api sm part 1

Part 1: A Review and Perspective of the Regulatory Guidance toSupport Designation and Justication of API Starting MaterialMargaret M. Faul,*, William F. Kiesman,*, Maciej Smulkowski, Steven Pfeier, Carl A. Busacca,

Magnus C. Eriksson, Fred Hicks,# and John D. Orr

Chemical Process Research and Development, Amgen Inc., Thousand Oaks, California 91320Chemical Process Research and Development, Biogen Idec, Cambridge, Massachusetts 02142Chicago Pharmaceutical Science Group, Takeda Development Center Americas, Inc., Deereld, Illinois 60015Process Development and Manufacturing, Kythera Biopharmaceuticals, Calabasas, California 91301Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Ridgeeld, Connecticut 06877#Takeda Pharmaceuticals International Company, Cambridge, Massachusetts 02139U.S. API Process Research and Development, Pharmaceutical Science and Technology, Eisai Inc., Andover, Massachusetts 01810

ABSTRACT: Designation and justication of active pharmaceutical ingredient starting material (API SM) is a standard part ofthe drug substance (DS) development and commercialization process. However, current industry practices are not wellunderstood and vary, depending on the individual companys interpretation of regulatory guidelines. In addition, regulators arealso applying varying interpretations to the designation of API SMs, further complicating progress in this arena. To increase theunderstanding of the strategies employed in selection and justication of API SMs the authors, members of the API andAnalytical Leadership Groups of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ),completed a broad industry survey of this topic among the 35 IQ Consortium member companies. To put the results of thissurvey into context, an understanding of the historical development of API SM regulations and the industry perspective isimportant and is summarized collectively for the rst time in this manuscript (Part 1). The detailed results of the survey aresummarized and published in a second manuscript (Part 2; Designation and Justication of API Starting Materials: CurrentPractices across Member Companies of the IQ Consortium). Part 3 of this series is expected to be published in the future andwill outline opportunities to improve the process in alignment with Q11.

INTRODUCTIONThe material in this manuscript was developed with the supportof the International Consortium for Innovation and Quality inPharmaceutical Development (IQ). IQ is a not-for-protorganization of pharmaceutical and biotechnology companieswith a mission of advancing science-based and scienticallydriven standards and regulations for pharmaceutical andbiotechnology products worldwide. Today, IQ represents 35pharmaceutical and biotechnology companies. Please visit www.iqconsortium.org for more information.One of the major aspects of drug substance (DS)

development is the designation and justication of the ActivePharmaceutical Ingredient Starting Material (API SM), thepoint in the synthesis of the DS where GMP processingbegins.1 However, designation of API SMs for DS manufacturecontinues to be a much debated topic and industry practices fortheir designation varies based upon company experience andinterpretation of regulatory guidances.2 The target of regulatorsis not aligned across regions and continuously reinterpreted. In2011, the API and Analytical Leadership Groups (LGs), withinthe IQ Consortium, established an API SM Working Group(WG), to assess how IQ member companies designate andjustify API SMs. The API SM WG chose to dene this area byposing three fundamental questions:

How has the regulatory perspective on API SMdesignation developed?

What are peer companies doing now? What should the industry do, if anything, to improve the

current process?

This manuscript, Part 1 of this series, answers question 1 andwill summarize the current regulatory guidances as well asprovide a perspective from industry and the regulators on themost important elements that should be addressed injustif ication of the API SMs. The accompanying manuscript,Part 2 will answer question 2, and outline the current practicesused by the IQ member companies to support their API SMjustication with the regulatory agencies. Part 3 of this series isexpected to be published in the future and will outlineopportunities to improve the process in alignment with Q11.

REVIEW OF CURRENT REGULATORY GUIDANCESFOR API SM DESIGNATION AND JUSTIFICATION

Regulatory Position. In 1987 the Food and DrugAdministration (FDA) released the Guideline for SubmittingSupporting Documentation in Drug Applications for theManufacture of Drug Substances3 and indicated that while

Received: February 17, 2014Published: April 10, 2014

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denition of an API SM applicable to all situations cannot begiven the following general criteria should be employed:

It is incorporated into the DS as an important structuralelement.

It is commercially available. It is a compound whose name, chemical structure,

chemical and physical properties, and impurity prole arewell-dened in the chemical literature.

This guidance indicated that the API SM needs to meetseveral, but not all, of these criteria. For instance, an API SMthat is not commercially available could be acceptable as long asit had well-dened properties in the chemical literature or ifadditional analytical testing for impurities could be provided.The requirements were clearly an attempt to require that thecomplete DS synthesis be provided in Section S.2.2 f rom simplecommercially available API SMs (the commercially availablerequirement was referred to as the Catalog requirement). Themajor failure of this guidance was that it required evaluation andcontrol of too many steps not related to f inal DS quality, did notprovide f lexibility in changes to early steps in the synthesis that didnot af fect quality, and did not allow for outsourcing of early steps tocontract manufacturers without a Post Approval Supplement. Inaddition, little clarity was provided to the industry on acceptabledef initions for the terms important structural element andcommercial availability. It also failed to recognize that most APISMs are not well characterized in the literature, particularly withrespect to their impurity prof iles because the scientif ic and patentliterature may address purity (assays) of chemicals, but very seldompresents their impurity prof iles, especially impurities at the levelrequired for control in DS manufacturing.In 1999, Moller et al.4 dened the elements of a scientically

based approach to the designation of API SMs. They believedthat the key issue concerned impurities that may be carriedthrough to the DS, introduced the concept that the number ofprocess steps that an API SM is removed from the DS wasimportant, and that full analytical control over substances usedin the manufacture of a DS should be judged during theevaluation of an API SM.Regulatory Position. In 2001 ICH Q7A provided a new

denition for API SMs as A raw material, intermediate or anAPI that is used in the production of an API and that isincorporated as a signicant structural fragment into thestructure of the API. It went on to describe that the API SMcan be an article of commerce, a material purchased from oneor more suppliers under contract or commercial agreement, orproduced in-house. In addition, API SMs are normally expectedto have dened chemical properties and structure. Thisguidance indicated that companies should designate and documentthe rationale for the selection of the API SMs, f rom which pointappropriate GMP, as def ined in ICH Q7A, should be applied tothe intermediate and/or DS manufacturing steps. However, whilethis guidance improved upon the basic def inition of an API SM, itdid not provide information on how to construct the elements of arationale for the justif ication of the API SMs.In 2003, a PhRMA working group, led by Mitchell, provided

a perspective on the challenges and opportunities of a science-based approach to starting-material denition.5 They recom-mended that the 1987 guidance should be re-examined andshift away from the traditional paradigm of commercialavailability and known in the literature to a new paradigmwhereby criteria for SMs would be based on scientically soundand relevant controls. Risk-based approaches were proposed,

suggesting that more stringent guidelines should be put in placeas the synthesis progresses. Later steps are most likely to impactDS quality; however, with the advancement of analyticalmethods, selecting a process intermediate, in the GMPsequence, as an API SM with an appropriate level of analyticalcontrol can also provide appropriate quality assurance.Decisions on the API SM should be based upon impact toDS quality, and PhRMA recommended a decision treeregarding the impact of the chosen API SM on the DS quality.If the decision tree indicated that the intermediate is not asuitable API SM candidate, since it did not provide sucientcontrol over the DS quality, then an intermediate earlier in thesynthesis should be evaluated. The article also mentioned thatchanges in vendor or manufacturing site for that API SMshould have no regulatory (i.e., ling) impact. This approachand decision tree was broadly leveraged as a framework byindustry in their approach to the designation of API SMs.Regulatory Position. In order to provide a clearer path for

API SM designation, a 2004 draft Guidance was issued by theFDA.2a It proposed a two tiered approach to the selection ofAPI SM with an exception being made for those API SMs thathave a signicant pre-existing nonpharmaceutical market. Theguidance proposed that the API SM should be selected andcontrolled in a way that the risk from future changes in thequality of the API SM aecting the identity, quality, purity, orpotency of the DS is minimized. To control these risks fourselection criteria for API SM without a signicant non-pharmaceutical market were described:

Propinquity: the proposed API SM should be separatedfrom the nal intermediate by several reaction steps thatresult in isolated and puried intermediates.

Isolated and puried: the proposed API SM should be anisolated and puried intermediate.

Carryover of impurities: the proposed API SM shouldnot be the source of signicant levels of impurities in theDS.6

Complexity of structure: the API SM should be readilydistinguishable from potential isomers and analogues sothat adequate controls can be established.

This guidance also proposed that a robust API SMspecication was required and that if a proposed advancedintermediate met all four criteria it could be considered as anAPI SM. Alternatively. if the API SM had a pre-existingpharmaceutical market. it would be an acceptable API SM.During a Hot Topics discussion at the 2004 DIA Annual

Meeting, Miller of the FDA reviewed the 2004 U.S. draftguidance and provided an outline of a hypothetical synthesisnoting the following:7

There was a tendency of the applicant to move API SMtowards DS.

The agencys tendency was to move the API SM awayfrom DS to control impurities, identity of the DS.

The agency wants to ensure that controls in the GMPsteps are appropriate to ensure the quality, andultimately, safety of the DS.

Miller subsequently went on to provide examples ofpropinquity (proximity/nearness), clarifying that an API SMshould be separated from the nal intermediate by severalreaction steps that result in isolated and puried intermediateswhile discussing how to dene a Commercial API SMintroduced late in the synthesis. Giralt later proposed that theexpectations for API SMs can be reduced to one statement

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The API SM should be selected and controlled so that the riskfrom future changes in the quality of the API SM aecting theidentity, quality, purity, or potency of the DS is minimized.8

These concepts introduced in the draf t FDA guidance were thesubject of much debate and there were ef forts in the regulatorycommunity to align around common principles. Af ter all of theseef forts the guidance document was withdrawn in 2006, because theFDA made the decision that all guidances should be harmonizedacross regions through the ICH process and the FDA should nothave separate guidance. Unfortunately, by the time it waswithdrawn it had already signif icantly inf luenced how manycompanies developed their API SM strategies and lef t a gap inproviding a path for companies to follow.Interestingly, at this point in time, although the pathway for

API SM designation was murky, many pharmaceuticalcompanies were beginning to embrace the idea of outsourcingtheir key raw materials and API SMs in order to focus theireorts on more value-added, later-stage activities. This changein business strategy added another layer of complexity to theprocess. In response to this Gavin et al. published a qualityevaluation strategy for outsourced API SM.9 They believed thata signicant component of any commercialization andregistration of a DS was the establishment of appropriateimpurity specications for the API SM. As multiple sources androutes of manufacture of the API SM became readily available,understanding the capability of the DS synthetic process fortolerating impurities introduced with the API SMs became apriority. Risk assessments and prior knowledge of actual andpotential synthetic routes were used to predict potentialimpurities in the intermediates and ultimately in the DS andguide purity method development.As the concept of design space began to grow, Illing

published a perspective that outlined three areas that should beapplied to API SM review: process control, analytical control,and change control.10 To demonstrate process control of theDS process, the applicant must determine whether theproposed API SM is made by custom synthesis or is acommodity reagent, that the process is well understood, andthat further scale-up will not present a risk to a patient. Next,the essence of a strong API SM justication is thedemonstration of adequate analytical control of the initialcharacterization of the API SM, an overview of stability, batchdata from various suppliers, assessment of how process changesimpact impurities and their levels, and the understanding ofselectivity of analytical methods for actual and potentialimpurities. Finally, evidence is needed that a robust changecontrol system is in place for both the applicants activities andthose of its suppliers, to ensure that improvements will notundermine patient safety. The change control programs of boththe applicant and vendor are a vital part of the overall control ofDS quality. The starting point for the assessment of potentialprocess modications are the original operating conditions andanalytical methods. It is essential to conrm that the analyticaltechniques are capable of detecting and controlling dierentimpurity proles that may result from a proposed change ofroute or process to the API SM. The change controlmechanism should assess potential changes for their inuenceon critical quality attributes of the DS. Seevers sought to informthe process for API SM designation and published a paper thatrecommended a regulatory strategy for communication withagencies at EOP2 meetings.11 He acknowledged that regulatorsseek to limit a sponsors choice of suppliers (sometimes to asingle supplier) and aim to limit the ability of sponsors to

switch suppliers of API SMs in order to ensure consistentquality. In addition, to limit the risk of new impurities in the DSregulators will want three things:

to have synthetic routes to the DS that are several stepsin length

to understand the API SM synthesis to request the manufacturer to use just one synthetic

route.

While these approaches allow a thorough understanding ofthe quality of the API SM, these limitations are in direct conictwith needs of sponsors to ensure uninterrupted supplies of APISMs from multiple suppliers and to drive continuousimprovement in the manufacturing processes for API SMs.Discussions with the FDA at the EOP2 meeting should includethe following:

analytical capability to detect impurities which may arisefrom dierent synthetic routes to an API SM (or fromthe reaction products of impurities in the API SM)

process purication capability to remove impurities acceptance criteria for the API SM so that any impurities

which may arise from supplier or synthetic route changeswill be detected and controlled to appropriate levels inthe nal DS.

Regulatory Position. In 2011 the ICH Q11 Guidance onDevelopment and manufacture of drug substances (chemicalentities and biotechnological/biological entities) was pub-lished which discussed some considerations for API SMselection and aimed to harmonize the denition and criteriafor selection of API SMs.2c Two sections on the API SM wereprovided: (i) general principles for choosing API SM derivedfrom custom synthesis, and (ii) information to be submitted inthe dossier. The following principles, paraphrased from Q11,were proposed for selection and designation of API SMs and toprovide a common framework on the regulatory expectationsrequired by all three ICH regions:

Changes in material attributes or operating conditionsthat occur at the beginning of the manufacturing processhave lower potential to impact DS quality. An increase innumber of steps and isolation points decreases carryoverrisk of impurities from API SM into DS.

Enough of the DS manufacturing process should bepresented to demonstrate how impurities are formed andremoved in the process, and how changes in the processcould aect the formation, fate, and purge of impurities.

Manufacturing steps that impact the impurity prole ofthe DS should be included in the manufacturing processdescription.

Each branch of the manufacturing process should beginwith one or more API SMs.

Performing manufacturing steps starting from the APISM under GMP, together with an appropriate controlstrategy, provides assurance of quality of the DS.

An API SM should be a substance of dened chemicalproperties, have adequate stability, and represent asignicant structural fragment of the DS. Nonisolatedintermediates are usually not appropriate API SMs.

Quality agreements by suppliers committing to reportingof changes

In addition, Q11 emphasized that an aggregate evaluation ofall six principles should be conducted and API SM justicationsshould strive for a balanced approach, such that if one of the six



principles is pursued with an aggressive strategy, additionalstrengthening of some of the other principles should beconsidered. For specic information that should be included inthe dossiers, ICH Q11 proposed the following:

Identify all proposed API SMs or source materials. Provide appropriate specications for both incoming and

puried API SMs. Justify proposed API SMs in terms of how they each

comply with the general principles for the selection ofthe API SMs. This is not necessarily needed forcommercially available chemicals.

The justication document can include the followinginformation related to the ability of the analytical methods todetect impurities in the API SMs: the fate and purge of thoseimpurities and their derivatives in subsequent processing stepsand how the proposed specication for each API SM willcontribute to the control strategyThe applicant should also provide, as part of the justication,

a ow diagram outlining the current synthetic route(s) for themanufacture of the DS, with the proposed API SMs clearlyindicated. Changes to the API SM specication and to thesynthetic route from the API SM to nal DS are subject toregional, postapproval change requirements as are requirementsconcerning API SM suppliers. In addition, where the API SMinformation is contained in submissions (i.e., sections S.2.2 vsS.2.3) it is also dependent upon the regional authority practices.Regarding commercially available API SMs, it was indicated

that the applicant does not need to justify the use of acommercially available chemical as an API SM. A commerciallyavailable chemical is usually one that is sold as a commodity ina pre-existing, nonpharmaceutical market in addition to itsproposed use as an API SM. Chemicals produced by customsyntheses are not considered to be commercially available. If achemical from a custom synthesis is proposed as an API SM, itshould be justied in accordance with the general principles forthe selection of API SMs. While Q11 clearly embraced the sciencedriven risk-based assessment of the propensity for API SMs toinf luence the quality of the f inal DS, overall it was too general andlef t a few specif ic points open to broad interpretation. Its mainpurpose was to provide a f ramework around the control strategies,risk assessment, and QbD development of the DS synthesis withselection of the API SM being represented as only a part of theguidance. Important concepts for designation of API SMs are lef t toExample 4 of the guidance which suggests a late-stage intermediateDS, two steps removed f rom the f inal intermediate and af ter thegeneration of the key chiral sites in the molecule can be successfullynegotiated as an API SM. Propinquity was not specif ically namedin the guidance but elements of propinquity were described.Unfortunately, no clear alternative was provided, leaving a concernthat the regulatory authorities will default to previous propinquitypractices and ignore the control strategy and risk assessmentdetails.12

One of the key gaps not addressed in ICH Q11, is how toaddress regulatory changes to the upstream synthesis to thecGMP designated API SM. FDA has no guidance in this area.Once the API SM is designated, the upstream synthesis may bechanged under cGMPs without any regulatory notication. Oneof FDAs concerns is control of future changes and thenotication requirements for this type of information.At the 2011 DIA meeting, Smith and Watson provided both

the regulatory and industry perspectives on aspects of the Q11guidance.13,14 Smiths expectations around the guidance

reiterated the shared general principles but also highlighted afew renements including:

Each branch of a manufacturing process begins with oneor more API SM, GMP (ICH Q7) applies to each branchbeginning with the rst use of a API SM.

Commonly available chemicals used to create salts,esters, or other simple derivatives should be consideredreagents.

He also suggested that information for Dossiers Submittedon the API SM should include:

appropriate specications justication of proposed API SMhow does each

comply with the general principles insight into the scientic rationale and compelling data.Watson focused not only on the examples of how an API SM

candidate can be evaluated against the Q11 general principlesbut also on the emerging outsourcing and the supply chainenvironment for API SMs with some case studies. He explainedthat, with the growth of outsourcing, most vendors are globalcompanies with diverse cultures and that the vendor-purchasedAPI SMs may or may not coincide with approved API SM in aregulatory submission. Heightened concern over the pastdecade on the potential for cross contamination due tomanufacturing in multipurpose facilities has become an addedrisk that needs to be managed.European Requirements. While ICH requirements apply

across regions within the EU, there is increasing concern withthe inconsistency of approaches from reviewers to support theAPI SM submissions. From 2010 to 2011, about two out ofthree CEP dossier applicants received a request to redenetheir API SMs due to their failure to demonstrate anappropriate control strategy from the API SM to the DS.15

To address their concerns, the EDQM Certications SteeringCommittee approved a new assessor guide, available only toassessors, for API SMs in 2012. This guide provided anoverview of the current API SM guidances, described thedierences between API SM and intermediates, provided adenition of a synthetic step, described the informationrequired to support use of purchased API SMs and dened therequirements to harmonize the assessment of applicationsacross reviewers. Specic prerequisites regarding the structure,complexity, and source of the API SM, the analytical controlstrategy documenting the fate and purge of impurities, and thedata required to justify the specications were discussed.15

While in alignment with Q11, it argued that propinquity is notan argument to support selection of the API SM; the number ofsteps from API SM to DS may be related to the overall controlstrategy. Thus, the closer the API SM is to the DS, the greaterthe information on the control strategy that is required todemonstrate that the sponsor has a full degree of processunderstanding and that the quality of the DS can be controlled.While not disclosing the questions to industry, their purpose isto ensure consistency regarding expectations for the applicantsand reviewers.16

Canadian Requirements:17 The guidance contained inICH Q11 is intended to address API SM designation andjustication at the time of NDA. FDA and EMA have not setout specic expectations regarding the disclosure of API SMsyntheses in regulatory lings for programs in late development(Phases 2 and 3). In contrast the Canadian authorities havecommunicated their expectations for sponsors as a regionalrequirement. The Canadian guidance document stipulates that



at phase 2 sponsors should provide details on the API SMsynthesis. The guidance sets forward the following expect-ations:18

The analytical control strategy on the API SM and GMPsteps should increase the closer the API SM is to the nalDS.

For API SMs which are commercially purchased, thesource and a copy of the provisional specications istypically considered acceptable.

For API SMs which are manufactured in-house, a copy ofthe synthetic scheme and provisional specicationsshould be justied. Specications should include one ormore specic identity tests, an analytical method thattests the potency of the API SM, including analyticalmethods for specied and unspecied impurities inaddition to the total impurities.

In order to assess the presence of all potential impurities,including regioisomeric and stereoisomeric impurities, toxicimpurities, residual solvents and residues of catalysts in the APISM, a brief narrative description of the synthesis leading to theAPI SM, from raw materials, with all the reagents, solvents, andintermediates specied, and the owchart of the synthesisshould be provided. Potential for the presence of adventitiousagents, including viral and bacterial agents, residual proteins,and transmissible spongiform encephalopathy (TSE) agents inthe API SM selected should be discussed.Genotoxic Impurities. Introduction of regulatory guide-

lines on control of genotoxic impurities (GTIs) signicantlyincreased requirements for control of DS manufacturingprocesses, including control of API SMs. Assessment andcontrol of genotoxic impurities at sub-ICH Q3A/B thresholdsrequired identication of actual and potential impurities,including those related to early stages of DS manufacturingprocess (pre-API SM steps), evaluation of their genotoxicpotential, development of sensitive analytical methods withdetection limits in ppms, testing at that level intermediates orDS for genotoxic impurities, and developing adequate controlstrategy for these impurities to ensure control at the thresholdof toxicological concern (TTC) level.19 Requirement forevaluation of potential impurities in early stages of the DSmanufacturing process soon precipitated, as described below,with increased requirements for control of the API SMmanufacturing process.The rst guideline, published by the EMEA (now EMA) in

2006, followed the ICH Q3A in denition of potentialimpurities which include impurities associated with rawmaterials that could contribute to the impurity prole of theDS. These impurities should be assessed for their genotoxicpotential, and if identied as genotoxic, controlled to acceptablelevel based on the TTC. Following the Guideline, EMEAQuestions and Answers (Q&A) documents provided anexcellent clarication of the Guideline and introduced theStaged TTC (higher than TTC) that could be applied duringdevelopment.20

The FDA Step 1 Guidance from 2008, similar to the EMEAGuideline, stated that the Guidance also applies to known APISMs or anticipated reaction products. Neither documentprovided any specics for evaluation and control of GTIsrelated to API SMs. However, in the past few years EMA andHealth Canada usually required, in addition to the evaluation ofactual API SM impurities, an evaluation of API SM potentialimpurities for their genotoxic potential and related risk to the

DS. The FDA asked for this evaluation usually only in specialcases, for example, when the API SM was introduced close tothe DS in the DS manufacturing process.The new ICH M7 Step 2 document (published Feb/2013)

provides a more comprehensive approach to addressing GTIs,including impurities related to API SMs. Key sections of theStep 2 document that address this topic are outlined below.

Section 5 Drug Substance and Drug Product ImpurityAssessment. This Guideline states that potential impuritieswhich should be evaluated for their genotoxic potential couldinclude starting materials, identied impurities in startingmaterial, and reasonably expected reaction by-products. Knowl-edge of the API SM synthesis, in particular the use ofmutagenic reagent, is an important factor in understanding thepotential impurities in the API SMs, especially when there is areasonable potential that such impurities may persist in theDS. The last statement does not provide clear requirementsfor evaluation and control of pGTIs related to the API SMs.These requirements are still under discussion by the ICHEWG. Industry experience in addressing GTIs since the rstEMEA Guideline increased understanding that genotoxicimpurities, being very reactive, are generally converted and/orpurged within the DS manufacturing process; therefore, the riskthat GTIs from API SMs could be present in DS is low.21

All identied actual and potential impurities in the DS shouldbe evaluated for mutagenic potential that includes literature anddatabase searches for carcinogenicity and bacterial mutagenic-ity. Data can be obtained from a computational toxicologyassessment using two complementary prediction method-ologies (for example the most popular platform, DEREK,along with Leadscope or Mcase). Any structural alert may beoverruled by negative bacterial mutagenicity assay (Ames test).In the absence of identication of a structural alert or ifbacterial mutagenicity assay is negative, an impurity can betreated as an ordinary impurity per ICH Q3A guidance. Astructural alert, without a negative bacterial mutagenicity testresult and all positive test results, requires control of impurity asGTI at or below the staged TTC.22

Section 8, Control. The Guideline provides four optionsfor development of a control strategy for DS; these options maybe used to control pGTIs related to API SMs:

Options 1 and 2 include a test for the impurity in thespecications of DS, intermediates, and raw materialswith an acceptance criterion at or below the acceptablelimit using an appropriate analytical procedure. It ispossible to apply periodic testing for these options.

Option 3: Include a test for the impurity in thespecication for a raw material, API SM or intermediate,or as an in-process control, with an acceptance criterionabove the acceptable limit using an appropriate analyticalprocedure coupled with demonstrated understanding offate and purge and associated process controls thatensure the level in the drug substance is below theacceptable limit without the need for any additionaltesting.

Option 4: Understanding of process parameters andimpact on residual impurity levels (including fate andpurge studies) with sucient condence that the level ofthe impurity in the DS will be below the acceptable limitsuch that no analytical testing is needed for this impurity.

Teasdale et al. introduced a simple method for calculation ofpurge factors that could be used to demonstrate control of



PGIs per options 3 and 4.23 For option 3, the Guidelineprovides an example of control of impurity from the API SM bythe API SM specication and the purge factor determined inthe laboratory-scale studies.The guideline also states that for genotoxic impurities

introduced in the last synthetic step, the testing of the DS(Option 1) would be expected unless otherwise justied. Thiswould include genotoxic API SMs and genotoxic impurities inAPI SMs introduced in the last step of DS manufacturing.From the industry perspective, options 3 and 4 are

particularly suitable for addressing GTIs from API SMs forwhich, as stated above, risk of presence in the DS is low. Ifbased just on scientic principles, justication of the controlstrategy per option 4 is not feasible; the common solution isdevelopment of acceptance criteria for GTIs in API SMs andjustication of those criteria per option 3.

Section 9 Documentation. The Guideline providesrequirements for documentation of the control of pGTIs thatshould be provided in dierent stages of the regulatory lings.For these and other requirements of the ICH M7 Step 2Guidance, refer to the guideline document.24

In recent years, the pharmaceutical industry has observedincreased requirements from countries outside the ICH,notably China and Korea, to include the evaluation and controlof pGTIs in the lings. Also, in 2012 Argentina issuedregulations on the control of genotoxic impurities.25 Now, afterthe ICH M7 Step 2 Guideline was published and with theanticipation that the nal document will be nalized in June2014, we can expect that more countries will follow suit.Related Expectations on Starting Materials for

Generic Drugs. This new Q&A guidance from the EDQMhas also been taken up by the European Generics MedicinesAssociation (EGMA) who has also published a position paperfor the EU on the Active Substance Master Files (ASMFs) andCEP Applications to ensure a consistent approach to deningAPI SMs by ASMF holders, DP manufacturers, and competentauthorities to understand the supply chain and ensure patientsafety. Their goal was to gain a harmonized understanding ofAPI SMs and a consistent understanding of documentationrequired. In addition to the expectations of the EDQM, theEGMA put knowledge and understanding of the origin and fateof impurities (including GTIs) as the most important aspect inthe denition and identication of API SMs. They support ascience and a risk-based approach (as opposed to a one sizets all) accompanied by an appropriate change control strategyas the best strategy.26

A similar approach to demonstrate a control strategy for thesynthesis of the API SMs around stereogenic impurities andGTIs/pGTIs in the ANDA ling was published by the Oce ofGeneric Drugs in 2012.27 This article highlighted generalprinciples for the selection of API SMs and also providedexamples of what would not be acceptable as an API SM. Thecase studies in this article are interesting and provide insightinto the FDAs current thinking on API SM designation.Although the topic was related to those of ANDA, in reality theconcepts apply to all DS.

CONCLUSIONToday, 27 years after the rst Guidance (1987), the followingstatements from the Guidance are still valid: What constitutesthe starting material may not always be obvious andgenerally the decision about what is the starting material hasbeen reached by agreement between the applicant and the FDA

chemist (i.e. reviewer) before submission of the NDA.However, with the evolution of the regulatory guidancesthere is a clear understanding that what the regulators deemmost important is for the applicant to demonstrate a controlstrategy to ensure the quality of the DS. While today there isalignment on the intent of Q11 which is to demonstrate acontrol strategy, there is not alignment on the application ofcontrol strategies (whether it is more appropriate to controlthrough propinquity alone or via enhanced process knowledge)to support the API SM justication. Moving forward, to alignthe focus of applicants and regulators on the critical factors inthe justication, it will be important to have a unied,international, common denition, and approach across alljurisdictions (i.e., not a regionalized approach) to both thedenition and documentation for API SMs. Despite thecontinued debate on this topic, limited work has beenpublished in this area to add clarication, and there are fewconcrete case studies where applicants have published theinformation submitted to justify their API SM in the regulatoryle. With the regulatory background and understandingoutlined in this manuscript (Part 1), the API and AnalyticalLGs of the IQ Consortium sought to build an understanding ofthe current practices within the IQ member companies on thisimportant topic, and this will be outlined in the accompanyingmanuscript representing Part 2 of this series.

AUTHOR INFORMATIONCorresponding Authors*Telephone: 805-447-0599.*E-mail: [email protected] authors declare no competing nancial interest.

ACKNOWLEDGMENTSThe authors would like to thank the following individuals andcompanies for their review of this manuscript: IngridMergelsberg (Merck, Inc.), John Pavey (Astra Zeneca), OliverThiel (Amgen), William Leong (Celgene), Daiichi Sankyo,Gilead Sciences Inc., Kythera Biopharmaceuticals.

REFERENCES(1) ICH Q7A Good Manufacturing Practices for Active PharmaceuticalIngredients; U.S. Department of Health and Human Services, Food andDrug Administration,Center for Drug Evaluation and Research(CDER): Rockville, MD, 2001; Reference Table.(2) (a) FDA Draft Guideline, Guidance for Industry: Drug Substance:Chemistry, Manufacturing, and Controls Information; U.S. Departmentof Health and Human Services, Food and Drug Administration,Center for Drug Evaluation and Research (CDER): Rockville, MD,Jan. 2004. Withdrawn Federal Register, Notice: June 1, 2006. (b)EMEA Guideline on the Chemistry of New Active Substances, CPMP/QWP/130/96, December 2003 Revision 1. (c) ICH Q11 Developmentand Manufacture of Drug Substances (Chemical Entities and Biotechno-logical/Biological Entities); U.S. Department of Health and HumanServices, Food and Drug Administration, Center for Drug Evaluationand Research (CDER): Rockville, MD, 2011.(3) Guideline for Submitting Supporting Documentation in DrugApplications for the Manufacture of Drug Substances; U.S. Departmentof Health and Human Services, Food and Drug Administration,Center for Drug Evaluation and Research (CDER): Rockville, MD,1987.(4) Moller, H.; Oldenhof, H. Drug Inf. J. 1999, 33, 755761.(5) Cupps, T.; Fritschel, B.; Mavroudakis, W.; Mitchell, M.; Ridge,D.; Wyvratt, J. Pharm. Technol. 2003, 3452.



(6) Carryover rule: Industry and regulatory agencies commonly use a0.1% threshold for the presence of new impurities in the DS todetermine equivalence of batches made before and after a change. Thepresence of new impurities in the API SM would require adetermination of their fate during subsequent processing stages.Results over ICH Q3A R2 (13) thresholds in the DS may requiretoxicological assessment.(7) Miller, S. Update on Drug Substance and Drug Product DraftGuidances; presented at the DIA Annual Meeting, Washington DC,U.S.A., June, 2004.(8) Giralt, R. Pharm. Technol. Eur. 2004, No. 6, 16.(9) Gavin, P. G.; Olsen, B. A.; Wirth, D. D.; Lorenz, K. T. J. Pharm.Biomed. Anal. 2006, 41, 12511259.(10) Illing, G. T.; Timko, R. J.; Billet, L. Pharm. Technol. 2008, 32,5257.(11) Seevers, R. H.; Kluttz, W. F. Pharm. Outsourcing; January/February 2010, 11 1.(12) In 2012 Eglovitch published two articles in the Gold Sheetrelated to the Q11 Guidance around API SMs. The rst articleprovided a perspective that industry and regulators were divided overthe Q11 denition of API SMs and some were concerned that Q11 didnot address control of the quality of the API SMs. The second articleacknowledged that Q11 provided a set of guiding principles forchoosing starting materials, illustrated how a risk assessment can beused to evaluate process changes, and demonstrated how priorknowledge can be used to develop new drug substances. (a) Eglovitch,J. S. Gold Sheet 2012, Vol. 46, No. 5. (b) Eglovitch, J. S. Gold Sheet2012, Vol. 46, No. 10.(13) Smith, J. Drug Substance Starting Materials and ICH Q11presented at the DIA Annual Meeting, Chicago, IL, U.S.A., June, 2011.(14) Watson, T. Drug Substance Starting Materials, Supply Chain andICH Q11 Guidance An Industry Perspective presented at the DIAAnnual Meeting, Chicago, IL, U.S.A., June, 2011.(15) Paulson, B., Ed. Int. Pharm. Quality, 2012, 3, (3), 1424.(16) This guide has not been ocially published. However inDecember 2013 the EMA QWP held a break out session to discuss thetopic Selection/Denition of Starting Materials for Synthetic DrugSubstances. This breakout session was preceded by a document fromEMA QWP that aimed to clarify the diculties faced with the currentinterpretation of the guidelines, focused on Q11 but also CPMPGuideline on Chemistry of New Active Substances. This is believed torepresent the framework of the assessor guide. This may lead to aWorking Group to def ine the expectations in more detail.(17) Health Canada: Quality (Chemistry and Manufacturing)Guidance: Clinical Trial Applications (CTAs) for Pharmaceuticals;Health Canada: Ottawa, Ontario, Date adopted 2008/11/12; EectiveDate 2009/06/01.(18) Drug and Health Products Pharmaceutical Sciences Q&A. Module3, Section 3.2.S for Drug Substances; Health Canada: Ottawa, Ontario,Date Adopted: 2012/05/25; Eective Date: 2012/06/22; HealthCanada API SM Expectations.(19) The Threshold of Toxicological Concern (TTC) is a conceptthat refers to the establishment of a level of exposure for all chemicals,whether or not there are chemical-specic toxicity data, below whichthere would be no appreciable risk to human health. The conceptproposes that a low level of exposure with a negligible risk can beidentied for many chemicals, including those of unknown toxicity,based on knowledge of their chemical structures.(20) EMEA/CHMP, Questions and Answers on the CHMP Guidelineson the Limits of Genotoxic Impurities, EMEA/CHMP/SWP/431994;2007; Rev. 3 Published September 2010.(21) Teasdale, A. Genotoxic Impurities: Strategies for Identication andControl; John Wiley and Sons: New York, 2010.(22) The Guidance provides an option for further hazard assessmentof an impurity with a positive bacterial mutagenicity result when, forexample, the level of the impurity cannot be controlled at anacceptable limit.

(23) Teasdale, A.; Elder, D.; Chang, S.-J.; Wang, S.; Thompson, R.;Benz, N.; Sanchez Flores, I. H. Org. Process Res. Dev. 2013, 17, 221230.(24) Federal Register 2013, 78(72), 2226922270.(25) Ministry of Health, Department of Policies, Regulation, andInstitutes (A.N.M.A.T). Regulation No. 0985, Buenos Aires, Argentina,16 February 2012.(26) Position Paper on the Denition of Active Substance StartingMaterials in Active Substance Master Files (ASMFS) and CEPApplications; European Generic Medicine Association: Brussells,Belgium, 2010.(27) Scott, B. FDA Perspectives: Designation of Regulatory StartingMaterials in the Manufacturing of Drug Substances: Impact on ANDAReview Time. Pharmaceutical Technology 2012, 36 (1), 6366.



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