Determine impurity level in relevant batches1

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DECISION TREE 1 ESTABLISHING ACCEPTANCE
CRITERION FOR A SPECIFIED IMPURITY IN A NEW DRUG
SUBSTANCE
Determine impurity level in relevant batches1
Isimpurity alsoa degradationproduct?
Estimate maximum increase in impurityat retest
date using data from relevantaccelerated and
long-term stability studies
YES
Determine mean upper confidence limit for the
impurity (Let this A)
NO
IsA or B greater than thequalifiedlevel?
Determine maximum likely level asA increase
in degradation product atappropriate storage
conditions.(Let this B)
NO
Acceptance criterion A or B(as appropriate)
YES
Acceptance criterion qualified levelor
establish new qualified level2
1 Relevant batches are those from development,
pilot and scale-up studies. 2 Refer to ICH
Guideline on Impurities in New Drug
SubstancesDefinition upper confidence limit
three times the standard deviation of batch
analysis data
2
DECISION TREE 2 ESTABLISHING ACCEPTANCE
CRITERION FOR A DEGRADATION PRODUCT IN A NEW
DRUG PRODUCT
Doesdegradationoccur during productmanufacture?
Estimate maximum increase in degradation product
at shelf life usingdata from relevant
accelerated andlong-term stability studies.
(Let this D)
NO
YES
Determine maximum likely level as drug substance
acceptance criterion2.((A or B) C D)
Estimate maximum increase in degradationproduct
during manufacture from relevantbatches1. (Let
this C)
Ismaximum likely level greaterthan
thequalifiedlevel?
NO
Acceptance criterion maximum likely level.
YES
Acceptance criterion qualified levelor
establish new qualified level3or new storage
conditions or reduce shelf life.
1 Relevant batches are those from development,
pilot and scale-up studies.2 Refer to Decision
Tree 1 for information regarding A and B.3 Refer
to ICH Guideline on Impurities in New Drug
Products.
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DECISION TREE 3 SETTING ACCEPTANCE CRITERIA FOR
DRUG SUBSTANCE PARTICLE SIZE DISTRIBUTION
No drug substance particlesize acceptance
criterion required for solution dosage forms.
Is the drug product a soliddosage form or liquid
containing undissolveddrug substance?
NO
YES
1. Is the particle size critical to
dissolution, solubility, or
bioavailability?2. Is the particle size
critical to drug product processability?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?
If NO to all
If YES to any
No Acceptance Criterion Required
Set Acceptance Criterion
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DECISION TREE 4 INVESTIGATING THE NEED TO
SETACCEPTANCE CRITERIA FOR POLYMORPHISMIN DRUG
SUBSTANCES AND DRUG PRODUCTS
Drug Substance
NO
Conduct polymorphismscreen on drug substance.
Candifferent polymorphsbe formed?
1.
No further action
YES
Characterize the formse.g., - X-ray Powder
Diffraction - DSC / Thermoanalysis
- Microscopy - Spectroscopy
2.
GO TO
2.
Do theforms havedifferent properties?(solubilit
y, stability,melting point)
NO
No further test oracceptance criterionfor drug
substance
YES
Is drugproduct safety,performance or efficacy
affected?
NO
YES
Set acceptance criterionfor polymorph contentin
drug substance
3.
GO TO
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DECISION TREE 4 INVESTIGATING THE NEED TO SET
ACCEPTANCE CRITERIA FOR POLYMORPHISMIN DRUG
SUBSTANCES AND DRUG PRODUCTS
Drug Product - Solid Dosage Form or Liquid
Containing Undissolved Drug Substance
N.B. Undertake the following processes only if
technically possibleto measure polymorph content
in the drug product.
3.
Doesdrug productperformance testingprovide
adequate control if polymorph ratio
changes(e.g., dissolution)?
Establish acceptance criteriafor the relevant
performance test(s).
YES
NO
Monitor polymorph form duringstability of drug
product.
Does achange occurwhich could affect safety or
efficacy?
NO
No need to set acceptance criteriafor polymorph
change in drug product.
YES
Establish acceptance criteriawhich are
consistent with safety and/or efficacy.
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DECISION TREE 5 ESTABLISHING IDENTITY, ASSAY
AND ENANTIOMERIC IMPURITY PROCEDURES FOR CHIRAL
NEW DRUG SUBSTANCES AND NEW DRUG
PRODUCTS CONTAINING CHIRAL DRUG SUBSTANCES
Consider the need forverifying chiral identity
indrug substance releaseand/or acceptance
testing.
YES
Is the newdrug substancechiral1?
Chiral identity, assay and impurity procedures
are not needed.
NO
AND RACEMIC
YESAND ONE ENANTIOMER
Needed for drug substance specification2
-chiral identity3 -chiral assay4
-enantiomeric impurity5Needed for drug product
specification6 -chiral assay4
-enantiomeric impurity5
1 Chiral substances of natural origin are not
addressed in this Guideline. 2 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. This essentially will be
the case when there are multiple chiral centers
(e.g., three or more), or when control at a step
prior to production of the final drug substance
is desirable. 3 A chiral assay or an
enantiomeric impurity procedure may be acceptable
in lieu of a chiral identity procedure. 4 An
achiral assay combined with a method for
controlling the opposite enantiomer is acceptable
in lieu of a chiral assay. 5 The level of the
opposite enantiomer of the drug substance may be
derived from chiral assay data or from a separate
procedure. 6 Stereospecific 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 form.
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DECISION TREES 7 SETTING ACCEPTANCE CRITERIA
FOR DRUG PRODUCT DISSOLUTION
What type of drug release acceptance criteria are
appropriate?
1.
Establish drug release acceptance
criteria.Extended release multiple time
pointsDelayed release two stages, parallel or
sequential
Is the dosageform designed to producemodified
release?
YES
NO
Is drug solubilityat 37 0.5C high
throughoutthe physiological pH range?(Dose/
solubility lt 250 mL(pH 1.2 - 6.8))
NO
YES
Is dosage formdissolution rapid?(Dissolution gt
80 in 15 minutesat pH 1.2, 4.0, and 6.8)
Generally single-point dissolutionacceptance
criteria with a lower limit are acceptable.
NO
YES
NO
Has a relationship beendetermined between
disintegrationand dissolution?
Generally disintegration acceptance criteria
with an upper time limit are acceptable.
YES
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DECISION TREES 7 SETTING ACCEPTANCE CRITERIA
FOR DRUG PRODUCT DISSOLUTION
What specific test conditions and acceptance
criteria are appropriate? immediate release
2.
Doesdissolution significantlyaffect
bioavailability?(e.g., have relevant
developmentalbatches exhibited
unacceptablebioavailability?)
Attempt to develop test conditions and
acceptance criteria which can distinguish
batches with unacceptable bioavailability.
YES
NO
Do changes informulation ormanufacturing
variables affect dissolution?(Use appropriate
ranges.Evaluate dissolutionwithin pH 1.2 - 6.8)
YES
Are these changes controlledby another procedure
and acceptancecriterion?
YES
NO
NO
Adopt appropriate test conditionsand acceptance
criteria without regard to discriminating power,
to pass clinically acceptable batches.
Adopt test conditions and acceptance
criteriawhich can distinguish these changes.
Generally, single point acceptance criteria are
acceptable.
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DECISION TREES 7 SETTING ACCEPTANCE CRITERIA
FOR DRUG PRODUCT DISSOLUTION
What are appropriate acceptance ranges? extended
release
3.
Are bioavailabilitydata available for
batcheswith different drug release rates?
NO
Is drug release independent ofin vitro test
conditions?
YES
YES
NO
Can an in vitro / in vivorelationship be
established?(Modify in vitro test conditionsif
appropriate.)
Use all available stability, clinical,
andbioavailability data to establish
appropriate acceptance ranges.
NO
YES
Use the in vitro / in vivocorrelation, along
withappropriate batch data, to establish
acceptance ranges.
Are acceptanceranges gt20 of thelabeled content?
Provide appropriatebioavailability datato
validate theacceptance ranges.
YES
NO
Finalize acceptance ranges.
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