0001
`
`PSG2025
`Catalent Pharma Solutions v. Patheon Softgels
`IPR2018-00422
`
`

`

`IMPURITIES IN NEW MEDICINAL PRODUCTS(CPMP/ICH/282/95)
`
`[ICH Harmonised Tripartite Guideline]
`
`TABLE OF CONTENTS
`
`1.
`
`INTRODUCTION......cccccccccccetevneereteceecereersneesessseseneaseaesneeennesneseneeenssersecgageneesnentanes 2
`
`1.1
`
`1.2
`
`1.3
`
`Objective of the Guideline... esse ceseeesereeeteetsensesteeeneeectaesesneenateeerseenenies 2
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`Background... cece ssccnseseesasenscenseneeseeseeessenecsenseeseesieteesnenirsnesnatenssesessesnaeeegs 2
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`Scope of the Guidelime ........ cc ccc cceteseceeeseesesseenensensesesnsecennesnerneseenaeeaseasneseeeneey 2
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`2.
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`GUIDELINES......ccccceccecccccccescececceneecenessaeeinecneeseeeeesensensnsssssesseeeeeensseseaneeaneneseseesneneenys 2
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`2.1
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`2.2
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`2.3.
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`2.4
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`2.5
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`2.6
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`3.
`
`4,
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`5.
`
`Amalytical Procedures... cece eter eeeeteseee cnet eres eeneernectnee sree rneeseuenasernenereesaaess 2
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`Rationale for the Reporting and Control of Impurities..............eee 3
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`Reporting Impurity Content of Batches .....0..... cise nee eters tenes tte renner enseneees 3
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`Specification Limits for Lmpurities .......... ccc terete teneeneeceeseeneetecneeeretassens 4
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`Qualification of Impurities... eect eee eeeeeereteeereenese tiene sencensssereereees 4
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`New Tmpuritiies 2.0.0 cece sscececsseenesssesseneneeneenecsersessesseseenesnesnaessenesseeseesesserseerertens 5
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`GLOSSARYocc ceccccccceccessecceseseeeteeeneeseneneecsunesneeenenseseseuepeanenaeesseereaeeneesnsecenecenenteneneennnes 6
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`ATTACHMENTI occccccccccscerseveeeseteesecsecennecrseseseesssesseesseseseseneeessasensensserieaeneeseeeenseegs 7
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`ATTACHMENTIl... .cccccccccccssesnscesteceeceeesaeersarsecsssesseeenssenssessaseneesarecseesineneeeseeseneens 9
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`CPMP/ICH/282/95
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`1/9
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`1.
`
`INTRODUCTION
`
`Objective of the Guideline
`1.1
`for marketing
`applications
`for
`recommendations
`guideline provides
`This
`guidance
`authorisation on the content and qualification of impurities in new medicinal products
`produced from chemically synthesised new active substances not previously registered in a
`memberstate.
`
`1.2
`Background
`This Guideline is an annex to the Impurities in New Active Substances Guideline which
`should be consulted for basic principles.
`
`Scope of the Guideline
`13
`This Guideline addresses only those impurities in medicinal products classified as degradation
`products ofthe active substanceor reaction products of the active substance with an excipient
`and/or immediate container/closure system (collectively referred to as “degradation products”
`in this Guideline). Impurities arising from excipients present in the product are not covered by
`this Guideline. This Guideline also does not address the regulation of products used during the
`clinical research stages of development. Biological/ biotechnological products, peptides,
`oligonucleotides,
`radiopharmaceuticals,
`fermentation and semi-synthetic products derived
`therefrom, herbal products, and crude products of animalorplant origin are not covered. Also
`excluded from this Guideline are: extraneous contaminants which should not occur in medicinal
`products and are more appropriately addressed as good manufacturing practice issues,
`polymorphic form, a solid state property of the new active substance, and enantiomeric
`impurities. Impurities present in the new active substance need not be monitored in medicinal
`products unless they are also degradation products.
`
`2.
`
`GUIDELINES
`
`Analytical Procedures
`2.1.
`The application for a marketing authorisation should include documented evidencethat the
`analytical procedures have beenvalidated and suitable for the detection and quantitation of
`degradation products. Analytical methods should be validated to demonstrate that impurities
`unique to the new active substance do not interfere with or are separated from specified and
`unspecified degradation products in the product.
`Degradation product levels can be measured byavariety of techniques, including those which
`compare an analytical response for a degradation productto that of an appropriate reference
`standard or to the response ofthe new active substance itself. Reference standards used in the
`analytical procedures
`for control of degradation products
`should be evaluated and
`characterised according to their intended uses. The active substance may be used to estimate
`the levels of degradation products. In cases where the response factors are not close,this
`practice may still be used if a correction factor is applied or the degradation products are, in
`fact, being overestimated. Specifications and analytical procedures used to estimate identified
`or unidentified degradation products are often based on analytical assumptions (¢.g.,
`equivalent detector response). These assumptions should be discussed in the application for
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`marketing authorisation. Differences in the analytical procedures used during development and
`those proposed for the commercial product should be discussed.
`
`2.2.
`Rationale for the Reporting and Control of Impurities
`The applicant should summarise those degradation products observed during stability studies
`of the medicinal product. This summary should be based on sound scientific appraisal of
`potential degradation pathways in the medicinal product and impurities arising from the
`interaction with excipients and/or the immediate container/closure system. In addition, the
`applicant should summarise any laboratory studies conducted to detect degradation products
`in the medicinal product. This summary 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 which are not
`degradation products, e.g., process impurities from the active substance and excipients and
`their related impurities. The impurity profile of the batches representative of the proposed
`commercial process should be compared with the profiles of batches used in development and
`any differences discussed.
`recommended storage
`Degradation products observed in stability studies conducted at
`conditions should be identified whenthe identification thresholds given in AttachmentI are
`equaled or exceeded (althoughit is commonpractice to round analytical results of between
`0.05 and 0.09 percent to the nearest number, ie., 0.1 percent, for the purpose of these
`guidelines such values would not be rounded to 0.1 percent). Whenidentification of a
`degradation productis not feasible, a summary of the laboratory studies demonstrating the
`unsuccessful effort should be included in the application for marketing authorisation.
`Degradation products below the indicated levels generally would not needto be identified.
`However,
`identification should be attempted for
`those degradation products that are
`suspected to be unusually potent, producing toxic or significant pharmacologic effects at
`levels lower than indicated.
`
`Reporting Impurity Content of Batches
`2.3.
`Analytical results should be provided in tabular format for all relevant batches of new
`medicinal product used for clinical, safety and stability testing, as well as batches which are
`representative of the proposed commercial process. Because the degradation test procedure
`can be an important support tool for monitoring the manufacturing quality as well as for
`deciding the expiration dating period of the product, the reporting level should be set below
`the identification threshold. The recommended target value for the reporting threshold
`(expressed as a percentage of the active substance) is found in Attachment
`I. A higher
`reporting threshold should only be proposed, with justification,
`if the target reporting
`threshold cannot be achieved.
`In addition, where an analytical method reveals the presence of impurities in addition to the
`degradation products (e.g., impurities arising from the synthesis of the active substance) the
`origin of these impurities should be discussed. Chromatograms, or equivalent data (if other
`methods are used), from representative batches including long-term and accelerated stability
`conditions should be provided. The procedure should be capable of quantifying at least at the
`reporting threshold and the chromatograms should show the location of the observed
`degradation products and impurities from the new active substance.
`The following information should be provided:
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`®
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`Batchidentity, strength and size
`
`Date of manufacture
`
`Site of manufacture
`
`Manufacturing process, where applicable
`
`Immediate container/closure
`
`Degradation product content, individual andtotal
`
`Use of batch
`
`Reference to analytical procedure(s) used
`
`Batch numberof the drug substance used in the drug product
`
`Storage conditions
`
`Specification Limits for Impurities
`2.4
`The specifications for a new medicinal product should include limits for degradation products
`expected to occur under recommended storage conditions. Stability studies, knowledge of
`degradation pathways, product development studies and laboratory studies should be used to
`characterise the degradation profile. Specifications should be set
`taking into account
`the
`qualification of the degradation products, the stability data, the expected expiry period, and
`the recommendedstorage conditions for the product, allowing sufficient latitude to deal with
`normal manufacturing, analytical and stability profile variation. The specification for the
`product should include, where applicable, limits for:
`
`®
`
`e
`
`Each specified degradation product
`
`Any unspecified degradation product
`
`Total degradation products.
`®
`Although some variation is expected, significant variation in batch to batch degradation
`profiles may indicate that the manufacturing process of the new medicinal product is not
`adequately controlled and validated. A rationale for the inclusion or exclusion of impurities in
`the specifications should be presented. This rationale should include a discussion of the
`impurity profiles observedin the safety and clinical studies, together with a consideration of
`the impurity profile of the product manufactured by the proposed commercialprocess.
`
`Qualification of Impurities
`2.5
`Qualification is the process of acquiring and evaluating data whichestablishes the biological
`safety of an individual degradation product or a given degradation profile at
`the level(s)
`specified. The applicant should provide a rationale for selecting degradation productlimits
`based on safety considerations. The level of any degradation product present
`in a new
`medicinal product which has been adequately tested and found safe in safety and/orclinical
`studies is considered qualified. Therefore,it is useful to include any available information on
`the actual content of degradation products in the relevant batchesat the time of use in safety
`and/orclinical studies. Degradation products whichare also significant metabolites, present in
`animal and/or humanstudies, do not need further qualification. It may be possible to justify a
`higher level of a degradation product than the level administered in safety studies. The
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`the amount of degradation
`justification should include consideration of factors such as:
`product administered in previous safety and/or clinical studies and found to be safe; the
`percentage changein the degradation product; and, other safety factors as appropriate.
`If data is not available to qualify the proposed specification level of a degradation product,
`studies to obtain such data may be needed (see ATTACHMENT IJ) when the usual
`qualification thresholds set out in ATTACHMENTI are equaled or exceeded. Higher or lower
`thresholds for qualification of degradation products may be appropriate for some individual
`products based onscientific rationale and level of concern, including drug class effects and
`clinical experience. For example, qualification may be especially important when there is
`evidence that such degradation products in certain medicinal 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 products whenthe level of concern for safety is less than usual
`based on similar considerations (e.g., patient population, drug class effects, and clinical
`considerations). In unusual circumstances, technical factors (e.g., manufacturing capability, a
`low active substance to excipient ratio, or the use of excipients that are also crude products of
`animal or plant origin) may be consideredaspart of the justification for selection of alternative
`thresholds. Proposals for alternative thresholds would be considered on a case-by-casebasis.
`The "Decision Tree for Safety Studies" (See Guideline for Impurities in New Drug Substances
`and ATTACHMENTII) describes considerations for the qualification of impurities when
`thresholds are equaled or exceeded. Alternatively, if data are available in the scientific literature
`then such data may be submitted for consideration to qualify a degradation product. If neither
`is the case, additional safety testing should be considered. The studies desired to qualify a
`degradation productwill depend on a numberoffactors, including the patient population,
`daily dose, route and duration of product administration. Such studies should normally be
`conducted onthe product or substance containing the degradation products to be controlled,
`although studies using isolated degradation products are considered acceptable.
`
`New Impurities
`2.6
`During the course of drug developmentstudies, the qualitative degradation profile of a new
`medicinal product may change resulting in new degradation products which exceed the
`identification and/or qualification threshold. In this event, these new degradation products
`should be identified and/or qualified. Such changes call for consideration of the need for
`qualification of the level of the impurity unless it is below the threshold values as set out in
`ATTACHMENTI.
`
`When a new degradation product equals or exceeds the threshold (for rounding, see section
`2.2),
`the "Decision Tree for Safety Studies" should be consulted. Safety studies should
`provide a comparisonofresults of safety testing of the product or substance containing a
`representative level of the degradation product with previously qualified material, although
`studies using the isolated degradation products are also considered acceptable (these studies
`maynot always haveclinical significance).
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`3.
`
`GLOSSARY
`
`in a
`
`Degradation Product: A molecule resulting from a chemical change in the substance brought
`about over time and/or bythe actionof, e.g., light, temperature, pH, or water or by reaction
`with an excipient and/or the immediate container/closure system (also called decomposition
`product).
`Degradation Profile: A description of the degradation products observed in the active
`substance or medicinal product.
`DevelopmentStudies: Studies conducted to scale-up, optimise and validate the manufacturing
`process for a medicinal product.
`Identified Impurity: An impurity for which a structural characterisation has been achieved.
`Impurity: Any componentofthe medicinal product whichis not the chemical entity defined
`as the active substance or an excipient in the product.
`Impurity Profile: A description of the identified and unidentified impurities present
`medicinal product.
`New Active Substance: The designated therapeutic moiety which has not been previously
`registered in a memberstate (also referred to as a new molecular entity or new chemical
`entity). It may be a complex, simpleester, or salt of a previously approved substance.
`Potential Degradation Product: An impurity which, from theoretical considerations, mayarise
`during or after manufacture or storage of the medicinal product. It may or may notactually
`appearin the substance or product.
`Qualification: The process of acquiring and evaluating data which establishes the biological
`safety of an individual impurity or a given impurity profile at the level(s) specified.
`Reaction Product: Productarising from the reaction of a substance with an excipientin the
`medicinal product or immediate container/closure system.
`Safety Information: The body of informationthat establishes the biological safety of an
`individual impurity or a given impurity profile at the level(s) specified.
`Specified Degradation Product: Identified or unidentified degradation product that is selected
`for inclusion in the new medicinal productspecifications and is individually listed and limited
`in order to assure the safety and quality of the new medicinal product.
`Toxic Impurity: An impurity having significant undesirable biologicalactivity.
`Unidentified Degradation Product: An impurity which is defined solely by qualitative
`analytical properties, e.g., chromatographic retention time,
`Unspecified Degradation Product: A degradation product whichis not recurring from batch to
`batch.
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`ATTACHMENTI
`
`THRESHOLDS FOR REPORTING OF DEGRADATION PRODUCTS
`IN NEW MEDICINAL PRODUCTS
`
`Maximum Daily Dose
`
`1
`
`<lg
`
`>] g
`
`Threshold?
`
`0.1%
`
`0.05%
`
`THRESHOLDS FOR IDENTIFICATION OF DEGRADATION PRODUCTS
`IN NEW MEDICINAL PRODUCTS
`
`Maximum Daily Dose!
`
`Threshold?
`
`< | mg
`
`1 mg - 10 mg
`
`>10 mg-2¢
`
`> 22
`
`1.0% or 5 ug TDI? whicheveris lower
`
`0.5% or 20 ug TDI whicheveris lower
`
`0.2% or 2 mg TDI whicheveris lower
`
`0.1%
`
`THRESHOLDS FOR QUALIFICATION OF DEGRADATION PRODUCTS
`IN NEW MEDICINAL PRODUCTS
`
`Maximum Daily Dose!
`
`Threshold?
`
`<10mg
`
`1.0% or 50 ug TDI whicheveris lower
`
`10 mg - 100 mg
`
`>100mg-2¢
`
`>2¢g
`
`0.5% or 200 ug TDI whicheveris lower
`
`0.2% or 2 mg TDI whicheveris lower
`
`0.1%
`
`' The amount of substance administered per day
`2 Total Daily Intake
`3 Threshold is based onpercentof the substance
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`CPMP/ICH/282/95
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`Thresholdsfor Identification, Qualification and Reporting of Degradation
`Products in New Medicinal Products
`
`
`
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`
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`|
`|
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`Identification
`
`0.4 |
`* « Qualification
`
`Reporting
`
`
`0
`
`500
`
`1000
`
`1500
`
`2000.
`
`Maximum Daily Dose expressed in mg of Active Substance
`
`Expandedscale:
`
`41
`
`pegs
`
`cad
`
`ESS
`
`cad
`
`se
`
`~@ Thresholds for Identification, Qualification and Reporting
`@, of Degradation Products in New Medicinal Products
`
`expressedasapercentageofActive
`
`
`
`ThresholdofDegradationProducts
`
`Substance
`
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`
`————— Identification
`=
`Qualification
`
`Reporting
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`Maximum Daily Dose expressed in mg of Active Substance
`
`20
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`ATTACHMENTII: DECISION TREE FOR SAFETY STUDIES
`
`Decrease degradation product
`
`Abovethreshold?
`
`
`
`NO Qualified>
`
`level below threshold
`
`
`YES
`
`Structure elucidated?
`
`YES
`
`Toxicity documented
`and sufficient?
`
`
`
`
`Acceptable
`
`justification?
`
`
`
`Considerpatient population
`and duration ofuse
`
`
`
`
`Consider need for:
`
`1. Genotoxicity studies (point mutation, chromosomal aberration)*
`
`
`2. General toxicity studies (one species, min. 14 days, max. 90 days)>°
`
`
`3. Other specific toxicity endpoints, as appropriate
`
`| YES
`
`Qualified
`
`
`
`Qualified
`
`
`
`Adverse Effects
`
`S
`
`NO
`
`
`Consider additional testing or removal/
`lowering level of degradation products
`
`
`
`a
`
`b
`
`If considered desirable, a minimum screen e.g., genotoxic potential, should be conducted. A study to
`detect point mutations and one to detect chromosomalaberrations, both in vitro, are seen as an acceptable
`minimum screen, as discussed in the ICH-Guidelines: “Specific Aspects of Regulatory Genotoxicity
`Tests” and “Genotoxicity: Definition of Core Battery Tests”,
`Ifgeneral toxicity studies are desirable, study(ies) should be designed to allow comparison ofunqualified
`to qualified material. The study duration should be based on available relevant information and performed
`in the species most likely to maximise the potential to detect the toxicity of an impurity. In general, a
`minimum duration of 14 days and a maximum duration of 90 days would be acceptable.
`c Onaceasebycase basis, single dose studies may be acceptable, especially for single-dose drugs, and when
`such studies are conducted using an isolated impurity. If repeat-dose studies are desirable, a maximum
`duration of 90 days would be acceptable.
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