active pharmaceutical ingredients presented by rutendo kuwana training workshop: training workshop...

Active pharmaceutical ingredients

Presented By

Rutendo Kuwana

Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.

Active Pharmaceutical Ingredients - Artemisinin based therapy2 |

Presentation approachPresentation approach

Discuss aspects of the information that is required for the API for WHO Prequalification

Use examples from literature as well as experience from the WHO PQ Project


Some definitionsSome definitions

Active Pharmaceutical Ingredient (API)

A substance or compound that is intended to be used in the manufacture of a pharmaceutical product as a therapeutically active compound (ingredient)


Some definitions (2)Some definitions (2)

Enantiomers

cpds with same molecular formula as substance but differ in spatial arrangement of atoms and are non-superimpossable mirror images

Polymorphism – occurrence of different crystalline forms of the same substance

Degradation product – molecule resulting from chemical change in substance due to e.g. light, temperature, pH, water, reaction with excipient, immediate container/closure


Some definitions (3)Some definitions (3)

Impurity – any component of the medicinal product which is not the chemical entity defined as the active substance or an excipient of the product

Identified Impurity – an impurity for which structural characterisation has been achieved

Unidentified degradation product – an impurity defined only by qualitative properties e.g. Rt


Available information on APIAvailable information on API

Applicants should collect and analyse available information of the API in a systematic approach. This approach

Leads to a sound scientific understanding of the API, with respect to properties, stability, specifications, etc.

Assists in API manufacture and DMF compilation Leads to the appropriate choice of API manufacturer (source) Assists in dossier compilation Is important for FPP pharmaceutical development Leads to reduction of time / cost


Literature information on APILiterature information on API

Standard works / series / books – such as: (Analytical) Profiles of Drug Substances and Excipients [eds: Florey / Brittain

– 31 volumes] The Merck Index (for structures, properties) Pharmaceutical Codex (12th edition) (“old” APIs)

Journals through search facilities such as International Pharmaceutical Abstracts, Chemical Abstracts, Analytical

Abstracts & internet

Pharmacopoeial monographs (current)

Analysis of structure & stereochemistry


Information from literature and structures

Information from literature and structures

APIs which are organic compounds, have unique chemical structures & stereochemistry

These structures, together with the solid/liquid state conditions, are basically responsible for chemical and physical properties of the APIs


GuidelinesGuidelines Guideline on Submission of Documentation for Prequalification of Multi-Source

(Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis [GuideGeneric]

Guidance on Variations to a prequalified Dossier [Variation Guide]

Guideline on Active Substance Master File Procedure [CPMP/QWP/227/02 Rev1]– Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure

[Draft]

Guideline on Summary of Requirements for Active Substances in the Quality Part of the Dossier [CPMP/QWP/297/97 Rev 1 corr]

ICH Q3A [R] Impurities Testing Guideline: Impurities in New Drug Substances [CPMP/ICH/2737/99]

ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances [CPMP/ICH/367/96 corr]

ICH Q2A Validation of Analytical Procedures: Definitions and Terminology [CPMP/ICH/381/95]

ICH Q2B Validation of Analytical Procedures: Methodology [CPMP/ICH/281/95]


Literature supportLiterature support

Literature information used in the dossier should always be accompanied by

Full traceable reference citations

Photocopies of publication or relevant pages


Properties of APIsProperties of APIs

Scenarios:

API not described in BP, Ph., JP, Ph.Eur., or USP (non - compendial) • Considered new

– (?) information on (adverse) drug reaction• Risk estimation high• Profound information necessary

API described in BP, Int.Ph., JP, Ph.Eur.,or USP (compendial)• Considered in use

– Information on (adverse) drug reaction (monitored)• Risk estimation based on available data• Information necessary limited to data beyond the monograph

– Essential control by the monograph


Properties of API(s)Properties of API(s)

APIs not described in BP, PhInt, PhEur or USP• a) evidence of chemical structure

– spectral data–Single crystal X-ray structure (sufficient) or–Spectrometric data (IR, 1H & 13C NMR, MS, etc.): QA certified

copies of the spectra and tabulated data with• assignments against structure/interpretation of data (narrative)

• b) evidence of chemical structure– Isomerism– Stereochemistry– Discussion of potential isomeric forms



Properties relevant/critical for the performance of the API• c) potential polymorphic forms

– Influence on physicochemical and physical characteristics (solubility, hardness, compressibility, density, melting point, etc.) Must be controlled

• d) particle size distribution– requirement for low solubility drugs (dissolution, bioequivalence)

• e) additional characteristics– critical characteristics to be controlled to ensure consistent

performance of the API (e.g. hygroscopicity)


Properties: non-compendial APIsProperties: non-compendial APIs

Proof of structure/stereochemistry correctness• correlation against API spectral data from peer reviewed literature,

preferable innovator publication (in tabulated form!!). Strongly recommended



APIs described in BP, PhInt, PhEur or USP– Evidence of chemical structure

• control of structure by suitable compendial identification tests– Properties relevant/critical for the performance of the API (not necessarily

covered by the monograph)• a) potential polymorphic forms

– Influence on physicochemical and physical characteristics (solubility, hardness, compressibility, density, melting point, etc.) Must be controlled

• b) particle size distribution– requirement for low solubility drugs (dissolution, bioequivalence)

• c) additional characteristics– critical characteristics to be controlled to ensure consistent

performance of the API (e.g. hygroscopicity)


Properties: Compendial APIsProperties: Compendial APIs

Physico-chemical and other relevant properties, e.g.

– Solubility in water (effect of pH), other solvents such as ether, ethanol, acetone and dichloromethane

– pKa, partition coefficient

– Existence/absence of polymorphs and pseudo-polymorphs e.g. solvates (with XRPD, DSC, IR)• e.g. Rifampicin polymorphs I and II

– Hygroscopicity

– Particle size



Categories of Antimalarials– APIs described in monographs of major international

pharmacopoeias ( 10 years)• Amodiaquine, Chloroquine, Dapsone, Quinine, Mefloquine,

Sulfadoxine/Pyrimethamine, Trimethoprim– APIs described in monographs of major international

pharmacopoeias (recently)• Arthemether, Artemisinin, Artemotil, Artenimol, Artesunate

– APIs not described in monographs of major international pharmacopoeias

• Chlorproguanil, Lumefantrine, Naphthoquine, Piperaquine, Pyronaridine

Active Pharmaceutical Ingredients - Artemisinin based therapy18 | 18

Malaria APIs: Table of occurrenceMalaria APIs: Table of occurrence

APIBPEPUSIntJPMIAPrCod

Artemether✓*✓

Artemisinin ✓*✓

Artemotil (arteether)✓*✓

Artenimol ✓*✗

Artesunate✓*✓

Active Pharmaceutical Ingredients - Artemisinin based therapy19 | 19

Malaria APIs: Table of occurrence (con.)Malaria APIs: Table of occurrence (con.)

APIBPEPUSIntJPMIAPrCod

Amodiaquine✓*✓✓✓

Lumefantrine✓

Mefloquine✓✓✓✓✓✓

Pyrimethamine✓*✓✓*✓✓✓

Sulfadoxine✓*✓✓*✓✓✓

Lumefantrine only malaria API without monograph


Properties of ArtemisininsProperties of Artemisinins

Artemisinin (C15H22O5)– 7 centers of asymmetry– 27 potential isomers– One isomer in biosynthesis– Chemical synthesis

• Feasible but uneconomical

Chemical derivatization at C-10 (carbonyl-moiety) converts C-10 into an additional stereoisomeric center:

• - and -isomers are formed

1

2

34

5

65a

8a7

8

910

1112

12a


Properties of ArtemisininsProperties of Artemisinins

Manufacturer proposals

Diastereomers may differ in their melting point/specific optical rotation

Melting rangeMelting rangeSpecific optical rotationSpecific optical rotation

a-Artemethera-Artemether100°C100°C

b-Artemetherb-Artemether84 - 86°C, 84 - 86°C, 86 – 90°C86 – 90°C+166°-+173°+166°-+173°, +168°-+173°, +168°-+173°20mg/ml C20mg/ml C22HH55OHOH

a-Artesunatea-Artesunate144°C, 143°C, 142-146°C144°C, 143°C, 142-146°C

132-135°C132-135°C, 131-134°C, 131-134°C

+2.5°-+3.5°, +2.5°-+3.5°, +4.5°-+6.5°+4.5°-+6.5°, +11°-+14°, +11°-+14°

10mg/ml CH10mg/ml CH22ClCl22

+11°-+14°, 40mg/ml CH+11°-+14°, 40mg/ml CH33Cl, +10°-+14° Cl, +10°-+14°

(CH(CH33Cl)Cl)

b-Artesunateb-Artesunate132-135°C132-135°C+2.5°-+3.5°+2.5°-+3.5°

aa~~bb~~ArtenimolArtenimol(in solution)(in solution)

+146° (15°C)+146° (15°C)

(?mg/ml MeOH)(?mg/ml MeOH)


Route(s) of synthesisRoute(s) of synthesis

API not described in BP, Int.Ph., JP,Ph.Eur., or USP (non-compendial APIs)– Controls of critical steps and intermediates

• Potential impact on the quality of the API and intermediates– Process conditions, test requirements and other relevant parameters to be

controlled within predetermined limits

• Examples of potentially critical steps– Mixing of multiple components– Phase change and phase separation steps– Steps where control of pH and temperature are critical– Introduction of an essential structural element or major chemical

transformation– Introduction/removal of significant impurities to the API– Final purification step– Steps with an impact on solid state properties/homogeneity of the API

API described in BP, Int.Ph., JP, Ph.Eur., or USP (compendial APIs)


Route(s) of synthesis (cont.)Route(s) of synthesis (cont.)

Requirements: The synthesis should– lead to the correct structure, stereochemistry and crystal form

& size (if relevant)– be well controlled and validated (GMP)– produce an API which meets acceptable standards of quality,

including limits of impurities (organic, inorganic, residual solvents)


The information required for the synthesis of the API may depend on

The information required for the synthesis of the API may depend on

Availability of a valid CEP - no synthesis information is then required. CEP must however have all appendices and applicant to submit other info not covered by CEP

Whether the quality of the is API controlled by a monograph in an acknowledged pharmacopoeia?

No official monograph is available for quality control - Detailed information required e.g. Open Part of DMF (from API

manufacturer) - Also signed declaration from API manuf that synthesis and purification

are as described in the dossier


Certification Scheme /EDQMCEP Option


Issued by EDQM for substances described in the Ph. Eur. www.edqm.eu under Certification.Pharm.Substances

Information which can be found on a quality CEP - CEP reference Number,- CEP holder, - Site of manufacture of the API, site of manufacture of declared starting material- Grade (particle size or sterile) (if applicable) - Ph. Eur. monograph according to which the Certification dossier has been evaluated, - Additional impurities and residual solvents not mentioned in the monograph, - Additional methods to those of the monograph as annexes,- If sterile API, Method of sterilization + mention that process and validation have been assessed - Re-test period (if applicable)- Packaging system and storage condition (if re-test period mentioned), - Date of validity of the CEP




A quality CEP certifies that the quality of the substance can be checked according to the Ph. Eur. by applying the analytical methods described in the specific Ph. Eur. monograph supplemented by those

appended to the CEP.


Synthesis : non-compendial APIsSynthesis : non-compendial APIs

A flow diagram of the synthesis process including structures & stereochemistry of starting materials & intermediates;

reagents; catalysts; solvents

A full description of each step / process, including: Reaction conditions (temp., time, moisture control, etc.) Quantities of reagents/solvents Size of production scale Purification of intermediates Final API purification method / crystallisation / solvent(s) Reprocessing (has to be justified, validated) Process controls Validation of critical steps, e.g. aseptic processes Discussion of (possible) process impurities

Organic, residual solvents and catalysts/inorganic


API described in BP, PhInt, PhEur or USPAPI described in BP, PhInt, PhEur or USP

– Impurities that are not included in the monograph• Process related impurities

– Key intermediates– Residual solvents– Potential organic impurities not covered by the monograph


Specifications of raw materials and intermediates used in synthesis

Specifications of raw materials and intermediates used in synthesis

Provide specifications for starting materials and intermediates (if isolated) reagents, solvents & catalysts

Class 1 solvents should not be used (ICH Q3C) Benzene, Carbon tetrachloride, 1,2-Dichloroethane,

1,1-Dichloroethene & 1,1,1-Trichloroethane

Provide a declaration on the use/non-use of material of animal or human origin (TSE) Risk of Transmitting Animal Spongiform Encephalopathy Agents (WHO

TRS 908, Annex 1 or EMEA/410/01 Rev.2)

To limit impurities in the API (For safety reasons)


WHAT IS A STARTING MATERIAL?WHAT IS A STARTING MATERIAL?

Contributes an important structural part of the API

Available in free trade

Compound well defined in chemical literature (name, chemical structure, chemical and physical properties, and impurity profile)

Synthesized by commonly known process


RE-DEFINITION OF STARTING MATERIALRE-DEFINITION OF STARTING MATERIAL

MARKS THE START OF THE MANUFACTURING PROCESS DESCRIBED IN AN APPLICATION Manufacturing steps before are not described Manufacturing steps before need not be performed in

accordance with GMP Changes in manufacturing steps before need not be reported

to WHO

EACH BRANCH OF A SYNTHESIS WILL BEGIN WITH ONE OR MORE STARTING MATERIALS


API specificationsAPI specifications

API not described in BP, Int.Ph., JP, Ph.Eur., or USP (non-compendial APIs)

API described in BP, Int.Ph., JP, Ph.Eur., or USP (compendial APIs)

General note

An API has only one set of specifications applicable at release and throughout the re-test period– an FPP may have two sets of specifications – release and shelf-life


Specifications: Non-Compendial APIsSpecifications: Non-Compendial APIs

ICH Q6A (new APIs and products) – for instance:

Requires justification for proposed specifications

Impurities to be characterised and limits set synthesis and degradation according to ICH Q3A(R) residual solvents according to ICH Q3C

Analytical methods with validation

Preparation and potency determination/specification of primary and secondary (working) standards, with CoAs

Valid CoAs for at least 2 batches


Non-compendial APIsTypical set of specifications

Non-compendial APIsTypical set of specifications

Appearance/description

Identification (at least one specific, e.g. IR spectrum)

Moisture content (or LOD: moisture + residual solvents)

Impurities - Related organic substances (synthesis or degradation)

specified unspecified and total organic impurities

- Inorganic impurities, including catalysts - Residual solvent(s)

Assay

Additional parameters important for specific API such as particle size, polymorphic form, microbial limits


Specs: Compendial APIsSpecs: Compendial APIs

The current monograph always applicable

Additional critical specifications that are not included in monograph e.g.– particle size & polymorphic form– synthesis related impurities resulting from specific process which may be

additional to monograph– residual solvents (specific to process)

Valid CoAs for at least 2 batches required

CEP normally states tests additional to the monograph – e.g. residual solvents & impurities


IMPURITIESIMPURITIES

Extraneous contaminant (foreign substances)

Toxic impurities

Concomitant components

Signal impurities


Classes of ImpuritiesClasses of Impurities

Organic

Inorganic

Residual solvents


Organic ImpuritiesOrganic Impurities

May arise during manufacturing process and storage

Starting materials

By products

Intermediates

Degradation products

Reagents, ligands and catalysts


Inorganic ImpuritiesInorganic Impurities

May be from manufacturing process and are normally known and identified:

Reagents, ligands and catalysts

Heavy metals

Inorganic salts

other materials (e.g. filter aids, charcoal etc.)


SolventsSolvents

Organic or inorganic liquids used during the manufacturing process

Toxicity generally known, therefore controls achievable

Limits to be based on pharmacopoeial standards or known safety data


IMPURITIESIMPURITIES

Identified impurity

Unidentified impurity

Specified impurity

Unspecified impurity


Impurity ThresholdsImpurity Thresholds

Identification threshold Limit above which, impurities found are to be identified either structurally or by a qualitative parameter e.g. RT in HPLC system

Qualification threshold Limit above which, impurities found are to be toxicologically qualified

Reporting threshold Limit from which, impurities should be analytically reported

Maximum Daily Dose

Reporting Threshold

Identification Threshold

Qualification Threshold

≤ 2g/day0.05%0.10% or 1mg per day intake (whichever is

lower)

0.15% or 1mg per day intake (whichever is

lower)

≥ 2g/day0.03%0.05%0.05%


ICH Guidelines for Identification and Qualification of impurities in bulk drugs and FPPs

ICH Guidelines for Identification and Qualification of impurities in bulk drugs and FPPs


IMPURITY EQUIVALENCEIMPURITY EQUIVALENCE

To demonstrate that different sources of the API or routes of synthesis are equivalent, checks on impurities are required to show that

No new impurity is observed in the intermediate above 0.1%

No new impurity is observed in API above the qualification threshold

Each existing impurity is within its stated limit

Total impurities are within the stated limit


IMPURITY EQUIVALENCE (2)IMPURITY EQUIVALENCE (2)

Each existing residual solvent is within its stated limit

New residual solvents, in either an intermediate or the API, are at or below the levels recommended in the ICH guide


IMPURITY EQUIVALENCE (3)IMPURITY EQUIVALENCE (3)

Ideally, impurities should be evaluated in isolated intermediates immediately following the process step in which they are produced

The impurity search can be extended to the next downstream intermediate and the evaluation process repeated until the final intermediate, even to the API


Potential impurities of ArtemisininsPotential impurities of Artemisinins

Starting material (extracted from herbal sources)– GuideGeneric:

• Starting materials from vegetable origin should be fully characterized and a contaminant profile should be established and submitted.

– CPMP/QWP/297/97 Rev 1 corr:• In the case of substances isolated form herbal sources, the potential for

impurities arising from cultivation and/or preparation (e.g. pesticide residues, fumigants, mycotoxins) should be addressed.


Potential impurities of Artemisinins IIPotential impurities of Artemisinins II

Impurities contained in the starting material - Artemisinin– Biosynthetic by-products

• Arteannuin B , Artemisitene, Artemisinic acid,– Extraction from fresh leaves with CHCl3 within 1 min > 97%

» Localisation in subcuticular space of the glands on the surface of the leaves

– Cultivation reagents• Pesticide residues, fumigants, mycotoxins

– Solvents from the extraction process• Hexane, benzene, acetonitril, ether, pentane, chloroforme…..(?) diesel, fuel

(?) [ICH Q3A (R)]


Potential impurities of Artemisinins IIIPotential impurities of Artemisinins III

Unreacted starting material– Artemisinin (starting material for derivatives)– Artemisinic acid (starting matrial for dihydroartemisinin)– Dihydroartemisinin (starting material for derivatives)

Unreacted intermediates, by-products– -Arthemether, -Artheether– /-Dihydroartemisinin – -Artesunate


Potential impurities of Artemisinins III cont.Potential impurities of Artemisinins III cont.

Reagents, catalysts, residual solvents– Methanol, acetonitril, chloroforme, acetone …– NaBH4, succinic acid/anhydride, triethylamine,

dimethylaminopyridine

Degradants– Stability of

• ester-derivative (Artesunate)• ether-derivative (Artemether, Arteether)• lactone (Artemisinin)

– Stability of artenimol (oxidation)– Susceptibility of endoperoxide bond to reduction

• Deoxyartemisinine (loss of active principle!)– Zn / AcOH or FeBr2 / THF


Site(s) of manufactureSite(s) of manufacture

The quality of APIs is dependent on– Manufacturing site

• Equipment, personal, technology…– Route of synthesis, operational conditions, IPCs…

• Impurity profile, stability (API & FPP)

The quality of an API may consequently impact the quality of a FPP– Change in manufacturing site

• Alternate API-manufacturers– Change in route of synthesis

• Alternate API-manufacturers


Stability testingStability testing

Stress testing of API (forced degradation) helps to identify the likely degradation products and pathways to establish stability of the molecule To verify specificity of stability assay method

e.g. Diode array detection for API peak purity !

Stability testing (regulatory) to provide evidence on how the quality of an API varies with time

under the influence of a variety of environmental factors such as temperature, humidity, and light; and

to establish a re-test period for the API and to recommended storage conditions


Stress testing (forced degradation) Typical conditions

Stress testing (forced degradation) Typical conditions

The conditions should

partially (e.g. 10-30%) decompose the API to primary degradation products

Conditions can be changed to get required degree of degradation

** Temperature should not come closer than 10°C from melting point

Stress factorConditions (e.g.)

Humidity≥ 75% RH (solid)

Heat **≥ 60°C (solid)

Heatwater

Acid0.1 M HCl

Base0.1 M NaOH

Oxidative3% H2O2

PhotolyticICH Q1B

Metal ions (optional)

0.05 M Fe2+ or Cu2+


Stress testing (forced degradation)Literature

Stress testing (forced degradation)Literature

Literature information and/or CEP– in support of and/or– to replace experimental data


Important ElementsImportant Elements

The API must be of required structure & stereochemistry

The physical properties must be well understood, e.g.– hygroscopicity, crystal properties and solubility

The synthesis process must be according to GMP to– consistently produce an API of required chemical and physical

quality– limit impurities according to defined standards


Important Elements (2)Important Elements (2)

The set of specifications should be based on validated analytical methods with appropriate acceptance criteria to which an API should conform to be considered acceptable

for its intended use throughout the retest period in the proposed packaging

active pharmaceutical ingredients presented by rutendo kuwana training workshop: training workshop...

Documents

pharmaceutical product

active substance

apis slide

registration of artemisinin

rt slide

api standard

api applicants

chemical abstracts