Integration of a disposable system in a traditional manufacturing process to terminal sterilization

Size: px

Start display at page:

Download "Integration of a disposable system in a traditional manufacturing process to terminal sterilization"

Lorena Shelton
10 years ago
Views:

1 Integration of a disposable system in a traditional manufacturing process to terminal sterilization G. Fiorentino QA Supervisor ITALFARMACO SPA Milano

2 ITALFARMACO Italy Milano plant LOCATION: Milan Italy TOTAL FACILITY AREA: m² NUMBER OF EMPLOYEES: About 160 OPERATIONS: Pharmaceutical Manufacturing

3 GROUP

4 ITALFARMACO Italy Milano plant

5 Case study description Implementation of a Single Use System in a traditional department for non cytotoxic drugs manufacturing (traditional technologies used) Reasons of the decision Project development: Choice of the system System set up System validation

6 Current traditional system 400L stainless steel preparation tank Single sterilizing filtration (terminal sterilization product): 100L stainless steel holding tank 4 vent filter 4 sterile filter (0.2 m) + 1 filter of reduction bioburden (0.45 m) Silicone Pt-cured connection tubings

7 Current traditional system Filling in Class C under LAF Class C compounding room Class A/B filtration surround C AUTOCLAVE (Sterilization of the filled ampoules) 7

8 Single Use System: Pro&Cons Advantages: Aseptic connections reduction Increase of the sterility assurance and decreased contamination risks Decrease of cleaning/cleaning validation activities Reduction of equipments costs and related activities (i.e. equipments sterilization costs) Decreased post-filling activities done by production operators

9 Single Use System: Pro&Cons Disadvantages/Risks: Possibility to introduce the Single Use System on the existing production line Single Use System costs (purchase and discharge) Increase of validation activities: Preliminary evaluation of the possibility to use the Single Use System with the defined product/s Validation related costs Regulatory risks/activities: Possible regulatory requests on Single Use System Regulatory variations necessary in case of registered products (related activities and costs) Impact on project timelines, costs and risks

(traditional and single use) Introduction of the Single Use System easy for a

10 Single Use System: conclusions Single Use System is easy introduced only in a phase/step of production process Possibility to use two alternative systems (traditional and single use) Introduction of the Single Use System easy for a product under development/new registration How to proceed with the Single Use Project??

11 Project development SUS SUS drawing SUS components: Silicone Pt-cured tubings T and Y propylene connectors Polycarbonate rapid connectors Defined system: Single Use System specific validation package

12 Validation aspects Separate validation of the filter and of the Single Use System Filter validation according to regulatory requests: Viability Challenge Extractables Integrity test values Adsorption Single Use System validation: start of combined work Italfarmaco-Supplier

13 Regulations and Guidance International Standards ICH Q1A: Stability testing of new Drug Products and Substances: Container closure system ICH Q3A, Q3B: Impurities in New Drug Substances and Products: Threshold (%) depending of the max daily dose ICH Q3C = E.P.5.4 = USP<467> (draft): Guidelines for residual solvents ICH Q7A: Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients ISO part 13: Identification and quantification of degradation products from polymeric medical devices ISO (2003): Plastics containers for intravenous injection US/North America 21 CFR Part : Equipment construction Canadian Food and Drug Regulations, GMP, Part C, Division 2, Section C : Equipment FDA CDER/CBER Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics Europe EU GMP, Medicinal products for human and veterinary use, European Commission, Volume 4, chapter 3, paragraph 3.39 EMEA/205/04 Guideline on Plastic Immediate Packaging Materials Other references PDA Technical report 26: Sterilizing Filtration of Liquids (2008) PQRI publication: Safety thresholds and best practices for extractables and leachables in Orally Inhaled and Nasal Drug Products ASTM E (2006): Standard guide for determining the impact of exctractables from non-metallic materials on the safety of Biotechnology Products BPSA (Bioprocess Systems Alliance) recommendations on extractables and leachables (2008)

14 Validation aspects Supplier qualification of the single components of Single Use System: Bag: Drop test; Resistance to gamma irradiation and to Freezing test; Connection testing; Shelf life studies (leak, tensile strength; sterility; Accelerated aging; Extractables/Leachables studies; Biological Safety tests; Physicochemical tests (endotoxin, particulate) Assembling: Burst testing; Creep rupture testing; Tensile stregth testing; Functional testing (soiling test), Closure integrity testing; Water flow/pressure drop data; Extractables testing; Shelf life studies; Autoclave testing; Biological Safety testing Supplier qualification (3rd parties) of the single components of Single Use System: Tubings: Materials certificates (including manufacturing environmental classification and generic extractables in WFI) Connections and reducers: Components certificates (including manufacturing environmental classification

15 Validation Adsorption study Compatibility study Leak Test Drop Test Burst test Extractables and Leachables

16 Cost comparison Costi fissi ogni utilizzo Lavaggio WFI Energia elettrica Chemicals Manodopera (realizzazione + documentazione) Sterilizzazione Energia elettrica Altre Utilities (CS,CA, CW) Usura serbatoio / steriliz.machine Manodopera (realizzazione + documentazione) Altre utilities (IS, CA) Usura Tank / Fixed lines + Washing machine Preparazione WFI (per final rinse) Accessori per preparazione Manodopera (realizzazione + documentazione)

17 Cost comparison Costi manutenzione-validazione / Year Manutenzione preventiva tank Sostituzione membrane e O-ring Sostituzione attuatori valvole Ispezione boroscopica integrità saldature Leak test Manodopera (per tutte le voci sopra) Fermo del sistema

18 Cost comparison Manutenzione preventiva Mixing Driver Manodopera per controllo parti elettriche e meccaniche Cleaning re-validation Manodopera Materiale occorrente per campionamenti Test QC Sterilization Cycle re-validation Costi sterilizzazione Materiale occorrente per RUNs sterilizzazione (IB, ecc..) Manodopera Test QC Fermo della macchina

19 Cost comparison Costo investimento iniziale Tank Mixing driver per tank Qualifica iniziale / Validazione

20 Evaluation VALUTAZIONE BAGs Vs TANKs Costo Totale per Utilizzi / Year -40% Costo Totale Manutenzione / Year -78% Costo Totale Steriliz.Cycle re-validation / Year -100% Costo Totale Steriliz.Cycle re-validation / Year -100% % Cost Saving BAG Vs TANK 29,4% STIMA PERIODO AMMORTAMENTO < 1 YEARS

21 ITALFARMACO Italy Milano plant Main advantages of SU Technology : 1) Decrease risk of cross contamination 2) Achieve greater assurance of sterility 3) Eliminate cleaning requirements 4) Reduce maintenance requirements 5) Decrease documentation requirements 6) Reduce production cycle time 7) Reduce water requirements 8) Reduce space requirements 9) Eliminate use of hazardous cleaning fluids 10) Reduce capital investment in facility and equipment

23 ITALFARMACO Italy Milano plant

24 ITALFARMACO Italy Milano plant

25 Business Drivers

26 Qualification

27 Implementation

28 Validating an SUS Process validation remains the responsibility of the pharmaceutical manufacturer Leveraging supplier data requires an understanding of how it was developed Materials of construction Testing procedures (e.g. pyrogens, heavy metals, solvents, E/L) System design may require features to facilitate validation Alternate receiving vessels to accommodate testing Integrity testing Desirable, but not necessarily realistic or achievable Campaigning Surge vessels, columns

29 Validating an SUS Conclusions Suppliers are an integral part of the quality system Unprecedented levels of transparency and data sharing and management are required Those who fully embrace true partnerships will be the most successful

30 Validating an SUS Materials management - no pain, limited gain Low impact mtls are relatively easy to alternate source Decreases exposure at a single supplier Gain experience of alternative suppliers quality system Financial benefits a consideration High impact materials require more work to qualify Addresses higher risks (supply interruptions, recalls) Lower frequency of use The back-up may fail before the primary Maintain high levels of support and service from suppliers

31 G. Fiorentino QA Supervisor

How single-use connections advance aseptic processing: Increased process flexibility and reliability, reduced costs

WHITE PAPER 7004 How single-use connections advance aseptic processing: Increased process flexibility and reliability, reduced costs By John Boehm Business Unit Manager Colder Products Company Today s