CANM Annual Meeting Toronto, Canada April 21-24, 2017

Transcription

1 CANM Annual Meeting Toronto, Canada April 21-24, 2017 Developing Nuclear Medicine Tracers in an Evolving Radiopharmacy World Shaun Ramdhany (B.Pharm, Certified Nuclear Pharmacist) VP- SPECT & PET Radiopharmacy Operations President- CARS (Canadian Association of RadioPharm Scientists)

2 Disclosures Employee of Isologic

3 Objectives: To explain Cause and Effect in the Radiopharmaceutical Sciences with regards to: 1) The need for Regulatory Constraints to protect our profession 2) Rx Pharmacoeconomics: Market Supply Chain and Geopolitical influences affecting Costs 3) Developing Agents: Invigorating Nuclear Medicine Departments 4) A Perspective of the future of Radiopharmaceutical Sciences

4 Chronology of Contamination Incidents Patient Injury & Deaths

5 Chronology of Contamination Incidents Patient Injury & Deaths

6 Impacts of a Compromised Quality Management System Date September 21, 2012 Location United States (23 States) Cause Fungal contamination of steroid medication Deaths 64 Non-Fatal Injuries 751 Litigation 400+ lawsuits filed against NECC Fungus (stained black) in infected brain tissue

7 1) The need for Regulatory Constraints to protect our profession Cause; Effect; Failed aseptic preparations due to compromised quality management systems Higher degree of regulatory scrutiny FDA, Health Canada, CNSC mandating minimum and harmonized compliance directives Lead to the enforcement of USP <797> ; cgmp with a focus on product quality and patient safety

8 FINGER-DAB RESULTS AFTER VARIOUS HANDWASHING METHODS Water many organisms still present on each finger tip Soap and Water fewer organisms than with water alone, but some still detectable Use of a Skin Sanitizer after washing removes all contamination

9 1) The need for Regulatory Constraints to protect our profession What Is USP <797>? Refers to chapter <797> "Pharmaceutical Compounding Sterile Preparations," in the United States Pharmacopeia (USP) National Formulary. First set of enforceable sterile compounding standards issued by the USP. USP <797> describes the guidelines, procedures and compliance requirements for compounding sterile preparations. Compound Sterile Product (CSP) CLASSIFICATIONS Classification Immediate Use Requirements Inject < 1Hr; No Environmental Controls; Aseptic; NMT 3 Sterile products / 2 septum Entries Low Risk Aseptic; NMT 3 Sterile Products/ 2 septum entries Medium Risk High Risk Aseptic; > 3 Sterile Prods; Multi-Dose Non-Sterile; Open System Transfers

10 1) The need for Regulatory Constraints to protect our profession To Whom Do USP <797> Standards Apply? UTILIZING THE USP USP <797> HAS SPECIFIC GUIDELINES FOR: Design of Facility Environmental and Engineering Controls Environmental Testing Personnel Training and Competency Testing Standard Operating Procedures and Documentation Quality Assurance Patient Monitoring and Adverse Reporting Storage and Dating

11 What are the cgmps? 1 cgmp stands for current good manufacturing practices. Dossier of current, scientifically sound methods, practices or principles Implemented and documented during every stage of product development and production Ensures consistent manufacturing of safe, pure, and potent product Enforced by Health Canada; US Food and Drug Administration (FDA); etc 1. U.S. Food and Drug Administration. Facts About Current Good Manufacturing Practices (cgmps). tm. Accessed February 27, 2016.

12 2) Rx Pharmacoeconomics: Market Supply Chain, Geopolitical and regulatory influences affecting Costs SPECT Nuclear Medicine: Cause Diminishing numbers of established Global Reactors producing Mo99 Diminishing cold-kit options and single-vendor supply Higher Input costs- regulatory and infrastructure upgrades to meet quality directives Effect Enhanced collaboration between new and existing reactor sitespreventing supply interruptions Alternate/ non-reactor synthesis technologies (LINAC, Cyclotron) Radiopharmacy personnel must me experts in implementing greater Efficiencies (Lean operations, Six Sigma process control)

13 2) Rx Pharmacoeconomics: Market Supply Chain, Geopolitical and regulatory influences affecting Costs

14 2) Rx Pharmacoeconomics: Market Supply Chain, Geopolitical and regulatory influences affecting Costs

15 2) Rx Pharmacoeconomics: Quality and Regulatory Costs cgmps = systems that assure proper design, monitoring, and control of manufacturing processes and facilities.$$$ Each of these QMS factors contribute to the unit-dose cost of each RP $$$

16 Rx SPECT Unit Dose Dispensing Flow Closed Aseptic System (1) (2) (3) (4)

17 Laminar Flow An airflow moving in a single direction and in parallel layers at constant velocity from the beginning to the end of a straight line vector Feb26 - cited HEPA Filtered Laminar/ First Air in Critical Zone area where septa are punctured Dispensing Paraphernalia (Dose Calibrator/Screen/Key & Mouse Pad) away from critical zone. Most optimum Radiation safety and Sterile arrangement

18 Cancer rates in Canada

19 3) Developing Agents: Invigorating Nuclear Medicine Departments Description of Theranostics, Personalized Medicine and Nanotechnology wrt Radiopharmaceuticals Cause; Cancer Patients are being treated at older ages co-morbidity and poor treatment candidates Patients less tolerant to cytotoxic chemo agents (Harsh S/E Profile) Treatment costs are increasing with uniform Tx approaches- nominal treatment successes Effect; Theranostics- couples diagnostic imaging and therapy in the same molecule Sensitivity & Specificity ; SE profile Personalized Medicine producing better treatment responses THERANOSTICS: RIGHT TREATMENT; FOR THE RIGHT PATIENT; AT THE RIGHT TIME AND AT THE RIGHT TIME

20 m nm (10 9 ) mm

21 Nanomedicine

22 Theranostic Nanomedicine in Molecular Imaging

23 Radioimmunotherapy Antitumor Effects and Normal Tissue Toxicity of 111In-Labeled Epidermal Growth Factor Administered to Athymic Mice Bearing Epidermal Growth Factor Receptor-Positive Human Breast Cancer Xenografts Paul Chen, PhD1, Ross Cameron, MD, PhD2, Judy Wang, MSc1, Katherine A. Vallis, MD, PhD3,4,5 and Raymond M. Reilly, PhD1,6,7 {J Nucl Med September 1, 2003 vol. 44 no } Nuclear Medicine and Biology, 2011; 38(1): A kit to prepare (111)In-DTPA-trastuzumab (Herceptin) Fab fragments injection under GMP conditions for imaging or radioimmunoguided surgery of HER2-positive breast cancer. Scollard DA, Chan C, Holloway CM, Reilly RM.

24 Monoclonal Antibodies Radioimmunotherapy and PRRT Peptide receptor radionuclide therapy (PRRT)- TX for specific type of cancer NETs Radiopeptide has high affinity for target receptor expressed on Tumor surface- Specificiity Toxicity Overexpression of Somatostation receptors in tumors (NET s ) Lab synthesized analogue Octreotide

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26 Radioiodinations - Iodine-131 Therapies

27 Meta-Iodobenguane (MIBG) Most common cancer in infants < 1 Y.O Most commo extra-cranial solid cancer in childhood Accounts for 7% of cancers in all children Ave. age for diagnosis 18 Months 90% of all cases diagnosed by 5 Y.O Very rare in kids > 10Y.o

28 MetaIodoBenguane (MIBG) Radioiodinations ]. Representation of the mechanisms involved in 131I- mibg uptake, retention, and efflux. Passive diffusion phenomenon and exocytosis, 131I-mIBG may be released by the uptake carrier working in a reverse mode. Red text and lines represent the mechanisms being explored to enhance 131I-mIBG uptake, retention, and cytotoxicity. Circle = 131I-mIBG, triangle = norepinephrine. HDAC = histone deacetylase; VMAT= vesicular monoamine transporter Some therapies radiosensitize neuroblastomas (while others directly increase NET expression or enhance its function. Nothing but NET: A Review of Norepinephrine Transporter Expression and Efficacy of I-131-mIBG Therapy (PDF Download Available). Available from: nd_efficacy_of_i-131-mibg_therapy [accessed Apr 20, 2017

29 Developing Agents: Invigorating Nuclear Medicine Departments

30 RadioTheranostics Concept Simplified Model of a RP showing: -Binding molecule which bind s Target -Linking molecule that bind the isotope -Theranostic molecule DOTATOC; DOTATATE; PSMA

31 Prostate Cancer-The Development of Radiotheranostic PSMA Ge-68/Ga-68 Generator System + Cold Kits formulations *Mobile Preparation system- for peripheral NM departments Require Radiopharmacy Subject Matter experts For preparation: -Radiochemists; Radiopharmacists; Quality and Regulatory experts, RSO to design SOP s -Process must meet cgmp conditions

32 Theranostics Advances Synthesis T1/2 Emitte r Energy Ga-68 Generator (Ge68/Ga68) 68.3 min β kev Lu-177 Reactor 6.73 days β/ϒ 490 kev(β) Y-90 Reactor 64.1 hrs β 2284 kev DOTA CHELATOR

33 3) Developing Agents: Invigorating Nuclear Medicine Departments Timescales for New Developments

34 Developing Agents in Neuroscience