Guidance for Industry
`Q3B(R) Impurities in New
`Drug Products
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`November 2003
`ICH
`
`Revision 1
`
`0001
`
`AGILA ET AL - EXHIBIT 1015
`
`

`
`Guidance for Industry
`Q3B(R) Impurities in New
`Drug Products
`
`Additional copies are available from:
`
`Office of Training and Communication
`Division of Drug Information, HFD-240
`Center for Drug Evaluation and Research
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`(Tel) 301-827-4573
` http://www.fda.gov/cder/guidance/index.htm
`
`or
`
`Office of Communication, Training and
`Manufacturers Assistance, HFM-40
`Center for Biologics Evaluation and Research
` Food and Drug Administration
`1401 Rockville Pike, Rockville, MD 20852-1448
` http://www.fda.gov/cber/guidelines.htm.
` (Tel) Voice Information System at 800-835-4709 or 301-827-1800
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`November 2003
`ICH
`Revision 1
`
`0002
`
`

`
`TABLE OF CONTENTS
`TABLE OF CONTENTS
`
`INTRODUCTION (1.0)........................................................................................................ 1
`I.
`INTRODUCTION (1.0) ...................................................................................................... .. 1
`I.
`II. RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION
`II. RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION
`PRODUCTS (2.0).......................................................................................................................... 2
`PRODUCTS (2.0) ........................................................................................................................ .. 2
`III. ANALYTICAL PROCEDURES (3.0) ................................................................................ 3
`III. ANALYTICAL PROCEDURES (3.0) .............................................................................. .. 3
`IV. REPORTING DEGRADATION PRODUCTS, CONTENT OF BATCHES (4.0)......... 4
`IV. REPORTING DEGRADATION PRODUCTS, CONTENT OF BATCHES (4.0) ....... .. 4
`V. LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS (5.0).................. 4
`V. LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS (5.0) ................ .. 4
`VI. QUALIFICATION OF DEGRADATION PRODUCTS (6.0).......................................... 6
`VI. QUALIFICATION OF DEGRADATION PRODUCTS (6.0) ........................................ .. 6
`GLOSSARY................................................................................................................................... 1
`GLOSSARY................................................................................................................................. .. 1
`ATTACHMENT 1 ........................................................................................................................ 3
`ATTACHMENT 1 ...................................................................................................................... .. 3
`ATTACHMENT 2 ........................................................................................................................ 5
`ATTACHMENT 2 ...................................................................................................................... .. 5
`ATTACHMENT 3 ........................................................................................................................ 7
`ATTACHMENT 3 ...................................................................................................................... .. 7
`
`0003
`
`0003
`
`

`
`Contains Nonbinding Recommendations
`
`Guidance for Industry1
`Q3B(R) Impurities in New Drug Products
`
`This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It
`does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
`You can use an alternative approach if it satisfies the requirements of the applicable statutes and
`regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
`implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
`number listed on the title page of this guidance.
`
`I.
`
`INTRODUCTION (1.0) 2
`
`This guidance provides recommendations for registration applications on the content and
`qualification of impurities in new drug products produced from chemically synthesized new drug
`substances not previously registered in a region or member state. This guidance revises the ICH
`guidance of the same title, which was issued in May 1997. The revised guidance clarifies the
`1997 guidance and makes some changes.3 The revision also provides consistency with more
`recently published ICH guidances (e.g., Q3A(R) Impurities in New Drug Substances, Q3C
`Impurities: Residual Solvents, and Q6A Specifications: Test Procedures and Acceptance Criteria
`for New Drug Substances and New Drug Products: Chemical Substances). This guidance
`complements the ICH Q3A(R) guidance, which should be consulted for basic principles along
`with ICH Q3C when appropriate.
`
`This guidance addresses only those impurities in new drug products classified as degradation
`products of the drug substance or reaction products of the drug substance with an excipient
`and/or immediate container closure system (collectively referred to as degradation products in
`this guidance). Generally, impurities present in a new drug substance need not be monitored or
`
`
`1 This guidance was developed within the Q3B(R) Expert Working Group of the International Conference on
`Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been
`subject to consultation by the regulatory parties, in accordance with the ICH process. This document was endorsed
`by the ICH Steering Committee at Step 4 of the ICH process, February 5, 2003. At Step 4 of the process, the final
`draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States.
`
`2 Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Steering Committee
`at Step 4 of the ICH process.
`3 For example, addressing reporting, identification, and qualification thresholds; listing impurities in specifications
`and making a clear distinction between ICH Q3B (listing impurities) and Q6A (setting specifications); and deleting
`the exception to conventional rounding practice (i.e., the provision recommending no rounding up to 0.1 percent for
`values between 0.05 and 0.09 percent).
`
`1
`
`0004
`
`

`
`Contains Nonbinding Recommendations
`
`specified in new drug product unless they are also degradation products (see ICH Q6A guidance
`on specifications).
`
`Impurities arising from excipients present in a new drug product or extracted or leached from the
`container closure system are not covered by this guidance. This guidance also does not apply to
`new drug products used during the clinical research stages of development. The following types
`of products are not covered in this guidance:
`
`• Biological/biotechnological products
`• Peptides
`• Oligonucleotides
`• Radiopharmaceuticals
`• Fermentation products and semi-synthetic products derived therefrom
`• Herbal products
`• Crude products of animal or plant origin
`
`Also excluded from this document are (1) extraneous contaminants that should not occur in new
`drug products and are more appropriately addressed as good manufacturing practice (GMP)
`issues, (2) polymorphic forms, and (3) enantiomeric impurities.
`
`FDA's guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
`be viewed only as recommendations, unless specific regulatory or statutory requirements are
`cited. The use of the word should in Agency guidances means that something is suggested or
`recommended, but not required.
`
`II.
`
`RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION
`PRODUCTS (2.0)
`
`The applicant should summarize the degradation products observed during manufacture and/or
`stability studies of a new drug product. This summary should be based on sound scientific
`appraisal of potential degradation pathways in the new drug product and impurities arising from
`the interaction with excipients and/or the immediate container closure system. In addition, the
`applicant should summarize any laboratory studies conducted to detect degradation products in
`the new drug product. This summary also should include test results of batches manufactured
`during the development process and batches representative of the proposed commercial process.
`A rationale should be provided for exclusion of those impurities that are not degradation
`products (e.g., process impurities from the drug substance and impurities arising from
`excipients). The impurity profiles of the batches representative of the proposed commercial
`process should be compared with the profiles of batches used in development, and any
`differences should be discussed.
`
`Any degradation product observed in stability studies conducted at the recommended storage
`condition should be identified when present at a level greater than (>) the identification
`thresholds given in Attachment 1. When identification of a degradation product is infeasible, a
`
`2
`
`0005
`
`

`
`Contains Nonbinding Recommendations
`
`summary of the laboratory studies demonstrating the unsuccessful efforts to identify it should be
`included in the registration application.
`
`Degradation products present at a level of not more than (≤) the identification threshold generally
`would not need to be identified. However, analytical procedures should be developed for those
`degradation products that are suspected to be unusually potent, producing toxic or significant
`pharmacological effects at levels not more than (≤) the identification threshold. In unusual
`circumstances, technical factors (e.g., manufacturing capability, a low drug substance to
`excipient ratio, or the use of excipients that are crude products of animal or plant origin) can be
`considered part of the justification for selection of alternative thresholds based on manufacturing
`experience with the proposed commercial process.
`
`III.
`
`ANALYTICAL PROCEDURES (3.0)
`
`The registration application should include documented evidence that the analytical procedures
`have been validated and are suitable for the detection and quantitation of degradation products
`(see ICH Q2A and Q2B guidances on analytical validation). In particular, analytical procedures
`should be validated to demonstrate specificity for the specified and unspecified degradation
`products. As appropriate, this validation should include samples stored under relevant stress
`conditions: light, heat, humidity, acid/base hydrolysis, and oxidation. When an analytical
`procedure reveals the presence of other peaks in addition to those of the degradation products
`(e.g., the drug substance, impurities arising from the synthesis of the drug substance, excipients
`and impurities arising from the excipients), these peaks should be labeled in the chromatograms
`and their origin(s) discussed in the validation documentation.
`
`The quantitation limit for the analytical procedure should be not more than (≤) the reporting
`threshold.
`
`Degradation product levels can be measured by a variety of techniques, including those that
`compare an analytical response for a degradation product to that of an appropriate reference
`standard or to the response of the new drug substance itself. Reference standards used in the
`analytical procedures for control of degradation products should be evaluated and characterized
`according to their intended uses. The drug substance can be used to estimate the levels of
`degradation products. In cases when the response factors are not close, this practice can still be
`used if a correction factor is applied or the degradation products are, in fact, being overestimated.
`Acceptance criteria and analytical procedures, used to estimate identified or unidentified
`degradation products, are often based on analytical assumptions (e.g., equivalent detector
`response). These assumptions should be discussed in the registration application.
`
`Differences between the analytical procedures used during development and those proposed for
`the commercial product should also be discussed.
`
`3
`
`0006
`
`

`
`Contains Nonbinding Recommendations
`
`IV.
`
`REPORTING DEGRADATION PRODUCTS, CONTENT OF BATCHES (4.0)
`
`Analytical results should be provided in the registration application for all relevant batches of the
`new drug product used for clinical, safety, and stability testing, as well as batches that are
`representative of the proposed commercial process. Quantitative results should be presented
`numerically, and not in general terms such as “complies”, “meets limit.” Any degradation
`product at a level greater than (>) the reporting threshold (see Attachment 1), and total
`degradation products observed in the relevant batches of the new drug product, should be
`reported with the analytical procedures indicated. Below 1.0 percent, the results should be
`reported to the number of decimal places (e.g., 0.06 percent) in the applicable reporting
`threshold; at and above 1.0 percent, the results should be reported to one decimal place (e.g., 1.3
`percent). Results should be rounded using conventional rules (see Attachment 2). A tabulation
`(e.g., spreadsheet) of the data is recommended. Degradation products should be designated by
`code number or by an appropriate descriptor (e.g., retention time). If a higher reporting
`threshold is proposed, it should be fully justified. All degradation products at a level greater than
`(>) the reporting threshold should be summed and reported as total degradation products.
`
`Chromatograms with peaks labeled (or equivalent data if other analytical procedures are used)
`from representative batches, including chromatograms from analytical procedure validation
`studies and from long-term and accelerated stability studies, should be provided. The applicant
`should ensure that complete degradation product profiles (e.g., chromatograms) of individual
`batches are available, if requested.
`
`For each batch of the new drug product described in the registration application, the
`documentation should include:
`
`• Batch identity, strength, and size
`• Date of manufacture
`• Site of manufacture
`• Manufacturing process
`•
`Immediate container closure
`• Degradation product content, individual and total
`• Use of batch (e.g., clinical studies, stability studies)
`• Reference to analytical procedure used
`• Batch number of the drug substance used in the new drug product
`• Storage conditions for stability studies
`
`V.
`
`LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS (5.0)
`
` The specification for a new drug product should include a list of degradation products expected
`to occur during manufacture of the commercial product and under recommended storage
`conditions. Stability studies, knowledge of degradation pathways, product development studies,
`and laboratory studies should be used to characterize the degradation profile. The selection of
`degradation products in the new drug product specification should be based on the degradation
`products found in batches manufactured by the proposed commercial process. Those individual
`
`4
`
`0007
`
`

`
`Contains Nonbinding Recommendations
`
`degradation products with specific acceptance criteria included in the specification for the new
`drug product are referred to as specified degradation products in this guidance. Specified
`degradation products can be identified or unidentified. A rationale for the inclusion or exclusion
`of degradation products in the specification should be presented. This rationale should include a
`discussion of the degradation profiles observed in the safety and clinical development batches
`and in stability studies, together with a consideration of the degradation profile of batches
`manufactured by the proposed commercial process. Specified identified degradation products
`should be included along with specified unidentified degradation products estimated to be
`present at a level greater than (>) the identification threshold given in Attachment 1. For
`degradation products known to be unusually potent or to produce toxic or unexpected
`pharmacological effects, the quantitation or detection limit of the analytical procedures should be
`commensurate with the level at which the degradation products should be controlled. For
`unidentified degradation products, the procedure used and assumptions made in establishing the
`level of the degradation product should be clearly stated. Specified unidentified degradation
`products should be referred to by an appropriate qualitative analytical descriptive label (e.g.,
`unidentified A, unidentified with relative retention of 0.9). A general acceptance criterion of not
`more than (≤) the identification threshold (Attachment 1) for any unspecified degradation
`product and an acceptance criterion for total degradation products should also be included.
` For a given degradation product, its acceptance criterion should be established by taking into
`account its acceptance criterion in the drug substance (if applicable), its qualified level, its
`increase during stability studies, and the proposed shelf life and recommended storage conditions
`for the new drug product. Furthermore, each acceptance criterion should be set no higher than
`the qualified level of the given degradation product.
`
` Where there is no safety concern, degradation product acceptance criteria should be based on
`data generated from batches of the new drug product manufactured by the proposed commercial
`process, allowing sufficient latitude to deal with normal manufacturing and analytical variation
`and the stability characteristics of the new drug product. Although normal manufacturing
`variations are expected, significant variation in batch-to-batch degradation product levels can
`indicate that the manufacturing process of the new drug product is not adequately controlled and
`validated (see ICH Q6A guidance on specifications, decision tree #2, for establishing an
`acceptance criterion for a specified degradation product in a new drug product).
` In this guidance, the use of two decimal places for thresholds (see Attachment 1) does not
`necessarily indicate the precision of the acceptance criteria for specified degradation products
`and total degradation products.
`
` In summary, the new drug product specification should include, where applicable, the following
`list of degradation products:
`
`
`• Each specified identified degradation product
`• Each specified unidentified degradation product
`• Any unspecified degradation product with an acceptance criterion of not more than
`(≤) the identification threshold
`• Total degradation products
`
`5
`
`0008
`
`

`
`Contains Nonbinding Recommendations
`
`VI.
`
`QUALIFICATION OF DEGRADATION PRODUCTS (6.0)
`
`Qualification is the process of acquiring and evaluating data that establishes the biological safety
`of an individual degradation product or a given degradation profile at the levels specified. The
`applicant should provide a rationale for establishing degradation product acceptance criteria that
`includes safety considerations. The level of any degradation product present in a new drug
`product that has been adequately tested in safety and/or clinical studies would be considered
`qualified. Therefore, it is useful to include any available information on the actual content of
`degradation products in the relevant batches at the time of use in safety and/or clinical studies.
`Degradation products that are also significant metabolites present in animal and/or human studies
`are generally considered qualified. Degradation products could be considered qualified at levels
`higher than those administered in safety studies based on a comparison between actual doses
`given in the safety studies and the intended dose of the new drug product. Justification of such
`higher levels should include consideration of factors such as: (1) the amount of degradation
`product administered in previous safety and/or clinical studies and found to be safe; (2) the
`increase in the amount of the degradation product; and (3) other safety factors, as appropriate. If
`the qualification thresholds given in Attachment 1 are exceeded and data are unavailable to
`qualify the proposed acceptance criterion of a degradation product, additional studies to obtain
`such data may be appropriate (see Attachment 3).
`
`Higher or lower thresholds for qualification of degradation products may be appropriate for some
`individual new drug products based on scientific rationale and level of concern, including drug
`class effects and clinical experience. For example, qualification can be especially important
`when there is evidence that such degradation products in certain new drug products or
`therapeutic classes have previously been associated with adverse reactions in patients. In these
`instances, a lower qualification threshold may be appropriate. Conversely, a higher qualification
`threshold may be appropriate for individual new drug products when the level of concern for
`safety is less than usual based on similar considerations (e.g., patient population, drug class
`effects, and clinical considerations). Proposals for alternative thresholds would be considered on
`a case-by-case basis.
`
`The Decision Tree for Identification and Qualification of a Degradation Product (Attachment 3)
`describes considerations for the qualification of degradation products when thresholds are
`exceeded. In some cases, reducing the level of degradation product (e.g., use of a more
`protective container closure or modified storage conditions) to not more than (≤) the threshold
`can be simpler than providing safety data. Alternatively, adequate data could be available in the
`scientific literature to qualify a degradation product. If neither is the case, additional safety
`testing should be considered. The studies considered appropriate to qualify a degradation product
`will depend on a number of factors, including the patient population, daily dose, and route and
`duration of new drug product administration. Such studies can be conducted on the new drug
`product or substance containing the degradation products to be controlled, although studies using
`isolated degradation products can sometimes be appropriate.
`
`Although this guidance is not intended to apply during the clinical research stage of
`development, in the later stages of development, the thresholds in this guidance may be useful in
`
`6
`
`0009
`
`

`
`Contains Nonbinding Recommendations
`
`evaluating new degradation products observed in new drug product batches prepared by the
`proposed commercial process. Any new degradation product observed in later stages of
`development should be identified (see the Decision Tree for Identification and Qualification of a
`Degradation Product in Attachment 3) if its level is greater than (>) the identification threshold
`given in Attachment 1. Similarly, qualification of the degradation product should be considered
`if its level is greater than (>) the qualification threshold given in Attachment 1. Safety studies
`should provide a comparison of results of safety testing of the new drug product or drug
`substance containing a representative level of the degradation product with previously qualified
`material, although studies using the isolated degradation products can also be considered.
`
`7
`
`0010
`
`

`
`Contains Nonbinding Recommendations
`
`GLOSSARY
`
`Degradation Product: An impurity resulting from a chemical change in the drug substance
`brought about during manufacture and/or storage of the new drug product by the effect of, for
`example, light, temperature, pH, water, or by reaction with an excipient and/or the immediate
`container closure system
`
`Degradation Profile: A description of the degradation products observed in the drug substance
`or drug product
`
`Development Studies: Studies conducted to scale-up, optimize, and validate the manufacturing
`process for a drug product
`
`Identification Threshold: A limit above (>) which a degradation product should be identified
`
`Identified Degradation Product: A degradation product for which a structural characterization
`has been achieved
`
`Impurity: Any component of the new drug product that is not the drug substance or an
`excipient in the drug product
`
`Impurity Profile: A description of the identified and unidentified impurities present in a drug
`product
`
`New Drug Substance: The designated therapeutic moiety that has not been previously
`registered in a region or member state (also referred to as a new molecular entity or new
`chemical entity). It can be a complex, simple ester, or salt of a previously approved substance.
`
`Qualification: The process of acquiring and evaluating data that establishes the biological
`safety of an individual degradation product or a given degradation profile at the levels specified
`
`Qualification Threshold: A limit above (>) which a degradation product should be qualified
`
`Reporting Threshold: A limit above (>) which a degradation product should be reported
`
`Specified Degradation Product: A degradation product that is individually listed and limited
`with a specific acceptance criterion in the new drug product specification. A specified
`degradation product can be either identified or unidentified
`
`Unidentified Degradation Product: A degradation product for which a structural
`characterization has not been achieved and that is defined solely by qualitative analytical
`properties (e.g., chromatographic retention time)
`
`1
`
`0011
`
`

`
`Contains Nonbinding Recommendations
`
`Unspecified Degradation Product: A degradation product that is limited by a general
`acceptance criterion, but not individually listed with its own specific acceptance criterion, in the
`new drug product specification
`
`2
`
`0012
`
`

`
`Contains Nonbinding Recommendations
`
`ATTACHMENT 1
`
`THRESHOLDS FOR DEGRADATION PRODUCTS
`IN NEW DRUG PRODUCTS
`
`Reporting Thresholds
`
`Maximum Daily Dose1
`≤ 1 g
`> 1 g
`
`Identification Thresholds
`
`Maximum Daily Dose1
`< 1 mg
`1 mg - 10 mg
`>10 mg - 2 g
`> 2 g
`
`Qualification Thresholds
`
`Maximum Daily Dose1
`< 10 mg
`10 mg - 100 mg
`>100 mg - 2 g
`> 2 g
`
`Threshold2,3
`0.1%
`0.05%
`
`Threshold2, 3
`1.0% or 5 µg TDI, whichever is lower
`0.5% or 20 µg TDI, whichever is lower
`0.2% or 2 mg TDI, whichever is lower
`0.10%
`
`Threshold2,3
`1.0% or 50 µg TDI, whichever is lower
`0.5% or 200 µg TDI, whichever is lower
`0.2% or 3 mg TDI, whichever is lower
`0.15%
`
`1 The amount of drug substance administered per day
`2 Thresholds for degradation products are expressed either as a percentage of the drug substance or as total daily
`intake (TDI) of the degradation product. Lower thresholds can be appropriate if the degradation product is
`unusually toxic.
`3 Higher thresholds should be scientifically justified.
`
`3
`
`0013
`
`

`
`Contains Nonbinding Recommendations
`
`Illustration of Thresholds for Reporting, Identification, and Qualification of Degradation
`Products in New Drug Products as a Function of Maximum Daily Dose
`
`(Note: Actual threshold values should be taken from the preceding table in this attachment.)
`
`Reporting
`Identification
`Qualification
`
`2000
`1500
`1000
`500
`Maximum Daily Dose Expressed in mg of Drug Substance
`
`2500
`
`Reporting
`Identification
`Qualification
`
`15
`10
`5
`Maximum Daily Dose Expressed in mg of Drug Substance
`4
`
`20
`
`1.00
`
`0.80
`
`0.60
`
`0.40
`
`0.20
`
`Percentage of Drug Substance
`
`0.00
`
`0
`
`Expanded Scale:
`
`1.00
`
`0.80
`
`0.60
`
`0.40
`
`0.20
`
`Percentage of Drug Substance
`
`0.00
`
`0
`
`0014
`
`

`
`Contains Nonbinding Recommendations
`
`ATTACHMENT 2
`ILLUSTRATION OF REPORTING DEGRADATION PRODUCT RESULTS FOR
`IDENTIFICATION AND QUALIFICATION IN AN APPLICATION
`
`50 mg Maximum Daily Dose
`
`Reported
`Result
`(%)
`(Reporting
`Threshold =
`0.1%)
`
`Not reported
`
`Total Daily
`Intake (TDI)
`of the
`Degradation
`Product
`(rounded
`result in µg)
`20
`
`Action
`Identification
`Qualification
`Threshold
`Threshold
`0.2%
`200 µg TDI
`(equivalent to
`0.4%)
`None
`
`None
`
`0.2
`
`0.31
`
`0.61
`
`100
`
`150
`
`300
`
`None
`
`Yes
`
`Yes
`
`None
`
`None1
`
`Yes1
`
`1.9 gram Maximum Daily Dose
`
`Reported
`Result
`(%)
`(Reporting
`Threshold =
`0.05%)
`
`Not reported
`
`0.08
`
`0.181
`
`0.191
`
`Total Daily
`Intake (TDI)
`of the
`Degradation
`Product
`(rounded
`result in mg)
`
`1
`
`2
`
`3
`
`4
`
`Action
`Qualification
`Threshold
`3 mg TDI
`(equivalent to
`0.16%)
`
`None
`
`None
`
`None1,2
`
`Yes1
`
`Identification
`Threshold
` 2 mg TDI
`(equivalent to
`0.11%)
`None
`
`None
`
`Yes
`
`Yes
`
`‘Raw’ Result
`
`(%)
`
`0.04
`
`0.2143
`
`0.349
`
`0.550
`
`‘Raw’ Result
`
`(%)
`
`0.049
`
`0.079
`
`0.183
`
`0.192
`
`1 After identification, if the response factor is determined to differ significantly from the original assumptions, it can
`be appropriate to re-measure the actual amount of the degradation product present and re-evaluate against the
`qualification threshold (see Attachment 1).
`
`5
`
`0015
`
`

`
`Contains Nonbinding Recommendations
`
`2 Although the reported result of 0.18% exceeds the calculated threshold value of 0.16%, in this case the action is
`acceptable since the TDI (when rounded) does not exceed 3 mg.
`
`6
`
`0016
`
`

`
`Contains Nonbinding Recommendations
`
`ATTACHMENT 3
`DECISION TREE FOR IDENTIFICATION AND QUALIFICATION OF A
`DEGRADATION PRODUCT
`
`Is degradation
`product greater than
`identification
`thresholdc?
`
`Yes
`
`No
`
`No action
`
`Structure
`identified?
`
`Yes
`
`Any
`known human
`relevant risksd?
`
`Yes
`
`Reduce to
`safe level
`
`No
`
`Reduce
`to not more than
`(≤) identification
`thresholdc?
`
`No
`
`Yes
`
`No further
`action
`
`Yes
`
`Reduce
`to not more than
`(≤) qualification
`thresholdc?
`
`No
`
`No
`
`Yes
`
`Greater
`than qualification
`thresholdc?
`
`No
`
`No action
`
`Consider patient population and duration of use
`and consider conducting:
`• Genotoxicity studies (point mutation,
`chromosomal aberration)a
`• General toxicity studies (one species, usually
`14 to 90 days)b
`• Other specific toxicity endpoints, as
`appropriate
`
`Reduce to
`safe level
`
`Yes
`
`Any
`clinically
`relevant adverse
`effects?
`
`No
`
`7
`
`Qualified
`
`0017
`
`

`
`Contains Nonbinding Recommendations
`
`Notes to Attachment 3
`
`a If considered desirable, a minimum screen (e.g., genotoxic potential), should be conducted. A study to detect point
`mutations and one to detect chromosomal aberrations, both in vitro, are considered an appropriate minimum screen.
`b If general toxicity studies are desirable, one or more studies should be designed to allow comparison of unqualified
`to qualified material. The study duration should be based on available relevant information and performed in the
`species most likely to maximize the potential to detect the toxicity of a degradation product. On a case-by-case
`basis, single-dose studies can be appropriate, especially for single-dose drugs. In general, a minimum duration of 14
`days and a maximum duration of 90 days would be considered appropriate.
`c Lower thresholds can be appropriate if the degradation product is unusually toxic.
`d For example, do known safety data for this degradation product or its structural class preclude human exposure at
`the concentration present?
`
`8
`
`0018