TERMINAL STERILISATION of HIGH VALUE DRUGS - PowerPoint Presentation

1. TERMINAL STERILISATION of HIGH VALUE DRUGS20 years of experience Dr Bruno TISSIER/ Tissier Pharma Consultingbruno.tissier@gmail.comApr 2nd 201911

2. INTRODUCTION2Currently , in the Health Industry , IRRADIATION is less used for Pharmaceutical Drugs than for Medical Devices Less than 50 Gamma Sterilized Pharmaceutical Drugs are sold in the EU Market (estimate) List is not published Most are Ophtalmic presentations (Eye drops / ointments) Antibiotics (Neomycine , Chloramphenicol , …) / ointmentsInjectables antibiotics (Tetracycline , …) And very few high value / High tech Drug Products Slow release injectable formulations of Hormones Complex Drug Device combinations ( injectable gel) S.Galy ,Univ Limoges , These , 1995

3. Gamma Irradiation is also Used for Pharma Active Ingredients ( API) or excipients Apr 2nd 20193Limited to bulk chemicals which can support high doses , without any major potency loss …3

4. WHY Gamma Irradiation is used ?Apr 2nd 20194Not only to sterilize a Drug Product , but to achieve sterility with a high confidence degree “Sterility Assurance Level” (“SAL”)For practical reasons : Sterilization of the final container ( “terminal sterilization” ) Sterilisation of ointments or complex formulations Sterilisation of drug / device combinations For economic reasonsCost / Risk /Speed / manufacturing cycle time Sterility tests may be avoidedFor technical considerations Reliability , Reproducibility , and Safety 4

5. Regulatory Environment for Drugs in EU Apr 2nd 20195Decision tree on sterilization processes EMEA,CPMP,054/98 Avr 2000Gamma irradiation is not recommended as terminal sterilization for AQUEOUS PRODUCTS 5

6. Regulatory Environment for Drugs in EU Apr 2nd 20196Decision tree on sterilization processes EMEA,CPMP,054/98 Avr 2000Gamma irradiation is recommended as terminal sterilization , before aseptic processing Accepted doses, 25 KGy or lower Reference to EN/ISO 11137But some EU Health Agencies still reluctant as Gamma Irradiation is considered as a “Non conventional sterilization method “ …..6

7. Conventional sterilization approach in Pharma IndustryApr 2nd 20197Terminal sterilization ( final container) Drug Product bioburden tested prior to sterilization Very Low bioburden specifications ( checked as in process control on samples ) Sterilisation by validated process ( dry/moist heat , gamma )End product Quality Control before release (test on samples ) 7

8. ISO/EN 556Apr 2nd 20198Sterility Assurance Level : SAL For the medical device to be labelled ‘STERILE’ the theoretical probability of there being a viable micro-organism present on the device shall be equal to or less than one in 1 x unitsIn the Pharma Industry , very low SAL are reached routinely , far below  8

9. Conventional Quality control process in Pharma IndustryApr 2nd 20199Test on finished products samplesPhysico /Chemical / Biological / …Endotoxins limit test( from G-bacteria membrane …),Sterility tests on finished ProductsWhat are the limitations of the Sterility test ? 9

10. What are the limitations of the Sterility test ? Apr 2nd 201910First order :The sterility test do not track down a contamination of the batch It is called : Risk of false negative => Release a non compliant batchSecond order : The sterility test show a contamination of the batch , which is due to a bad operation during sterility testingIt is called : Risk of false positive => Reject a compliant batch !!10

11. First Order limitation Apr 2nd 201911Test on samples (size , representativeness ? )Low (and unacceptable ) probability to detect a contamination at a low level Example : If a batch is contaminated at a level of 10% , then the False Negative Probability of the conventional sterility test is 14%11

12. Sterility test on samples►lack of representativenessApr 2nd 201912Batch = 3000 unitsSample : 20 unitsFalse negative probabilityIf a batch is contaminated at a level of 10% , then theFalse negative probability ,of the conventional sterilitytest is 14%Contamination Level (%)12

13. Second Order limitation Apr 2nd 201913Contamination during sampling or during the sterility test A “contamination” is detected Consequence => The batch is rejected while compliant !!Called : Risk of false positive (*)Risk rating depending on handling conditions :Fully Manual operation : >5% (membrane test) Handling Into isolator with closed Sterility Test device : 1,25%ISOLATOR : <1% ( no public data )(*) B. Green & W.Litsky Pharm Technology Vol 3 nr11 13

14. Mitigation / 1 Apr 2nd 201914In order to avoid such Risks , and taking into account the effectiveness and the reliability of the gamma irradiation process , we were able to accumulate data / evidences to prove to Health Authorities that it is safe to replace the conventional sterility test by Parametric Release EU GMP Annex 17: Real Time Release Testing and Parametric Release 14

15. Mitigation / 2 Apr 2nd 201915EU GMP Annex 17(*): Real Time Release Testing and Parametric Release In specific circumstances, where authorised, based on product knowledge and process understanding, information collected during the manufacturing process can be used instead of end-product testing for batch release.Possible to apply RTRT : Real Time Release Testing (*) EudraLex Volume 4 Annex 17 rev 1 26Dec201815

16. In routine manufacturing batches of Drugs ProductsApr 2nd 201916Process development &/ validation , done according to ISO 11137-2, Sterilization of health care products—Radiation-Part 2VDmax process is the method of choice for drugs (For routine Drug Production Batches) Establishing the sterilization dose, is used to establish a minimum sterilization dose of 15 kGy for products with an average bioburden <1.5 CFU or 25 kGy for products with an average bioburden <1,000 CFU. The number of devices required to conduct a validation is the same as indicated under AAMI TIR 33 – VDmax.Dosimetry and biological indicators are needed during PV 16

17. If mean Biocharge ≤217Then verification Dose () is 3,6kGy Then Minimum Sterilisation dose to get SAL () is 15,2 kGy  if ≤ 2 positive on n=100 samples , vérification is compliant ISO 11137-2, VD Max Method 1 / example -2/ SAL

18. However / One issue with VD max method The current GMP deployed in a ISO 5 (EU 1997 A/B) or better … clean room environment with trained and experienced operators , lead to negative bioburdenNeed to develop specific qualification / validation strategy adapted to the DP , to justify using ISO 11137- VD max method18

19. Section II :Application to TERMINAL STERILISATION of HIGH VALUE DRUGSMore than 20 years of experience …Apr 2nd 20191919

20. Slow release injectable formulations of High tech Drug ProductsApr 2nd 201920Injectable Slow release formulation of Hormonal products with release over months20

21. And High complex packaging / API into a medical device = Combination ProductsApr 2nd 201921Example of Complex Medical device https://www.fda.gov/CombinationProducts/21

22. Process scheme /Aseptic ManufacturingFillBulkActive IngredientexcipientProcessCore medical deviceAssemblyAdded parts of MDPack Bag / Pouch / blisterFinished DPApr 2nd 201922

23. Process scheme /Clean Manufacturing & terminal Sterilisation FILLBulkActive ingredientexcipientProcessCore medical deviceAssemblyAdded parts of MDPACKBag / Pouch / blisterFinished DPTerminal sterilisation in the final containerApr 2nd 201923

24. Drug Product development Apr 2nd 201924Preformulation studies are critical to check the gamma compatibility of the formulation (at foreseen maximum dose )Drug formulation ( purity , potency…)Container suitability (material, ...)Packaging integrity , Leachables , tightness after Gamma exposure, …Drug product critical parameters ( H2O , O2 , temperature , …)Small scale developmentStability studies (peroxydes , …) …=>Define Critical Process parameters and confidence interval 24

25. From Drug development to routine Pharmaceutical drug manufacturing Apr 2nd 201925Use decision tree for Sterilisation process choice Radiosterilisation process must be envisaged as early as possible in the drug development Terminal gamma-sterilisation (i.e. the final container ) is the best option Gamma irradiation process validation Dosimetric ,Bio Indicators & Product validation (chemical , Pharmacological …) Geometry of the load , Irradiations conditions ( temperature ,H2O residual , O2 , …) Dose mapping , ( mini /maxi , range issue ) …. Effects on Drug Products & devices?Temperature ? How to follow temperature during Irradiation ? …Full documentation / validation report / Critical Process Parameters 25

26. One specific issue : Technology Transfer & LCMApr 2nd 201926Life Cycle Management / … examples From small scale to large batchesChange of gamma irradiator process / From batch to continuous process Example : Product overload to source overload Change / duplicate of gamma irradiation facility Co60 Source potency and facility design Mainly for business safety & Recovery Action Plan ICH Q12 Post approval changes and Continuous Improvement => May need to file Amendments to DP Licences ( Variations ,Modifications AMM , SUPAC, …) Process validation to be performed each 12 month and at each Co60 source reloading / reorganization 26

27. In Routine Operations Apr 2nd 201927Regulatory constraints :In most countries , One Qualified Person is needed at supplier during operationsIn France , a Responsible Pharmacist is required during Operations + Pharmaceutical establishment status of the Company Manufacturing / quality agreement with the Gamma Irradiation supplier Accessibility and sustainability …Apply GMP conditions & specific GMP training of supplier team .Strong Environment monitoring and control (in Manufacturing process) systematic bioburden tests, Dose mapping studies : each 12 month , or after each Co60 reloadStability studies on routine batches supplier / partner periodic Quality & Compliance audit 27

28. Irradiation Gamma / specific container to be developpedApr 2nd 201928

29. Specific loading pattern is needed to meet targeted parametersApr 2nd 201929

30. IHB / Somatuline BT / Jan 05Automatic loadingApr 2nd 201930

31. Apr 2nd 201931Feedback on 20+ years of experience of development / Manufacturing of several major injectable drugs and drug-device combinations treated / sterilized routinely by gamma Irradiation (Co60)31

32. Key learnings 32Development:Gamma irradiations considered from scratch , associated with Parametric releaseNeed a strong drug development file /with data , and scientific rationale support Regulatory Be prepared to be challenged by MOH authorities / agencies / inspections …Drug product Manufacturing Licences were finally granted by all major Drug control agencies , US FDA , JPN , China SFDA , EU , Russia , …Operations Manufacturing of more than 250 batches per year for more than 20 years Partnering : Select a set of 2 reliable radiation companies able to face international regulations (and audits ) , and accommodate growing volumes Supplier failure risk must be mitigated / Continuous improvement process in place

33. Operational Results and discussionApr 2nd 201933High Safety & reliability : Gamma irradiation process was able to consistently provide a High SAL of 10-6 and belowTime saved in the manufacturing cycle : By using Gamma-irradiation and Parametric release , Drug Product cycle time was shorten by 1 month .Less working capital requiredFinancial savings on COG’s :No batch rejectedNo more sterility test needed (in Routine and in Stability studies) Decrease the number of retained samples by batch ( 20x2 or x3) No sterility tests during stability studies ( except at T=0) No risk of batch rejection , due to false positive sterility testing 33

34. ConclusionApr 2nd 201934For 20+ years , we are convinced that Gamma-Irradiation is the process of choice to provide a very high Sterility Assurance Level for injectable Pharmaceutical Drugs , able to support gamma rays Important savings if coupled with Parametric release Strong Partnership and full collaboration / transparency and partnership / training are needed between customer and gamma irradiation facility / supplierCarefully consider regulatory hurdles for Post Approval Changes 34

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