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| 2 | 7.1 | 17 | Drug Substance | 3.2.S.1 General Information ([1-13C]pyruvic acid) The active ingredient in Hyperpolarized Pyruvate (13C) Injection is hyperpolarized [1-13C]pyruvate. The drug substance is defined as [13C]pyruvic acid, which is neutralized to [1-13C]pyruvate during the compounding process. In several pre-clinical and clinical studies and during evaluation of stability, pyruvic acid has been used instead of [1-13C]pyruvic acid (see Sections 3.2.P.2.2.1 Formulation Development for Hyperpolarized Pyruvate (13C) Injection and Section 8.1 Introduction for Item 8 Pharmacology and Toxicology Info). In the Section 3.2.S Drug Substance, data are presented for both pyruvic acid and for [1-13C]pyruvic acid. For simplicity, the terminology used in headings and captions is [1-13C]pyruvic acid. Batches containing pyruvic acid are specified by footnotes. 3.2.S.1.1 Nomenclature ([1-13C]pyruvic acid) The drug substance used for compounding of Hyperpolarized Pyruvate (13C) Injection is [1-13C]pyruvic acid. Company code: W6578 Chemical name: [1-13C]pyruvic acid CAS registry number: 127-17-3 3.2.S.1.2 Structure ([1-13C]pyruvic acid) Figure 1 Structure of [1-13C]pyruvic acid Molecular formula: C H O 3 4 3 Molecular weight: 89.06 3.2.S.1.3 General Properties ([1-13C]pyruvic acid) Appearance: Colorless to yellow, clear, viscous liquid pKa:Ka:aranWater solubility: Complete The structure of [1-13C]pyruvic acid has been confirmed by spectroscopic analysis (see Section 3.2.S.3.1 Elucidation of Structure and other Characteristics). |
| 3 | 7.2 | 28 | Drug Product Part 1 | 3.2.P DRUG PRODUCT (STERILE FLUID PATH COMPONENTS) Hyperpolarized Pyruvate (13C) Injection (drug product) is a sterile solution for intravenous injection. The compounding of Hyperpolarized Pyruvate (13C) Injection is performed by an automated compounding device known as SpinLab. For each patient dose, SpinLab utilizes a single sterile fluid path which contains the following three drug product components: • Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt • TRIS/EDTA buffer solution • Sterile Water for Injection (WFI) The following 3.2.P sections describe the individual drug product components. For aspects related to the compounding of the drug product, Hyperpolarized Pyruvate (13C) Injection, reference is made to 3.2.P for Hyperpolarized Pyruvate (13C) Injection. Commercially available USP quality Sterile Water for Injection (Hospira Inc., USA) is provided by the clinical site. Aspects of this drug product component will therefore not be addressed. |
| 4 | 3.2.P.2.1 | 29 | Components of the Drug Product (Drug Product Kit Components) | 3.2.P.2.1.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt (a) Drug substance The drug substance, [1−13C]pyruvic acid, is a colorless to yellow, clear, viscous liquid. [1−13C]Pyruvic acid is described in Section 3.2.S Drug Substance. Upon neutralization in the TRIS/EDTA buffer solution, the [1−13C]pyruvic acid is converted to [1−13C]pyruvate. (b) Excipients AH111501 sodium salt is a stable trityl radical, and is added to [1−13C]pyruvic acid to enable hyperpolarization. AH111501 sodium salt is a green to black, fine to granular powder. AH111501 sodium salt is further described in Section 3.2.A.3 Novel Excipients. 3.2.P.2.1.2 TRIS/EDTA buffer solution The TRIS/EDTA buffer solution is an aqueous solution containing 333 mM TRIS, 600 mM NaOH and 333 mg/l Na EDTA. 2 TRIS is used as buffer to stabilize the pH of the Hyperpolarized Pyruvate (13C) Injection at a physiologically acceptable level. NaOH is added to neutralize the [1−13C]pyruvic acid in Mixture of [1−13C]pyruvic acid and 15 |
| 5 | 3.2.P.2.2 | 30 | Drug Product (Drug Product Kit Components) | 3.2.P.2.2.1 Formulation Development (a) Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is dissolved in WFI and neutralized/buffered in TRIS/EDTA buffer solution to form a solution with a physiologically acceptable pH. The concentration of AH111501 sodium salt of 15 mM has been chosen for optimization of 13C nuclear polarization in Hyperpolarized Pyruvate (13C) Injection. For clinical trials GE-101-001 and GE-101-003, pyruvic acid was used instead of [1-13C]pyruvic acid. For these trials the Pyruvate Injection was not compounded hence; in order to mimic the maximum content of AH111501 in Hyperpolarized Pyruvate (13C) Injection, the kit component used during the clinical trials GE-101-001 and GE 101-003 was Mixture of pyruvic acid and 0.2 mM AH111501 sodium salt. In addition, some pre-clinical studies were performed using pyruvic acid instead of [1- 13C]pyruvic acid. See Section 3.2.P.2.2.1 Formulation development for Hyperpolarized Pyruvate (13C) Injection and section 8.1 Introduction for Item 8 Pharmacology and Toxicology Info) for further details. The amount of [1-13C]pyruvic acid and AH111501 sodium salt mixture per cryovial is 1.47 g, which upon dissolution in the total volume of WFI and TRIS/EDTA buffer solution, gives 250 mM [1- 13C]pyruvate in the final Hyperpolarized Pyruvate (13C) Injection. (b) TRIS/EDTA buffer solution The function of TRIS/EDTA buffer solution is to neutralize the [1-13C]pyruvic acid to [1- 13C]pyruvate and to assure a physiologically acceptable pH of the drug product Hyperpolarized Pyruvate (13C) Injection. TRIS/EDTA buffer solution has not been used during pre-clinical studies or during clinical trials GE-101-001 and GE-101-003. For these studies, the Mixture of [1-13C]pyruvic acid and AH111501 sodium salt was dissolved in a single, manual step in TRIS/EDTA dissolution medium. For compounding of Hyperpolarized Pyruvate (13C) Injection, the Mixture of [1- 13C]pyruvic acid and 15 mM AH111501 sodium salt will first be dissolved in WFI and then neutralized and buffered in TRIS/EDTA buffer solution. See Section 3.2.P.2.2.1 Formulation Development for Hyperpolarized Pyruvate (13C) Injection for details. The amount of [1-13C]pyruvic acid to be dissolved is 1.67 g (equivalent to 18.75 mmol). This amount of acid is neutralized and buffered with 22.5 ml of TRIS/EDTA buffer solution (equivalent to 8.33 mmol of TRIS and 15.00 mmol of NaOH) to a target pH of 7.6 (at 37°C) in the Hyperpolarized Pyruvate (13C) Injection. Sample not for submission mM AH111501 sodium salt to [1−13C]pyruvate in the Hyperpolarized Pyruvate (13C) Injection. Na EDTA has been included in the formulation as a chelating agent to capture traces of 2 paramagnetic metal ions that might be present. 3.2.P.2.2 Drug Product (Drug Product Kit Components) 3.2.P.2.2.1 Formulation Development (a) Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is dissolved in WFI and neutralized/buffered in TRIS/EDTA buffer solution to form a solution with a physiologically acceptable pH. The concentration of AH111501 sodium salt of 15 mM has been chosen for optimization of 13C nuclear polarization in Hyperpolarized Pyruvate (13C) Injection. For clinical trials GE-101-001 and GE-101-003, pyruvic acid was used instead of [1-13C]pyruvic acid. For these trials the Pyruvate Injection was not compounded hence; in order to mimic the maximum content of AH111501 in Hyperpolarized Pyruvate (13C) Injection, the kit component used during the clinical trials GE-101-001 and GE 101-003 was Mixture of pyruvic acid and 0.2 mM AH111501 sodium salt. In addition, some pre-clinical studies were performed using pyruvic acid instead of [1- 13C]pyruvic acid. See Section 3.2.P.2.2.1 Formulation development for Hyperpolarized Pyruvate (13C) Injection and section 8.1 Introduction for Item 8 Pharmacology and Toxicology Info) for further details. The amount of [1-13C]pyruvic acid and AH111501 sodium salt mixture per cryovial is 1.47 g, which upon dissolution in the total volume of WFI and TRIS/EDTA buffer solution, gives 250 mM [1- 13C]pyruvate in the final Hyperpolarized Pyruvate (13C) Injection. (b) TRIS/EDTA buffer solution The function of TRIS/EDTA buffer solution is to neutralize the [1-13C]pyruvic acid to [1- 13C]pyruvate and to assure a physiologically acceptable pH of the drug product Hyperpolarized Pyruvate (13C) Injection. TRIS/EDTA buffer solution has not been used during pre-clinical studies or during clinical trials GE-101-001 and GE-101-003. For these studies, the Mixture of [1-13C]pyruvic acid and AH111501 sodium salt was dissolved in a single, manual step in TRIS/EDTA dissolution medium. For compounding of Hyperpolarized Pyruvate (13C) Injection, the Mixture of [1- 13C]pyruvic acid and 15 mM AH111501 sodium salt will first be dissolved in WFI and then neutralized and buffered in TRIS/EDTA buffer solution. See Section 3.2.P.2.2.1 Formulation Development for Hyperpolarized Pyruvate (13C) Injection for details. The amount of [1-13C]pyruvic acid to be dissolved is 1.67 g (equivalent to 18.75 mmol). This amount of acid is neutralized and buffered with 22.5 ml of TRIS/EDTA buffer solution (equivalent to 8.33 mmol of TRIS and 15.00 mmol of NaOH) to a target pH of 7.6 (at 37°C) in the Hyperpolarized Pyruvate (13C) Injection. Sample not for submission 3.2.P.2.2.2 Overages (a) Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt There are no overages included in the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt. (b) TRIS/EDTA buffer solution There are no overages included in the TRIS/EDTA buffer solution. 3.2.P.2.3 Manufacturing Process Development (Drug Product Kit Components) 3.2.P.2.3.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Terminal sterilization of the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is not possible due to degradation of [1-13C]pyruvic acid. The current process is therefore performed by aseptic processing. 3.2.P.2.3.2 TRIS/EDTA buffer solution Terminal sterilization of TRIS/EDTA buffer solution in various container closure systems has been tested, but generation of particles occurred during sterilization. This is probably caused by the high pH of the TRIS/EDTA buffer solution. The current process is therefore performed by aseptic processing. 3.2.P.2.4 Container Closure System (Sterile Fluid Path Components) 3.2.P.2.4.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The compounding process for Hyperpolarized Pyruvate (13C) Injection requires a custom made container closure system, the sterile fluid path, for the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt. This container closure system is described in more detail in Section 3.2.P.7 Container Closure System. 3.2.P.2.4.2 TRIS/EDTA buffer solution The compounding process for Hyperpolarized Pyruvate (13C) Injection requires a custom made container closure system, the sterile fluid path, for the TRIS/EDTA buffer solution. This container closure system is described in more detail in Section 3.2.P.7 Container Closure System. 3.2.P.2.5 Microbiological Attributes (Sterile Fluid Path Components) 3.2.P.2.5.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Not applicable. The mixture of [1-13C]pyruvic acid and 15 mM AH111501 is compounded immediately prior to patient administration. A sample of the final Hyperpolarized Pyruvate (13C) Injection is tested for |
| 6 | 3.2.P.2.3 | 31 | Manufacturing Process Development (Drug Product Kit Components) | 3.2.P.2.3.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Terminal sterilization of the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is not possible due to degradation of [1-13C]pyruvic acid. The current process is therefore performed by aseptic processing. 3.2.P.2.3.2 TRIS/EDTA buffer solution Terminal sterilization of TRIS/EDTA buffer solution in various container closure systems has been tested, but generation of particles occurred during sterilization. This is probably caused by the high pH of the TRIS/EDTA buffer solution. The current process is therefore performed by aseptic processing. Sample not for submission 3.2.P.2.2.2 Overages (a) Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt There are no overages included in the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt. (b) TRIS/EDTA buffer solution There are no overages included in the TRIS/EDTA buffer solution. 3.2.P.2.3 Manufacturing Process Development (Drug Product Kit Components) 3.2.P.2.3.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Terminal sterilization of the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is not possible due to degradation of [1-13C]pyruvic acid. The current process is therefore performed by aseptic processing. 3.2.P.2.3.2 TRIS/EDTA buffer solution Terminal sterilization of TRIS/EDTA buffer solution in various container closure systems has been tested, but generation of particles occurred during sterilization. This is probably caused by the high pH of the TRIS/EDTA buffer solution. The current process is therefore performed by aseptic processing. 3.2.P.2.4 Container Closure System (Sterile Fluid Path Components) 3.2.P.2.4.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The compounding process for Hyperpolarized Pyruvate (13C) Injection requires a custom made container closure system, the sterile fluid path, for the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt. This container closure system is described in more detail in Section 3.2.P.7 Container Closure System. 3.2.P.2.4.2 TRIS/EDTA buffer solution The compounding process for Hyperpolarized Pyruvate (13C) Injection requires a custom made container closure system, the sterile fluid path, for the TRIS/EDTA buffer solution. This container closure system is described in more detail in Section 3.2.P.7 Container Closure System. 3.2.P.2.5 Microbiological Attributes (Sterile Fluid Path Components) 3.2.P.2.5.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Not applicable. The mixture of [1-13C]pyruvic acid and 15 mM AH111501 is compounded immediately prior to patient administration. A sample of the final Hyperpolarized Pyruvate (13C) Injection is tested for Sample not for submission sterility and pyrogenicity subsequent to patient administration. 3.2.P.2.5.2 TRIS/EDTA buffer solution Not applicable The TRIS/EDTA buffer solution is compounded immediately prior to patient administration. A sample of the final Hyperpolarized Pyruvate (13C) Injection is tested for sterility and pyrogenicity subsequent to patient administration. 3.2.P.3.1 Manufacturer(s) (Sterile Fluid Path Components) 3.2.P.3.1.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The compounding of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt for clinical use is conducted in accordance with compliance of USP <797> and the regulations promulgated by the California State Board of Pharmacy at the licensed pharmacy on the following academic campus: University of California, San Francisco Department of Clinical Pharmacy San Francisco, California 94118 3.2.P.3.1.2 TRIS/EDTA buffer solution The compounding of TRIS/EDTA buffer solution for clinical use is conducted in accordance with compliance of USP <797> and the regulations promulgated by the California State Board of Pharmacy at the licensed pharmacy on the following academic campus: University of California, San Francisco Department of Clinical Pharmacy San Francisco, California 94118 3.2.P.3.2 Single Dose Compounding Formula (Sterile Fluid Path Components) 3.2.P.3.2.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is compounded by aseptic processing. The compounding formula for a single dose prepared immediately prior to patient administration is given in Table 1. Table 1 Compounding formula for Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Ingredient Quantity per container [1-13C]pyruvic acid 1.44 g AH111501 sodium salt 27.7 mg |
| 7 | 3.2.P.2.4 | 31 | Container Closure System (Sterile Fluid Path Components) | 3.2.P.2.4.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The compounding process for Hyperpolarized Pyruvate (13C) Injection requires a custom made container closure system, the sterile fluid path, for the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt. This container closure system is described in more detail in Section Sample not for submission 3.2.P.2.2.2 Overages (a) Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt There are no overages included in the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt. (b) TRIS/EDTA buffer solution There are no overages included in the TRIS/EDTA buffer solution. 3.2.P.2.3 Manufacturing Process Development (Drug Product Kit Components) 3.2.P.2.3.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Terminal sterilization of the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is not possible due to degradation of [1-13C]pyruvic acid. The current process is therefore performed by aseptic processing. 3.2.P.2.3.2 TRIS/EDTA buffer solution Terminal sterilization of TRIS/EDTA buffer solution in various container closure systems has been tested, but generation of particles occurred during sterilization. This is probably caused by the high pH of the TRIS/EDTA buffer solution. The current process is therefore performed by aseptic processing. 3.2.P.2.4 Container Closure System (Sterile Fluid Path Components) 3.2.P.2.4.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The compounding process for Hyperpolarized Pyruvate (13C) Injection requires a custom made container closure system, the sterile fluid path, for the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt. This container closure system is described in more detail in Section 3.2.P.7 Container Closure System. 3.2.P.2.4.2 TRIS/EDTA buffer solution The compounding process for Hyperpolarized Pyruvate (13C) Injection requires a custom made container closure system, the sterile fluid path, for the TRIS/EDTA buffer solution. This container closure system is described in more detail in Section 3.2.P.7 Container Closure System. 3.2.P.2.5 Microbiological Attributes (Sterile Fluid Path Components) 3.2.P.2.5.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Not applicable. The mixture of [1-13C]pyruvic acid and 15 mM AH111501 is compounded immediately prior to patient administration. A sample of the final Hyperpolarized Pyruvate (13C) Injection is tested for Sample not for submission sterility and pyrogenicity subsequent to patient administration. 3.2.P.2.5.2 TRIS/EDTA buffer solution Not applicable The TRIS/EDTA buffer solution is compounded immediately prior to patient administration. A sample of the final Hyperpolarized Pyruvate (13C) Injection is tested for sterility and pyrogenicity subsequent to patient administration. 3.2.P.3.1 Manufacturer(s) (Sterile Fluid Path Components) 3.2.P.3.1.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The compounding of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt for clinical use is conducted in accordance with compliance of USP <797> and the regulations promulgated by the California State Board of Pharmacy at the licensed pharmacy on the following academic campus: University of California, San Francisco Department of Clinical Pharmacy San Francisco, California 94118 3.2.P.3.1.2 TRIS/EDTA buffer solution The compounding of TRIS/EDTA buffer solution for clinical use is conducted in accordance with compliance of USP <797> and the regulations promulgated by the California State Board of Pharmacy at the licensed pharmacy on the following academic campus: University of California, San Francisco Department of Clinical Pharmacy San Francisco, California 94118 3.2.P.3.2 Single Dose Compounding Formula (Sterile Fluid Path Components) 3.2.P.3.2.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is compounded by aseptic processing. The compounding formula for a single dose prepared immediately prior to patient administration is given in Table 1. Table 1 Compounding formula for Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Ingredient Quantity per container [1-13C]pyruvic acid 1.44 g AH111501 sodium salt 27.7 mg |
| 8 | 3.2.P.2.5 | 31 | Microbiological Attributes (Sterile Fluid Path Components) | 3.2.P.2.5.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Not applicable. The mixture of [1-13C]pyruvic acid and 15 mM AH111501 is compounded immediately prior to patient administration. A sample of the final Hyperpolarized Pyruvate (13C) Injection is tested for Sample not for submission 3.2.P.2.2.2 Overages (a) Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt There are no overages included in the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt. (b) TRIS/EDTA buffer solution There are no overages included in the TRIS/EDTA buffer solution. 3.2.P.2.3 Manufacturing Process Development (Drug Product Kit Components) 3.2.P.2.3.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Terminal sterilization of the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is not possible due to degradation of [1-13C]pyruvic acid. The current process is therefore performed by aseptic processing. 3.2.P.2.3.2 TRIS/EDTA buffer solution Terminal sterilization of TRIS/EDTA buffer solution in various container closure systems has been tested, but generation of particles occurred during sterilization. This is probably caused by the high pH of the TRIS/EDTA buffer solution. The current process is therefore performed by aseptic processing. 3.2.P.2.4 Container Closure System (Sterile Fluid Path Components) 3.2.P.2.4.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The compounding process for Hyperpolarized Pyruvate (13C) Injection requires a custom made container closure system, the sterile fluid path, for the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt. This container closure system is described in more detail in Section 3.2.P.7 Container Closure System. 3.2.P.2.4.2 TRIS/EDTA buffer solution The compounding process for Hyperpolarized Pyruvate (13C) Injection requires a custom made container closure system, the sterile fluid path, for the TRIS/EDTA buffer solution. This container closure system is described in more detail in Section 3.2.P.7 Container Closure System. 3.2.P.2.5 Microbiological Attributes (Sterile Fluid Path Components) 3.2.P.2.5.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Not applicable. The mixture of [1-13C]pyruvic acid and 15 mM AH111501 is compounded immediately prior to patient administration. A sample of the final Hyperpolarized Pyruvate (13C) Injection is tested for Sample not for submission sterility and pyrogenicity subsequent to patient administration. 3.2.P.2.5.2 TRIS/EDTA buffer solution Not applicable The TRIS/EDTA buffer solution is compounded immediately prior to patient administration. A sample of the final Hyperpolarized Pyruvate (13C) Injection is tested for sterility and pyrogenicity subsequent to patient administration. 3.2.P.3.1 Manufacturer(s) (Sterile Fluid Path Components) 3.2.P.3.1.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The compounding of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt for clinical use is conducted in accordance with compliance of USP <797> and the regulations promulgated by the California State Board of Pharmacy at the licensed pharmacy on the following academic campus: University of California, San Francisco Department of Clinical Pharmacy San Francisco, California 94118 3.2.P.3.1.2 TRIS/EDTA buffer solution The compounding of TRIS/EDTA buffer solution for clinical use is conducted in accordance with compliance of USP <797> and the regulations promulgated by the California State Board of Pharmacy at the licensed pharmacy on the following academic campus: University of California, San Francisco Department of Clinical Pharmacy San Francisco, California 94118 3.2.P.3.2 Single Dose Compounding Formula (Sterile Fluid Path Components) 3.2.P.3.2.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is compounded by aseptic processing. The compounding formula for a single dose prepared immediately prior to patient administration is given in Table 1. Table 1 Compounding formula for Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Ingredient Quantity per container [1-13C]pyruvic acid 1.44 g AH111501 sodium salt 27.7 mg |
| 9 | 3.2.P.3.1 | 32 | Manufacturer(s) (Sterile Fluid Path Components) | 3.2.P.3.1.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The compounding of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt for clinical use is conducted in accordance with compliance of USP <797> and the regulations promulgated by the California State Board of Pharmacy at the licensed pharmacy on the following academic campus: University of California, San Francisco Department of Clinical Pharmacy San Francisco, California 94118 3.2.P.3.1.2 TRIS/EDTA buffer solution The compounding of TRIS/EDTA buffer solution for clinical use is conducted in accordance with compliance of USP <797> and the regulations promulgated by the California State Board of Pharmacy at the licensed pharmacy on the following academic campus: University of California, San Francisco Department of Clinical Pharmacy San Francisco, California 94118 Sample not for submission sterility and pyrogenicity subsequent to patient administration. 3.2.P.2.5.2 TRIS/EDTA buffer solution Not applicable The TRIS/EDTA buffer solution is compounded immediately prior to patient administration. A sample of the final Hyperpolarized Pyruvate (13C) Injection is tested for sterility and pyrogenicity subsequent to patient administration. 3.2.P.3.1 Manufacturer(s) (Sterile Fluid Path Components) 3.2.P.3.1.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The compounding of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt for clinical use is conducted in accordance with compliance of USP <797> and the regulations promulgated by the California State Board of Pharmacy at the licensed pharmacy on the following academic campus: University of California, San Francisco Department of Clinical Pharmacy San Francisco, California 94118 3.2.P.3.1.2 TRIS/EDTA buffer solution The compounding of TRIS/EDTA buffer solution for clinical use is conducted in accordance with compliance of USP <797> and the regulations promulgated by the California State Board of Pharmacy at the licensed pharmacy on the following academic campus: University of California, San Francisco Department of Clinical Pharmacy San Francisco, California 94118 3.2.P.3.2 Single Dose Compounding Formula (Sterile Fluid Path Components) 3.2.P.3.2.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is compounded by aseptic processing. The compounding formula for a single dose prepared immediately prior to patient administration is given in Table 1. Table 1 Compounding formula for Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Ingredient Quantity per container [1-13C]pyruvic acid 1.44 g AH111501 sodium salt 27.7 mg Sample not for submission 3.2.P.3.2.2 TRIS/EDTA buffer solution The product comprises an aqueous solution of TRIS, NaOH, and Na2EDTA. The product is compounded by aseptic processing. The compounding formula for a single dose prepared immediately prior to patient administration is given in Table 2. Table 2 Compounding formula for TRIS/EDTA buffer solution 1Quantity of sterile TRIS/EDTA buffer solution aseptically instilled into receiving vessel of sterile fluid path is 18 mL. 3.2.P.3.3 Description of Manufacturing Process and Process Controls (Drug Product Kit Components) 3.2.P.3.3.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The preparation of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is performed in an ISO 7 area. [1-13C]Pyruvic acid and AH111501 sodium salt are weighed out and added to the preparation vessel in successive order. The solution is allowed to stir to ensure a homogenous solution prior to filtration. As the solution is transferred from the preparation vessel in an ISO 7 area to the filling vessel in an ISO 5 area, it is filtered through two 0.2 μm sterilizing filters. Filling is performed in an ISO 5 area (LAF unit). The filling weight is calibrated to target; each cryovial shall contain 1.47 g of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt, therefore, the filling weight depends on the assay of the specific batch of [1-13C]pyruvic acid used. Each container is weighed during the filling operation. The compounding process is illustrated in Figure 1. |
| 10 | 3.2.P.3.2 | 32 | Single Dose Compounding Formula (Sterile Fluid Path Components) | 3.2.P.3.2.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is compounded by aseptic processing. The compounding formula for a single dose prepared immediately prior to patient administration is given in Table 1. Table 1 Compounding formula for Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Ingredient Quantity per container [1-13C]pyruvic acid 1.44 g AH111501 sodium salt 27.7 mg Sample not for submission sterility and pyrogenicity subsequent to patient administration. 3.2.P.2.5.2 TRIS/EDTA buffer solution Not applicable The TRIS/EDTA buffer solution is compounded immediately prior to patient administration. A sample of the final Hyperpolarized Pyruvate (13C) Injection is tested for sterility and pyrogenicity subsequent to patient administration. 3.2.P.3.1 Manufacturer(s) (Sterile Fluid Path Components) 3.2.P.3.1.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The compounding of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt for clinical use is conducted in accordance with compliance of USP <797> and the regulations promulgated by the California State Board of Pharmacy at the licensed pharmacy on the following academic campus: University of California, San Francisco Department of Clinical Pharmacy San Francisco, California 94118 3.2.P.3.1.2 TRIS/EDTA buffer solution The compounding of TRIS/EDTA buffer solution for clinical use is conducted in accordance with compliance of USP <797> and the regulations promulgated by the California State Board of Pharmacy at the licensed pharmacy on the following academic campus: University of California, San Francisco Department of Clinical Pharmacy San Francisco, California 94118 3.2.P.3.2 Single Dose Compounding Formula (Sterile Fluid Path Components) 3.2.P.3.2.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is compounded by aseptic processing. The compounding formula for a single dose prepared immediately prior to patient administration is given in Table 1. Table 1 Compounding formula for Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt Ingredient Quantity per container [1-13C]pyruvic acid 1.44 g AH111501 sodium salt 27.7 mg Sample not for submission 3.2.P.3.2.2 TRIS/EDTA buffer solution The product comprises an aqueous solution of TRIS, NaOH, and Na2EDTA. The product is compounded by aseptic processing. The compounding formula for a single dose prepared immediately prior to patient administration is given in Table 2. Table 2 Compounding formula for TRIS/EDTA buffer solution 1Quantity of sterile TRIS/EDTA buffer solution aseptically instilled into receiving vessel of sterile fluid path is 18 mL. 3.2.P.3.3 Description of Manufacturing Process and Process Controls (Drug Product Kit Components) 3.2.P.3.3.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The preparation of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is performed in an ISO 7 area. [1-13C]Pyruvic acid and AH111501 sodium salt are weighed out and added to the preparation vessel in successive order. The solution is allowed to stir to ensure a homogenous solution prior to filtration. As the solution is transferred from the preparation vessel in an ISO 7 area to the filling vessel in an ISO 5 area, it is filtered through two 0.2 μm sterilizing filters. Filling is performed in an ISO 5 area (LAF unit). The filling weight is calibrated to target; each cryovial shall contain 1.47 g of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt, therefore, the filling weight depends on the assay of the specific batch of [1-13C]pyruvic acid used. Each container is weighed during the filling operation. The compounding process is illustrated in Figure 1. |
| 11 | 3.2.P.3.3 | 33 | Description of Manufacturing Process and Process Controls (Drug Product Kit Components) | 3.2.P.3.3.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The preparation of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is performed in an ISO 7 area. [1-13C]Pyruvic acid and AH111501 sodium salt are weighed out and added to the preparation vessel in successive order. The solution is allowed to stir to ensure a homogenous solution prior to filtration. As the solution is transferred from the preparation vessel in an ISO 7 area to the filling vessel in an ISO 5 area, it is filtered through two 0.2 μm sterilizing filters. Filling is performed in an ISO 5 area (LAF unit). The filling weight is calibrated to target; each cryovial shall contain Sample not for submission 3.2.P.3.2.2 TRIS/EDTA buffer solution The product comprises an aqueous solution of TRIS, NaOH, and Na2EDTA. The product is compounded by aseptic processing. The compounding formula for a single dose prepared immediately prior to patient administration is given in Table 2. Table 2 Compounding formula for TRIS/EDTA buffer solution 1Quantity of sterile TRIS/EDTA buffer solution aseptically instilled into receiving vessel of sterile fluid path is 18 mL. 3.2.P.3.3 Description of Manufacturing Process and Process Controls (Drug Product Kit Components) 3.2.P.3.3.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The preparation of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is performed in an ISO 7 area. [1-13C]Pyruvic acid and AH111501 sodium salt are weighed out and added to the preparation vessel in successive order. The solution is allowed to stir to ensure a homogenous solution prior to filtration. As the solution is transferred from the preparation vessel in an ISO 7 area to the filling vessel in an ISO 5 area, it is filtered through two 0.2 μm sterilizing filters. Filling is performed in an ISO 5 area (LAF unit). The filling weight is calibrated to target; each cryovial shall contain 1.47 g of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt, therefore, the filling weight depends on the assay of the specific batch of [1-13C]pyruvic acid used. Each container is weighed during the filling operation. The compounding process is illustrated in Figure 1. Sample not for submission Figure 1 Flow chart illustrating the manufacturing process of Mixture of [1- 13C]pyruvic acid and 15 mM AH111501 sodium salt 3.2.P.3.3.2 TRIS/EDTA buffer solution The preparation of TRIS/EDTA buffer solution is performed in an ISO 7 area. Approximately 90% of the total amount of WFI is added to the preparation vessel. TRIS, Na EDTA and NaOH are added successively, allowing each one to dissolve completely by 2 sufficiently stirring between each addition. The bulk solution is adjusted to its final weight by addition of WFI and allowed to stir to ensure a homogenous solution prior to filtration. As the solution is transferred from the preparation vessel in an ISO 7 area to the filling vessel in a ISO 5 area, it is filtered through two 0.2 μm sterilizing filters. Aseptic filling of the TRIS/EDTA buffer solution into the receiving vessel of the sterile fluid path is performed in an ISO 5 area (LAF unit). Weight controls are taken regularly during filling to assure acceptable fill volume for the whole batch. |
| 12 | 3.2.P.3.4 | 36 | Controls of Critical Steps and Intermediates (Sterile Fluid Path Components) | 3.2.P.3.4.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt A schematic representation of the process flow and the in-process controls is presented in Figure 1, Section 3.2.P.3.3.1. In addition, environmental monitoring (microbiological and non-viable particles) of the production area is performed. 3.2.P.3.4.2 TRIS/EDTA buffer solution A schematic representation of the process flow and the in-process controls is presented in Figure 2, Section 3.2.P.3.3.2. In addition, environmental monitoring (microbiological and non-viable particles) of the production area is performed. |
| 13 | 3.2.P.3.5 | 36 | Process Validation and/or Evaluation (Sterile Fluid Path Components) | 3.2.P.3.5.1 Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt The aseptic compounding process has been validated by simulation of the aseptic process using a microbial nutrient medium. No growth has been observed in any of the media fill batches. Monitoring of the clean room and personnel is carried out and controlled on a routine basis to assure an environment suitable for aseptic processing. 3.2.P.3.5.2 TRIS/EDTA buffer solution The aseptic compounding process has been validated by simulation of the aseptic process using a microbial nutrient medium. No growth has been observed in any of the media fill batches. Monitoring of the clean room and personnel is carried out and controlled on a routine basis to assure an environment suitable for aseptic processing. |
| 14 | 3.2.P.6 | 39 | Reference Standards or Materials (Sterile Fluid Path Components) | Sample not for submission automated compounding device, SpinLab, only if the procedures for aseptic compounding the solution are satisfied. The project and utility of SpinLab for automatic compounding of the Hyperpolarized pyruvate (13C) injection drug product is in early development and preliminary specifications may be developed and evaluated as this project continues in the development phase. Considering the early stage of the project and only single doses are compounded immediately prior to patient administration by licensed pharmacy personnel, the specifications are considered justified. 3.2.P.5.6.2 TRIS/EDTA buffer solution A sterile fluid path containing the TRIS/EDTA buffer solution, which is prepared immediately prior to patient administration, will be released by a licensed pharmacist for compounding by the automated compounding device, SpinLab, only if the procedures for aseptic compounding the solution are satisfied. The project and utility of SpinLab for automatic compounding of the Hyperpolarized pyruvate (13C) injection drug product is in early development and preliminary specifications may be developed and evaluated as this project continues in the development phase. Considering the early stage of the project and only single doses are compounded immediately prior to patient administration by licensed pharmacy personnel, the specifications are considered justified. 3.2.P.6 Reference Standards or Materials (Sterile Fluid Path Components) Not applicable. 3.2.P.7 Container Closure System (Sterile Fluid Path) The fluid path system is a single, sterile drug product container, container closure system that provides for rapid and complete dissolution of a frozen hyperpolarized drug product and transports the resulting hyperpolarized drug product solution from its initial location within a polarizer system to a final sterile Medrad syringe outside the polarizer system for clinical administration—injection into a patient. The empty sterile fluid path (Figure 1A) is provided in a double bag plastic tray with a lid of the following approximate size: 60 cm (L) x 35.6 cm (width) x 10.2 cm (depth)/unit or 23.6 inch (L) x 14.0 inch (width) x 4.0 inch (depth)/unit The empty sterile fluid path is designed to be a single-use drug product container, container closure system which upon arrival to a licensed pharmacy, can be aseptically manipulated so that it can be charged with the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt, TRIS/EDTA buffer, and sterile water for injection. The key components of the empty sterile fluid path system that are in contact with the drug product are composed of USP Plastic Class V as follows: - A Radel R Plastic sample vial which will serve to contain a mixture of the drug substance [1- 13C] Pyruvic Acid and the Electron Paramagnetic Agent (EPA) excipient, tris(8-carboxyl- 2,2,6,6-tetra(2-( l-methoxy-2,2-d2-ethyl) )-benzo[ l ,2-d:4,5-d']bis(dithiole-4-yl)methyl sodium Sample not for submission salt, AH111501 Sodium Salt. - A Radel R Plastic syringe which will serve to contain sterile water for injection. - A Radel R Plastic receiver vessel which will serve to contain an aqueous solution of (hydroxymethyl)aminomethane (TRIS), disodium ethylenediaminetretraacetate (Na EDTA) 2 and sodium hydroxide (NaOH). - A Radel R plastic casing containing the EPA ultrahigh molecular weight polyethylene filters. - A Tygon plastic tubing connecting the Receiver vessel to the Sterile filter. - The rest of the assembly is composed of Radel R Plastic co-axial and transfer tubes and Udel plastic valves. The Dynamic seal is designed and integrated into the empty sterile fluid path however it is not in contact with the drug product. The QC appendage is designed and integrated into the empty sterile fluid path, however it is not in contact with the drug product as an aliquot of the drug product is transferred to the QC appendage. Commercially available SSQK 65/115VS Syringe Kits (Bayer Inc., USA) containing a sterile 65 mL Qwik-Fit Syringe which is aseptically added to the sterile empty fluid path for collection of the final drug product, Hyperpolarized Pyruvate (13C) Injection, will not be addressed here and is depicted as Administration syringe. Figure 1A Depiction of empty sterile fluid path in packaging. Figure 1B Basic anatomy of an empty sterile fluid path. |
| 15 | 3.2.P.7 | 39 | Container Closure System (Sterile Fluid Path) | The fluid path system is a single, sterile drug product container, container closure system that provides for rapid and complete dissolution of a frozen hyperpolarized drug product and transports the resulting hyperpolarized drug product solution from its initial location within a polarizer system to a final sterile Medrad syringe outside the polarizer system for clinical administration—injection into a patient. The empty sterile fluid path (Figure 1A) is provided in a double bag plastic tray with a lid of the following approximate size: 60 cm (L) x 35.6 cm (width) x 10.2 cm (depth)/unit or Sample not for submission automated compounding device, SpinLab, only if the procedures for aseptic compounding the solution are satisfied. The project and utility of SpinLab for automatic compounding of the Hyperpolarized pyruvate (13C) injection drug product is in early development and preliminary specifications may be developed and evaluated as this project continues in the development phase. Considering the early stage of the project and only single doses are compounded immediately prior to patient administration by licensed pharmacy personnel, the specifications are considered justified. 3.2.P.5.6.2 TRIS/EDTA buffer solution A sterile fluid path containing the TRIS/EDTA buffer solution, which is prepared immediately prior to patient administration, will be released by a licensed pharmacist for compounding by the automated compounding device, SpinLab, only if the procedures for aseptic compounding the solution are satisfied. The project and utility of SpinLab for automatic compounding of the Hyperpolarized pyruvate (13C) injection drug product is in early development and preliminary specifications may be developed and evaluated as this project continues in the development phase. Considering the early stage of the project and only single doses are compounded immediately prior to patient administration by licensed pharmacy personnel, the specifications are considered justified. 3.2.P.6 Reference Standards or Materials (Sterile Fluid Path Components) Not applicable. 3.2.P.7 Container Closure System (Sterile Fluid Path) The fluid path system is a single, sterile drug product container, container closure system that provides for rapid and complete dissolution of a frozen hyperpolarized drug product and transports the resulting hyperpolarized drug product solution from its initial location within a polarizer system to a final sterile Medrad syringe outside the polarizer system for clinical administration—injection into a patient. The empty sterile fluid path (Figure 1A) is provided in a double bag plastic tray with a lid of the following approximate size: 60 cm (L) x 35.6 cm (width) x 10.2 cm (depth)/unit or 23.6 inch (L) x 14.0 inch (width) x 4.0 inch (depth)/unit The empty sterile fluid path is designed to be a single-use drug product container, container closure system which upon arrival to a licensed pharmacy, can be aseptically manipulated so that it can be charged with the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt, TRIS/EDTA buffer, and sterile water for injection. The key components of the empty sterile fluid path system that are in contact with the drug product are composed of USP Plastic Class V as follows: - A Radel R Plastic sample vial which will serve to contain a mixture of the drug substance [1- 13C] Pyruvic Acid and the Electron Paramagnetic Agent (EPA) excipient, tris(8-carboxyl- 2,2,6,6-tetra(2-( l-methoxy-2,2-d2-ethyl) )-benzo[ l ,2-d:4,5-d']bis(dithiole-4-yl)methyl sodium Sample not for submission salt, AH111501 Sodium Salt. - A Radel R Plastic syringe which will serve to contain sterile water for injection. - A Radel R Plastic receiver vessel which will serve to contain an aqueous solution of (hydroxymethyl)aminomethane (TRIS), disodium ethylenediaminetretraacetate (Na EDTA) 2 and sodium hydroxide (NaOH). - A Radel R plastic casing containing the EPA ultrahigh molecular weight polyethylene filters. - A Tygon plastic tubing connecting the Receiver vessel to the Sterile filter. - The rest of the assembly is composed of Radel R Plastic co-axial and transfer tubes and Udel plastic valves. The Dynamic seal is designed and integrated into the empty sterile fluid path however it is not in contact with the drug product. The QC appendage is designed and integrated into the empty sterile fluid path, however it is not in contact with the drug product as an aliquot of the drug product is transferred to the QC appendage. Commercially available SSQK 65/115VS Syringe Kits (Bayer Inc., USA) containing a sterile 65 mL Qwik-Fit Syringe which is aseptically added to the sterile empty fluid path for collection of the final drug product, Hyperpolarized Pyruvate (13C) Injection, will not be addressed here and is depicted as Administration syringe. Figure 1A Depiction of empty sterile fluid path in packaging. Figure 1B Basic anatomy of an empty sterile fluid path. |
| 16 | 7.3 | 41 | Drug Product Part 2 | 3.2.P DRUG PRODUCT (HYPERPOLARIZED PYRUVATE [13C] INJECTION) Hyperpolarized Pyruvate (13C) Injection (drug product) is a sterile solution for intravenous injection. Compounding the Hyperpolarized Pyruvate (13C) Injection requires the following drug product components: • Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt • TRIS/EDTA buffer solution • Sterile Water for Injection (WFI) Hyperpolarized Pyruvate (13C) Injection is compounded at the clinical site utilizing an automated compounding device, known as SpinLab, according to USP <797> Pharmaceutical Compounding – Sterile Preparations, just prior to administration. For each patient does, SpinLab utilizes a single sterile fluid path that is composed of a cryovial which contains the mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt. The cryovial is lowered into the polarizer and polarized for up to 120 minutes at a temperature of approximately 0.8 K. After polarization, the mixture of [1- 13C]pyruvic acid and 15 mM AH111501 sodium salt is flushed out of the cryovial with heated and pressurized sterile WFI within the sterile fluid path then passed through a mechanical filter for removal of AH111501, then emptied into a receiver vessel containing sterile WFI and TRIS/EDTA buffer solution. A sample of solution from the receiver vessel is automatically extracted for testing by an automated quality control instrument (QC System). While the QC System processes the solution sample, the remaining solution in the receiver vessel is passed through a sterilizing filter (0.2 μm) and then enters the final drug product container for patient administration, a 65 mL MedRad syringe. Based on the results from the QC System, the final release authorization for administration to humans will be performed by a licensed pharmacist. The following 3.2.P sections describe the Hyperpolarized Pyruvate (13C) Injection. For aspects related to the drug product components required for compounding the Hyperpolarized Pyruvate (13C) Injection, reference is made to section 3.2.P for Drug Product Kit Components. |
| 17 | 3.2.P.2.1 | 42 | Components of the Drug Product (Hyperpolarized Pyruvate (13C) Injection) | The drug substance, [1−13C]pyruvic acid, is a colorless to yellow, clear, viscous liquid. [1−13C]Pyruvic acid is described in Section 3.2.S Drug Substance. After neutralization in the TRIS/EDTA buffer solution, the [1−13C]pyruvic acid is present as [1−13C]pyruvate. 3.2.P.2.1.2 Excipients AH111501 sodium salt is a stable trityl radical, and is added to [1−13C]pyruvic acid to enable hyperpolarization. After hyperpolarization and compounding, the solution is passed through a filter to remove the AH111501 from the drug product. AH111501 sodium salt is a green to black, fine to granular powder. AH111501 sodium salt is further described in Section 3.2.A.3 Novel Excipients. The TRIS/EDTA buffer solution is an aqueous solution containing 333 mM TRIS, 600 mM NaOH and 333 mg/l Na EDTA. 2 TRIS is added as a buffer to stabilize the pH of the Hyperpolarized Pyruvate (13C) Injection at a physiologically acceptable level. NaOH is added to neutralize the [1−13C]pyruvic acid in the Mixture of [1−13C]pyruvic acid and 15 mM AH111501 sodium salt to [1−13C]pyruvate in the Hyperpolarized Pyruvate (13C) Injection. Na EDTA has been included in the formulation as a chelating agent to capture traces of 2 Sample not for submission Table 1 Composition of Hyperpolarized Pyruvate (13C) Injection Hyperpolarized Pyruvate (13C) Injection is supplied via a sterile disposable Medrad Qwik-Fit Syringe® for contrast media with a fill volume of 65 mL. 3.2P.2.1 Components of the Drug Product (Hyperpolarized Pyruvate (13C) Injection) 3.2.P.2.1.1 Drug substance The drug substance, [1−13C]pyruvic acid, is a colorless to yellow, clear, viscous liquid. [1−13C]Pyruvic acid is described in Section 3.2.S Drug Substance. After neutralization in the TRIS/EDTA buffer solution, the [1−13C]pyruvic acid is present as [1−13C]pyruvate. 3.2.P.2.1.2 Excipients AH111501 sodium salt is a stable trityl radical, and is added to [1−13C]pyruvic acid to enable hyperpolarization. After hyperpolarization and compounding, the solution is passed through a filter to remove the AH111501 from the drug product. AH111501 sodium salt is a green to black, fine to granular powder. AH111501 sodium salt is further described in Section 3.2.A.3 Novel Excipients. The TRIS/EDTA buffer solution is an aqueous solution containing 333 mM TRIS, 600 mM NaOH and 333 mg/l Na EDTA. 2 TRIS is added as a buffer to stabilize the pH of the Hyperpolarized Pyruvate (13C) Injection at a physiologically acceptable level. NaOH is added to neutralize the [1−13C]pyruvic acid in the Mixture of [1−13C]pyruvic acid and 15 mM AH111501 sodium salt to [1−13C]pyruvate in the Hyperpolarized Pyruvate (13C) Injection. Na EDTA has been included in the formulation as a chelating agent to capture traces of 2 |
| 18 | 3.2.P.2.2 | 43 | Drug Product (Hyperpolarized Pyruvate (13C) Injection) | 3.2.P.2.2.1 Formulation Development The drug product kit components used for compounding of Hyperpolarized Pyruvate (13C) Injection in the polarizer differ slightly from the components used for pre-clinical studies and clinical studies GE-101-001 and GE-101-003 (see Section 8.1 Introduction for Item 8 Pharmacology and Toxicology Info). These differences are explained in the following sections and are summarized in Table 1. (a) Pyruvic acid and [1-13C]pyruvic acid Drug product used for clinical studies GE-101-001 and GE-101-003 was not hyperpolarized. As the need for 13C enriched material was not present, the drug substance used was pyruvic acid, whereas the drug substance used for compounding of Hyperpolarized Pyruvate (13C) Injection is [1-13C]pyruvic acid. Some pre-clinical safety studies were also conducted using pyruvic acid (see Section 8.1 Introduction for Item 8 Pharmacology and Toxicology Info). (b) Content of AH111501 sodium salt AH111501 is removed during compounding of Hyperpolarized Pyruvate (13C) Injection, and the content of this excipient in the final drug product is NMT 3.0 μM. To mimic this situation for clinical studies GE-101-001 and GE-101-003, 0.2 mM AH111501 sodium salt was added to the pyruvic acid in order to obtain 3.0 μM AH111501 in the Pyruvate Injection. For most of the pre- clinical studies (see Section 8.1 Introduction for Item 8 Pharmacology and Toxicology Info) and for compounding of Hyperpolarized Pyruvate (13C) Injection, 15 mM AH111501 sodium salt is added to the [1-13C]pyruvic acid. (c) Content of [1-13C]pyruvate in drug product The drug product was initially formulated to contain 500 mM [1-13C]pyruvate. For this formulation, a Mixture of [1-13C]pyruvic acid and AH111501 sodium salt, containing 2.23 g [1- 13C]pyruvic acid, was dissolved in 50 ml TRIS/EDTA dissolution medium, containing 360 mM NaOH, 200 mM TRIS and 100 mg/l Na EDTA. Because pre-clinical studies using this 2 formulation revealed cardiovascular effects (see Sections 8.2.4.3 Effects on the Cardiovascular Systems (CVS) in the Pentobarbital/Fentanyl Anesthetized Dog, subsections a and b, for Item 8 Pharmacology and Toxicology Info) the product was later reformulated to contain 250 mM [1- 13C]pyruvate. For this formulation, Mixture of [1-13C]pyruvic acid and AH111501 sodium salt, containing 2.23 g [1-13C]pyruvic acid, was dissolved in 100 ml TRIS/EDTA dissolution medium, containing 180 mM NaOH, 100 mM TRIS and 100 mg/l Na EDTA. Some pre- clinical studies 2 were performed with the formulation targeted 500 mM [1-13C]pyruvate. For most pre-clinical (see Section 8.1 Introduction for Item 8 Pharmacology and Toxicology Info) and all clinical studies, the Pyruvate (13C) Injection is targeted to contain 250 mM [1-13C]pyruvate. (d) TRIS/EDTA dissolution medium and TRIS/EDTA buffer solution For clinical studies GE-101-001 and GE-101-003 and pre-clinical studies, the Mixture of pyruvic acid and AH111501 sodium salt was dissolved in TRIS/EDTA dissolution medium in a single step by manual dissolution (see section 3.2.P.2.3 Manufacturing Process Development). The |
| 19 | 3.2.P.2.3 | 45 | Manufacturing Process Development (Hyperpolarized Pyruvate (13C) Injection) | The procedure for compounding of Hyperpolarized Pyruvate (13C) Injection was not used for pre- clinical studies or clinical studies GE-101-001 and GE-101-003. The Pyruvate (13C) Injection for these studies was prepared by manual mixing of the drug product kit components as described in the following section. Prior to mixing the drug product kit components, the components were allowed to reach ambient room temperature. 100 mL of TRIS/EDTA dissolution medium was then added to the vial containing the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt. Immediately, the vial was vigorously shaken for at least 30 seconds to assure homogeneity. The vial was then heated in a 80°C water bath for 10 minutes and cooled in cold tap water for 5 minutes. The vial is then stored in a 37°C water bath for a maximum of 4 hours before use. |
| 20 | 3.2.P.3.3 | 46 | Description of Manufacturing Process and Process Controls (Hyperpolarized Pyruvate (13C) Injection) | Hyperpolarized Pyruvate (13C) Injection is compounded at the clinical site prior to administration. For compounding, the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is hyperpolarized by Dynamic Nuclear Polarization (DNP) for approximately 60 minutes at 1.2 K. After hyperpolarization, the Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt is dissolved in sterile WFI and the AH111501 is then removed from the hyperpolarized solution by mechanical filtration. The hyperpolarized solution is then neutralized, buffered and diluted in TRIS/EDTA buffer solution and subsequently passed through a sterilizing filter (0.2 μm) into the final drug product container, an empty sterile disposable Medrad syringe. The SpinLab system used for hyperpolarization and compounding is located in an area adjacent to the MR scanner room. All compounding process steps are in accordance with USP <797> Pharmaceutical Compounding – Sterile Preparations. Immediately after compounding, the Hyperpolarized Pyruvate (13C) Injection is sampled and tested by an automatic quality control instrument (QC System). The final release authorization for administration to humans will be performed by a licensed pharmacist. After release, the Hyperpolarized Pyruvate (13C) Injection will be delivered to the adjoining MR scanner room for patient administration. 3.2.P.3.3.1 Process description (a) Compounding and filling of empty sterile fluid path All process steps for compounding and filling of the empty sterile fluid path (SFP) used in SpinLab to prepare the hyperpolarized (13C) pyruvate injection are performed within a cleanroom ISO 5 area. A clean, sterile, empty SFP is aseptically removed from its packaging and placed into the ISO 5 area. The sterile water for injection (38 g) is aseptically introduced into the dissolution syringe of the SFP and another 18.5 g of sterile water for injection is aseptically introduced into the receiving vessel. The sterile TRIS/EDTA buffer (18 g) is aseptically introduced into the receiving vessel. A mixture of [1-13C]pyruvic acid and 15 mM AH111501 is prepared and then sterilized using a sterilizing filter (0.2 µm) and 1.47 g of the sterile solution is placed into the sterile cryovial. The cyrovial containing the sterile mixture of [1-13C]pyruvic acid and 15 mM AH111501 is then attached to the empty sterile fluid path and sealed utilizing a laser welder. The cryovial is then |
| 21 | 3.2.P.3.4 | 50 | Controls of Critical Steps and Intermediates (Hyperpolarized Pyruvate (13C) Injection) | A schematic representation of the process flow and the in-process controls is presented in Figure 1 in Section 3.2.P.3.3.1 (a). The polarizer software application monitors and controls critical system and process functions and settings such as data communication and temperature settings. Malfunctions or settings detected to be outside pre-set ranges are communicated to the operators via software-generated alarms that prevent further processing. Control of the mechanical functionality of process hardware, such as valves and fittings, and of the He driving pressure, is performed manually by the operator. The final release analyses performed by the QC System ensure that the compounding process has executed as intended and that the Hyperpolarized Pyruvate (13C) Injection is within specifications (see Table 1 in Section 3.2.P.5.1). The post-administration integrity test of the sterilizing filter assesses whether the filter was functional during use. |
| 22 | 3.2.P.3.5 | 50 | Process Validation and/or Evaluation (Hyperpolarized Pyruvate (13C) Injection) | 3.2.P.3.5.1 IQ/OQ/PQ Program The clean room, polarizer, process equipment and QC system have gone through an extensive IQ/OQ/PQ program prior to use during clinical trials. The clean room and equipment were found to be suitable for their intended use. 3.2.P.3.5.2 Microbiological aspects The compounding process has been validated by simulation of the process using a microbial nutrient medium. No growth has been observed in any of the media fill batches. The microbiological quality has also been demonstrated by sterility and microbial endotoxin testing of repeated runs (n=6). 3.2.P.3.5.3 Compounding process consistency The consistency of the compounding process has been evaluated by repeated (n=10) compounding of Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt and TRIS/EDTA buffer solution. All batches were within specifications (see Section 3.2.P.5.4 Batch Analyses for details). As the QC System only determines a limited set of quality parameters, all batches were also analyzed for related substances of [1-13C]pyruvate and TRIS, assay of [1-13C]pyruvate, osmolality and particulate contamination. Because of limited analytical capability at the site of compounding (UCSF), samples were shipped to GE Healthcare and analyses were performed 8 to 34 days after compounding. The formation of AH112615 after compounding (see Section 3.2.P.5.5 Characterization of Impurities) causes a decrease in the assay of [1-13C]pyruvate. Because of this |
| 23 | 3.2.P.4 | 51 | Control of Excipients (Hyperpolarized Pyruvate (13C) Injection) | There are no excipients added during compounding of Hyperpolarized Pyruvate (13C) Injection. All excipients in the drug product are attributed to the drug product kit components; Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium and TRIS/EDTA buffer solution. Excipients in the drug product kit components are discussed in Section 3.2.P.4 Control of Excipients for Drug Product Kit Components and Section 3.2.A.3 Novel Excipients. Sample not for submission effect, and as the HPLC method does not detect AH112615, for this study determination of [1- 13C]pyruvate content was performed by quantitative 1H NMR analysis using acetate as an internal standard for calibration. It has been shown that the content of AH112615 immediately after compounding is negligible (see Section 3.2.P.5.5 Characterization of Impurities). To determine the content of [1-13C]pyruvate at time of compounding at UCSF, the AH112625 peak was therefore integrated as [1-13C]pyruvate. The formation of AH112615 also causes a decrease in osmolality with time after compounding. For this study the osmolality at time of compounding at UCSF was therefore calculated from the measured osmolality and the content of AH112615 (determined by 1H NMR) at time of analysis. Results from these analyses are stated in Table 1. As can be seen from these results, the assay of [1-13C]pyruvate in (Hyperpolarized Pyruvate (13C) Injection) varied in the range of 222-252 mM with an average of 241 ± 12 mM. Although the observed assay displays a larger variance than would be expected from the drug product kit components used the results are considered to demonstrate an acceptable process consistency. It should be noted that even though the QC system does not determine the assay of [1-13C]pyruvate, the determination of pH constitute a relevant indirect control of this parameter. The level of control obtained through the determination of pH has been investigated in a study where a sample of Mixture of [1- 13C]pyruvic acid and 15 mM AH111501 sodium salt was titrated with TRIS/EDTA buffer solution diluted in sterile WFI. Results from this study are shown in Figure 1. As can be seen from Figure 1 the pH of the solution is a well defined function of the [1- 13C]pyruvate concentration. As expected, the pKa of TRIS is observed at approximately 8.1 and the depletion of buffer capacity towards the acidic range is observed at approximately 280 mM. Estimated from the observed relationship, the specification to pH (6.7 to 8.0) is equivalent to approximately 210 to 270 mM Pyruvate. With regards to the efficacy of the drug product, the 13C NMR determined by the QC system is proportional to the concentration of [1-13C]pyruvate (see Section 3.2.P.5.2.1 Analytical Procedures). As the 13C nuclear polarization reported by the QC system assumes a fixed concentration of [1-13C]pyruvate, it varies linearly with the actual concentration of [1- 13C]pyruvate. Hence, this parameter represents a more relevant assurance of product efficacy than the assay of [1-13C]pyruvate alone. Osmolality varied in the range of 484-513 mOsm/kg with an average of 501 ± 12 mOsm/kg. Particulate contamination was well within the pharmacopoeia limits for all batches. The purity profile observed during this study was as expected from the purity profile of the drug product kit components. No new impurities were observed. With regards to the purity profile of Hyperpolarized Pyruvate (13C) Injection at time of compounding at UCSF, reference is made to 3.2.P.5.5 Characterization of Impurities. 3.2.P.4 Control of Excipients (Hyperpolarized Pyruvate (13C) Injection) There are no excipients added during compounding of Hyperpolarized Pyruvate (13C) Injection. All excipients in the drug product are attributed to the drug product kit components; Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium and TRIS/EDTA buffer solution. Excipients in the drug product kit components are discussed in Section 3.2.P.4 Control of Excipients for Drug Product Kit Components and Section 3.2.A.3 Novel Excipients. 3.2.P.4.1 Specification (Hyperpolarized Pyruvate (13C) Injection) Not applicable. |
| 24 | 3.2.P.4.1 | 51 | Specification (Hyperpolarized Pyruvate (13C) Injection) | Sample not for submission effect, and as the HPLC method does not detect AH112615, for this study determination of [1- 13C]pyruvate content was performed by quantitative 1H NMR analysis using acetate as an internal standard for calibration. It has been shown that the content of AH112615 immediately after compounding is negligible (see Section 3.2.P.5.5 Characterization of Impurities). To determine the content of [1-13C]pyruvate at time of compounding at UCSF, the AH112625 peak was therefore integrated as [1-13C]pyruvate. The formation of AH112615 also causes a decrease in osmolality with time after compounding. For this study the osmolality at time of compounding at UCSF was therefore calculated from the measured osmolality and the content of AH112615 (determined by 1H NMR) at time of analysis. Results from these analyses are stated in Table 1. As can be seen from these results, the assay of [1-13C]pyruvate in (Hyperpolarized Pyruvate (13C) Injection) varied in the range of 222-252 mM with an average of 241 ± 12 mM. Although the observed assay displays a larger variance than would be expected from the drug product kit components used the results are considered to demonstrate an acceptable process consistency. It should be noted that even though the QC system does not determine the assay of [1-13C]pyruvate, the determination of pH constitute a relevant indirect control of this parameter. The level of control obtained through the determination of pH has been investigated in a study where a sample of Mixture of [1- 13C]pyruvic acid and 15 mM AH111501 sodium salt was titrated with TRIS/EDTA buffer solution diluted in sterile WFI. Results from this study are shown in Figure 1. As can be seen from Figure 1 the pH of the solution is a well defined function of the [1- 13C]pyruvate concentration. As expected, the pKa of TRIS is observed at approximately 8.1 and the depletion of buffer capacity towards the acidic range is observed at approximately 280 mM. Estimated from the observed relationship, the specification to pH (6.7 to 8.0) is equivalent to approximately 210 to 270 mM Pyruvate. With regards to the efficacy of the drug product, the 13C NMR determined by the QC system is proportional to the concentration of [1-13C]pyruvate (see Section 3.2.P.5.2.1 Analytical Procedures). As the 13C nuclear polarization reported by the QC system assumes a fixed concentration of [1-13C]pyruvate, it varies linearly with the actual concentration of [1- 13C]pyruvate. Hence, this parameter represents a more relevant assurance of product efficacy than the assay of [1-13C]pyruvate alone. Osmolality varied in the range of 484-513 mOsm/kg with an average of 501 ± 12 mOsm/kg. Particulate contamination was well within the pharmacopoeia limits for all batches. The purity profile observed during this study was as expected from the purity profile of the drug product kit components. No new impurities were observed. With regards to the purity profile of Hyperpolarized Pyruvate (13C) Injection at time of compounding at UCSF, reference is made to 3.2.P.5.5 Characterization of Impurities. 3.2.P.4 Control of Excipients (Hyperpolarized Pyruvate (13C) Injection) There are no excipients added during compounding of Hyperpolarized Pyruvate (13C) Injection. All excipients in the drug product are attributed to the drug product kit components; Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium and TRIS/EDTA buffer solution. Excipients in the drug product kit components are discussed in Section 3.2.P.4 Control of Excipients for Drug Product Kit Components and Section 3.2.A.3 Novel Excipients. 3.2.P.4.1 Specification (Hyperpolarized Pyruvate (13C) Injection) Not applicable. |
| 25 | 3.2.P.5.2 | 53 | Analytical Procedures (Hyperpolarized Pyruvate (13C) Injection) | The 13C nuclear polarization of Hyperpolarized Pyruvate (13C) Injection undergoes an exponential decay with a time constant of approximately 69 seconds. In order to preserve an acceptable imaging efficacy, the time between start dissolution and start of administration to the patient has to be NMT 50s (see Section 3.2.P.8.1 Stability Summary and Conclusions). Due to this limited user window, analyses to control Hyperpolarized Pyruvate (13C) Injection are performed using an automated analytical system (QC System) that determines a limited set of parameters within a time span of approximately 10s. This QC System is specifically developed for the analysis of Hyperpolarized Pyruvate (13C) Injection immediately prior to administration to the patients. The QC accessory participates in the dissolution process by managing the state of the sterile fluid path. Specifically, the QC accessory controls the upper slide valve, which is used to isolate the receiver from the EPA filter, and the lower slide valve which controls fluid flow to the cuvettes and the Administration syringe. After a dissolution is complete, the QC accessory closes the upper slide valve, measures the temperature of the receiver, and opens the lower slide valve to allow the mixed solution to be drawn out. Once the cuvettes and NMR bulb are filled, the QC measures the pyruvate concentration, EPA concentration, and pH. The percent polarization is also measured. Once the Administration syringe is filled, the QC checks that the volume is above the level of a threshold sensor. All measurement results are reported to the Hyperpolarizer, where they are interpreted and displayed on the screen for an operator to decide how to proceed. After completed analysis, the software performs a comparison of the results to a pre-set list of specifications (see Table 1 in Section 3.2.P.5.1 Specifications) and reports the compliance or non-compliance of the Hyperpolarized Pyruvate (13C) Injection to the specifications. Control of additional parameters is assured through testing performed on the combination of the drug product kit components; Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt dissolved in WFI and TRIS/EDTA buffer solution (Pyruvate (13C) Injection) (see Section |
| 26 | 3.2.P.5.3 | 55 | Validation of Analytical Procedures (Hyperpolarized Pyruvate (13C) Injection) | The analytical procedures are appropriately validated for the current development phase and are suitable for intended use. The validation performed at this stage is summarized in Table 1. Table 1 Validation of analytical procedures performed at this stage Sample not for submission 3.2.P.5.2.5 Volume The volume measurement in the QC is a threshold measurement performed at the Administration syringe after the fluid movement is complete. This measurement is a capacitive measurement that was tuned by the manufacturer during system setup. The sensor was also tuned to have its threshold centered at a nominal volume of 38 mL. 3.2.P.5.3 Validation of Analytical Procedures (Hyperpolarized Pyruvate (13C) Injection) The analytical procedures are appropriately validated for the current development phase and are suitable for intended use. The validation performed at this stage is summarized in Table 1. Table 1 Validation of analytical procedures performed at this stage 3.2.P.5.4 Batch Analyses (Hyperpolarized Pyruvate (13C) Injection) Hyperpolarized Pyruvate (13C) Injection has not been used for pre-clinical studies or clinical studies GE-101-001 and GE-101-003. For the clinical studies, non-polarized Pyruvate Injection has been used. Different formulations of Pyruvate (13C) Injection have been used during non- clinical studies and clinical studies GE-101-001 and GE-101-003. The drug product kit components used for compounding of Hyperpolarized Pyruvate (13C) Injection have been formulated such that the drug product is equivalent to the drug product used for clinical studies GE-101-001 and GE-101-003, as discussed in Section 3.2.P.2.2.1 Formulation Development. Results for batches of Hyperpolarized Pyruvate (13C) Injection are presented in Table 1 and Table 2. Table 1 Batch data for Hyperpolarized Pyruvate (13C) Injection |
| 27 | 3.2.P.5.4 | 55 | Batch Analyses (Hyperpolarized Pyruvate (13C) Injection) | Hyperpolarized Pyruvate (13C) Injection has not been used for pre-clinical studies or clinical studies GE-101-001 and GE-101-003. For the clinical studies, non-polarized Pyruvate Injection has been used. Different formulations of Pyruvate (13C) Injection have been used during non- clinical studies and clinical studies GE-101-001 and GE-101-003. The drug product kit components used for compounding of Hyperpolarized Pyruvate (13C) Injection have been formulated such that the drug product is equivalent to the drug product used for clinical studies GE-101-001 and GE-101-003, as discussed in Section 3.2.P.2.2.1 Formulation Development. Results for batches of Hyperpolarized Pyruvate (13C) Injection are presented in Table 1 and Table 2. Table 1 Batch data for Hyperpolarized Pyruvate (13C) Injection Sample not for submission 3.2.P.5.2.5 Volume The volume measurement in the QC is a threshold measurement performed at the Administration syringe after the fluid movement is complete. This measurement is a capacitive measurement that was tuned by the manufacturer during system setup. The sensor was also tuned to have its threshold centered at a nominal volume of 38 mL. 3.2.P.5.3 Validation of Analytical Procedures (Hyperpolarized Pyruvate (13C) Injection) The analytical procedures are appropriately validated for the current development phase and are suitable for intended use. The validation performed at this stage is summarized in Table 1. Table 1 Validation of analytical procedures performed at this stage 3.2.P.5.4 Batch Analyses (Hyperpolarized Pyruvate (13C) Injection) Hyperpolarized Pyruvate (13C) Injection has not been used for pre-clinical studies or clinical studies GE-101-001 and GE-101-003. For the clinical studies, non-polarized Pyruvate Injection has been used. Different formulations of Pyruvate (13C) Injection have been used during non- clinical studies and clinical studies GE-101-001 and GE-101-003. The drug product kit components used for compounding of Hyperpolarized Pyruvate (13C) Injection have been formulated such that the drug product is equivalent to the drug product used for clinical studies GE-101-001 and GE-101-003, as discussed in Section 3.2.P.2.2.1 Formulation Development. Results for batches of Hyperpolarized Pyruvate (13C) Injection are presented in Table 1 and Table 2. Table 1 Batch data for Hyperpolarized Pyruvate (13C) Injection |
| 28 | 3.2.P.5.5 | 56 | Characterization of Impurities (Hyperpolarized Pyruvate (13C) Injection) | A determination of the impurities in Hyperpolarized Pyruvate (13C) Injection is not part of the analyses performed by the QC System. Hence, documentation and control of the impurities in the drug product rests on analyses performed during the release testing of Pyruvate (13C) Injection (see Section 3.2.P.5.5 Characterization of Impurities for Drug Product Kit Components) and the results from process verification studies. 3.2.P.5.5.1 Differences in dissolution procedures The manual procedure for the compounding of Pyruvate (13C) Injection during preparation of samples for analysis is identical to the procedure used during pre-clinical safety studies and clinical studies GE-101-001 and GE-101-003. The dissolution process during compounding of Hyperpolarized Pyruvate (13C) Injection is different from the manual procedure, particularly with regards to parameters such as time, temperature, flow rates and pressure. These differences influence the purity profile such that the impurities in manually dissolved Pyruvate (13C) Injection, to some extent, are different from those in Hyperpolarized Pyruvate (13C) Injection. These effects and the purity profile of Hyperpolarized Pyruvate (13C) Injection are discussed in Sections 3.2.P.5.5.2, 3.2.P.5.5.3 and 3.2.P.5.5.4. 3.2.P.5.5.2 Transformation between AH113462 and AH112623 During and after manual compounding of Pyruvate (13C) Injection, the major impurity in the drug substance, AH113462/E, transforms through AH113462/K to AH112623 (see Section 3.2.P.5.5.1 (a) Transformation of the [1-13C]pyruvic acid purity profile for Drug Product Kit Components). As the dissolution step during the semi-automated compounding of Hyperpolarized Pyruvate (13C) Injection takes place in less than 10 seconds and the product is administered within 50s from start of dissolution, the transformation from AH113462/E to AH112623 will not be complete. The drug product used in the pre-clinical safety studies and for clinical studies GE-101-001 and GE-101- |
| 29 | 3.2.P.8.1 | 61 | Stability Summary and Conclusion (Hyperpolarized Pyruvate (13C) Injection) | The stability-indicating parameter for Hyperpolarized Pyruvate (13C) Injection is the level of 13C nuclear polarization, which decays rapidly after compounding. The stability testing performed has therefore been limited to determination of the 13C nuclear polarization and relaxation time (T1). 3.2.P.8.1.1 Batches tested Stability testing has been performed on six samples of Hyperpolarized Pyruvate (13C) Injection compounded from Mixture of [1-13C]pyruvic acid and 15 mM AH111501 sodium salt batch FFF106/140-806 and TRIS/EDTA buffer solution batch FFF106/142-806. 3.2.P.8.1.2 Storage conditions and testing frequency Testing was performed inside an MRI scanner located next to the clean room where the compounding of the sample took place. For testing frequency, see Section 3.2.P.8.1.3 Analytical Procedures and Specification. 3.2.P.8.1.3 Analytical procedures and specification The level of 13C nuclear polarization was determined using a 3T MRI scanner. The hyperpolarized 13C NMR signal was obtained using a 5 degree RF pulse. During the relaxation of the non-equilibrium polarization, a total of 64 spectra with 5 degree pulse and TR=3s were collected; the first of which was used for calculating 13C polarization. The relaxation time (13C T1) was calculated by fitting these data to a mono-exponential decay curve. After relaxation to thermal equilibrium, a thermal 13C NMR spectrum was collected (90 degree pulse, 64 averages, TR=10s, after addition of 10 μl Gd/ml solution) in order to calculate the 13C polarization. No shelf-life specifications have been established for Hyperpolarized Pyruvate (13C) Injection. Assurance of quality at time of administration rests on analyses performed before release and the time limit for administration after the dissolution step is completed, which is stated in the imaging |
| 30 | 3.2.P.8.2 | 62 | Post-approval Stability Protocol and Stability Commitment (Hyperpolarized Pyruvate (13C) Injection) | Sample not for submission protocol. 3.2.P.8.1.4 Summary of results The stability results are presented in Section 3.2.P.8.3 Stability Data. 3.2.P.8.1.5 Conclusion With a relaxation time of 69s, the polarization decreases by 7% (relative) each 5 seconds. To optimize imaging signal, administration should hence take place as quickly as practically possible. To assure the level of polarization during clinical use, and hence a certain level of imaging signal, the drug product will be administered within 50s from time of start dissolution. With a release specification of NLT 15.0% and a relaxation time of 69s, this user window limit will assure a polarization of NLT 7.3% at time of administration. 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment (Hyperpolarized Pyruvate (13C) Injection) Not applicable. 3.2.P.8.3 Stability Data (Hyperpolarized Pyruvate (13C) Injection) The average relaxation time determined for the six samples investigated was 68.8 ± 1.3s, with a range of 67.1 to 71.0s. A line derived from the stability results on Hyperpolarized Pyruvate (13C) Injection is shown in Figure 1. In Figure 1, the line represents a sample released at specification limit (NLT 15.0% at start of dissolution), decaying with the average measured relaxation time (69s). |
| 31 | 3.2.P.8.3 | 62 | Stability Data (Hyperpolarized Pyruvate (13C) Injection) | The average relaxation time determined for the six samples investigated was 68.8 ± 1.3s, with a range of 67.1 to 71.0s. A line derived from the stability results on Hyperpolarized Pyruvate (13C) Injection is shown in Figure 1. In Figure 1, the line represents a sample released at specification limit (NLT 15.0% at start of dissolution), decaying with the average measured relaxation time (69s). Sample not for submission protocol. 3.2.P.8.1.4 Summary of results The stability results are presented in Section 3.2.P.8.3 Stability Data. 3.2.P.8.1.5 Conclusion With a relaxation time of 69s, the polarization decreases by 7% (relative) each 5 seconds. To optimize imaging signal, administration should hence take place as quickly as practically possible. To assure the level of polarization during clinical use, and hence a certain level of imaging signal, the drug product will be administered within 50s from time of start dissolution. With a release specification of NLT 15.0% and a relaxation time of 69s, this user window limit will assure a polarization of NLT 7.3% at time of administration. 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment (Hyperpolarized Pyruvate (13C) Injection) Not applicable. 3.2.P.8.3 Stability Data (Hyperpolarized Pyruvate (13C) Injection) The average relaxation time determined for the six samples investigated was 68.8 ± 1.3s, with a range of 67.1 to 71.0s. A line derived from the stability results on Hyperpolarized Pyruvate (13C) Injection is shown in Figure 1. In Figure 1, the line represents a sample released at specification limit (NLT 15.0% at start of dissolution), decaying with the average measured relaxation time (69s). |