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Evaluation of quality and interchangeability of medicinal products Training workshop for evaluators from National Medicines Regulatory Authorities in East Africa Community 10-14 September 2007, Dar Es Salaam, Tanzania. Presented by Rutendo Kuwana. Active pharmaceutical ingredients.

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presented by rutendo kuwana

Evaluation of quality and interchangeability of medicinal productsTraining workshop for evaluators from National Medicines Regulatory Authorities in East Africa Community10-14 September 2007, Dar Es Salaam, Tanzania

Presented by

Rutendo Kuwana

Active pharmaceutical ingredients

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)

presentation approach
Presentation approach

Collect and interpret available information on the APIs (pre dossier studies), such as:

  • Literature, all aspects (chemical/physical)
  • Monographs in pharmacopoeia (example: ARVs)
some definitions
Some definitions


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 2
Some definitions (2)

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 api
Available information on API

Applicants should collect and analyse available information of the API in 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
literature information on api
Literature 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
information from literature structure rifampicin
Information from literature & structure: Rifampicin

hydrolysis (to 25-desacetyl)


(to quinone) (to 3-formyl)

Oxidation to N oxide

light sensitive

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


  • 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)


  • 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 - reacts with aldehydes/lactose
  • see presentation: FPPs – formulation problems?
  • Can hydrolyze under stress conditions to e.g. 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


  • 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
Literature support

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)
  • Photocopies of publication or relevant pages
properties of apis
Properties of APIs


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

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

Information from literature (important)

properties non compendial apis
Properties: non-compendial APIs
  • 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 spectral data from peer reviewed literature, preferable innovator publication (in tabulated form!!). Strongly recommended
  • Physico-chemical properties
properties compendial apis
Properties: 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
      • See Nevirapine (later in this presentation)
    • Hygroscopicity e.g. Ethambutol hydrochloride in FDC tablet
    • Particle size
properties for compendial apis example solubility of tb apis
Properties for 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 for safety reasons

properties apis example solubility protease inhibitors mg ml
Properties APIsExample: solubility protease inhibitors(mg/ml)

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

properties compendial apis pseudo polymorphism nevirapine
Properties Compendial APIsPseudo-polymorphism nevirapine

Int. Ph. monograph Nevirapine (anhydrous & hemihydrate)

  • Identification test C

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
properties compendial apis pseudo polymorphism nevirapine 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


The reaction is not reversible at room temperature

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
route s of synthesis
Route(s) of synthesis


  • API not described in BP, Int.Ph., JP,Ph.Eur., or USP(non-compendial APIs)
  • Specifications of raw materials and intermediates used in the synthesis of non-compendial APIs
  • 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
  • Is a valid CEP is available? - no synthesis information required. CEP must however have all appendices and applicant to submit other info not covered by CEP
  • 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 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

synthesis non compendial apis
Synthesis 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
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 (Safety reasons)

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 material


  • 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 Agency


chemical synthesis
  • Indinavir is a chiral molecule with 5 stereogenic centers
  • Only stereoisomer observed in the API is the 4-(R)-epimer.
  • It is stereoselectively prepared in six steps.
  • The enantiomeric purity of the API and other ingredients is ensured by the route of manufacture and quality control on intermediate products (starting materials and intermediate indinavir free base) rather than a test for specific rotation.
chemical equivalence 1
  • The stereochemistry is well under control during the synthesis
  • Racemization after the synthesis is extremely unlikely
  • Formation of epimers cannot be excluded but should be detectable by the purity tests applied.
  • Potential impurities from synthesis, stereoisomeric impurities and degradants have been identified. Minimised or removed by control on the reaction parameters and in-process controls
  • High humidity, which leads to formation of degradants, is avoided.
chemical equivalence 2
  • The API is very pure
  • The limit for any single impurity is not more than 0.1 %
  • limit for the sum of all impurities is not more than 0.5 %
  • Due to the high doses to be given in clinical use (> 2 g/day), the qualification threshold as defined in the ICH guideline on impurities, is 0.05 %.
physicochemical equivalence

Indinavir Sulfate Ethanolate

  • Freely Soluble In Aqueous Solutions
  • PARTICLE SIZE Not Critical
  • Relatively Loose Bulk Density
api stability tests
  • Indinavir is highly hygroscopic at relative humidity above 60 %
  • In the presence of moisture and/or elevated temperatures, the API undergoes conversion to an amorphous material or to a hydrate crystal form and to the formation of degradation products i.e. lactone and several unidentified impurities occur
chemical structure38
  • Nevirapine does not contain an assymetric carbon atom (a chiral centre)
  • The nitrogen in position 11 shows weekly basic properties
  • Other functional groups are not very reactive under everyday manufacturing environmental conditions
chemical information

C15H14N4O (anhydrate for tablets)266.30

C15H14N4O·1/2 H2O (hemihydrate

for oral suspension)275.35

CAS number: 129618-40-2

NEVIRAPINE is lipophilic (partition coefficient 83) and is essentially nonionized at physiologic pH. As a weak base (pKa 2.8), NEVIRAPINE is known to be soluble at acidic pH values.

physico chemical information
  • Aqueous solubility (anhydrate) (90 μg/ml at 25°C).
  • NEVIRAPINE anhydrous is a white to off-white crystalline powder.
  • No potential toxicity was found in intermediates found in the synthesis of NEVIRAPINE
  • NEVIRAPINE is milled in order to obtain an acceptable particle size distribution.
specification stability
  • Innovator results showed that Nevirapine is highly stable even under stressed conditions over a 24 month study period
  • No degradants were detected and all the results remained within the specifications.
desk conclusion

Critical API parameters:

  • Particle size of themicronized drug substance
api specifications
API 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 apis
Specifications: 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 apis typical 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 apis
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)
  • Valid CoAs for at least 2 batches required

CEP normally states tests additional to the monograph

    • e.g. residual solvents & impurities
  • Extraneous contaminant (foreign substances)
  • Toxic impurities
  • Concomitant components
  • Signal impurities
classes of impurities
Classes of Impurities
  • Organic
  • Inorganic
  • Residual solvents
organic impurities
Organic Impurities

May arise during manufacturing process and storage

  • Starting materials
  • By products
  • Intermediates
  • Degradation products
  • Reagents, ligands and catalysts
inorganic impurities
Inorganic 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.)

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

  • Identified impurity
  • Unidentified impurity
  • Specified impurity
  • Unspecified impurity
impurity equivalence
  • 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 equivalence55
  • 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 equivalence56

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

stability testing
Stability 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
    • 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 testing forced degradation literature
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, light sensitivity
    • Indinavir sulfate (earlier slide)
      • Intra-molecular reaction – heat, moisture, acid, base
    • Efavirenz (see next slides)
      • Hydrolysis – pH dependent
stress testing forced degradation efavirenz 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)

stress testing forced degradation efavirenz 2
Stress testing (forced degradation)Efavirenz (2)

The data (generated at 60°C) shows that

  • Efavirenz is quite stable
  • Maximum stability at pH 4 (Suspension possible?)
  • Carbon dioxide formation

(30 mg/ml solution, 100 ml bottle:

1% decomposition ≈ 2 ml CO2

important elements
Important 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