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ICH Q11 – Definisjon av startmaterialer – Fleksibilitet og dokumentasjonskrav

ICH Q11 – Definisjon av startmaterialer – Fleksibilitet og dokumentasjonskrav. Andreas Sundgren LMI 17. april 2012. Definition of Starting Materials. Non-scientific approach : Justification based on complexity/non-complexity of starting materials.

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ICH Q11 – Definisjon av startmaterialer – Fleksibilitet og dokumentasjonskrav

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  1. ICH Q11 – Definisjon av startmaterialer– Fleksibilitet og dokumentasjonskrav Andreas Sundgren LMI 17. april 2012

  2. Definitionof Starting Materials Non-scientificapproach: • Justificationbasedoncomplexity/non-complexityof starting materials. • Justificationbasedoncommercialavailability • Focusonnumberofsteps, less focusonthemanufacturingprocess as a whole.

  3. Definitionof Starting Materials Q11 – A scientific approach: • A starting material should be a substance of defined chemical properties and structure. • Steps that impact the impurity profile of the drug substance should normally be included in the manufacturing process • Changes in material attributes or operating conditions that occur near the beginning of the manufacturing process have lower potential to impact the quality .

  4. No GMP requirements • No detailed description • MA holder might have limited access to documentation • Limited change control Starting Material • GMP requirements • Detailed documentation • MA holder has access to relevant documentation • Full change control ActiveSubstance

  5. Definitionof Starting Materials Considerstheirprocessesconfidential Differentqualitycontrol standards Not same defined SM Intermediate Starting Material Manufacturer Starting Material Manufacturer Starting material Active substance Starting Material Manufacturer Errors in communication Starting Material Supplier

  6. Definitionof Starting Materials A or D as Starting Material? Formationofstereochemicalcenter All significantimpurities from Step 4-6

  7. Definitionof Starting Materials Dacceptable as Starting Material providedthat: • Dcan be fullyidentified from tests in the Starting Material specifications. • Full controlof all potential stereoisomers.

  8. Definitionof Starting Materials A or D as Starting Material? Stereochemistrycontrolled by themanufacturingprocess Identity not fullycontrolled by Specifications Indicatesthat A should be defined as Starting Material E, F etc

  9. Definitionof Starting Materials Secondexample: Indicatesthattheproposed SM (E) should be redefined to D Concernsregarding (genotoxic) impurities in Step 4 Proposed SM

  10. Definitionof Starting Materials Proposed SM Impurities from themanufactureof D should be insignificant. Informationonthemanufacturingprocess for D important? All significantimpurities from Step 4-6

  11. Definitionof Starting Materials Commercial availability: • Commodity in a pre-existing, non-pharmaceutical market • Chemicals produced by custom synthesis are not considered to be commercially available • If a justification is needed, it is most likely not commercially available

  12. Definitionof Starting Materials Commercial availability: • A compound that, based on the manufacturing process, is more expensive to produce by an in-house manufacturing process than to buy from a manufacturer using a “specialised” manufacturing process. • Typically manufactured by well established processes

  13. Definitionof Starting Materials Examples: Insufficientcontrolofimpurities Stereochemistrybasedon SM man. process One step Purification ”?” Starting Material Active Substance

  14. Definitionof Starting Materials Examples: SM Latanoprost Necessity to include a large part of the manufacturing process within GMP? Typicaldaily dose is 3g

  15. Definitionof Starting Materials Examples: SM Benzydamine

  16. Definitionof Starting Materials N-nitrosoaminegenotoxic? Examples: Indicates that the N-nitrosoamine and control of related impurities should be included in the manufacturing process. Benzydamine SM N-nitrosoamine

  17. Design Space & DocumentationRequirements Chapter 6, 7 & 8 in ICH Q11 Should be read in conjuctionwith Q8, Q9 & Q10 Guidelines discussesapproach, not requirements. Presentation by the ICH QualityImplementationWorking Group: http://www.ich.org/uploads/media/Q-IWG_Web_Key_Messages.pdf

  18. Design Space & DocumentationRequirements What is a design space? • ”…themultidimensional combination and interactionof input varables and process parameters that have beendemonstrated to provideassuranceofquality.” • Workingwithin a design space is not considered as a change. • The Guidelines applicablealso to one or twodimensions, e.g. flexibility for one parameter?

  19. Design Space & DocumentationRequirements What is a design space? • Enhancedapproach - Operational ranges for one or more process parameters (forms a Design Space.) • Traditionalapproach – Setvalues for process parameters.

  20. Design Space & DocumentationRequirements Traditional vs. Enhanced? • …4 kg of NH4Cl is added to thereactionmixture… • …4-5 kg of NH4Cl is added to thereactionmixture… • …NH4Cl is added to thereactionmixtureuntil a pH of 5-6 is obtained… • …1-8 kg of NH4Cl is added to thereactionmixture… • …NH4Cl (8 kg MAX) is added to thereactionmixture… • …NH4Cl is added to thereactionmixture… NH4Cl Traditional? Enhanced?

  21. Design Space & DocumentationRequirements • The manufacturer / developer possesses much more knowledge and expertise on their own manufacturing processes than any external reviewer. • The intention with the documentation is to convince any external reviewer that the quality control is sufficient. • The process description should be still be reproducible.

  22. Design Space & DocumentationRequirements ICH QualityImplementationWorking Group: • Design Space need to be clearly presented and justified in regulatorysubmission • Design Space need to be described in sufficient details in regulatory filing • Description should include critical and non critical parameters to assure complete understanding • Designation of criticality need to be justified in regulatory submission based on QRM and/or experimentalresults

  23. Design Space & DocumentationRequirements ICH QualityImplementationWorking Group: • Critical parameter ranges/model are considered a regulatory commitment and non-critical parameter ranges support the review of the filing • Critical parameter changes within design space are handled by the Quality System and changes outside the design space need appropriate regulatory notification • Non-critical parameters would be managed by Quality System

  24. Design Space & DocumentationRequirements Identify Quality Attributes Critical Quality Attributes? Identify potentially Critical Process Parameters Experimental data and/or scientific discussion Critical Process Parameters?

  25. Design Space & DocumentationRequirements R-enantiomer • Potentially • CriticalProcess parameters: • Solvent ratio • Temperature • QualityAttributes: • S-enantiomer Critical?-Yes Acceptable limit 0.3%

  26. Design Space & DocumentationRequirements Design ofExperiments at laboratotyscale (10g):

  27. Design Space & DocumentationRequirements Design ofExperiments at laboratotyscale (10g):

  28. Design Space & DocumentationRequirements Design ofExperiments at laboratotyscale (10g): ImpurityContent (%) Solvent ratio

  29. Design Space & DocumentationRequirements Shouldalso be included in S.2.2 DescriptionofManufacturingProcess

  30. Design Space & DocumentationRequirements Secondexample: Design ofExperiments for threeprocess parameters S-enantiomerabove 0.3% S-enantiomerbelow 0.3% Solvent ratio pH Temperature

  31. Design Space & DocumentationRequirements Secondexample: Design ofExperiments for threeprocess parameters • Operationalboundariesshould be included in section S.2.2 and could be presented as a; • figure • function • or • range Above 0.3% Solvent ratio Below 0.3% Temperature

  32. Design Space & DocumentationRequirements • Full Design ofExperimentsonlaboratoryscale (10 g?) • Verificationonlargerscalecomparable to commercialscale (100 kg?) • Suitablesetofexperiments • Equipmentcomparable to that used at commercialscale • Not necessary to challangetheedgeoffailure

  33. Design Space & DocumentationRequirements Summary of expectations from the documentation: S.2.6 Manufacturing Process Development • Critical & non Critical Quality Attributes • Critical & non Critical Process Parameters • Based on experimental data unless justified on a rigid scientific discussion • Verification on commercial scale S.2.2 Description of Manufacturing Process • Criteria for process parameters clearly depicted • Specified scale and expected yields

  34. Design Space & DocumentationRequirements Wrongcategory Type IB change in the manufacturing process Most likely not acceptable Scope: In order to enhance the manufacturing process... Present: 10 kg ofintermediate is dissolved in 100 Lof water and 5 kg ofreagent is added. The reaction is stirred at 50ºC for 30minutes. The reactionmixure is extractedwith3 ˟ 40 L ofethylacetate… Proposed: The intermediate from last step is dissolved in water followed by additionofreagent (Max. 10 kg). The reaction is stirreduntilcompletion. The reactionmixure is extractedwithethylacetate…

  35. Design Space & DocumentationRequirements

  36. Design Space & DocumentationRequirements ?

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