Summary Basis of Decision for Xofigo
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Xofigo is located below.
Recent Activity for Xofigo
SBDs written for eligible drugs 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. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Xofigo
Updated:
The following table describes post-authorization activity for Xofigo, a product which contains the medicinal ingredient radium Ra-223 dichloride. 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 that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02418398 - 1,100 KBq/mL, radium Ra-223 dichloride, solution, intravenous
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| NC # 234574 | 2019-12-18 | Issued NOL 2020-04-15 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to make a change to the container closure system for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 225598 | 2019-03-11 | Issued NOL 2019-08-01 | Submission filed as a Level II (120 day) Notifiable Change to update the PM to reflect revisions in the Company Core Data sheet. As a result of the NC, modifications were made to the Action and Clinical Pharmacology section and the References section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 219463 | 2018-08-23 | Issued NOL 2018-11-26 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change testing procedures for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued. |
| Dear Healthcare Professional Letter posted | Not applicable | Posted 2018-11-08 | Dear Healthcare Professional Letter posted, containing important safety information for healthcare professionals. |
| NC # 218307 | 2018-07-17 | Issued NOL 2018-09-28 | Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Warnings and Precautions sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| Drug product (DIN 02418398) market notification | Not applicable | Date of notification 2018-07-26 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. Date of first sale: 2014-05-08. |
| DIN 02418398 issued | Not applicable | DIN issued 2018-06-13 | DIN issued pursuant to section C.01.014.2(1) of the Food and Drug Regulations. |
| NC # 208285 | 2017-08-04 | Issued NOL 2017-11-28 | Submission filed as a Level II (120 day) Notifiable Change to update the PM to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Warnings and Precautions, Action and Clinical Pharmacolgy, Clinical Trials, and Special Handling Instructions sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 198397 | 2016-09-16 | Issued NOC 2017-04-18 | Submission filed as a Level I - Supplement for the approval of an alternate manufacturing site for the drug substance and drug product. There were no changes to the drug substance or the drug product specifications as a result of the proposed changes. The information was reviewed and considered acceptable. An NOC was issued. |
| NC # 195339 | 2016-05-19 | Issued No Objection Letter 2016-07-29 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacturing process for the drug substance and a modification of radioactive strength. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 193020 | 2016-03-02 | Issued Screening Rejection Letter 2016-03-15 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacturing process for the drug substance and a modification of radioactive strength. The submission was issued a Screening Rejection Letter as some of the changes filed were considered appropriate for an SNDS. However, upon further consideration, the sponsor was allowed to re-file the submission as an NC (# 195339) with additional data. |
| NC # 185061 | 2015-06-10 | Issued No Objection Letter 2015-09-18 | Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to make revisions with regard to the recent reassessment of the NIST (National Institute of Standards and Technology) standardization and the corresponding revision of the NIST standard reference material (SRM). Based on the revised NIST standardization, the values for the patient dose, product strength, and labelled vial activity were re‑calculated, and numerical changes were required for the labelled activity of Xofigo. As a result of this NC, the Product Monograph and labelling were revised to include the updated numerical value of the patient dose and radioactivity concentration of the Xofigo solution. This change does not affect the actual amount of radioactivity administered to the patient and therefore will not impact the safety or efficacy of Xofigo. The submission was reviewed and a No Objection Letter was issued. |
| NC# 184784 | 2015-05-25 | Issued No Objection Letter 2015-09-01 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to seek approval for changes in test sites for nitrate testing, chloride testing, and heavy metal testing as well as several minor changes to the testing process. There were no changes to the specifications for the drug substance or drug product. The supporting data for the proposed changes are considered satisfactory, and a No Objection Letter was issued. |
| NC # 182184 | 2015-02-17 | Issued No Objection Letter 2015-06-22 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to propose the inclusion of a new stopper supplied by West Pharma in place of the existing stopper in order to mitigate drug shortages caused by particulate matter in the final product. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. The Sponsor informed practitioners of the change through a Dear Health Care Professional Letter (DHCPL). |
| NDS # 161312 | 2013-01-03 | Issued NOC 2013-12-12 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Xofigo
Date SBD issued: 2014-03-04
The following information relates to the new drug submission for Xofigo.
Radium Ra 223 dichloride, 1,100 kBq/mL (27 microcurie/mL), solution of injection, intravenous
Drug Identification Number (DIN):
- Not Applicable
Bayer Inc.
New Drug Submission Control Number: 161312
On December 12, 2013, Health Canada issued a Notice of Compliance to Bayer Inc. for the radiopharmaceutical product Xofigo.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Xofigo is favourable for the treatment of patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease.
1 What was approved?
Xofigo, a therapeutic radiopharmaceutical, was authorized for the treatment of patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease. Xofigo contains the radioactive isotope radium 223 which as a substance can act in a manner similar to calcium, a major component of bones. Xofigo goes to where the cancer has spread in the bone and gives off radiation (alpha particles) which kills the tumor cells without major effects to the healthy cells.
Xofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo was approved for use under the conditions stated in the Xofigo Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Xofigo (1,100 kBq/mL, radium Ra 223 dichloride) is presented as a solution for injection. In addition to the medicinal ingredient, the solution for injection contains hydrochloric acid, sodium chloride, sodium citrate, and water for injection.
For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Xofigo Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Xofigo approved?
Health Canada considers that the benefit/risk profile of Xofigo is favourable for the treatment of patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease.
Prostate cancer is the most common non-cutaneous malignancy in men worldwide. Prostate cancer is unique amongst solid tumors in that the greatest threat to a patient's survival and quality of life is posed by bone metastases rather than visceral involvement. Indeed, nearly all treatments are directed toward eradicating or limiting osseous metastases or palliating its side effects.
Xofigo has been shown to be efficacious in the treatment of patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease. The market authorization was based on a pivotal Phase III study and results that figured significantly in Health Canada's evaluation of the safety and efficacy of the product.
Although the most commonly reported treatment emergent adverse event (TEAE) is bone pain, it was observed more frequent in the placebo group (62%) than the therapy group (50%). Other commonly reported treatment emergent adverse events were nausea, anemia, fatigue, and diarrhea. Discontinuation of treatment due to adverse events occurred in 17% of patients on Xofigo and 21% of patients who received placebo.
Bone marrow suppression was observed for patients treated with Xofigo and is listed in the Serious Warnings and Precautions Box of the Xofigo Product Monograph. Hematological evaluation of the patient must, therefore, be performed at baseline and prior to every dose of Xofigo. Additionally, radiopharmaceuticals should be administered only by health professionals who are appropriately qualified for the use of radioactive prescribed substances in or on humans.
A Risk Management Plan (RMP) for Xofigo was submitted by Bayer Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
Overall, the therapeutic benefits seen in the pivotal study adequately established the clinical efficacy for the proposed use. Xofigo has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety concerns are listed in a Serious Warnings and Precautions Box in the Xofigo Product Monograph. Further evaluation will take place upon the submission of the requested studies after they become available.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 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 Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Xofigo?
Submission Milestones: Xofigo
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2012-04-11 |
| Submission filed: | 2013-01-03 |
| Screening | |
| Screening Acceptance Letter issued: | 2013-02-15 |
| Review | |
| Quality Evaluation complete: | 2013-11-22 |
| Clinical Evaluation complete: | 2013-12-06 |
| Labelling Review complete: | 2013-12-11 |
| Notice of Compliance (NOC) issued by Director General: | 2013-12-12 |
The Canadian regulatory decision on the clinical review of Xofigo was based on a critical assessment of the Canadian data package. Foreign reviews completed by the United States Food and Drugs Administration (FDA) were used as an added reference.
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.
In addition to the requirements outlined in the Food and Drugs Act and Regulations, the sponsor previously agreed to undertake future studies as requested by the United States FDA; further to the commitments listed below, data and information from such studies will also be available to Health Canada.
- An observational study [number (n) = 1,200] to assess the long-term safety of radium Ra 223 dichloride 50 kBq/kg every 4 weeks for 6 doses in patients with castration-resistant prostate cancer with bone metastases.
- A randomized clinical study to assess the safety of radium Ra 223 dichloride in patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.
- A study of short and long-term safety of re-treatment of patients with castration-resistant prostate cancer and bone metastases with radium Ra 223 dichloride.
- A study to optimize the dosing regimen of Xofigo by conducting a randomized Phase II clinical study to evaluate the efficacy and safety of Xofigo at a dose higher than 50 kBq/kg in patients with castration-resistant prostate cancer with bone metastases. Depending on the results of the Phase II study, a randomized Phase III study may be needed to further confirm the appropriateness of the dosing regimen determined in the Phase II study.
The data and information resulting from the studies noted above is anticipated to be submitted to Health Canada as a Supplemental New Drug Submission (SNDS) for review.
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 and have been market notified (that is, the company has told Health Canada the product is being marketed).
- 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 Clinical basis for decision
Clinical Pharmacology
Prostate cancer is the most common non-cutaneous malignancy in men worldwide. Prostate cancer is unique amongst solid tumors in that the greatest threat to a patient's survival and quality of life is posed by bone metastases rather than visceral involvement.
Radium Ra 223 dichloride is a therapeutic alpha particle-emitting radiopharmaceutical. The active moiety is the isotope radium-223 (as radium Ra 223 dichloride) that mimics calcium and selectively targets bone, specifically areas of bone metastases, by forming complexes with the bone mineral hydroxyapatite. The high linear energy transfer of alpha emitters (80 keV/micrometre) leads to a high frequency of double-strand DNA breaks in adjacent cells, resulting in a localized anti-tumor effect on bone metastases. The fraction of energy emitted as alpha particles is about 95%, with β-particles and γ-rays accounting for approximately 5%.
The pharmacokinetics and biodistribution data were obtained from three Phase I studies. The majority of the data was obtained from two studies, on was conducted in 6 patients [from two separate injections (6 weeks apart) at a dose of 100 kBq/kg BW] and the other in 10 patients (at a dose of 50, 100 or 200 kBq/kg BW). Biodistribution was assessed based on whole body gamma counts and whole body images acquired in gamma energy windows of radium Ra 223.
Xofigo (radium Ra 223 dichloride) is incorporated primarily into bone or is secreted into the intestine. No significant uptake was seen in other organs such as heart, liver, kidneys, urinary bladder, and spleen at 4 hours post injection. The volume of distribution was estimated as being higher than the blood volume, indicative of distribution to peripheral compartments.
Based on the data submitted, the injected activity remaining in the blood is 20% at 15 minutes, 4% at 4 hours and less than 1% at 24 hours post-injection. The level of activity in the bone was determined to be in the range of 44% to 77% at 4 hours post injection. In the intestine, activity was already observed 10 minutes post injection, and the level of activity was in the range of 19% to 69% at 4 hours post injection. Fecal excretion was the major route of elimination from the body. Based on radioactivity excreted in urine, renal elimination is a minor route.
For further details, please refer to the Xofigo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Study BC1 06 (ALSYMPCA - ALpharadin in SYMptomatic Prostate CAncer) was a single pivotal Phase III, randomized, double-blind, placebo-controlled international study conducted in patients with symptomatic castration-resistant prostate cancer (CRPC) that had metastasized to the bone. atients were randomized 2:1 to receive either radium-223 dichloride (50 kBq/kg BW) plus best standard of care (BSoC) or placebo plus BSoC. Patients of either group received 6 intravenous administrations, each separated by an interval of 4 weeks.
The primary endpoint of the study was overall survival (OS). Secondary endpoints included changes and time to progression in levels of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), time to occurrence of skeletal-related events (SRE), safety and impact on quality of life and health economics. The main secondary efficacy endpoints were analyzed using a statistical methodology which controlled the Type 1 error rate. Enrollment in the study was completed with 921 randomized patients.
The study's independent data monitoring committee (IDMC) evaluated the efficacy and safety of the data from a planned interim analysis which was performed after approximately 50% of the required endpoint events (that is deaths) were observed. At the interim analysis, 314 deaths had occurred. Based on the pre-specified O'Brien-Fleming-type alpha spending function, the two sided alpha level for the interim analysis was 0.00275. The result obtained showed that treatment with Alpharadin had a statistically significant effect on the overall survival (p-value = 0.00185). This p-value was below the pre-specified threshold level of significance required to declare the primary endpoint met.
This led to IDMC's recommendation for early termination of the study for efficacy superiority. Therefore, the interim analysis is considered the definitive analysis for efficacy and constitutes the primary evidence that Xofigo prolongs OS. The results from the pre-planned interim analysis in Study BC1 06 showed a statistically significant prolongation of OS in CRPC patients with bone metastases and without known visceral metastases, treated with Xofigo; the survival results were supported by a delay in the time to first on-study symptomatic skeletal event (SSE), a composite, clinically meaningful secondary endpoint which favoured the Xofigo arm. Based on the significant benefit of Xofigo treatment over placebo, the IDMC recommended the study be concluded and unblinded early and patients in the placebo arm be offered a full course of Xofigo.
For more information, refer to the Xofigo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of Xofigo has been evaluated in a double-blind, randomized, multiple dose, placebo-controlled, multicenter, Phase III study (ALSYMPCA) in castration-resistant prostate cancer patients with symptomatic bone metastases. Safety is based on 901 patients treated with either radium-223 dichloride [number (n) = 600] or placebo (n = 301). The dose of Xofigo administered intravenously was 50 kBq/kg body weight scheduled at 4 week intervals for up to 6 injections, compared to matching placebo.
In the pivotal study, all randomized patients constituted the intent-to-treat (ITT) population (n = 921). The most common reason for early withdrawal was death in both treatment groups (39.4% Xofigo; 46.3% placebo). Adverse events (AEs) accounted for patient withdrawals in 4.6% of Xofigo and 7.2% of placebo patients. For the safety population (n = 901) a total of 93% (558/600) patients in the Xofigo group and 96.3% (290/301) in the placebo group reported at least one treatment emergent adverse event (TEAEs). A smaller proportion of patients in the Xofigo arm (46.8%, 281/600) experienced serious TEAEs than in the placebo arm (60.1%, 181/301).
The most commonly reported TEAEs [greater than or equal to (≥) 25% in either group] were bone pain (50.0% Xofigo; 62.1% placebo), nausea (35.5% Xofigo; 34.6% placebo), anemia (31.2% Xofigo; 30.6% placebo), fatigue (25.7% Xofigo; 25.6% placebo) and diarrhea (25.2% Xofigo; 15.0% placebo).
Haematological events were typically higher in the Xofigo group than the placebo group. The Grade 3 - 4 AEs in the Xofigo treatment arm compared to placebo were anemia [12.8% versus (vs.) 13.0%], thrombocytopenia (6.3% vs. 2.0%; respectively), neutropenia (2.2% vs. 0.7%; respectively), leukopenia (1.3% vs. 0.3%; respectively), and pancytopenia (1.2% vs. 0.0%; respectively).
The radiation exposure from Xofigo treatment may be associated with an increased risk of cancer and hereditary defects. No cases of XOFIGO-induced cancer, including sarcomas of the bone, have been reported in clinical trials in follow-up of up to three years but the expected latency period for the development of secondary solid malignancies greatly exceeds the duration of follow-up for patients in the trial.
Discontinuation of treatment due to AEs occurred in 16.5% of patients in the Xofigo treatment arm and 20.6% in the placebo treatment arm. There was also an increase in discontinuations due to bone marrow suppression in Xofigo-treated patients compared to placebo-treated patients (4.0% vs. 2.0%; respectively); in addition to discontinuations due to metastases to non-skeletal sites (1.1% vs. 0.3%). Xofigo was not evaluated for theeatment of visceral metastatic prostate cancer.
There were 518 deaths reported in the safety population during the study: 54.5% (327/600) in the Xofigo treatment group and 63.5% (191/301) in the placebo treatment group. These deaths were due to disease progression in 48.2% of the Xofigo treated-patients and 49.5% in the placebo-treated patients. Between 24-weeks to <1 year of initiating treatment, 22.2 % of patients [number (n) = 133] in the Xofigo treatment group died compared to 25.6% (n = 77) in the placebo treatment group. The most common AEs with an outcome of death were related to progression of disease on both arms (8.8% vs. 11% in the Xofigo and placebo arms respectively). Approximately, one-third of deaths in each treatment group were associated with a TEAE [96/327 reported deaths in the Xofigo group and 67/191 reported deaths in the placebo group; or per safety population, 16.0% (96/600) in Xofigo, 22.3% (67/301) in placebo arms]. Death was considered possibly or probably related to treatment in 1.3% (n = 8) deaths in Xofigo group (0.3% (n = 1) in placebo).
Overall, Xofigo was generally well-tolerated and appropriate warnings and precautions are in place in the approved Xofigo Product Monograph to address the identified safety concerns.
For more information, refer to the Xofigo Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Pharmacodynamic studies demonstrated that during decay of Radium Ra 223, Xofigo radiation is an effective cell killer, with no dose rate effect from alpha particles and a minimal dose rate effect due to the small amount of β-particles. The underlying mode of action is the induction of double strand breaks in the deoxyribonucleic acid (DNA) molecule. In addition to this direct cytotoxic effect, inhibition of osteoclast differentiation and osteoblast activity likely accounts for, in part, the in vivo efficacy.
Administration of Xofigo to mice, rats and dogs resulted in treatment-related findings across all toxicology studies which were attributable to radiobiological toxicity. Treatment-related osteosarcomas were observed in rats, with an increase in incidence noted after repeated administration.
Genotoxicity and carcinogenicity studies were not conducted since the radioactive properties and primary mode of action of alpha-emitting isotopes (direct damage to DNA) are sufficient to characterize it as genotoxic and, accordingly, may increase the incidence of carcinogenicity. No specific reproductive or developmental toxicity studies were conducted.
There were no signals for unexpected toxicities and it was concluded that the non-clinical studies adequately support the safety of Xofigo by intravenous injection in castration-resistant prostate cancer with bone metastases.
For more information, refer to the Xofigo Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Xofigo (Radium Ra 223 dichloride) offers a unique mode of action as an alpha-particle-emitting therapeutic radiopharmaceutical, differing from both beta-emitters (emitter of beta radiation), and other systemic treatments which tend to be either anti-hormonal or chemotherapeutic agents. Alpha-emitting radiopharmaceuticals represent a new class of cancer therapy for the treatment of patients with symptomatic castration-resistant prostate cancer with bone metastases. Unlike beta-emitting radiopharmaceuticals, alpha-pharmaceuticals have a more localized action and are much more potent, causing double-strand DNA breaks leading to cell death.
Radium Ra 223, the active moiety, is a calcium mimic and an alpha-emitter targeting areas with increased bone formation such as skeletal metastases. With its relatively long half-life, 11.4 days, this radiopharmaceutical has a four week shelf-life allowing for worldwide use.
Based on the review of the Quality data submitted, Bayer Inc. has provided adequate evidence to support the consistent manufacture of Xofigo, of acceptable quality.
Characterization of the Drug Substance
The active moiety of the radium-223 dichloride is 223Ra2+. Potential other chemical forms are metallic radium or ions with different valence than 2+: however, it is known from literature that the heavier alkaline earth metals, and thus radium, will only exist in one oxidation state (2+) in an aqueous solution. Based on this, it is concluded that radium-223 will always be present as divalent cations (223Ra2+) in the drug substance solution.
Literature sources and the various studies performed have demonstrated that free radium-223 in solution will always be present as divalent cations (223Ra2+) and the weak association with the counter ions present in the solution does not affect the chemical properties of 223Ra2+. Therefore, a radiochemical test to identify and quantify the amount of radium-223 existing as free 223Ra2+ is not considered to add any quality indicating value and is accordingly not included in the drug substance and drug product specifications.
The only organic solvent used during production is methanol in the drug substance production process. Methanol is specified in the drug substance specification with not more than 1,000 parts per million (ppm), which is more stringent than the International Conference on Harmonisation (ICH) Guideline Q3C "Impurities: Residual Solvents" limit of not more than 3,000 ppm.
No organic solvents are used during manufacture of the excipients and the drug product.
The medicinal product complies with the requirements of the ICH Guideline Q3C "Impurities: Residual Solvents".
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The manufacturing process of the drug substance consists of a series of stages which include in-growth of radium-223, evaporation to dryness, dissolution, radium-223 separation, actinium-227 recovery, numerous purification steps for radium-223, dilution and mixing. The manufacturing process of the drug product consists of a series of stages which include dilution of the drug substance and mixing, filling into vials and finally terminal sterilization by autoclaving. All containers, tubing and resins in the production process in contact with the drug substance are single-use disposables.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the Radium Ra 223 dichloride with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with International Conference on Harmonisation (ICH) guidelines.
Stability of the Drug Substance and Drug Product
The holding time stability data from pilot scale and production scale batches support the drug substance holding time of seven days at ambient room temperature and humidity conditions in the drug substance dedicated production cell.
The stability profile of the production scale batches is comparable with the stability profile of the pilot scale batches.
The drug substance solution remains stable under the test conditions for seven days.
The stability data support the drug product shelf life of 28 days in all climatic zones, when stored at room temperature below 40°C.
Facilities and Equipment
The separation and purification to form the drug substance solution is performed in a dedicated manufacturing line for radium-223 dichloride drug substance solution and drug product. The operation takes place inside dedicated lead shielded containments (for radiation protection reasons) in controlled areas [classified according to current Good Manufacturing Practices (cGMP) and radiation protection regulations].
The production of the drug product is performed in a dedicated manufacturing line for radium-223 (clean room and classified according to cGMP and radiation protection regulations).
The clean rooms and environmental control for the production of drug substance and drug product are qualified in accordance with the European Union and United States of America Good Manufacturing Practices (GMP) standards for clean room. Tests are performed at rest and in operation for viable and non-viable particles. This evaluation was considered acceptable by Health Canada; therefore no on-site evaluation was conducted.
Adventitious Agents Safety Evaluation
All substances used in the manufacturing process of radium-223 dichloride solution for injection have been assessed with respect to potential risks associated with the transmission of spongiform encephalopathies (TSE) according to the "Note for guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products" (EMA/410/01).
No materials of animal or human origin are used during the manufacture of the drug substance and the drug product.
Some of the materials used in the production equipment are manufactured with tallow derivatives as processing aids. The manufacturers certified that these tallow derivatives are category 3 materials and have undergone rigorous steps during manufacturing, and thus meet the requirements of the European Guideline "Note for guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products" (EMA/410/01), section 6.4, Tallow Derivatives. Therefore, radium-223 dichloride solution for injection can be regarded as safe with respect to TSE according to the European guideline.