DECISION TREE #1: ESTABLISHING ACCEPTANCE …

1 Determine impurity level in relevant batches1 Determine mean + upper confidence limit for the impurity (Let this = A) ACCEPTANCE criterion = A or B(as appropriate)Isimpurity alsoa degradationproduct?IsA or B greater than thequalifiedlevel? ACCEPTANCE criterion = qualified levelor establish new qualified level2 Estimate maximum increase in impurityat retest date using data from relevantaccelerated and long-term stability studiesDetermine maximum likely level as:A + increase in degradation product atappropriate storage conditions.(Let this = B)YESYESNONODECISION tree #1: ESTABLISHING ACCEPTANCE CRITERION FOR A SPECIFIED IMPURITY IN A NEW DRUG SUBSTANCE1 Relevant batches are those from development, pilot and scale-up to ICH Guideline on Impurities in New Drug SubstancesDefinition: upper confidence limit = three times the standard deviation of batch analysis dataDECISION tree #2: ESTABLISHING ACCEPTANCE CRITERION FOR A DEGRADATION PRODUCT IN A NEW DRUG PRODUCTD oesdegradationoccur during productmanufacture?

2 Estimate maximum increase in degradation product at shelf life usingdata from relevant accelerated andlong-term stability studies. (Let this = D)Determine maximum likely level as drug substance ACCEPTANCE criterion2.((A or B) + C + D)Ismaximumlikely level greaterthan thequalifiedlevel?Estimate maximum increase in degradationproduct during manufacture from relevantbatches1. (Let this = C) ACCEPTANCE criterion = maximum likely criterion = qualified levelor establish new qualified level3or new storage conditionsor reduce shelf Relevant batches are those from development, pilot and scale-up to DECISION tree 1 for information regarding A and to ICH Guideline on Impurities in New Drug Products. DECISION tree #3: SETTING ACCEPTANCE CRITERIA FOR DRUG SUBSTANCE PARTICLE SIZE DISTRIBUTIONIs the drug product a soliddosage form or liquid containing undissolveddrug substance?

3 No drug substance particlesize ACCEPTANCE criterion required for solution dosage Is the particle size critical to dissolution,solubility, or bioavailability?2. Is the particle size critical to drug productprocessability?3. Is the particle size critical to drug product stability?4. Is the particle size critical to drug product content uniformity? 5. Is particle size critical for maintaining product appearance?Set ACCEPTANCE CriterionNo ACCEPTANCE Criterion RequiredIf YES to anyIf NO to allNOYESDECISION tree #4: INVESTIGATING THE NEED TO SETACCEPTANCE CRITERIA FOR POLYMORPHISMIN DRUG SUBSTANCES AND DRUG PRODUCTSDrug polymorphismscreen on drug further actionCandifferent polymorphsbe formed?GO TONONOYESDo theforms havedifferent properties?(solubility, stability,melting point)Is drugproduct safety,performance or efficacy affected?GO TO Characterize the , - X-ray Powder Diffraction- DSC / Thermoanalysis- Microscopy- SpectroscopyNo further test oracceptance criterionfor drug substanceYESSet ACCEPTANCE criterionfor polymorph contentin drug tree #4: INVESTIGATING THE NEED TO SET ACCEPTANCE CRITERIA FOR POLYMORPHISMIN DRUG SUBSTANCES AND DRUG PRODUCTSDrug Product - Solid Dosage Form or Liquid Containing Undissolved Drug : Undertake the following processes only if technically possibleto measure polymorph content in the drug productperformance testingprovide adequate control if polymorph ratio changes( , dissolution)?

4 Establish ACCEPTANCE criteriafor the relevant performance test(s).Monitor polymorph form duringstability of drug need to set ACCEPTANCE criteriafor polymorph change in drug achange occurwhich could affect safety or efficacy?Establish ACCEPTANCE criteriawhich are consistent with safety and/or tree #5: ESTABLISHING IDENTITY, ASSAY AND ENANTIOMERIC IMPURITY PROCEDURES FOR CHIRAL NEW DRUG SUBSTANCES AND NEW DRUG PRODUCTSCONTAINING CHIRAL DRUG SUBSTANCESYESAND RACEMICC onsider the need forverifying chiral identity indrug substance releaseand/or ACCEPTANCE the newdrug substancechiral1?Chiral identity, assay and impurity procedures are not ONE ENANTIOMERN eeded for drug substance specification:2-chiral identity3-chiral assay4-enantiomeric impurity5 Needed for drug product specification6:-chiral assay4-enantiomeric impurity51 Chiral substances of natural origin are not addressed in this As with other impurities arising in and from raw materials used in drug substance synthesis, controlof chiral quality could be established alternatively by applying limits to appropriate starting materials or intermediates when justified from developmental studies.

5 This essentially will be the case when there are multiple chiral centers ( , three or more), or when control at a step prior to production of the final drug substance is A chiral assay or an enantiomeric impurity procedure may be acceptable in lieu of a chiral identity An achiral assay combined with a method for controlling the opposite enantiomer is acceptable in lieu of achiral The level of the opposite enantiomer of the drug substance may be derived from chiral assay data or from a separate testing of drug product may not be necessary if racemization has been demonstrated to be insignificant during drug product manufacture and during storage of the finished dosage the drug substance/excipientsterile?Does drug substance/excipientsynthesis/processing involvesteps which inherently reduce microorganisms?Does scientific evidence demonstrate thatreduction steps result in microorganism levels < ACCEPTANCE criteria limits (and the absence ofcompendial indicator organisms)in the drug substance/excipient?

6 Provide supporting data. Microbial limits ACCEPTANCE criteria and testing may not be further microbial limits testing or ACCEPTANCE criteria are each lot for microbial limits and freedom from compendialindicator lots on a skip-lot basis for microbial limits and freedom fromcompendial indicator microbial limit ACCEPTANCE criteriaas per the harmonized pharmacopeial monograph. DECISION tree #6: MICROBIOLOGICAL QUALITY ATTRIBUTES OF DRUG SUBSTANCE AND EXCIPIENTS Is the drug substance/excipientcapable of supporting microbial growth or viability?Are monitoring microorganism/indicator levels consistently below ACCEPTANCE criteria levels?Provide supporting data. Microbial limits ACCEPTANCE criteria and testing may not be microbial limit ACCEPTANCE criteriaas per the harmonized TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT type of drug release ACCEPTANCE criteria are appropriate?

7 Is the dosageform designed to producemodified release?YESE stablish drug release ACCEPTANCE release: multiple time pointsDelayed release: two stages, parallel or sequentialIs drug solubilityat 37 C high throughoutthe physiological pH range?(Dose/ solubility <250 mL(pH - ))NOContinued on next single-point dissolutionacceptance criteria with a lower limitare dosage formdissolution rapid?(Dissolution > 80% in 15 minutesat pH , , and ) Has a relationship beendetermined between disintegrationand dissolution?Generally disintegration ACCEPTANCE criteria with an upper time limit are TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT specific test conditions and ACCEPTANCE criteria are appropriate? [immediate release]Doesdissolution significantlyaffect bioavailability?( , have relevant developmentalbatches exhibited unacceptablebioavailability?)

8 Attempt to develop test conditions and acceptancecriteria which can distinguish batches with unacceptable changes informulation ormanufacturing variables affect dissolution?(Use appropriate dissolutionwithin pH - )Are these changes controlledby another procedure and acceptancecriterion?Adopt appropriate test conditionsand ACCEPTANCE criteria without regard to discriminating power, topass clinically acceptable test conditions and ACCEPTANCE criteriawhich can distinguish these changes. Generally, single point ACCEPTANCE criteriaare acceptable. DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT are appropriate ACCEPTANCE ranges? [extended release]YESNONOYESYESNOYESNOAre bioavailabilitydata available for batcheswith different drug release rates?Is drug release independent ofin vitrotest conditions?Can an in vitro / in vivorelationship be established?

9 (Modify in vitrotest conditionsif appropriate.)Use all available stability, clinical, andbioavailability data to establish appropriate ACCEPTANCE the in vitro / in vivocorrelation, along withappropriate batch data, to establish ACCEPTANCE acceptanceranges >20% of thelabeled content?Provide appropriatebioavailability datato validate theacceptance ACCEPTANCE the drug product a dry dosage form ( solid oral or dry powder)?Do production lots consistently meet microbial limits ACCEPTANCE criteria?Establish preservative chemical ACCEPTANCE criteria and perform preservative effectiveness validation of product containing less than or equal to the minimum specified preservative concentration, or demonstrate the inherent antimicrobial activity of the drug product. Establish microbial limit ACCEPTANCE criteriaas per the harmonized microbial limits testing on a lot-by-lot limits ACCEPTANCE criteria and testing may not be the drug product contain antimicrobial preservatives or possess inherent antimicrobial activity?

10 Perform skip-lot testing for microbial limits, or provide scientific justification for no routine microbial limits testing. DECISION tree #8: MICROBIOLOGICAL ATTRIBUTES OF NON-STERILE DRUG PRODUCTSYESNOYESYESNONODoes scientific evidence demonstrategrowth inhibitory properties of the drug product?YESNO