Evaluation of starting materials for PMIs (potentially mutagenic

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Evaluation of starting materials for PMIs (potentially mutagenic impurities) – a vortioxetine case study Nevenka Kragelj Lapanja, Borut Zupan#i#, Renata Toplak #asar, Sabina Jurca, and Bojan Doljak Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00239 • Publication Date (Web): 04 Dec 2017 Downloaded from http://pubs.acs.org on December 4, 2017

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Organic Process Research & Development

Evaluation of starting materials for PMIs (potentially mutagenic impurities) – a vortioxetine case study Nevenka Kragelj Lapanja,*,† ,‡ Borut Zupančič,† Renata Toplak Časar,† Sabina Jurca† and Bojan Doljak ‡ †

Lek Pharmaceuticals d.d., Verovškova 57, 1526 Ljubljana, Slovenia

‡

Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia

ACS Paragon Plus Environment

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GRAPHICAL ABSTRACT


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KEYWORDS: drug substance, starting material, mutagenicity, purge factors

ABSTRACT: The nature of the starting material (SM) and the presence of (potentially) mutagenic impurities (PMIs) can correlate strongly, since many syntheses involve the use of potentially mutagenic electrophilic (alkylating) agents as SMs. Since the regulatory guidelines are far from clear and straightforward, selection of the appropriate SMs is a very challenging task for pharmaceutical companies. Here, the principal criteria for the selection of SMs have been identified based on the existing guidelines. Three SMs in the synthesis of vortioxetine drug substance were selected and justified on the basis of their incorporation into the structure of the API, on whether they have defined chemical properties and structure or not, on the number of synthetic steps between the SM and the API, on commercial availability and formation of impurities and their control. Determination of a theoretical purge factor (TPF) was successful in evaluating the risk of using potentially mutagenic SM 1 and SM 3, with their related impurities, and the effect of a non-mutagenic SM 2 on the quality and safety of the API. This approach enables the use of selected SMs to be justified.


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INTRODUCTION:

The use or formation of potentially mutagenic impurities (PMIs) and the selection of appropriate starting materials (SMs) are two regulatory topics that have attracted a lot of attention in pharmaceutical industry in recent years. In 2006 the first guideline addressing the control of genotoxic impurities (GTIs) in marketing applications was published by the European Medicines Agency (EMA, formerly EMEA).1 After several updates and refinements of the existing PMI/GTI guidelines, the ICH M7 guideline2 was published in June 2014. Today it is adopted by all major regulatory bodies, and is the primary guideline followed by pharmaceutical companies to assess and control formation of PMIs in pharmaceuticals. Although SM selection is at first sight a completely different thematic, it can correlate strongly with the issue of PMIs. Many syntheses involve the use of electrophilic (alkylating) agents that, if carried over to the API, could react with biological matrices (including DNA) in patients. For this reason many starting materials, reagents or intermediates employed in syntheses have mutagenic potential.3 The designation and justification of the SM is an essential part of the development of drug substances, their registration and production. However, selection of the appropriate SM is a very challenging task for pharmaceutical companies, since the regulatory guidelines are not clear and straightforward. Both industry and regulators have varying interpretations of the guidance.4 The point at which an API SM is entered into the process is the point from which the appropriate good manufacturing practice (GMP) should be applied. It must include validation of critical process steps that could impact the quality of the API.5 The first criteria for the definition of an API SM were proposed in 1987 by the Food and Drug Administration (FDA).6 Since then detailed guides have been developing and many different perspectives published. The


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development of the guidelines that concern SM selection and justification is presented in Table 1. Table 1: A brief history of the development of guidelines for SM Year

Issue

1987

FDA, Guideline for submitting

1994

Key points

•

The SM is incorporated as an

supporting documentation in

important/significant structural

drug applications for the

element/fragment into the structure of the drug

manufacture of drug

substance 5, 6, 9, 10, 11, 13, 14, 15, 16; however, it

substances6

should not have a structure that is very similar

EMA, Investigation of Chiral Active Substances

in relative size and complexity to the structure

7

of the drug substance.12 This criteria should not be used as the sole basis for the SM selection.16

2000

ICH Q7: Good manufacturing

•

significantly used on non-pharmaceutical

practice guide for active pharmaceutical ingredients 2003

SM may be commercially available (it is market) 5, 6, 10, 14; however, commercial

5

availability should not be used as the only

PhRMA, Perspectives on drug

criteria for the justification of SM. 11, 12, 15

substance regulatory filing •

issues: starting materials,

SM should be isolated and purified substance. 9, 10, 13, 14

reprocessing, retesting and •

critical controls8 2003

EMA, Guideline on the

(including stereochemistry if the SM

possesses a stereogenic center of the chiral

chemistry of new active

API7, 14).

substances9 2010

SM should be fully/appropriately characterized 10, 11, 14

FDA, Guidance for industry –

•

SM should have a defined name, chemical structure, chemical and physical properties.5, 6,

Drug substance – Chemistry,

9, 10, 11, 13

Manufacturing, and Controls •

Information10 2010

profile.6, 9, 10, 11, 12, 14, 15

EGA, Position paper on the definition of active substance starting materials in active

SM should have a well-defined impurity

•

Sufficient synthetic steps (at least 2 or more steps) should be between the SM and API. 10,


5


2012

2012

substance master files (ASMFs)

12, 13, 14, 15

and CEP applications11

steps that involve formation and/or purge of

EDQM, Top ten deficiencies:

key impurities or genotoxic impurities, final

new applications for

purification steps) should be included in the

Certificates of Suitability12

description of the process. 12, 13, 15

ICH Q11: Development and

•

2013

SM should have a well-defined specification. 6,

•

The name and address of the manufacturers of

biotechnological/biological

the SM and a flow chart for its synthesis

entities)13

should be provided. 9, 12, 14, 15

WHO, Guideline on submission

•

Decisions on the selecting an SM should be

of documentation for a multiple

based on its impact on the drug substance

source (generic) finished

quality (later steps are most likely to affect the

pharmaceutical product 2014

All critical parameters or steps (e.g.,

9, 12, 13, 14, 15, 16

manufacture of drug substances (chemical entities and

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14

drug substance quality).8

EMA, Reflection paper on the requirements for selection and

•

Criteria for SMs should be based on scientifically sound and relevant controls.8

justification of starting materials for the manufacture of chemical active substance15 2016

ICH Q11: Development and manufacture of drug substances (chemical entities and biotechnological/biological entities) draft Questions and answers (regarding the selection and justification of starting materials)16

Of all the guidelines and publications presented in Table 1, more attention will be paid to the ICH Q11 guideline13 and the most recently published document Questions and Answers to the ICH Q11 (draft version published in 2016, final document in 2017)16 . According to ICH Q11,


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the applicant should provide a justification for the selection of an SM. The justification could be based on the ability of analytical procedures to detect impurities in SM, the fate and purge of those impurities and their derivatives in subsequent processing steps, and the contribution of the proposed SM specification to the control strategy. According to the guideline, all manufacturing steps that have an impact on the impurity profile of the API should be included in the dossier. Impurities created or introduced in the early stages of the manufacturing process are more likely to be removed in the subsequent steps, while when there are only a small number of steps between the proposed SM and the final API, impurities resulting from poor segregation / cleaning pre-SM may carry through to the final API. As part of the justification, a flow chart should be provided with proposed SMs clearly designated. An applicant generally need not justify the use of a commercially available chemical.13 The criteria given in ICH Q11 are further explained in ICH Q11 Questions and answers document.16 It is emphasized that SM selection should not be based solely on the ‘significant structural fragment’ criterion. The principle ‘significant structural fragment’ is intended to help distinguish between reagents, catalysts, solvents, or other raw materials from materials that do contribute significantly to the molecular structure of the drug substance. It is also explained that it is not always necessary to include all steps involving mutagenic reagents or impurities, or to establish regio- or stereo- chemical configurations, in the process description in the section 3.2.S.2.2, provided the ICH Q11 general principles are addressed. This illustrates example 4 given by ICH Q11: if an impurity that originates from the synthetic steps prior to the proposed SM is controlled in SM, it is not necessary to include all manufacturing steps that impact the drug substance impurity profile in Section 3.2.S.2.2 of the application. When deciding


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whether enough of the manufacturing process for a drug substance is described in section 3.2.S.2.2 of the application, the following considerations should be applied: •

The chemical transformation steps that affect the impurity profile of the drug substance should be identified.

•

The steps immediately upstream of those steps that impact the impurity profile of the drug substance should then be examined. If those steps include a purification step or require adequate control to prevent the impact on the impurity profile of the drug substance, they should also be included in section 3.2.S.2.2.

•

If the evaluation were to result in a small number of chemical transformation steps, addition of one or more additional steps is highly encouraged.

Further it is also explained which tests should be included in the specification of SM and what information should be provided for commercially available and not commercially available chemicals. Specification of SM should include tests for identity and purity. Acceptance criteria for assay, related substances, residual solvents, reagents, elemental impurities and MIs could also be included. The use of a custom synthesized chemical as an SM should be justified in line with ICH Q11, while the use of a commercially available chemical need not to be justified. For commercially available SMs it can also be acceptable for them to enter late in the synthesis (e.g. in the last chemical transformation step). For SMs that are not commercially available chemicals, an applicant should provide flow chart for the synthesis of SM, including information concerning actual and potential impurities. For SMs that are commercially available chemicals, basic information should be provided on the SM (chemical name, chemical formula and molecular weight), on the impurity profile and concerning how the control strategy for the manufacturing process justifies the SM specification. Questions and answers document16 also explains at which


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level an impurity should be considered to have impact on the impurity profile of the drug substance: •

For non-mutagenic impurities: impurity present in the drug substance at a level above the ICH Q3A Identification Threshold

•

For mutagenic impurities: impurity present in the drug substance above 30 % of the ICH M7 acceptable intake

ICH M7 principles can be used to determine which manufacturing steps impact on the profile of MIs in the drug substance.16 Although there has been much of debate on the SM topic, limited work has been published to add clarifications of the grey areas of the guidelines. There are also very few concrete case studies published in which applicants give information on how they justified their API SMs in their regulatory submissions.4 As the approved SM is the starting point for GMP and variations (postapproval reporting of changes of approved marketing authorization application to health authorities), pharmaceutical companies tend to present very short synthetic routes. On the other hand, regulatory authorities request more data in order to be able to evaluate the risk to quality and safety of the API. In this article a case study will be presented, introducing the key principles of SM selection in the synthesis of vortioxetine drug substance, with an emphasis on the MIs principle. METHODOLOGY: Based on existing guidelines covering the SM issue, presented in Table 1, we have identified principal criteria for selecting SMs. Based on the criteria identified, knowledge of the process and product properties, three proposed SMs in the synthesis of vortioxetine drug substance are presented. Each proposed SM was determined by a risk based approach and justified by considering its incorporation into the structure of the API, whether it has defined chemical


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properties and structure or not, the number of synthetic steps between the SM and API, commercial availability and impurity formation and control. The main focus was on the impurity profile of proposed SMs, especially of SM 1 and SM 3 which were identified to be potentially mutagenic. To assess mutagenicity and to determine which manufacturing steps impact on the profile of MIs in the drug substance, principles described in ICH M72 were used, i.e. database and literature searches for carcinogenicity and bacterial mutagenicity were conducted or a Structure-Activity-Relationship (SAR) assessment was performed (two complementary (Q)SAR methodologies Derek Nexus 4.1.0 and Sarah Nexus 1.2.0 by Lhasa Ltd. were used). To study the fate of possible impurities in the downstream process and to evaluate risk to the quality and safety of the API, a theoretical purge factor (TPF) determination, proposed by Teasdale et al.3,17, was used. This approach has already been used to assess some of the PMIs in the vortioxetine synthetic process and recently published.18 In this article the same principle as that described in 201518 has been used (Table 2), with the exception of one minor modification regarding the recrystallization process parameter, i.e.. the same scale as for solubility process is used. Table 2. Physicochemical parameters and associated purge factors Physicochemical parameter

Purge factors

reactivity (R)

highly reactive = 100 moderately reactive = 10 low reactivity/unreactive = 1

solubilitya (S)

freely soluble = 10 moderately soluble = 3 sparingly soluble = 1

volatility (V)

boiling point > 20 °C below that of the reaction/process solvent = 10


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boiling point ± 10 °C that of the reaction/process solvent = 3 boiling point > 20 °C above that of the reaction/ process solvent = 1 Ionisability (I)

ionisation potential of MI significantly different from that of the desired productb

physical processes – freely soluble = 10 recrystallization (PP)c moderately soluble = 3 sparingly soluble = 1 a

This relates to solubility within the context of an isolation process, whereby the impurity in question, if highly soluble, will remain within mother liquors and hence be purged from the desired product. bThis relates to a deliberate attempt to partition the desired product/MI between an aqueous and an organic layer, typically achieved by manipulation of the pH to change the ionized/unionized state of one of the components. cThis relates to solubility within the context of an individual recrystallization process designed to remove impurities.

Scores for each physicochemical property were multiplied together to obtain TPFs for individual process steps. These were then multiplied together to obtain an overall theoretical purge factor (OTPF). Theoretical purge factors for certain process steps (TPF): TPF1 = R1 x S1 x V1 x I1 x PP1 TPF2 = R2 x S2 x V2 x I2 x PP2 TPF3 = R3 x S3 x V3 x I3 x PP3 Overall theoretical purge factor (OTPF): OTPF = TPF1 x TPF2 x TPF3 Experimental purge factors (EPF) were determined based on spiking experiments and depletion studies made during process development. MI was added or spiked to the intermediate, which was then transformed to the next intermediate. After isolation of the intermediate, the amount of MI in question was determined.


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DISCUSSION: Vortioxetine drug substance is prepared by a 3-step synthetic route (Scheme 1). The synthesis starts with aromatic nucleophilic substitution between chloronitrobenzene (SM1) and 2,4dimethylthiophenol (SM 2). In the next step, the intermediate (2,4-dimethylphenyl)(2nitrophenyl)sulfane (3) is transformed to 2-((2,4-dimethylphenyl)thio)aniline (4) by reduction of the nitro group. In the last step a piperazine ring is formed by reaction of 4 with bis(2chloroethyl)amine hydrochloride (SM 3) to give vortioxetine hydrochloride (5) which is later transformed to the final vortioxetine drug substance. Scheme 1. Synthesis of vortioxetine drug substance with designated starting materials

In the synthesis of vortioxetine drug substance, chloronitrobenzene, 2,4-dimethylthiophenol and bis(2-chloroethyl)amine hydrochloride are proposed as SMs, as indicated (Scheme 1). As is


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evident from the guidelines covering SMs, selection of SMs should be appropriately justified. Based on the regulatory guidelines presented in Table 1, we have identified the following principal criteria for the selection of SMs: •

Incorporation into the structure of the API

•

Defined chemical properties and structure

•

Number of synthetic steps between the SM and API

•

Commercial availability

•

Impurity formation and control

Based on the above criteria, SMs in the synthesis of vortioxetine drug substance were selected. A justification of the proposed SMs is provided below. As presented in Table 3, all three proposed SMs are isolated substances of defined chemical structure and properties. They are incorporated as significant structural fragments into the structure of the API; however, each of them individually does not have a structure that is very similar in relative size and complexity to the structure of API. Moreover, all molecules of the proposed SMs are known in the chemical literature (their chemical names and CAS numbers are known). When defining the number of synthetic steps between the proposed SMs and API, only steps in the synthesis in which covalent bonds are formed or broken were counted. According to the guidelines, neither recrystallization nor salt formations are considered as chemical transformation steps.15 In line with this guidance, SM 1 and SM 2 are found three steps away from the final API. Moreover, all intermediates between the SMs and the final API are isolated and purified. SM 3 is introduced in the last step of the synthesis, therefore justification based on other criteria should be considered. In line with the definition of commercially available SMs provided by ICH Q11 (i.e., A commercially available chemical is usually one that is sold as a commodity in a pre-existing, non-


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pharmaceutical market in addition to its proposed use as starting material.)13, only SM 1 and SM 3 can be classified as commercially available SMs, as they are widely used on the nonpharmaceutical market (Table 3). According to the ICH Q11 Q&A document16 it is acceptable for commercially available SMs to be introduced in the last chemical transformation prior to the drug substance. This means that SM 3 need not to be further justified concerning ‘number of synthetic steps between the SM and API’ criterion. SM 2 is a custom synthesized chemical used as SM/intermediate in the synthesis of drug substance.


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Table 3: Proposed starting materials (SMs) basic information and their incorporation into the structure of API SM 1

SM 2

SM 3

1-chloro-2-nitrobenzene

2,4-dimethylthiophenol

bis(2-chloroethyl)amine hydrochloride

88-73-3

13616-82-5

821-48-7

Molecular formula

ClC6H4NO2

C8H10S

C4H10Cl3N

Molecular weight

157.55 g/mol

138.23 g/mol

178.49 g/mol

yellow solid with a characteristic odor

clear yellow liquid

white to beige crystalline powder

Chemical name CAS number Structural formula

Description Incorporation into the structure of API

S

S

S

N

N

N

NH HCl


NH HCl

NH HCl

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Use (pharmaceutical/nonpharmaceutical)

Pharmaceutical and nonpharmaceutical use. 1-chloro-2-nitrobenzene is widely used as a precursor in the production of many dyes and other effect chemicals.19

Pharmaceutical use. 2,4dimethylthiophenol is used as an intermediate in chemical synthesis of drug substance.


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Pharmaceutical and nonpharmaceutical use. Bis(2-chloroethyl)amine hydrochloride is widely used as a building block for piperazine derivatives which are used in the manufacture of plastics, resins, pesticides, brake fluid, corrosion inhibitors, and other industrial materials.20, 21, 22

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In line with ICH Q1113 requirements, the SMs should be determined by a risk based approach. The main focus should be on discussion of formation and fate and purge of impurities. The fate of potential impurities in the downstream process should be well known and potential impurities that could impact the quality and safety of the API should be appropriately controlled. As already stated, for the synthesis of vortioxetine drug substance potentially mutagenic SM 1 and SM 3 are used (Table 4). Due to their use, other potential MIs can form during the synthesis that could affect the quality of API. For this reason, focus was laid on SM 1 and SM 3 and their impurity profile to justify the appropriateness of SM selection. By comparing SMs with and without mutagenic potential, impact of mutagenicity on the selection of SM can be shown. The hazard assessment was performed in line with ICH M72, including analysis of all actual and potential impurities (starting materials, reagents and intermediates in the route of synthesis from the SMs to the drug substance, impurities associated with these materials, by-products and degradation products) by conducting database and literature searches for carcinogenicity and bacterial mutagenicity. Whenever such data was not available, a Structure-Activity-Relationship (SAR) assessment was performed. Based on the results, the substances were classified into one of five classes with respect to mutagenic and carcinogenic potential (Table 4). Table 4. Mutagenicity information for proposed starting materials (SMs) Structure of SM

Mutagenicity data

Class

Literature data:

Class 1 (known mutagenic carcinogen)

Positive bacterial mutagenicity assay.23 Animal carcinogen.24 In silico prediction:

SM 1 In silico evaluation not needed.


AI: 157 µg/day (based on TD50 =157 mg/kg/day24 )

17


Literature data: No data available.

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Class 5 (nonmutagenic)

In silico prediction:

SM 2

Derek: No alert. Sarah: No alert Literature data: Positive bacterial mutagenicity assay.25

SM 3

In silico prediction: In silico evaluation not needed.

Class 2 (known mutagen with unknown carcinogenic potential)

As SM 1 and SM 3 are commercially available chemicals, justification of their use in line with ICH Q1113 principles would not be needed. However, in the regulatory application the applicant should provide basic information on the SMs (chemical name, chemical formula and molecular weight), information on the impurity profile, and how the control strategy for the manufacturing process justifies the SM specification.16 As stated in the ICH Q11 Questions & Answers document16, well documented, publicly available synthetic routes of commercially available SMs can provide important information that should be considered when evaluating potential impurities. SM 1 is typically synthesized by nitration of chlorobenzene in the presence of sulfuric acid. A mixture of o- and p- isomers is normally formed as presented in Scheme 2.19 Scheme 2: Synthesis of SM-1 (based on Booth19)


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Based on the scientific knowledge and available information, the impurity profile of proposed SM 1 has been studied. Impurities that can be formed during the synthesis of SM 1 are presented in Chart 1. Chart 1: Possible impurities originating from SM 1

According to the ICH Q1113, all synthetic steps critical to the quality of the API should be included in the synthetic scheme from SM to final API. Critical steps are also those involving formation and/or purge of key impurities, those that employ or generate MIs, and final purification steps. Since SM 1 and SM 3 possess mutagenic potential, we took a closer look at the precursors of these SMs to ensure that all critical steps are introduced later in the synthesis. Synthesis of SM 1 starts with chlorobenzene, which is classified by ICH Q3C26 as a Class 2 solvent with a limit of 360 ppm. Thus, mutagenicity appears only after nitration and formation of alerting aromatic nitro compound. Mutagenicity information for impurities related to SM 1 is presented in Table 5.


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Table 5. Mutagenicity information for impurities originating from SM 1 Structure of impurity

Mutagenicity data

Class

Literature data:

ICH Q3C26 Class 2 solvent with limit of NMT 360 ppm

Literature search not needed. Chlorobenzene (I)


Class 1 (known Mutagenic and genotoxic in vitro and in vivo. Group 2 carcinogen) carcinogen.2 AI: 117 µg/day In silico prediction: (determined in line with In silico evaluation not needed. Addendum to ICH M72) Class 5 Literature data: (non-mutagenic) Negative bacterial mutagenicity assay.27, 28 Literature data:

1-Chloro-4nitrobenzene (II)

1-Chloro-3nitrobenzene (III)

In silico prediction: In silico evaluation not needed. Literature data: Positive bacterial mutagenicity assay.29, 30

1-Chloro-2,4dinitrobenzene (IV)

Class 5 (non-mutagenic)

Negative carcinogenicity studies.31, 32 In silico prediction: In silico evaluation not needed.

Literature data: No data available. In silico prediction: 1-Chloro-2,6dinitrobenzene (V)

Derek: Alert (aromatic nitro compound) Sarah: Positive prediction


Class 3 (Alerting structure, unrelated to the structure of drug substance; no mutagenicity data)

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According to the toxicological evaluation, impurities II and V originating from SM 1 constitute a risk for mutagenicity/carcinogenicity. To assess the significance and potential impact of these two impurities on the quality and safety of the API, a TPF was determined which was in some cases supported with spiking experiments (depletion studies). Based on the results of depletion studies, an EPF was determined. Results are presented in Table 6. Table 6. Theoretical and experimental purge factors for SM 1 and its associated mutagenic impurities Impurity

Synthetic Reactivity stage (R)

Solubility

Volatility Ionisability Physical (V) (I) processes (Pp)

TPF

(S) (Recrystallization)

SM 1

II

V

Step 1

100

1

1

1

1

100

Step 2

100

1

1

1

1

100

Step 3a

10

10

1

1

10

1000

Step 3b

10

10

1

1

1

100

OTPF

1.0 x 109

EPF

8.0 x 1011

Step 1

100

1

1

1

1

100

Step 2

100

1

1

1

1

100

Step 3a

10

10

1

1

10

1000

Step 3b

10

10

1

1

1

100

OTPF

1.0 x 109

EPF

not determined

Step 1

100

1

1

1

1

100

Step 2

100

1

1

1

1

100

Step 3a

10

10

1

1

10

1000

Step 3b

10

10

1

1

1

100


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OTPF

1.0 x 109

EPF

not determined

Table 7. Depletion of SM 1 during the stages of synthesis Stage

Concentration of SM 1 before isolation/ recrystallization [%]

Concentration of SM 1 after isolation/ recrystallizationa

Depletion [%]

Purge factor

Stage 1

0.82b

< 0.05 %

94

16.4

Stage 2

1.6a

< QLc

100

3200

Compound 3

Isolated compound IV

2.0b

< QLc

100

4000

Crude compound 6

Recrystallized compound 6

1.9b

< QLc

100

3800

Compound 6

Isolated drug substance

Stage3a

Stage 3b

Overall purge factor 8.0 x 1011 a

Analytically determined.

b

Based on the amount of the impurity spiked separately in each synthetic stage.

c

QL is 5 ppm

Based on the daily dose of 20 mg of vortioxetine drug substance and a TTC limit of 1.5 µg/day, the acceptable limit for any MI present in vortioxetine drug substance is 75 ppm. Acceptable concentration limit for SM 1 derived from a compound-specific acceptable daily intake of 157 µg/day is 7850 ppm; however ICH M7 recommends that when calculating acceptable intakes from compound-specific risk assessments, an upper limit would be 0.5 %, i.e. 5000 ppm. According to Teasdale’s principle3,17, a TPF of 1.1 x 104 for SM 1 (this TPF is based


22

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on the ratio 1:1 of SM 1 and SM 2 used for the reaction) would be required to preclude the need for any further investigation or analytical testing. Acceptable concentration limit for impurity II derived from a compound-specific acceptable daily intake of 117 µg/day is 5850 ppm. In this instance we use the limit of 0.5 % since it is lower than compound-specific acceptable limit. The required purge for impurities II and V was determined, based on the assay of SM 1, which is controlled to not less than 98 %. Based on the fact that not more than 2 % of the impurities could be present in SM 1, a TPF of 400 for impurity II and 2.7 x 104 for impurity V would be required to preclude the need for any further investigation or analytical testing. The TPFs for SM 1 and its associated MIs II and V are high enough to predict with sufficient confidence that they will be effectively purged through the process. For SM 1, EPF was also determined which is even 800 fold higher than TPF. For other, non-mutagenic impurities, impact on quality and safety of the API would also need to be assessed. Here it is proposed that TPF determination could also be applied for non-mutagenic impurities, wherein the ICH Q3A limit would be applied for determination of the required purge. Further, we will take a closer look at another SM with mutagenic potential, SM 3. SM 3 is synthesized from diethanolamine using thionyl chloride in chloroform (Scheme 3). Scheme 3: Synthesis of SM 3 (based on Sinha et al.33)


23


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Impurity profile of SM 3 was also studied. Impurities that are possible to be formed in the synthesis of SM 3 are presented in Chart 2. Chart 2: Possible impurities originating from SM 3

Table 8. Mutagenicity information for impurities originating from SM 3 Structure of impurity

Mutagenicity data

Class

Literature data:

Class 1 (known carcinogen)

Negative bacterial mutagenicity assay. diethanolamine (VI)

Animal carcinogen. Non-mutagenic carcinogen.34 In silico prediction:

AI: 170 µg/day (determined from LOEL = 40 mg/kg/day34)

In silico evaluation not needed. Literature data: No data available. 2-((2chloroethyl)amino)etha nol (VII)

In silico prediction: Derek: Alert (alkylating agent, nitrogen or sulphur mustard) Sarah: Equivocal


Class 3 (Alerting structure, unrelated to the structure of drug substance; no mutagenicity data)

24

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Literature data: Positive bacterial mutagenicity assay.35, 36 tris(2-chloroethyl)amine (VIII)


Literature data: No data available. 4-(2chloroethyl)morpholine (IX)

In silico prediction: Derek: Alert (alkylating agent, nitrogen or sulphur mustard) Sarah: Equivocal Literature data: Positive bacterial mutagenicity assay.37

1,4-bis(2chloroethyl)piperazine (X)

Class 2 (known mutagen with unknown carcinogenic potential)

In silico prediction:

Class 3 (Alerting structure, unrelated to the structure of drug substance; no mutagenicity data) Class 2 (known mutagen with unknown carcinogenic potential)

In silico evaluation not needed.

As evident, the synthesis of SM 3 starts with diethanolamine (VI) which is known carcinogen. Moreover, mutagenic reagent thionyl chloride is used for the formation of SM 3. According to the ICH Q11 Q&A document16, it is not always necessary to include all steps involving mutagenic substances in the process description in the application. Impurity VI that originates from the synthetic steps prior to the proposed SM 3 is controlled by SM specification where SM 3 assay is limited to 98.0 % and therefore maximum 2.0 % of impurity VI could be present in SM 3. Moreover, TPFs have been determined (Table 9) which show that impurity VI has no impact on the impurity profile of the final API.


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Table 9. Theoretical and experimental purge factors for SM 3 and its associated impurities Impurity


Solubility (S)


TPF

(Recrystallization) SM 3

VI

VII

VIII

IX

Step 3a

100

3

1

1

3

900

Step 3b

10

3

1

1

1

30

OTPF

2,7 x 104

EPF

3.0 x 105

Step 3a

100

3

1

1

3

900

Step 3b

10

3

1

1

1

30

OTPF

2,7 x 104

EPF

not determined

Step 3a

100

3

1

1

3

900

Step 3b

10

3

1

1

1

30

OTPF

2,7 x 104

EPF

not determined

Step 3a

100

3

1

1

3

900

Step 3b

10

3

1

1

1

30

OTPF

2,7 x 104

EPF

not determined

Step 3a

100

3

1

1

3

900

Step 3b

10

3

1

1

1

30

OTPF

2,7 x 104

EPF

not determined


26

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X

Step 3a

100

3

1

1

3

900

Step 3b

10

3

1

1

1

30

OTPF

2,7 x 104

EPF

not determined

TPF of 5.9 x 105 for SM 3 (this TPF is based on the ratio 1:1 of SM 3 and intermediate 4 used for the reaction) would be required to preclude the need for any further investigation or analytical testing. The required purge for impurities associated with SM 3 was determined, based on the assay of SM 3, which is controlled to not less than 98 % and therefore maximum 2 % of the impurities could be present in SM 3. A TPF of 2.7 x 104 would be required to preclude the need for any further investigation or analytical testing. Acceptable concentration limit for impurity VI was derived from a compound-specific acceptable daily intake of 170 µg/day and is 8500 ppm. In this instance we use the limit of 0.5 % since it is lower than compound-specific acceptable limit. Therefore, a TPF of 400 would preclude the need for any further investigation or analytical testing. EPF for SM 3 was determined in 201518 and is 3.0 x 105. Based on TPF presence of SM 3 in the final API cannot be excluded (the value of TPF indicates the level of SM 3 to be between 10 and 100 times below the appropriate limit) and further investigation should be performed (e.g., purge and spike experiments). For this reason, the absence of SM 3 in the final API has been confirmed by carry-over study. Results show that the level of SM 3 in the final API is below 30 % of acceptable concentration limit for Class 2 and Class 3 MIs (75 ppm) which justifies the non-inclusion of a routine test in the final API specification. Based on carry-over study for SM 3 we can reasonably expect that impurity VI, if residing in the final API, is present in levels well below 30 % of 75 ppm, which is significantly lower compared to compound-specific concentration limit for impurity VI, i.e. 8500 ppm. For


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impurities associated with SM 3 TPFs are high enough to predict with sufficient confidence that they will be effectively purged through the process. While SM 1 and SM 3 are commercially available molecules, SM 2 is custom synthesized. As already noted in the introduction, regulatory guidelines state different requirements for commercially available and commercially unavailable SMs. With regards to the documentation that needs to be provided in the regulatory application, the name and address of the SM suppliers should be provided for SMs that are not commercially available, including a flow chart for the synthesis of the SM, showing all reagents, catalysts and solvents used. Moreover, the SM should be fully characterized. Information about the actual and potential impurities in the proposed SM should be included. Since information on the synthesis of such SMs is usually not publicly available, the SM manufacturer would need to disclose this kind of information to the applicant for inclusion in the application. Afterwards, the impact of the impurities originating from the SM on the impurity profile of the final API would need to be assessed. As already proposed, the TPF determination tool could be used to assess the impact of impurities related to SM 2 on the quality and safety of the API. In support of this proposal, a TPF determination is provided for impurities originating from SM 2 (Table 10). A representative synthetic scheme for the synthesis of SM 2 is provided in Scheme 4 and possible impurities originating from SM 2 are presented in Chart 3. Scheme 4: Synthesis of SM 2 (based on Uchiro et al.38)


28

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Chart 3: Possible impurities originating from SM 2


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Table 10. Theoretical purge factors for SM 2 and its associated impurities Impurity


Solubility (S)


TPF

(Recrystallization) SM 2

XI

XII

XIII

XIV

Step 1

100

3

1

3

1

900

Step 2

1

1

1

1

1

1

Step 3a

1

10

1

1

10

100

Step 3b

1

10

1

10

1

100

OTPF

9.0 x 106

Step 1

100

3

1

3

1

900

Step 2

1

1

1

1

1

1

Step 3a

1

10

1

1

10

100

Step 3b

1

10

1

10

1

100

OTPF

9.0 x 106

Step 1

100

3

1

3

1

900

Step 2

1

1

1

1

1

1

Step 3a

1

10

1

1

10

100

Step 3b

1

10

1

10

1

100

OTPF

9.0 x 106

Step 1

100

3

1

3

1

900

Step 2

1

1

1

1

1

1

Step 3a

1

10

1

1

10

100

Step 3b

1

10

1

10

1

100

OTPF

9.0 x 106

Step 1

100

3

1

3

1

900

Step 2

1

1

1

1

1

1

Step 3a

1

10

1

1

10

100

Step 3b

1

10

1

10

1

100


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XV

XVI

XVII

OTPF

9.0 x 106

Step 1

1

3

1

1

1

3

Step 2

1

1

1

1

1

1

Step 3a

1

10

1

1

10

100

Step 3b

1

10

1

1

1

10

OTPF

3.0 x 103

Step 1

1

3

1

1

1

3

Step 2

1

1

1

1

1

1

Step 3a

10

10

1

1

10

1000

Step 3b

1

10

1

1

1

10

OTPF

3.0 x 104

Step 1

10

3

1

1

1

30

Step 2

1

1

1

1

1

1

Step 3a

10

10

1

1

10

1000

Step 3b

10

10

1

1

1

100

OTPF

3.0 x 106

Based on the ICH Q3A guideline, a limit of not more than 0.10 % would be acceptable for any unidentified impurity present in a drug substance, which corresponds to not more than 1000 ppm. This would lead to a TPF of 4.7 x 104 for SM 2 (this TPF is based on the ratio 1:1 of SM 1 and SM 2 used for the reaction). If considering that the assay of SM 2 is controlled to not less than 92 %, the total amount of impurities present in SM 2 would not be higher than 8 %. This means that a TPF of 8000 would be required to preclude the need for any further investigation or analytical testing. For SM 2 and its associated impurities, except for impurity XV, TPFs are high enough to predict with sufficient confidence that they will be effectively purged through the process. However, since SM 2 is not commercially available molecule, information about the actual and


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potential impurities in the proposed SM should be provided by the applicant. This means that specified impurities potentially present in SM 2 would need to be determined and specification would need to be set based on experimental purge results. More focus should be put on impurity XV which theoretically has lower ability to purge through the process. Based on the above we can argue that the proposed SMs are chosen appropriately. Moreover, based on the presented case study it was shown that recrystallization that has been designed and introduced in step 3a of the synthetic process as the principal purification step, can have a very important impact on the purge of impurities. However, according to the guidelines, recrystallization is not considered a chemical transformation step and cannot be used in the ‘number of synthetic steps between the SM and the API’ criterion for the justification of SM. Although the recrystallization step does not involve formation or cleavage of covalent bonds, it can contribute significantly to the quality of the final API. The impact of recrystallization and salt formation steps on impurity profile of the final API was already recognized by authorities.15 However, neither recrystallizations nor salt formations are considered chemical transformation steps, because it is necessary to provide information on earlier synthetic steps in order to understand the risk of impurity carryover and to demonstrate that the proposed control strategy sufficiently mitigates this risk.15 Furthermore, the information on purification steps is usually not shared with the drug product applicants due to confidential information and know how of the drug substance manufacturer. Consequentially, this kind of detailed information is also not disclosed to the authorities within the drug product application. Moreover, physical purification steps can have very diverse effect, some are very effective and others have very limited effect on the purging of impurities. For this reason it is very difficult for the authorities to evaluate the risk based on limited data provided by drug substance manufacturers. We propose that purification


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steps should constitute an important part of SM justification, provided that sufficient information is disclosed in support of this justification. By comparing TPF determination for mutagenic and non-mutagenic impurities we can see that the principle is exactly the same in both cases, except that the required purge is usually higher in case of MIs since the acceptable limits are usually lower.

CONCLUSION: For the selection and justification of SMs, all the principles described in regulatory guidelines should be considered. Although not all of the principles have to be met, and one criterion could overrule another, a rationale should be provided to justify that kind of scenario. In the case study presented in this article both commercially available and commercially unavailable SMs were used. Generally it would be acceptable to provide less justification and documentation for the commercially available SM. Nevertheless, the impurity profile of the SM should be studied in both cases and its impact on the quality of the final API should be assessed. TPF determination has been proved to be very useful for evaluating risk of potentially mutagenic SM 1 and its related MIs to the quality and safety of the API. Based on the determined TPFs we can conclude that SM 1 and its associated PMIs will be effectively purged through the process, which supports the justification of SM with regards to the impurity profile criterion. Moreover, we propose that this approach could also be used to assess other, non-mutagenic impurities and, as such, constitute an integral part of selection and justification of SMs. By using the TPF approach for the assessment of impact of non-mutagenic SM 2 and its associated impurities to the quality and safety of the API we have shown that the principle can be effectively used for all kind of impurities. The TPF for SM 3 indicated the need for further investigation, while the TPFs for


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impurities associated with SM 3 were high enough to predict with sufficient confidence that they will be effectively purged through the process. The high capacity of the process to purge SM 3 was already shown in 201518 and was now confirmed again by performing additional carry over study. We also propose that the purification steps (recrystallization) should not be totally excluded from the ‘number of synthetic steps between the SM and API’ criterion for the justification of SM, as they can have a very important impact on the purge of impurities. Alternatively, purification steps could also present an important part of SM justification in conjunction with the impurity formation control criterion.


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ASSOCIATED CONTENT Supporting Information. / AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Address: Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia Phone number: +38614769500 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Sources / Notes / ACKNOWLEDGMENT We would like to thank Tjaša Zlobec for providing mutagenicity data.

ABBREVIATIONS


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AI, acceptable intake, API, active pharmaceutical ingredient; ASMF, Active substance master file; DMSO, dimethyl sulphoxide; DNA, deoxyribonucleic acid; EGA, The European Generic and Biosimilar Medicines Association; EDQM, European Directorate for the Quality of Medicines; EMA, European medicines agency; EPF, Experimental purge factor; FDA, Food and drug administration; GMP, good manufacturing practice; GTI, genotoxic impurity; ICH, International conference on harmonization; LOEL, lowest observed effect level; MI, mutagenic impurity; NMT, not more than; OTPF, Overall theoretical purge factor; QL, quantitation limit; (Q)SAR , (Quantitative) Structure-Activity Relationships; PMI, potentially mutagenic impurity; PhRMA, Pharmaceutical Research and Manufacturers of America; SM, starting material; TD50, median toxic dose; TPF, Theoretical purge factor; TTC, Threshold of Toxicological Concern; WHO, World health organization. REFERENCES 1. EMEA/CHMP, Guideline on the Limits of Genotoxic impurities, CPMP/SWP/5199/02. 2006. 2. ICH M7 (R1), Step 4, March 31, 2017. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/ M7_R1_Addendum_Step_4_2017_0331.pdf (accessed May 2017). 3. Teasdale, A.; Fenner, S.; Ray, A.; Ford, A.; Phillips, A. Org. Process Res. Dev. 2010, 14, 943-945. 4. Faul, M.M.; Kiesman, W.F.; Smulkowski, M.; Pfeiffer, S.; Busacca, C.A.; Eriksson, M.C.; Hicks f., Orr J.D. Org. Process Res. Dev. 2014, 18, 587-593. 5. ICH Q7, Step 4, November 10, 2000. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q7/Step4/Q7_ Guideline.pdf (accessed May 2017). 6. FDA, Guideline for submitting supporting documentation in drug applications for the manufacture of drug substances, February 1987. 7. EMA, Investigation of chiral active substance, April 1994. 8. Cupps, T.; Fritschel, B.; Mavroudakis, W.; Mitchell, M.; Ridge, D.; Wyvratt, J. (PhRMA) Pharm. Technol. 2003, 34-52. 9. EMEA/CPMP, Guideline on the chemistry of new active substances, CPMP/QWP/130/96, Rev 1. 2003. (superseded by EMA/CHMP, Guideline on the chemistry of active substances, EMA/454576/2016. 2016.)


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10. FDA, Guidance for industry - Drug substance Chemistry, Manufacturing, and Controls Information, August 2010. 11. Jamil, J.M. (EGA) EGA position paper on the definition of active substance starting materials in active substance master files (ASMFs) and CEP applications, 2010. 12. EDQM, Top Ten Deficiencies: New Applications for Certificates of Suitability (2011), 2012. http://www.edqm.eu/medias/fichiers/paphcep_12_15.pdf. (accessed January 2017) 13. ICH Q11, Step 4, May 1, 2012. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Ste p_4.pdf (accessed May 2017). 14. WHO, Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product: quality part, 2013. http://www.who.int/medicines/areas/quality_safety/quality_assurance/TRS986annex6.pdf?ua=1 (accessed January 2017) 15. EMA, Reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substance, 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500 175228.pdf (accessed August 2017) 16. ICH Q11 Questions and answers, Step 4, August 23, 2017. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11IWG _Step4_QA_2017_0823.pdf (accessed September 2017) 17. Teasdale, A.; Elder, D.; Chang, S.-J.; Wang, S.; Thompson, R.; Benz, N.; Sanchez Flores, I. H. Org. Process Res. Dev. 2013, 17, 221-230. 18. Lapanja, N.; Zupančič, B.; Toplak Časar, R.; Orkić, D.; Uštar, M.; Satler, A.; Jurca, S.; Doljak, B. Org. Process Res. Dev. 2015, 19 (11), 1524-1530. 19. Booth, G. Nitro Compounds, Aromatic. In Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH: Weinheim, 2005. 20. Lewis, R. J. Sr. Hawley's Condensed Chemical Dictionary 14th edition; John Wiley & Sons, Inc. New York: New York, 2001, p. 881. 21. Kuney, J. H.; J.M. Mullican (eds). Chemcyclopedia; American Chemical Society: Washington, DC, 1994, p. 102. 22. https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+1093 (accessed August 2017) 23. http://www.inchem.org/documents/sids/sids/CHLORONITROB.pdf (accessed August 2017) 24. https://toxnet.nlm.nih.gov/cpdb/chempages/1-CHLORO-2-NITROBENZENE.html (accessed August 2017) 25. http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+genetox:@term+@DOCNO+1879 (accessed August 2017) 26. ICH Q3C (R6), Step 4, October 20, 2016. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3C/Q3C__R 6___Step_4.pdf (accessed May 2017). 27. http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+ccris:@term+@DOCNO+3094 (accessed May 2017) 28. http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@DOCNO+1323 (accessed May 2017) 29. http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+ccris:@term+@DOCNO+1799 (accessed May 2017)


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30. http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@DOCNO+5306 (accessed May 2017) 31. https://toxnet.nlm.nih.gov/cpdb/chempages/1-CHLORO-2%2C4-DINITROBENZENE.html (accessed May 2017) 32. https://echa.europa.eu/registration-dossier/-/registereddossier/10503/7/8/?documentUUID=87b0fb22-4af3-46bd-a6ca-4941e74f598f (accessed May 2017) 33. Sinha, G. K.; Pandey, B.; Sinha, A. Orient. J. Chem. 2010, 26(4), 1401-1406. 34. https://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr478.pdf (accessed August 2017) 35. Marhan, J. Folia Microbiol. (Prague, Czech Repub.) 1995, 40(5), 457-461. 36. http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@DOCNO+6395 (accessed August 2017) 37. Balbinder, E.; Reich, C. I.; Shugarts, D.; Keogh, J.; Fibiger, R.; Jones, T.; Banks, A. Cancer Res. 1981, 41(7), 2967-2972. 38. Uchiro, H.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 3179-3182. 39. ICH Q3A (R2), Step 4, October 25, 2006. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3A_R2/Step 4/Q3A_R2__Guideline.pdf (accessed August 2017)


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Evaluation of starting materials for PMIs (potentially mutagenic

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