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WHO workshop on Quality, good manufacturing practice and bioequivalence with a focus on antituberculotics Jiaxing, China 5 to 9 November 2007. Active Pharmaceutical Ingredients (APIs). Theo Dekker, D.Sc. Research Institute for Industrial Pharmacy

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WHO workshop on

Quality, good manufacturing practice and bioequivalence with a focus on antituberculotics

Jiaxing, China

5 to 9 November 2007

Active Pharmaceutical Ingredients(APIs)

Theo Dekker, D.Sc.

Research Institute for Industrial Pharmacy

North-West University, Potchefstroom, South Africa

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)

This session deals only with non-biological APIs

presentation approach
Presentation approach
  • Collect and interpret available information on the APIs (pre-development studies – desk research), such as:
    • Literature, all aspects (chemical/physical)
    • Monographs in pharmacopoeia
  • Dossier requirements for APIs
    • Generic guideline pages 4 – 9
    • CEP
    • API Master File Procedure

Generic guideline under revision

part 1
Part 1

Available information on API

(for API and FPP manufacturer)

why information on api
Why information on API?

Outcomes of a systematic study of published data include:

  • Sound scientific understanding of the API, with respect to
    • chemical aspects such as stereochemistry, stability & degradation
    • physical aspects such as solubility, polymorphism & spectrometric data
    • analytical aspects
  • Scientific knowledge assisting risk management
  • Essential for pharmaceutical development
    • Reduction of time / cost
  • Assists in compilation of dossier, APIMF…
where how to find information
Where/how to find information
  • Standard works / series / books – such as:
    • (Analytical) Profiles of Drug Substances and Excipients [eds: Florey / Brittain – 32 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
      • Peer reviewed journals
  • Pharmacopoeial monographs
  • Analysis of structure & stereochemistry (and literature)
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 pharmacopoeias (current) and standard works contain the APIs for treatment of TB


  • Merck The Merck Index (14th ed, 2001)
  • Apr Analytical Profiles of Drug Substances and Excipients to vol. 32 (name changed few times)
  • Codex Pharmaceutical Codex (12th ed, 1994)
information from literature and structures
Information from literature and structures
  • APIs which are organic compounds, have unique chemical structures, including 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)

light sensitive


(to N-oxide)


hydrolysis(to 3-formyl rifamycin)


(to quinone)

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


  • Hydroquinone group
    • Main degradation of API (to rifampicinquinone)
    • 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 & structureRifampicin (discussion – 2)


  • 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)
information from literature structure rifampicin discussion 3
Information from literature & structureRifampicin (discussion – 3)

Special storage conditions?

International Pharmacopoeia:

  • Rifampicin should be kept in
    • a tightly closed container
      • (exclude exposure to air - moisture and oxygen)
        • (container of low permeability)
    • protected from light and
    • stored at a temperature not exceeding 15°C, or
    • in an atmosphere of nitrogen at a temperature not exceeding 30°C
      • (absence of air oxygen)
rifampicin impurities tlc
Rifampicin impurities (TLC)
  • Reference: IntPh related substances test for rifampicin
    • Silica gel R1
    • CHCl3/methanol : 85/15
    • Daylight detection
  • Limits for tablets (see also BP for capsules)

a Rifampicin test substance: 20 mg/ml

b Quinone: 0.8 mg/ml (4.0%)

c N-oxide: 0.3 mg/ml (1.5%)

d 3-Formyl rifamycin: 0.1 mg/ml (0.5%)

e Rifampicin: 0.2 mg/ml (1.0%)

a b c d e

information from literature structure isoniazid
Information from literature & structure Isoniazid

Small molecule (quite stable)

  • Basic amino functions
  • Can hydrolyze under stress conditions to inter alia isonicotinic acid & hydrazine
  • Primary amine - react with aldehydes, for example
    • reducing sugars / lactose
    • 3-Formyl rifamycin(rifampicin degradation product)

see presentation: FPPs – formulation problems?

p aminosalicylic acid
p-Aminosalicylic acid
  • Weak basic group – reaction with reducing sugars?
  • Carboxylic acid and phenolic group: acidic
    • Sodium salt available (monograph in USP, BP/Ph.Eur.)
  • Decarboxylate
    • Limit test for m-aminophenol in monographs (API & tablets)
    • More stable in alkaline medium than in acid medium
      • Enteric coated granules

+ CO2

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
part 2
Part 2.

Dossier requirements for APIs

Refer to:

  • Generic guideline (Section 2) *
  • PQIF *
  • Guideline on APIMF procedure

* Under revision

classification of apis non biological
Classification of APIs (non-biological)

Active Pharmaceutical Ingredient

New Chemical Entity (NCE)

Well-known API

Pharmacopoeial API

Monograph for APIin pharmacopoeia

Non-pharmacopoeial API

No monograph for APIin pharmacopoeia

used in innovator


Lower Risk Higher `

high risk apis
High-risk APIs
  • FPP is not registered in ICH region& associated countries
  • API is not official in the internationally used major pharmacopoeias and ICH guidelinesshould be used for evaluation
  • Reference standard/comparator is not available for:
    • Pharmaceutical equivalence studies
    • Bioequivalence studies
  • Require particular attention bynational DRAs as regards assessment of applications for marketing authorization / prequalification
low risk apis
Low-risk APIs
  • CEP (Certificate of suitability) is submitted with dossier
  • APIMF (Active Pharmaceutical Ingredient Master File)
    • Open part (Applicant)
    • Closed part(WHO or DRA)
  • Pharmacopoeia monograph
    • Literature evidence of stability
    • Synthesis impurities and degradants are controlled by monograph
    • Class1 solvents excluded; class2 / class 3 solvents controlled
  • FPP is registered in the ICH region(DRA)
section 2 api scientific information
Section 2. API scientific information

One of the following options (in order of preference)

  • A valid quality CEP (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
  • An APIMF (API Master File)
    • Submitted by API manufacturer
    • Contains all information requested in Section 2 of Generic guideline
    • APIMF procedure - preferred
  • 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
content of dossier
Content of dossier

2.1 Nomenclature (INN, Systematic, etc.) ■

2.2 Properties (structure, stereochemistry, etc) **

2.3 Site of manufacture ■

2.4 Route of synthesis (impurities, etc) **

2.5 Specifications **

2.6 Container closure system (packaging) ■

2.7 Stability testing

■See guidelines – not discussed

** The requirements may differ, depending on whether API is pharmacopoeial or non-pharmacopoeial

2 2 properties of apis
2.2 Properties of APIs

Three scenarios:

2.2.1 API not described in IntPh, PhEur or USP (non-pharmacopoeial)

2.2.2 API described in IntPh, PhEur* or USP (pharmacopoeial)

2.2.3 Information from literature

    • See examples in other parts of presentation
  • All TB APIs in 7th Invitation for EOI are pharmacopoeial
    • except levofloxacin (S-enatiomer of ofloxacin)
    • Thus focus on pharmacopoeial APIs

* PhEur including BP

2 2 1 properties apis non pharmacopoeial
2.2.1 Properties APIsNon-pharmacopoeial
  • 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


      • correlation against API data from peer reviewed literature, preferable innovator publication (in tabulated form!!). Strongly recommended
        • e.g. 1H & 13C NMR (tabulated comparison) & optical rotation
  • Physico-chemical properties as discussed under paragraph 2.2.2 (next slide)
2 2 2 properties apis pharmacopoeial
2.2.2 Properties APIsPharmacopoeial
  • Verification of structure
    • Infrared spectrum against official reference standard
  • Physico-chemical and other relevant properties, e.g.
    • Solubility in water (effect of pH), and organic solvents
    • Existence/absence of polymorphs and pseudo-polymorphs e.g. solvates (with XRPD, DSC, IR)
      • See presentation on FPPs (rifampicin)
    • Hygroscopicity
      • Ethambutol hydrochloride in 4FDC tablet (FPP presentation)
    • Particle size
2 2 properties apis polymorphism
2.2. Properties APIsPolymorphism
  • Polymorphism (ICH Q6A - see decision trees)
    • The occurrence of different crystalline forms of the same API. This may include
      • solvates/hydrates (e.g. nevirapine anhydrous and hemihydrate, see PhInt monographs)
      • amorphous forms (rifampicin in dissolution presentation)
  • Different polymorphic forms of the same API
    • may affect product performance, bioavailability or stability
      • then the appropriate solid state should be specified & controlled
  • Polymorphism is especially important
    • when the API is of (very) low solubility in water medium (BCS)
2 2 properties of apis example solubility tb apis
2.2. Properties of APIsExample: solubility TB APIs

1 Merck Index 14th ed 2 Pharmaceutical Codex 12th ed

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

2 4 route s of synthesis
2.4 Route(s) of synthesis
  • See Guideline on APIMF procedure on the PQ website
    • Some notes at end of session
  • Recommended reference document
    • ICH guideline Q7: Good manufacturing practice guide for active pharmaceutical ingredients
2 4 route s of synthesis33
2.4 Route(s) of synthesis


The synthesis should

  • lead to the correct structure, stereochemistry andpolymorphic form & particle size (if relevant)
  • be well controlled, with critical steps validated (GMP)
  • produce an API which consistently meets acceptable standards of qualityand safety, including limits of impurities
    • organic & inorganic impurities, residual solvents and
    • proof of TSE safety
2 4 1 synthesis of apis non pharmacopoeial detailed
2.4.1 Synthesis of APIsNon-pharmacopoeial (detailed)
  • A flow diagram of process, including e.g.
    • structures (starting materials & intermediates), reagents, catalysts, solvents
  • A full description of each step in the process, including
    • reaction conditions, purification, reprocessing, quantities, batch size
    • in-process controls, critical steps (to be validated)
  • Discussion of (possible) process impurities
    • Organic, residual solvents and catalysts / inorganic
  • Description of alternative processes
    • demonstrate that impurity profile remains unchanged
2 4 1 synthesis of apis non pharmacopoeial continued
2.4.1 Synthesis of APIsNon-pharmacopoeial (continued)
  • Provide specifications for
    • starting materials and intermediates (if isolated)
    • reagents, solvents & catalysts
  • 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)

Limit impurities in the API (matter of safety)

2 4 2 synthesis of apis pharmacopoeial
2.4.2 Synthesis of APIsPharmacopoeial
  • An brief outline of synthesis
    • a flow chart and a brief description of the manufacturing method, including names of solvents, reagents and catalysts
  • Information on the final steps of synthesis, including
    • purification and crystallization procedures
  • Declaration on use/non-use of TSE risk materials

If a valid CEP is submitted

    • No information required
2 4 route s of synthesis37
2.4 Route(s) of synthesis
  • Class 1 solvents should not be used in the manufacture of APIs, excipients, & products unless unavoidable and justified (ICH QC3)
  • Example: Manufacture of ethambutol hydrochloride
    • 1,2-dichloroethane used as reagent (not as solvent)
    • Must form part of API specifications, limit 5 ppm (no skip testing)
2 5 1 specifications non pharmacopoeial apis
2.5.1 SpecificationsNon-pharmacopoeial 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(R2)
    • residual solvents according to ICH Q3C(R3)
  • Analytical methods with validation [ICH Q2(R1)]
  • Preparation and potency determination/specification of primary and secondary (working) standards, with CoAs

Provide valid CoAs for at least 2 batches

2 5 specifications reference standards
2.5. SpecificationsReference standards

Primary and secondary standards

  • General guidelines for the establishment, maintenance and distribution of chemical reference substances (Revision)
    • WHO, Technical Report Series 943 (2007)
      • Annex 3
2 5 specifications reference standards40
2.5. SpecificationsReference standards

PhInt chemical reference substances

  • International Chemical Reference Substances (ICRS)are established and maintained on the advice of the WHO Expert Committee on Specifications for Pharmaceutical preparations
  • International Infrared Reference Spectra
  • WHO Collaborating Centre for Chemical Reference Substances (Apoteket AB, Centrallaboratoriet, ACL Prismavägen 2,SE-141 75 Kungens Kurva, Sweden)
    • Fax: (+) 46 8 740 60 40
    • Email:
2 5 1 specifications non pharmacopoeial apis typical set of specifications
2.5.1 Specifications: Non-pharmacopoeial APIsTypical set of specifications
  • Appearance/description
  • Identification (at least one specific, e.g. infrared spectrum)
  • Moisture content or LOD(moisture + residual solvents)
  • Impurities
    • Related organic substances (synthesis and degradation)
      • specified (identified and unidentified), including optical isomers
      • 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 specifications pharmacopoeial apis
2.5.2 SpecificationsPharmacopoeial APIs
  • Name the monograph and include copy thereof
    • The current monographalways applicable
  • Additional critical specifications not included in monograph e.g.
    • particlesize & polymorphic form
    • impurities, resulting from specific synthesis process
      • which may be additional to monograph, with
        • additional analytical method, validated
    • residual solvents (specific to process)
  • Provide valid CoAs for at least 2 batches
2 7 stability testing
2.7 Stability testing

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
section 2 submission of data on api certification of suitability cep option
Section 2. Submission of data on APICertification of Suitability (CEP) option
  • Issued by EDQM (European Directorate for Quality of Medicines) for substances described in the
  • 2 types of CEPs
    • Quality CEP and TSE CEP
  • A quality CEP certifies that
    • the quality of the substance is suitably controlled according to the PhEur by applying the analytical methods described in the PhEur monograph
      • supplemented by those appended to the CEP
cep continued information on quality cep
CEP (continued)Information on quality CEP
  • CEP certificate number
  • Name of substance and particulars of CEP holder and manufacturing site
  • That the substance is suitably controlled by the monograph in the specified PhEur edition
  • Any additional tests not in PhEur monograph with appended methods, e.g.
    • Impurities, residual solvents with limits
      • These tests are compulsory for control of the substance
  • May state the retest date, and storage requirements
  • Date of validity of CEP
  • Declaration of access (FPP manufacturer)
section 2 submission of data on api api master file apimf option
Section 2. Submission of data on APIAPI Master File (APIMF) Option
  • Procedure implemented since January 2007,
  • To protect the "know-how" of the manufacturer of the API
    • While giving the full information on manufacture of the API to the WHO PQ team of assessors
    • While giving a part of the information to the applicant to Prequalification/ manufacturer of the finished product
  • An APIMF is composed of
    • Applicant's (Open) Part & Restricted (Closed) Part
  • API manufacturer should provide the FPP applicant with
    • Applicant's part of APIMF + Letter of access
apimf option continued
APIMF Option (continued)
  • API manufacturer should submit to the WHO PQ team
    • the Applicant's + Restricted Part + Letter of access to WHO team
    • An APIMF is to be submitted onlyin support of a FPP dossier
  • An APIMF is not an independent dossier of API
  • Scope only open to APIs
    • pharmacopoeial and non-pharmacopoeial
  • The content of an APIMF
    • See Annex 1 of the APIMF guide for content
    • Corresponds to data required in section 2 of the prequalification quality dossier
      • without difference between pharmacopoeial and non-pharmacopoeial APIs
closing remarks
Closing remarks
  • The data submitted must demonstrate that the API is suitable for usein production of the FPP with respect to safety, efficacy & quality
  • The chemical & physical properties must be well understood, e.g.
    • stability (re-test period), hygroscopicity, crystal properties & 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
  • APIspecifications should fully control the API with respect to:
    • identity
    • impurities (organic, inorganic, residual solvents, TSE)
    • content (assay)
    • physical attribute (solvates, polymorphic form, particle size, …)