dawley rats. The injected gallium (⁶⁸Ga) chloride eluate cleared slowly from the blood and was eliminated in urine, with some retention in the liver. Residual radioactivity of ⁶⁸Ge was generally very low, with the highest levels found in the urine, liver, thyroid, and spleen. The amount of residual ⁶⁸Ge deposited in bone was a major concern, as it can lead to significant radiation dose over time. However, the amount of residual ⁶⁸Ge detected in bone was very low. Effective doses for humans were estimated by extrapolating from the data collected in rats, and the dose determined for women was slightly higher than the dose determined for men. This discrepancy has been attributed to the small sample size, and to the administration of the same radioactive dose to female and male rats, even with differences in body weight. Although extrapolating pharmacokinetic data from laboratory animals to humans has limitations caused by physiological differences and scaling, it is acceptable for estimating radiation absorbed doses in humans because the ⁶⁸Ge/⁶⁸Ga‑generator eluate is not intended for direct administration to patients.

The results of the study showed that the contribution of ⁶⁸Ge to the radiation burden was very low. The estimated human radiation burden due to the eluate is slightly higher than values determined for the intended ⁶⁸Ga‑labelled diagnostic radiopharmaceuticals like ⁶⁸Ga‑DOTA‑1‑NaI3‑octreotide (⁶⁸Ga‑DOTA‑NOC) and ⁶⁸Ga‑DOTA‑(Tyr³)‑octreotide (⁶⁸Ga‑DOTA‑TOC). This was attributed to the slower clearance of the eluate from the blood and its retention in the liver and spleen.

For more information, refer to the GalliaPharm Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Clinical basis for decision

The gallium (⁶⁸Ga) chloride eluate produced in the GalliaPharm generator is intended for the in vitro radiolabelling of specific carrier molecules (such as dodecane tetraacetic acid [DOTA]‑conjugated peptides) for diagnostic imaging with positron emission tomography (PET). The eluate is not intended for direct administration to patients. The pharmacology, efficacy, and safety of the generator are not determined by the gallium (⁶⁸Ga) chloride eluate, but by the clinical properties of the final radiolabelled drug product. Therefore, the clinical data submitted were minimal.

Clinical Safety

As with any diagnostic radiopharmaceutical, the proportion of unbound radionuclide is expected to be very low. Published data cited by the sponsor show that gallium is irreversibly complexed by DOTA (a commonly used chelator for binding radiometals to biomolecules). The amount of unbound ⁶⁸Ga following the administration of ⁶⁸Ga‑DOTA‑conjugated peptides is therefore not clinically relevant.

Accidental injection with the eluate is also a safety concern. Although there is no data available for the dosimetry of gallium (⁶⁸Ga) chloride in humans, it was estimated based on data collected in non‑clinical studies. Additionally, radiation dose estimates are available for gallium (⁶⁸Ga) citrate, and these estimates were based on human dosimetry data for gallium 67 (⁶⁷Ga) citrate, which is authorized for infection imaging. This information is considered sufficient to characterize the radiation risk to patients in the event of accidental exposure or unexpected higher levels of unbound ⁶⁸Ga in the ⁶⁸Ga‑labelled drug product. Both sets of radiation dose estimates are included in the labelling for the generator. Due to the short physical half‑life of ⁶⁸Ga, no specific action is required.