1

GENOTOXIC IMPURITIES IN PHARMACEUTICAL PRODUCTS -AN INDUSTRY PERSPECTIVE

Dr. Vijayavitthal T. Mathad
V.P-R&D, Megafine Pharma (P) Ltd Nashik- Maharastra, India
USP-IPC, 8th Annual Scientific Meeting 11-12 Feb, 2009 Hyderabad, India

Importance of Pharmaceutical Industries Impurities and their classification Genotoxicity and Genotoxic Impurities Guidelines on Genotoxic Impurities
Existing Scenario Changing Scenario

Genotoxic impurities: Concerns and challenges

GTIs: Approaches to Chemical Synthetic Process Assessments with Case studies Toxicological Assessment Testing Strategy Case Study: Removal of Genotoxic Impurity
Ongoing Strategy Evaluation Final Thoughts

Pharmaceutical industries (Discovery and Generics) play an important role to help the people to lead healthier lives. Drug discovery: identification of the lead, SAR, The candidate, safety and efficacy tests, and clinical trials etc.
Birth of many chemical routes from discovery phase to first time commercialization. An eagle eye is needed to evaluate the impurity profile from phase to phase. As highly complex activities are involved and needs team of scientists with different disciplines to manage the project successfully.

Filing IND, NDA, BLA (Biologics license application), and getting marketing approval, etc., (Birth of a product patent-API& formulations)
Exorbitantly high price of the Medicine during the Market exclusivity period

Generic version entrance with low cost: DMF, ANDA filings, (legal battles !!!), and marketing approvals etc., (Birth of process patents-API & formulations)
Different processes, different chemistry, different synthetic route, different intermediates, reagents, solvents etcneeds strict evaluations to get regulatory approvals.

Regulatory market Vs. Non regulatory: reasonable quality for less regulatory world? Pharma

Business

A Pharmaceutical Substance or a Drug is a Chemical Substance which is known to cure the disease. It is said to be chemically pure or single entity when it is 100% pure by all means When it is synthesized in the laboratory using many chemicals and their transformations, invariably it may get contaminated with different kinds of substances (Known or unknown) which are called as impurities. Normally impurities are liable to present in drug substances due to inefficiency to perform transformations which are 100% not Chemospecific/selective, Regeospecific/selective, and Stereospecific/selective reactions unlike nature and life does. Hence, it is always been the focus of pharma Industries to identify, synthesize, characterize, and eliminate from the product to make it safe to consume.

Definitions:
Is defined as presence of any foreign matter or substance which differs from the drug substance in terms of its structure, pharmacological, and toxicological effects Any component of the drug product which is not the chemical entity defined as the drug substance or excipients in the drug product.

Chemical substances capable of causing direct or indirect damage to

DNA or Chromosomes and lead to change in the expression of Gene thereby leading to Mutated Gene. Which may lead to formation of defective protein Create disorder in the metabolic processes Affect the DNA repair Mechanism

e.g. Alkylating agents, diols, epoxides, nitroso groups, formaldehyde, petroleum hydrocarbons, lead, arsenic, etc
One of the first chemical agent known to cause genetic problem is Cl-CH2-CH2-S-CH2-CH2-Cl (Mustard gas)

A series of DNA bases such as Adenine (A), Gaunine (G), Cytosine (C), Uracil (U) and Thymine (T) linked together that code for one entire protein or enzyme is called Gene. Group of Genes arranged in series form a Chromosome. Few chemical agents, Xenobiotics , and their metabolites can damage DNA by covalently binding to a base to form an adduct Oxyradicals can oxidize bases to their glycols Free radicals can produce breaks in the2 DNA molecule NH NH2 O O
N N Adenine N N H HN H2N N H Guanine O HN O N H CH3 [O] HN O N H N N H O HN N H O R HN N H HO OH O CH3 H OH sugar

Cytosine O

Uracil (R=H) Thymine (R=CH 3) CH3 OH OH H

DNA Modification

The study of the adverse effects of physical or chemical agents on the genetic material of cells (DNA or Chromosomes) and subsequent expression of these changes Extensive knowledge about the chemical functional groups that can react with DNA causing mutagencity and concern regarding initiation of tumor process is available in the literature (Ashby et al, 1988, 1991, &1993; Beningi et al 2004)

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Mutagenesis: the formation of mutations Carcinogenesis: the formation of Cancers Some forms of Teratogenesis: Damage to the DNA History of Chemical Carcinogens
1761: Dr John Hill first suggested that snuff caused cancer in nose 1975: Sir Pott: Chimney sweeps and scrotal cancer is due to Benzo(a) Pyrene (BaP) and their derivatives Thalidomide tragedy

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Impurities will be present in API, and subset may have genotoxic liabilities Impurities which are Mutagenic are primary concern Hence there is a need of Suitable guidelines and commitment from Pharmaceutical Industries to address this issue in the Drug substance and Drug products which are consumables of a common man to attain good health. A patient should not buy a minimum dose of carcinogen along with drug product How the quality of drug products are controlled ?? unknowingly for free of cost!!.

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What is quality? (EXISTING SCENARIO)

Material meeting the set of desired specifications as per customer need(customer are regulatory agencies, customers who buy drug substance and drug products, patients who consume product, etc.,) Typically quality chart consists of
Controlling known impurities less than 0.15% Unknown impurities less than 0.10% Total: NMT 0.5%

Along with all other specs such as RS/OVI, M/C, Assay by HPLC, ROI, Polymorph, color, identification tests, PS, BD, etc

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Existing ICH Q3 guideline is not clear on how to handle Genotoxic impurities

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ICH Guidelines
Q3A (R2): Impurities in New Drug Substances Q3B (R2): Impurities in New Drug Products Q3C (R3): Impurities: Residual Solvents

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EMEA Guidelines (European Medicines Agency)

EMEA/CHMP/QWP/251344/2006-Guideline on limit of genotoxic impurities for new drug substances and products.
Issued in June-2006 Came in to effect from- Jan 2007

US-FDA Guidelines
Draft Guidance for Industry (CDER-FDA): Genotoxic and Carcinogenic impurities in Drug substance and products: Recommended Approaches (Dec 2008)

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Both of these guidelines describe Recommended approaches for:

Initial toxicological assessment of GTIs
Std battery of tests!

Handling of GTIs and Carcinogenic Impurities

Prevention of their formation Reduction of their levels
Acceptable levels to support marketing applications Acceptable levels during clinical development

Additional characterization of genotoxic and carcinogenic risk Considerations for Flexibility in Approach and Decision tree

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Most discussed issues of concerns on the Genotoxicity and carcinogenicity Impurities are
Toxicological assessment of impurities
Evaluation of genotoxicity or carcinogenicity

Classification and qualifications GTI Testing strategy GTI Control strategy Analytical testing related challenges Fixing the limit of specifications based on the classification and qualification in the drug etc.

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The guideline recommends dichotomizing genotoxic impurities in to those there is

Presence of sufficient (experimental)evidence for threshold related mechanism These can be addressed using ICH Q3C (R3). This approach calculates Permitted Daily Exposure (PDE) which is derived using No Observed Effect level (NOEL) from the most relevant animal study and incorporating various uncertainty factors

without sufficient (experimental) evidence for threshold related mechanism These GTI can be addressed by controlling the levels to As Low As Reasonably Practicable (ALARP) ALARP specifies that every effort should be made to prevent the formation of such impurities during the synthesis, if that is not possible technical effort should be made post

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PhARMA Committed to minimizing levels of mutagenic impurities As Low As Reasonable Practicable (ALARP) levels PhARMA drafted the guidance in the form of GTI task force white paper that extended the scope of TTC approach to all phases of clinical development (Regul. Toxicol. Pharmacol, 2006, 44, 198-211) PhARMA white paper also introduces staged TTC concept for a limited exposure that balances duration of clinical trials, availability of analytical methods, maturity of a synthetic route, and potential risk. EMEA responded to number of questions in June 2008 regarding GTI limits and CHMP committee agreed with the use of staged TTC concept.

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Allowable Daily intake (ADI) for Genotoxic Impurities of unknown carcinogenic potential during clinical development depending on duration of exposure
Genotoxic and carcinogenic impurity threshold. Allowable daily intake ( g/day) for different duration Duration of Clinical trial Exposure < 14 days 14 days to 1 Month 1 to 3 Months 3 to 6 Months 6 to 12 Months 12 Months

120

60

20

10

1.5

ADI for shorter duration than 12 months are based on linear extrapolation (Bose et al., 2004, ) from TTC value of 0.15 g/day (Cheeseman et al., 1999, Kroes et al., 2004)

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Approaches to detect (challenges to chemists and bilogists)

Evaluation of its birth in synthetic path or Evaluation of its entry in to API or in to drug product Approaches for Identification (Understand Mol structure)

Approaches to assess the genotoxicity (challenges to biologists and toxicologists-test strategy)

Ames test (is it possible for all whose str. is unknown ? And sample physically not available) Structural alerts (evaluation with known structural alerts) Computational toxicology assessment (statistical programs)
OSIRIS property explorer (www.organic-chemsitry,org/prog/peo) Multi CASE (www.multicase.com) DEREK (http://Ihasalimeted.org MDL-QSAR TOPKAT MC4PC Progol etc.

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Suitable analytical methods (challenges to analytical chemists?)

Detection in ppm/ppb levels Appropriate instruments (HPLC, LC-MS, LC-MS-MS, GC-MS, NMR, etc) Sensitivity of instrument and conditions

Reporting Limit (challenges to regulators)

Appropriate guideline for calculating the reporting limit (EU, US-FDA and maintaining the commonality across the globe to help the manufacturers) Requirements for new, generic and well established products

GTIS: Approaches to Assessment, Testing decision, Analytical determination and Control in Drug substance
GTI Testing Strategy
GTI Testing Strategy

Chemical Rationale
Demonstrate Rejection

Chemical Process

Toxicology Assessment

Testing / Control

Pierson et al. oprd, 2009 Feb (ASAP)

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In chemistry language-process is an amalgam of

Synthetic organic reactions using starting materials, intermediates reagent, solvent and often a catalyst.
For all starting materials and By-products that have genotoxic Alerting Structure, isolation or preparation of material may be required for MiniAmes test for further tox assessment.

Robust and accurate analytical methods which elute all impurities , starting materials, by-products, impurities in the key starting materials is of a great challenge. Fight between process chemists and analytical chemists!!!
Degradation impurities and their Genotoxicity??

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Understanding whether the impunities aroused from Key starting materials (e.g. 2-flurotoluene, 2acetylnaphthelene)? Impurity profile for key starting material Key raw materials Reagents (e.g. Vitride; 2-methoxy ethanol, methane sulfonic acid, tosylchloride, thionylchloride when used in presence of THF etc)? Side reactions: by-products? Over reactions ? Over reduction (Ketone to alcohol to alkene to alkane/Over oxidized products (sulfide to sulfoxide to sulfone or N-oxides)? Catalysts? Solvents? Functional isomers, positional isomers, stereo isomers, and geometrical isomers (Case Study-I)?

H3C

CH3 CH3

CH3 N

Terbinafine
CH3 H3C H3C CH3 N H H H CH3 N CH3 N H H CH3 N H

CH3 CH3 CH3

(E)-4[4,4-dimethyl-pent-yn-(E)-ylidene]-N1,N5-dimethylN1,N5-bis-napthalen-1-yl methyl-pent-2-ene-1,5-diamine

(E)-4[4,4-dimethyl-pent-yn-(Z)-ylidene]-N1,N5-dime thyl-N1,N5-bis-napthalen-1-yl methyl-pent-2-ene-1,5-diamine

EE-Genotoxic

EZ-isomer

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Investigation of root cause:

Exhaustive investigation revealed that the formation of impurity is due to the cross reaction at intermediate stage at trace levels (From acrolein)

Synthesis / Isolation of Impurity

Brainstorming sessions on synthesis of pure impurity and dropped the idea based on the out-come on the parallel work on purification. Successfully enhanced the Impurity level in the reaction from
0.1% to 10% by changing the reaction condition.

Further enrichment to 97 % by preparative

Purification of API to reduce the impurity

Process established to reduce the Impurity from ~200ppm to Less than 6ppm (of Existing API)

Design of Process (Elimination of impurity)

Extensive study on Design /Optimization of process resulted in impurity level (Less than 2ppm). Changes in the Process at early stages (Key starting material) of Terbinafine made this possible

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Comparison of impurity profile between flask process in the lab with reactor process in the plant Variation in mass transfer, heat transfer due to varied stirring pattern and heating profile may alter the reaction profile and lead to different impurity profile. Impurities due to changeover: efficient cleaning procedures when GTI is introduced in the last step(Case study-II) Impurities due to altered source for key raw materials after commercialization due to cost (careful vigilance of QA/RA in new vendor qualification)

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Alkyl mesylates (CH3SO2O-R)

Alkyl mesylates have long been a regulatory concern, as they are reactive, direct acting, genotoxic, and possibly carcinogenic alkylating agents.

API as Mesylate salts ??

API such as Nelfinavir mesylate attract increased suspicion from regulators. Leading to reluctance among the manufactures to develop such salt form Roche has called back this drug because of the presence of ethyl mesylate formed because of improper changeover.
O HO N H SPh N OH H CONHBu-t H O SPh N H N OH H CONHBu-t H
. SO2 Me

MSA

HO

NE/IXA

NE/IXA

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Focus on Impurity Profile During Optimization

Change proportions of reactions components Take advantage of different mechanisms Interchanging of the reaction addition modes Change functional groups if Structural Alert possessing genotoxicity is found
Modification of synthetic routes accordingly by changing the key starting materials Start with Different Intermediates which are safe

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Potential source of Genotoxic impurities include starting material, reagents, intermediates, side reactions and impurities
O NH2 H H

+
HO Tyramine

Step-1

Step-2
formaldehyde (GTI)

C
Step-3

+ Alert Str - in vitro testing

Pierson et al. oprd, 2009 Feb (ASAP)

O H3C

Step-3A

+ Alert Str + in vitro test

NH2

Acetonitrile

Step-4 Step-5

acetamide (GTI)

API

+ Alert Str + in vitro test

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Chemical str involved in simulated synthetic route are submitted for toxicological assessment Review of route by process chemists, analytical chemists and toxicologists to identify likely reaction by-products and the potential for carry through to the API Utilizing in silico evaluation and expert opinion, GTI alert structure are identified among the compounds for which no data are available (see next slide for alerts). Commercial software applications used for this purpose include
TOPKAT MultiCASE DEREK

With the above assessment, compounds representing potential impurities can be classified according to risk potential (Muller et al. 2006).

STRUCTURAL ALERTS FOR GENOTOXICITY AND CARCINOGENICITY ASSESSMENT a

b c H3C O r S O O NO2 N N OH C(X)4 t q O N O NH N h N N CH3 d

a. b. c. d. e.

CH3 g CH3 f CH3 i j

f. g. h. i. j. k. l. m. n. o. p. q. r. s.

H H3C s O N

H2N

CHCl

N(CH2CH2Cl) 2 CHCl N H O 2N N n O H2N o u O m O O l N Cl k

H3C

Ashby and Tennant, 1989

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Alkyl esters of P or S Acid Aromatic Nitro groups Aromatic Azo groups Aromatic ring N-Oxide Aromatic mono or dialkyalamino Alkyl hydrazines Alkyl aldehydes N-Methyl alcohol derivatives Monohaloalkanes A large family of N & S mustards N-chloramines Propiolactones &propiosultones Aromatic or aliphatic Aziridinyls Alkyl halides (both Ar and aliph.) Urethenes (Carbamates) Alkyl N-Nitrosamines Aromatic amines, N-Hydroxy derivatives and derived esters Epoxides Alkene derivatives ??

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Classification

Definition
Impurities known to be both genotoxic (Mutagenic) and carcinogenic Impurities known to be genotoxic (mutagenic), but with unknown carcinogenic potential Alerting structure found, unrelated to parent structure and of unknown genotoxic (mutagenic) potential Alerting structure found, related to the parent API No alerting structure or indication of genotoxic potential

Class 1 Class 2 Class 3 Class 4 Class 5

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Compounds that yield negative results in the alert assessment are placed in Class-5 and no additional action beyond normal impurity monitoring is required Compounds showing positive results (Class-3 &4) in the alert assessment are submitted for in vitro mutagenicity test. If test is negative, this overrides the alert assessment and compounds are placed in Class-5 Compounds giving positive mutagenicity results are placed in Class-2 and a toxicological limit is established on the basis of the intended clinical use.
The toxicological limit for a GTI is the level in the API at which exposure poses a negligible cancer risk over the background at the maximal therapeutic dose.

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Classification

Qualification strategy Goal: Eliminate in final drug product by purification or try to find the route cause and address it. If not possible, set specification using Allowable daily intake

Class 1

TTC PDE

Class 2

values based on Daily TTC concept Develop Permitted staged Exposure if thresholded mechanism If not sufficient evidence of threshold mechanismAllowable daily intake values based on staged TTC concept Derive Potential Allowable daily intake values based on TTC Test impurity for direct DNA reactivity (e.g. bacterial reverse Thorough genetic toxicology testing of the parent API is mutation assay) and place in appropriate class (2 or 5). usually sufficient to qualify the structurally for ordinary s Specification established using guidance similar impurity. impurities

Class 3

ICH

Class 4 Class 5

GTI Testing Strategy: Toxicology Assessment

Class 1 : Genotoxic carcinogens Class 2 : Genotoxic but carcinogencity unknown Class 3: Alert unrelated to parent Class 5: No alerts

Eliminate impurity? Threshold mechanism

Yes / Not tested

Class 4: Alert unrelated to parent

Impurity genotoxic ? 1 API genotoxic 2

No

Not possible

Risk assessmen t? 3 Limited data

Not established

Established No

(Staged) TTC (See table 1)

PDE (e.g. ICH Q3 appendix 2)

Control as an ordinary impurity

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Starting material, Intermediates, reagents, and by-products known to be genotoxic, a tox limit is obtained regarding the acceptable limit in the API For by-products that having alert structure, isolation and preparation may be required for mini Ames test The need for toxicology assessment depends upon where the GTI is introduced in the process and opportunities for the removal A decision tree for tox assessment is discussed in next slide Theoretical by-products that are not anticipated to be formed are not assessed, nor is special test is conducted to look for them. (This is inline with EMEA guidance recommendation that assessment of genotoxicity be limited to those impurities that might reasonably be expected on the basis of the chemical reactions and conditions involved.

Decision Tree: Control Strategy for Genotoxic Impurities

Confirmed GTI* Enter Decision Tree
Where, GTI is an intermediate, reagent. Observed by product or likely byproduct

Is GTI introduce d in final step?

Is Is GTI GTI introduced introduced penultimate penultimate step? step?

Is GTI introduced > 4 steps from API

Provide chemical rationale for removal (or test, if necessary)

Y
Test API and impose limit based on toxicology assessment

Y Y
Found in Found in penultimate penultimate at a level of at a level of concern? concern?

N
Test to demonstrate absence or rejection efficiency (or provide chemical rationale for removal, if possible)

N
Demonstrate absence and/or removal efficiency or establish specification for registration

Pierson et al. oprd, 2009 Feb (ASAP)

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Specification should be applied based on the toxicology assessment If sufficient data are generated to show the GTI is not present or efficiently rejected, it may be possible to omit the regulatory specification
If API is a salt of methanesulfonic acid and final step involves Ethanol or Methanol, Genotoxic esters such as methyl or ethyl mesylate may form

It can be demonstrated that such esters are efficiently removed by the process

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Total recall of Roches AIDs drug Viracept (Nelfinavir Mesylate) due to presence of ethyl mesylate and the cancellation of its European marketing authorization by EMEA.
Chem. Ind., 9 July 2007, New York Times, 23 July 2007

Batches of the drug Manufactured at Roches plant in Switzerland were apparently contaminated with traces of ethyl mesylate arising from reactor cleaning procedures Supplies of the drug in USA are not affected as they are produced at Pfizer in a different facility; However the availability of this important medicine in third world countries has been severely disrupted

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If the GTI is shown to be below toxicological limit for API in the penultimate intermediate, no testing is required for API The need for specification at limit at the penultimate intermediate should be considered on the basis of stage of development If the GTI is present at the level of concern in the penultimate stage, a specification is applied to the APIto verify adequate removal in the last step

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Sufficient data are established to show the rejection of GTI in any of the subsequent intermediate step through spiking studies, no special testing or control is required for the scale-up of intermediates used in the production of API for clinical trials. If the removal is not adequate in the intermediate, a specification limit for the API will be necessary based on (Maximum daily Dose) MDD.

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Provide Chemical rationale when the probability of the GTI carrying through to the API is negligible. This can be based on
Reactivity of the GTI in subsequent step No of purification steps that will encounter Its solubility in the extraction solvents Its solubility in ML while filtration Analytical tests which demonstrate the rejection No testing for the impurity is required

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Formaldehyde:
Formaldehyde generated at 5th sage of a 10 step process and further involve
4 crystallizations 1 re-slurry purification step, prior to formation of API

+B
3 steps

D
2 steps

The rationale for not requiring analytical testing to control formaldehyde was based on the number of opportunities for removal Aqueous extraction utilized in the step 5 and 6 and would likely be removed as it is soluble in water Formaldehyde boils at -19 deg C and would be removed during the solvent exchange. Step-6 used reducing agent that would reduce residual formaldehyde

( By-product farmaldehyde)

2 steps

K
3 steps

API

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Medicinal Chemistry Route

Design of Alternate Strategy

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The Zeneca Pharmaceuticals drug candidate ZD-2079 (22) (a beta-3 agonist) 22 entered development in 1991, intended for the treatment of non-insulin dependent diabetes. The medicinal chemistry route to 22 presented a number of challenges for scaleup. The generation of toxic vinyl bromide gas 20 in step 1 (due to base promoted dehydrobromination) was unavoidable given that the reaction of dibromoethane with phenolic starting material 18 required base. Vinyl bromide 20 is known to have genotoxic properties and cannot be readily removed by scrubbing on a plant scale. An alternative strategy for providing the two-carbon unit in step 1 involved ethanolamine derivatives by reaction of N-benzylethanolamine (23) with thionyl chloride. A risk assessment concluded that the threat to worker Reaction of 24 with the sodium salt of 4-hydroxylphenylacetamide (18) provided amine 21 in 64% yield

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Application of the staged TTC limits as defined in the Muller white paper Acceptance of the principle but no positive confirmation of the limits. What safety testing is required to provide proof of absence of genotoxicity? Ames confirmed as sufficient but if data from other tests is equivocal there is no guidance as to how to balance this. Where there is more than one potentially genotoxic impurity present how should these be addressed? Single combined limit or individual limits? Application in disease areas where the condition concerned is life threatening e.g. Oncology. Many treatments themselves depend on being DNA reactive e.g. Platinoids.

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GTIS should be addressed on ongoing basis during development from discovery to entry of generic version
Dose and duration associated with the clinical trials will change,
a revised toxicology assessment is needed and toxicology limit has to be assessed

If the route has changed

New intermediates, RMs and new Imp profile has to be assessed

If the acceptable toxicology limit has changed

The capability of the process and analytical methods for control at new level need to be assessed

If the acceptable level has changed

previously manufactured API must be assessed for suitability prior to use in subsequent trials. Finally generation of additional data on impurity rejection to support registration should be considered

Decision tree for Assessment of Acceptability of GTIs

EMEA 2006 GT I
Test data Indicate concern

Sufficient evidence of threshold related mechanism of genotoxicity

Use alternative w/o GTI

Presence of GTIun avoidable?

Calculate PDE (NOEL/UF analysis Safe exposure?

Y
Reduce to as low as reasonable level

N
Reduce to safe level

Level as low as reasonably practical?

No further action

Y N Negligible risk
Does estimated intake exceed TTC of 1.5 g/day?

Y Restrict or reject applied use N

Intake level of 1.5 g/day acceptable?

51

Negligible/ acceptable risk

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Every generic pharma companies getting this common deficiency

Does pharma companies have to address them in their old applications??

Each Generic companies have more than 100 DMF filings

Few companies target 25 to 35 DMFs per year

India is one of the highest DMF filer in USFDA What if, they get this deficiency for each of their old product?? How should they address?

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Assessment and control of GTIs in chemical process development is challenging, owing to the evolving nature of the synthetic process, variable points of entry of GTIs in the process, and the need for analytical measurements with adequate selectivity and sensitivity. Application of the approach results in process knowledge and controls that ensure the quality of drug substances throughout development. Although not described in detail here, degradation products in API and drug product also need to be assessed. Challenge is how to predict adequately potential genotoxic impurities from structures in synthesis scheme; further regulations needed? Impossible to eliminate all impurities & Often it is impractical to detect all those trace ones A systematic approach that is consistent with patient safety and regulatory guidelines has been presented to meet these challenges.

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Although medicinal products are required to be safe, safety does not mean zero risk. A safe product is one that has reasonable risks, given the magnitude of the benefits expected and the alternatives available. & All substances are poisons; there is none that is not a poison. The right dose differentiates a poison from a remedy

THANK YOU

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QUESTIONS?

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CH3 OH NH CH3 NH F O CH3

3-(methylamino)-1-phenylpropan-1-ol Resolution

O NH CH3

Hydrolysis HCL salt formation Purification

O NH Mandalte salt CH3

Atomoxetine HCl

Impurities
O OH NH CH3 -H2O Oxazine H formaldehyde H O N CH3

1. Formaldehyde is used in the synthesis of 3(methylamino)-1-phenyl-1propanol (PMPO) 2. Toxicological limit for HCHO was fixed at NMT 16 ppm 3. Though 4 stages are involved after the use of HCHO, its reversible reaction with PMPO could lead al. OPRD, HCHO in Wirth etto traces of 2004, 4, the 513 API

Cat H+ H2O
CH3 F

CH3 CH3

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V.T. Mathad et al, OPRD, 2004, 8, 266

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O O S Cl Cl O

ClO
+

O S

OH

Cl

O O

O S

O Cl

Cl-

ClO Cl O

O S Cl

O Cl Bis( 4-chlorobutyl)ether

Cl

SO2