Cost of GMP in Nuclear Medicine (Cold Kit)

Transcription

1 Cost of GMP in Nuclear Medicine (Cold Kit) Sanjay K Sharma MSc, PhD, PChem Director, Scientific and Operations Edmonton Radiopharmaceutical Centre Edmonton-Alberta

2 What is ERC Edmonton Radiopharmaceutical Centre-AHS Products Cold Kits- MDP-10, MDP-21, DISIDA, DTPA, MAA, SC, AS, Pyro Iodine- 131 I-Ther (Inj.), Oral 131 I-Diag (Inj.), Oral 131 I-mIBG (Diag.), 123 I-mIBG SPECT 13 Products PET FDG Clinical trial 177 Lu-DOTA-TATE, Na 18 F Clients 30 (AB and in Canada) 2

3 Introductory Statements and Considerations All conclusions are derived from economical considerations, not technical Very good science is not sufficient to bring a drug on the market Radiopharmaceutical industry (RPI) is now fully mature but does not have the funds to fully develop RPs Today Conventional Pharma Industry (CPI) is not (yet) interested in RPs (and absolutely not in diagnostics) Regulatory constraints will not be weaker in the future Awareness about potential and successes of radiopharmaceuticals is very weak 3

4 Health Care-CANADA Canadians are very attached and proud of their health care system (Quality) Canadians are very supportive of the principles of the Canada Health Act But this Quality of Health Care is associated with a COST to the providers This Cost is effecting the field of Medicine too In Nuclear Medicine, as in other medical fields, we are under increasing pressure to lower costs and to gain the most benefit from the dollars we spend. 4

5 Not here to argue with any Regulators But 5

6 Radiopharmaceuticals Hold promise for diagnosing disease Monitoring disease progression Tracking therapeutic response Knowledge of physiology and pathophysiology 6

7 Radiopharmaceuticals Radionuclide Itself 99m Tc Pert, Na 18 F Pendant/Molecular Scaffold 99m Tc-MDP, 99m Tc-DISIDA, 99m Tc MIBI etc 68 Ga-DOTA/TATE/TOC, 18 FAlkF Tracer Incorporated Estradiol, 11 C, 13 N, 15 O 7

8 Challenges for Radiopharmaceuticals Comparison with therapeutic agents Same path of development as therapeutic agents Target Validation Lead candidate identification High Affinity Target/Non-Target distribution Adequate clearance Low Toxicity Multiple phase clinical trials Similar Regulatory submissions 8

9 Drug Development 9

10 Economics of Diagnostic Agents Market of therapeutic drugs world wide is close to $962.1 billion Market of Diagnostic agents worldwide is $3.8 billion Pfizer alone is $6.5 billion Small/Specaility category of therapeutic drugs Handful of players involved in Diagnostic agents development 10

11 How we are Surviving Academia Active and Research academic investigators Funds/Grants are drying Administrative hurdles Strict regulatory guidelines Industries Small to medium sized industries Low revenue Strict Regulatory requirements 11

12 What Happened? Regulations of Therapeutics drugs implemented on Diagnostic Agents All the developments and clinical productions of Diagnostic agents still in Academia or in Hospitals Huge infrastructure investment (retrofitting) Quality Assurance Department 12

13 Where we stand today 13

14 an Analogy 14

15 What is GMP Good Manufacturing Practice (GMP) is a concept in pharmaceutical regulation which aims to ensure consistent production of a safe and effective product. The three main components are Facilities Documentation Training. 15

16 Importance of GMP 1937 Elixir Sulfanilamide (diethyl glycol as a solvent) 100 deaths 1960 Thalidomide Tragedy Birth defects 2012 New England Compounding Center 48 died fungal meningitis infections 16

17 Importance of GMP GMP is based on good science GMP generate more paper One of the pillars of science is that you can prove it. We re in the prove it business. We need to ensure that the GMPs for radiopharmaceuticals don t stray from this concept. 17

18 There is a Cost to Quality/Compliance I do think that additional work is needed to help Centralized Radiopharmacies get the best bang for their quality dollar. Industry and Health Canada are ultimately on the same side and have the same goal. High quality product Ensure patient safety 18

19 Elements of GMP Facility Design to control operations Adequate documentations/records Production and process controls Quality Assurance/Quality Control Validations Environment Monitoring Equipment's Validation Qualification Environment Processes Validation Monitoring Personnel Training and Certification 19

20 Environmental Monitoring Environmental monitoring describes the processes and activities that need to take place to characterize and monitor the quality of environment Environmental Monitoring is a surveillance system for microbiological control of cleanrooms and p\other controlled environments. It is a process which provides monitoring, testing and feedback to the biological quality levels in aseptic environments. 20

21 Monitoring Frequencies Daily Monitoring LAF/Passbox/Manufacturing Room/ Hallways Monthly Monitoring Manufacturing area/equipments Quarterly Monitoring All the above plus Compressed air Half Yearly Monitoring Operators (Media Fills)/Personnel Yearly HVAC/AHU/BAS system validation Occasional Monitoring As and when required 21

22 HVAC Monitoring Monitored yearly Parameters Temperature/RH Air Velocity Air Change Filter Integrity Non-viable air borne particles Vialble Air Borne particles 22

23 Validation Validation is establishing documented evidence which provides a high degree of assurance that a specific process or equipment will consistently produce a product or result meeting its predetermined specification and quality attributes Confirmation by examination and provisions of objective evidence that the specified requirement have been fulfilled 23

24 Phases of Validation Design Qualification (DQ) Documented verification of the design of equipment and manufacturing facility Installation Qualification (IQ) Documented verification that the equipment is installed as designed Operational Qualification (OQ) Documented verification of equipment or system performance in the target operating range Process/Performance Qualification (PQ) Documented verification that the equipment or system operates as expected 24

25 Key validation documents Validation Master Plan (VMP) User Requirements Functional Specifications Validation Protocols Standard Operating Procedures (SOPs) Validation Final Reports Change Control System 25

26 Validation contd. 26

27 Equipment Qualification and Cost Design, Requirement, Purchasing Regulatory requirements for Validation Establishing documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics 27

28 Design-Validation Relationship 28

29 Re-Qualification Event Driven Replacement of critical Components Change in process or procedure Change in personnel Failure Investigation Time Driven Change of the little things over time Poorly maintained system Routine system failure Environment dependent 29

30 Success and Difficulties in Validation Success Getting Validation personnel involved early in the process Well defined user requirements and specifications Integrating Validation into design-build-test-use cycle Good Communication Difficulties Inadequate definition of system requirements/specifications Poor Protocols Inadequate resolution/explanation of failures/deviations Poor planning 30

31 Summary of Validation As the User, know your requirements and processes Validation is a lifecycle approach. Its not a one time and done Be cognizant of change control Understand the functionality of the units being qualified 31

32 Equipment Validation-Vial Filler Customized Unit Semi Automatic Unit Filling under Class A Nitrogen Purging Half Stopper Pressure Crimping Semi Reject Station Star Wheel for 10, 20, 2 ml vials Different Volume dispensing $169,

33 Cost of OQ and PQ on Vial Filler Size of Vial Filling Precision Study-50% of the Batch Size # Vials # Runs Total Vials $/vial Total Cost 20 ml , ml , ml ,500.0 Total = $

34 Cost of OQ and PQ on Vial Filler Production Stimulation-50% of the Batch Size Size of Vial # Vials # Runs Total Vials $/vial Total Cost 20 ml ml ml Septum Crimp Total = $

35 Cost of OQ and PQ on Vial Filler Size of Vial Performance Qualification Full Batch Size # Vials # Runs Total Vials $/vial Total Cost 20 ml ml ml Septum Crimp Total = $ 42,

36 Processes Validation Product using 20 ml vial Three runs Cost for process Material cost $ /run Material cost for three runs $ Time A minimum of 10 working days Staff A minimum of two staff (not including QA, Scientific) A total of $47,000.00/Processes validation of this product * The API required for this product is manufactured by ERC 36

37 Processes Validation Product using 10 ml vial Three runs Cost for process Material cost $ /run Material cost for three runs $ Time A minimum of 10 working days Staff A minimum of two staff (not including QA, Scientific) A total of $ /Processes validation of this product * The API required for this product is manufactured by ERC 37

38 Processes Validation Cost Product Cost 20 ml Vial (two Products) $94, ml Vial (six Product) $390, Total $484,

39 Validation of a Lyophilizer Lyophilization is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase The process consists of three separate unique and interdependent processes, freezing, primary drying (sublimation) and secondary drying (desorption) 39

40 Validation Establishing a commercial lyophilization process can be very challenging Successful validation requires robust development studies, equipment qualification and process validation. Not enough focus on developing the freezing phase which is the most important phase of the cycle. Continued Processes Validation (CPV): Ongoing assurance is gained during routine production that the process remains in a state of control 40

41 Lyophilizer Qualification Equipment Qualification Temperature mapping Leak test Condenser capacity Processes Qualification Depending on the number of products Stability of the products Excipient 41

42 Cleaning (CIP) and Sterilization Perform between each run Clean-in-place(CIP) manual or automatic - CIP cycle-initial rinse, recirculation, final rinse, drying - CIP-CV should demonstrate total chamber coverage (riboflavin) WFI is preferred - Cleaning agent validation is required - Cleaning processes needs validation Sterilization - Should be sterilized after CIP, Typically Steam sterilization - Sterilization-Validation - Heat distribution and biological indicators - Unit should be dry after sterilization 42

43 Cost of PQ on Lyophilizer Three type of vials Two runs 50% Load 750 x 2 x 5.40 = $ x 2 x 5.40 = $11, x 2 x 3.40 = $17, % Load 1500 x 2 x 5.40 = $16, x 2 x 5.40 = $23, x 2 x 3.40 = $34, Total = 110,

44 Processes Validation-Lyophilizer Number of product API cost Number of runs Pre-release Specifications Sampling size 44

45 Product Validation Product (1, 2200 vials), API (ERC), Runs (3), Specification test (10), Sample size (250 vials) API (416 x 3) $ Vials (2200 x 3 x 5.4) $ Specifications (10 x 3) Internal Test - Visual, Leak Test, Labelling/24h Stability, Tin Assay, Endotoxin External Test - N 2 /O 2 content, Chemical content, Sterility, Biological Distribution/Functional Imaging $ Total =

46 ? Total cost of validation of this one product Vial Filler IQ +OQ + PQ + PV =$ Lyo IQ + OQ +PQ + PV =$ $

47 Questions? Is it necessary to do all this? Can we afford all this cost? Should we stop making these products? Is there any solution? YES NO NO??????? 47

48 ? How to persuade someone to begin developing a new agent To make a sale of $1-2 million to recover the cost An example of a Kit which only ERC produces Total sale should be ~ vials/year Estimated Revenue $1,000,000.0 our total production is ~8400 vial/year Revenue of ~$300,

49 49

50 Options Decrease the cost of bringing a drug to the market Charge more for a unit of drug Increase use of drug 50

51 Suggestions More discussions within CARS-CANM-BGTD Increase relationship/partnership between Industries and Academia Harmonized Market Authorization 51

52 Thank you for listening 52