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Active Pharmaceutical Ingredients (APIs) (special reference to TB and HIV/AIDS). World Health Organization Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence Kiev - Ukraine 3 to 7 October 2005. Theo Dekker, D.Sc., consultant to WHO Research Institute for Industrial Pharmacy

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active pharmaceutical ingredients apis special reference to tb and hiv aids

Active Pharmaceutical Ingredients (APIs)(special reference to TB and HIV/AIDS)

World Health Organization

Training Workshop on Pharmaceutical Quality, GMP and Bioequivalence

Kiev - Ukraine

3 to 7 October 2005

Theo Dekker, D.Sc., consultant to WHO

Research Institute for Industrial Pharmacy

North-West University, Potchefstroom, South Africa

iiftgd@puk.ac.za

what is an api
What is an API?

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)

Marketing Authorization of Pharmaceutical Products with special Reference to Multisource (Generic) Products: a Manual for a Drug Regulatory Authority

(WHO, Blue Book)

presentation approach
Presentation approach
  • Collect and interpret available information on the APIs (pre-dossier studies), such as:
    • The possible manufacturer(s)
    • Literature, all aspects (chemical/physical)
    • Monographs in pharmacopoeia (example: ARVs)
  • Dossier requirements for APIs
    • Guideline pages 4 - 9
part 1 available information on api for api and or fpp manufacturer
Part 1. Available information on API(for API and/or FPP manufacturer)
  • Why is it important to collect and analyse available information of the API through a systematic approach?

Some outcomes:

    • Sound scientific understanding of the API, with respect to properties, stability, specifications, etc.
    • Assists in API manufacture and DMF compilation
    • Sound choice of API manufacturer (source)
    • Assists in dossier compilation
    • Important for FPP pharmaceutical development
    • Reduction of time / cost
info on potential api manufacturer s
Info on potential API manufacturer(s)

The decision on the API manufacturer should be finalised before starting or early during FPP development studies

    • Changes afterwards may be major of nature
  • Is the manufacturer reliable / reputable?
  • Manufacturing authorization and GMP compliant?
  • Is the open part of DMF available and according to all requirements?
  • Is a valid CEP available?
  • Does API comply with required quality standards?
literature information
Literature information

Know your API, through:

  • 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
examples of existing information on apis in pharmacopoeia and some standard works
Examples of existing information on APIs in pharmacopoeia and some standard works

Tables on the next pages show which pharmacopoeia and standard works contain the APIs for treatment of

TB (6th EOI), HIV/AIDS (6th EOI) and Malaria (4th EOI)

  • Abbreviations:
    • BP British Pharmacopoeia: 2004, addendum 2005
    • EP European Pharmacopoeia: 5.12 (July 2005)
    • US USP 28, second supplement (August 2005)
    • Int International Pharmacopoeia: 3rd edition (4th due)
    • MI Merck Index (13th ed, 2001)
    • JP Japanese Pharmacopoeia (web; December 2001)
    • Apr Analytical Profiles of Drug Substances and

Excipients to vol. 31 (name of series changed twice)

    • Cod Pharmaceutical Codex (12th ed, 1994) (“old APIs)
hiv aids antiretrovirals arvs
HIV/AIDS: Antiretrovirals (ARVs)

* Including dosage forms

d Int. Ph., Draft monograph: http://www.who.int/medicines/

hiv aids anti infective apis
HIV/AIDS: Anti-infective APIs

Monographs exist for most of the APIs listed under the following headings:

  • Antibacterial and antimycobacterial agents (other than MTB) (8)
  • Antiprotozoal and Antifungal agents (9)
  • Antiviral agents (2)
  • Anti-cancer drugs (4)
  • Palliative Care drugs (6)

In total 29 APIs

malaria apis table of occurrence
Malaria APIs: Table of occurrence

# Not included in 4th EOI

✗ Dihydroartemisinin (under Artemisinin)

malaria apis table of occurrence con
Malaria APIs: Table of occurrence (con.)

Lumefantrine only malaria API without monograph

api monographs summary
API monographs: summary

Anti TB APIs

  • Monographs for all APIs

HIV/AIDS: antiretroviral (ARV) APIs:

  • Monographs for 9 out 13 on EOI list
  • Fast development, others soon expected

Antimalaria APIs

  • Monographs for all artemisinin-related APIs
  • Monographs for all others on EOI list
    • except lumefantrine
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
information from literature structure rifampicin
Information from literature & structure Rifampicin

hydrolysis (to 25-desacetyl)

(to N-oxide)

oxidationhydrolysis

(to quinone) (to 3-formyl)

oxidation

light sensitive

information from literature structure rifampicin discussion 1
Information from literature & structure Rifampicin (discussion - 1)

Oxidation

  • Hydroquinone group
    • Main degradation of API (to rifampicin quinone)
    • Enhances solubility in alkaline medium
  • Tertiary amine
    • Moderately prone towards oxidation (to N-oxide)
    • Enhances solubility in acid medium
  • Oxidation enhanced by
    • Metal ions
    • Low pH
information from literature structure rifampicin discussion 2
Information from literature & structure Rifampicin (discussion - 2)

Hydrolysis

  • Hydrazone (imine) group
    • Hydrolysis to 3-formyl rifamycin
  • 25-acetyl (ester) group
    • Hydrolysis to 25-desacetyl rifampicin (minor)

Light sensitive

    • Due to conjugation in molecule (unsaturated)

Storage of bulk raw material(BP/Ph.Eur.):

    • Store under nitrogen in an airtight container, protected from light at temperature of ≤ 25ºC
information from literature structure isoniazid
Information from literature & structure Isoniazid

Small molecule (quite stable)

  • Basic amino functions
  • Primary amine - react with aldehydes/lactose

see presentation: FPPs – formulation problems?

  • Can hydrolyze under stress conditions to inter alia isonicotinic acid & hydrazine
  • Oxidize in presence of strong oxidants (e.g. permanganate), with metals as catalyst
information from literature structure indinavir sulfate
Information from literature & structure Indinavir sulfate

Basic amino atoms (2)

forms H2SO4 salt

ethanol in crystal

Unstable

  • 2 main degradation products
    • moisture and temp. sensitive
    • acid / base enhanced
    • Intra-molecular reaction

+

Kreutz, J. Pharm. Biomed. Anal., 19, 725-735 (1999) and Crixivan® EPAR

literature support style
Literature support style

Literature information used in the dossier should always be accompanied by

  • Full traceable reference citations, for instance:
    • Devani, M.B., Shishoo, C.J., Doshi, K.J. & Patel, H.B. Kinetic studies of the interaction between isoniazid and reducing sugars. Journal of Pharmaceutical Sciences, 74, 427-432 (1985)
    • Hassan, M.M.A., Jado, A.I., & Zubair, M.U. Aminosalicylic acid. In Florey, K., ed. Analytical Profiles of Drug Substances, vol. 10. New York: Academic Press, p. 1-27 (1981)
  • Photocopies of publication or relevant pages
section 2 dossier requirements for active pharmaceutical ingredient api
Section 2. Dossier requirements for Active Pharmaceutical Ingredient (API)

Refer to Section 2 of:

Guideline on Submission of Documentationfor Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs)used in the Treatment of HIV/AIDS, Malaria and Tuberculosis(Main guideline, hand-out)

As from page 4/50

api content of dossier 4 50
API: content of dossier 4/50

2.1 Nomenclature (INN, Systematic, etc.) 4/50 ■

2.2 Properties (structure, stereochemistry, etc) 4/50**

2.3 Site of manufacture 5/50 ■

2.4 Route of synthesis (impurities, etc) 5/50**

2.5 Specifications 6/50**

2.6 Container closure system (packaging) 7/50 ■

2.7 Stability testing8/50

■See guidelines – not discussed

** The requirements may differ, depending on when or when not the API is described in acknowledged pharmacopoeia

section 2 api information format 4 50
Section 2. API information format4/50

One of the following options (in order of preference)

  • A valid CEP (European Certificate of Suitability)
    • with all appendices
    • Provide information, which may not be covered by the CEP, under points 2.2.2, 2.5.2, 2.6 and 2.7
  • Open part of the DMF (Drug Master File)
    • Compiled by API manufacturer
    • DMF must contain all information listed under Section 2
  • By completing Section 2 (by applicant)
    • Submit a signed declaration by API manufacturer that the synthesis and subsequent purification is conducted as described in the dossier
2 2 properties of apis 4 50
2.2 Properties of APIs 4/50

Three scenarios:

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

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

2.2.3 Information from literature(important)

    • See examples in rest of presentation
  • All TB APIs in 6th Invitation for EOI fall in category 2.2.2
  • Some ARV APIs in 6th Invitation for EOI fall in category 2.2.2
2 2 1 properties non compendial apis 4 50
2.2.1 Properties non-compendial APIs 4/50
  • Proof of structure/stereochemistry correctness
    • 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

or

      • correlation against API spectral data from peer reviewed literature, preferable innovator publication (in tabulated form!!). Strongly recommended
  • Physico-chemical properties as discussed under paragraph 2.2.2 (next slide)
2 2 2 properties compendial apis 4 50
2.2.2 Properties compendial APIs 4/50
  • 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)
      • See presentation on FPPs (rifampicin)
      • See nevirapine (later in this presentation)
    • Hygroscopicity: see FPP presentation
      • Ethambutol hydrochloride in 4FDC tablet
    • Particle size
2 2 2 properties compendial apis example solubility of tb apis
2.2.2 Properties compendial APIsExample: solubility of TB APIs

1 Merck Index 13th ed 2 Pharmaceutical Codex 12th ed

* Dichloromethane has similar properties to chloroform as solvent, but preferred on safety reasons

2 2 1 and 2 2 2 properties apis example solubility protease inhibitors mg ml
2.2.1 and 2.2.2 Properties APIsExample: solubility protease inhibitors(mg/ml)

GC Williams & PJ Sinko, Advanced Drug Delivery Reviews, 39, 211-238 (1999)

2 2 2 properties compendial apis pseudo polymorphism nevirapine 1
2.2.2 Properties compendial APIsPseudo-polymorphism nevirapine (1)

Int. Ph. monograph Nevirapine (anhydrous & hemihydrate)

  • Identification test C (quote)

Carry out the examination as described under “Spectrophotometry in the infrared region”.

    • For the anhydrous substance, the infrared (IR) absorption spectrum is concordant with the spectrum obtained from anhydrous nevirapine RS or with the reference spectrum of anhydrous nevirapine
    • For the hemihydrate, the IR absorption spectrum shows a characteristic sharp absorbance at about 3503 cm−1; after heating the test substance for one hour at 140°C and cooling, the IR absorption spectrum is concordant with the spectrum obtained from anhydrous nevirapine RS or with the reference spectrum of anhydrous nevirapine
2 2 2 properties compendial apis pseudo polymorphism nevirapine 2
2.2.2 Properties compendial APIsPseudo-polymorphism nevirapine (2)

Interpretation of this IR identification test:

  • Nevirapine anhydrous (one test)
    • IR spectrum against nevirapine anhydrous RS
  • Nevirapine hemihydrate (two tests, conform to both)
    • IR spectrum shows signal at 3503 cm-1 (water) and
    • Heat converts the hemihydrate to the anhydrous form
      • IR spectrum against nevirapine anhydrous RS

- ½H20

Nevirapine, ½H20 ————> Nevirapine

heat

The reaction is not reversible at room temperature

ir spectra
IR-spectra

Nevirapine ½H20

3503 cm-1

O-H signal (water)

Spectra not concordant

(do not match)

Nevirapine anhydrous

no crystal water

no O-H signal

nevirapine overlay ir spectra
Nevirapine: Overlay IR spectra

Nevirapine anhydrous

Nevirapine hemihydrate: after heated at 140°C

spectra concordant

2 4 route s of synthesis 5 50
2.4 Route(s) of synthesis 5/50

Three scenarios:

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

2.4.2 Specifications of raw materials and intermediates used in the synthesis of non-compendial APIs

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

2 4 route s of synthesis cont
2.4 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
    • Is a valid CEP is available? - no synthesis information
    • Is the quality of the API controlled by a monograph in an acknowledged pharmacopoeia?
    • No official monograph is available for quality control
      • Detailed information required
2 4 1 synthesis non compendial apis 5 50
2.4.1 Synthesis non-compendial APIs 5/50

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
2 4 2 specifications of raw materials and intermediates used in 2 4 1 synthesis 5 50
2.4.2 Specifications of raw materials and intermediates used in 2.4.1 synthesis 5/50

Provide specifications for

  • starting materials and intermediates (if isolated)
  • reagents, solvents & catalysts

Class 1 solventsshould 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)

Why? To limit impurities in the API (matter of safety)

2 4 2 synthesis compendial apis
2.4.2 Synthesis compendial APIs

Provide

  • An outline of the route of synthesis
    • a simplified flow chart and a qualitative description of the manufacturing method, including the names of solvents, reagents and catalysts
  • Information on the final steps of synthesis
    • including purification procedures

If a valid CEP is submitted

    • No information – simplified flow chart suggested
2 5 api specifications 6 50
2.5 API specifications 6/50

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

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

General note

An API hasonly 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
2 5 1 specifications non compendial apis
2.5.1 Specifications: Non-compendial APIs

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

  • Provide 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

2 5 1 specifications non compendial apis typical set of specifications
2.5.1 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
2 5 2 specs compendial apis
2.5.2 Specs: 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)
  • Provide valid CoAs for at least 2 batches

CEP normally states tests additional to the monograph

    • e.g. residual solvents & impurities
2 7 stability testing 8 50
2.7 Stability testing 8/50

2.7.1 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
    • Diode array detection for API peak purity !

2.7.2 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

ICH Q1A(R2)

2 7 1 stress testing forced degradation 8 50 typical stress reaction conditions
2.7.1 Stress testing (forced degradation) 8/50Typical stress reaction conditions

The conditions should

  • partially (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

2 7 1 stress testing forced degradation literature
2.7.1 Stress testing (forced degradation)Literature
  • Literature information and/or CEP
    • in support of and/or
    • to replace experimental data

Examples of literature information

    • Rifampicin (earlier slides)
      • Oxidation, hydrolysis
    • Indinavir sulfate (earlier slide)
      • Intra-molecular reaction – heat, moisture, acid, base
    • Efavirenz (see next slides)
      • Hydrolysis – pH dependent
2 7 1 stress testing forced degradation efavirenz 1
2.7.1 Stress testing (forced degradation)Efavirenz (1)
  • Non-hygroscopic
  • 4 Polymorphs
    • Form 1 pharmaceutical

(EPAR Sustiva®)

  • Hydrolysis main degradation
    • pH dependent
    • Maximum stability at pH 4
    • 2 Degradants isolated
      • structures elucidated
    • Pathways postulated

Maurin, Pharm. Res. 19, 517 (2002)

pH / rate profile of

degradation at 60°C

2 7 1 stress testing forced degradation efavirenz 2
2.7.1 Stress testing (forced degradation)Efavirenz (2)

The data (generated at 60°C)

  • in figure and table

shows that

  • Efavirenz is quite stable
    • In Guideline Supplement 2 list !
  • Maximum stability at pH 4
    • Suspension possible?
  • Carbon dioxide formation !!!
    • 30 mg/ml solution, 100 ml bottle:

1% decomposition ≈ 2 ml CO2

Degradation products / routes

  • Next page

T½ at 60°C (calculatedfrom data of Maurin)

some conclusions
Some conclusions

The data submitted must demonstrate that the API is suitable for use in production of the FPP with respect to safety, efficacy and quality

Important elements are:

  • 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
  • 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