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Active Pharmaceutical Ingredients (APIs). Workshop on GMP and Quality Assurance of Multisource Tuberculosis Medicines Kuala Lumpur – Malaysia 21-25 February 2005. Theo Dekker, D.Sc., consultant to WHO Research Institute for Industrial Pharmacy

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active pharmaceutical ingredients apis

Active Pharmaceutical Ingredients (APIs)

Workshop on GMP and Quality Assurance of

Multisource Tuberculosis Medicines

Kuala Lumpur – Malaysia

21-25 February 2005

Theo Dekker, D.Sc., consultant to WHO

Research Institute for Industrial Pharmacy

North-West University, Potchefstroom, South Africa

iiftgd@puk.ac.za

abbreviations
Abbreviations

API Active pharmaceutical ingredient

BP British Pharmacopoeia

CEP EU certificate of suitability

EOI Expression of interest

FDC Fixed dose combination

FPP Finished pharmaceutical product

GMP Good manufacturing practices

ICH International Conference onHarmonization

Int.Ph. International Pharmacopoeia

Ph.Eur.European Pharmacopoeia

SmPC Summary of product characteristics

TB Tuberculosis

USP United States Pharmacopeia

presentation approach
Presentation approach
  • Collect and interpret all available information on the APIs (pre-dossier studies):
    • The possible manufacturer(s)
    • Literature, all aspects
    • Monographs in pharmacopoeia
  • Dossier requirements
    • Nomenclature
    • Properties
    • Manufacturing and site
    • Specifications
    • Container closure
    • Stability testing / re-test period
part 1 available information on api
Part 1. Available information on API
  • Collecting and interpretation of all available information of the API through a systematic approach, should always be done upfront. Some outcomes:
    • Sound choice of API source (manufacturer)
    • Sound scientific understanding of the API, with respect to properties, stability, specifications, etc.
    • Assists in FPP pharmaceutical development
    • Assists in dossier compilation
    • Reduction of time / cost
  • Forms part of Product Profile Report
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?
  • Is the open part of DMF available and according to all requirements?
  • Is a valid CEP available?
  • GMP inspection of API site by FPP manufacturer
literature information
Literature information

Know your API before development, through:

  • Standard works / series / books – such as:
    • (Analytical) Profiles of Drug Substances and Excipients [ed: (Florey) Brittain) – 30 volumes]
    • The Merck Index (for structures, properties)
    • Pharmaceutical Codex (12th edition)
  • Journals through search facilities such as
    • International Pharmaceutical Abstracts, Chemical Abstracts, Analytical Abstracts & internet
  • Pharmacopoeial monographs (current)
  • Analysis of structure & stereochemistry
examples of existing api information in standard works
Examples of existing API information in standard works
  • In the table on the next pages it is indicated in which standard works the APIs, appearing in the 5th invitation for Expression of Interest (TB), is included. Abbreviations:
    • Apr = Analytical Profiles of Drug Substances and

Excipients (contains chapters on APIs)

    • BP = British Pharmacopoeia
    • Cod = Pharmaceutical Codex (12th ed, 1994)
    • EP = Ph.Eur.
    • Int = International Pharmacopoeia
    • US = USP
    • MI = Merck Index (13th ed, 2001)
table of api occurrence con
Table of API occurrence (con.)

Apology: JP was not available at time of preparation

example solubility from 2 literature sources
Example: solubility from2 literature sources

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

information from the structures
Information from the 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
  • It is thus always appropriate to analyse the structure of the API, especially if limited literature information is available
  • Few examples to follow
rifampicin structure
Rifampicin structure

hydrolysis

oxidation hydrolysis

3 formyl rifamycin formation
3-Formyl rifamycin formation

Source: S. Singh et al. Pharm. Pharmacol. Commun., 6, 405-410 (2000)

rifampicin structure and properties
Rifampicin structure and properties

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
rifampicin structure and properties 2
Rifampicin structure and properties (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
isoniazid structure
Isoniazid structure

Small molecule (quite stable)

  • Basic amino functions
  • Primary amine - react with aldehydes/lactose(see presentation: Pharmaceutical R&D Considerations)
  • Can hydrolyze under stress conditions to inter alia isonicotinic acid & hydrazine
  • Oxidize in presence of strong oxidants (e.g. permanganate), with metals as catalyst
pyrazinamide structure
Pyrazinamide structure

Small molecule (quite stable)

  • Basic amino functions (in aromatic ring)
  • Amide group can hydrolyse under strong conditions to pyrazinoic acid & ammonia
  • USP ID test C: Boil 20 mg with 5 ml of 5 N sodium hydroxide: the odor of ammonia is perceptible
  • Forms metal complexes (slight pink bulk API / product?)
  • Sublimes when heated
pyrazinamide synthesis
Pyrazinamide synthesis
  • Reagents: NaOH, water as solvent, touch of EDTA
    • Product directly crystallised from the reaction mixture
    • No residual solvents (only water used)
    • 2-CPZ to be included as a possible synthesis impurity in API specifications
    • EDTA for metal complexation (prevent colouration)
ethambutol hydrochloride structure
Ethambutol hydrochloride structure

Small molecule

  • Basicamino groups (in free base)
  • No vulnerable groups for degradation under mild conditions (2-aminobutanol – synthesis impurity)
  • 2 chiral carbon atoms, optically active (test)
  • Hygroscopic (solubility in water: 50% m/m)
  • Can dissolve in absorbed water at high relative humidity
  • Forms metal complexes
  • USP: Preserve in well-closed containers
p aminosalicylic acid
p-Aminosalicylic acid

+ CO2

  • Carboxylic acid and phenolic group: acidic
  • Weak basic group (amphoteric)
  • Saturated solution: pH of 3.0-3.5 (USP)
  • Sodium salt available (monograph in USP)
  • Labile: Decarboxylatewhen heated
  • Limit test for m-aminophenol in USP (API & tablets)
  • More stable in alkaline medium than in acid medium
  • Store in cool place!!
cycloserine
Cycloserine

R-configuration

  • Optically activeH20
  • Stable in anhydrous solid state, protected from water
  • Degrades in solution, or when solid is exposed to moisture
  • Pathway1: Dimerisation through one molecule attacking other
  • Pathway 2: Hydrolysis to ß-aminoxy-D-alanine
  • Stability: alkaline medium > neutral >> acid medium
  • Dissolution medium capsules: buffer pH 6.8 !!! (USP)
  • Primary amine: react with aldehydes/ketones
ofloxacin moxifloxacin
Ofloxacin Moxifloxacin
  • Structurally related as encircled (see also ciprofloxacin)
  • Both APIs contain acid and basic groups
  • Chirality: both intrinsic chiral (optically active)
    • Ofloxacin: 1 chiral centre: racemate (±) used
    • Moxifloxacin: 2 chiral centra: S,S-enatiomer used
  • Both APIs have enone system (in circle): photosensitive?
amikacin semi synthetic
Amikacin – semi synthetic

Kanamycin

APIs differ only here

4 x NH2 groups, 2H2SO4 salthydrolysis

literature information sources
Literature information sources

The information on the APIs mentioned in the previous slides are backed by inter alia:

  • Analytical Profiles of Drug Substances and Excipients (ed: Florey/ Brittain) (see next slide)
  • The Pharmaceutical Codex: Principles and Practice of Pharmaceutics. 1994. Lund, W., ed. 12th edition, London: The Pharmaceutical Press
  • The Merck Index, 13th edition (2001)
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 the relevant pages
part 2 dossier requirements for active pharmaceutical ingredient api
Part 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 (hand-out)

As from page 3/33

part 2 dossier requirements for active pharmaceutical ingredient api 3 33
Part 2. Dossier requirements for Active pharmaceutical ingredient (API) 3/33

2.1 Nomenclature (INN, Systematic, CAS, etc.)

2.2 Properties (structure, stereochemistry, etc)

2.3 Site of manufacture

2.4 Route of synthesis (impurities, etc)

2.5 Specifications (pharmacopoeia?)

2.6 Container closure system

2.7 Stability testing – re-test period & storage

-

  • Open part of Drug Master File - submit (DMF)
  • CEP (only limited information required)
2 2 properties of apis 3 33
2.2 Properties of APIs 3/33

Three aspects:

2.2.1 API not described in BP, Int.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 (discussed)

  • All the APIs on 5th Invitation for EOI fall in category 2.2.2, except moxifloxacin
2 2 1 properties non compendial apis
2.2.1 Properties non-compendial APIs
  • Structure, stereochemistry, MF and RMM
  • Proof of structure/stereochemistry correctness
    • Single crystal X-ray structure (sufficient) or
    • Spectrometric data (IR, 1H & 13C NMR, MS, etc.) in form of QA certified copies of the spectra and tabulated of data with- assignments against structure or- correlation against API spectral data from peer reviewed literature, preferable by the innovator (in tabulated form!!). Strongly recommended for non-compendial APIs
  • Physico-chemical properties as discussed on next slide
2 2 2 properties compendial apis
2.2.2 Properties compendial APIs
  • Physicochemical and other relevant properties of the API, such as
    • Solubility in water, other solvents such as ether, ethanol, acetone, and buffers of different pH
    • pKa, partition coefficient
    • Existence/absence of polymorphs and pseudo-polymorphs e.g. solvates (with XRPD, DSC, IR)
    • Polymorphism: see presentation Pharmaceutical R&D Considerations (rifampicin)
    • Hygroscopicity: see presentation Pharmaceutical R&D Considerations (ethambutol hydrochloride in 4FDC tablet)
    • Particle size
2 3 sites of manufacture 3 33
2.3 Sites of manufacture 3/33

For each facility where all/part of manufacturing occurs:

  • Name of manufacturer
  • Street address
  • Postal address
  • Phone & fax numbers
  • E-mail addresses
2 4 route s of synthesis 4 33
2.4 Route(s) of synthesis 4/33

Three aspects:

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

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

2.4.3 Specifications of raw materials and intermediates used in the synthesis

2 4 1 synthesis non compendial apis
2.4.1 Synthesis non-compendial APIs
  • A flow diagram of the synthesis process, that includes inter alia chemical structures of starting materials and intermediates, reagents, catalysts, conditions, solvents and purification steps
    • Example: see pyrazinamide synthesis (slide 21)
  • A full description of each process, including purification and reprocessing (justified)
  • (Possible) process impurities should be discussed:
    • Organic compounds
    • Catalysts and other inorganic impurities
    • Residual solvents
2 4 2 synthesis compendial apis
2.4.2 Synthesis compendial APIs
  • Valid CEP available
    • Only outline of synthesis necessary
  • No CEP
    • Same as for non-compendial APIs
2 5 api specifications 4 33
2.5 API specifications 4/33

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

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

General note

An API has only one set of specifications, applicable at release and throughout the re-test period (FPPs may have two sets of specifications)

2 5 1 specs non compendial apis
2.5.1 Specs: non-compendial APIs

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

  • Provide justification for proposed specifications
  • Impurities (synthesis, degradation & residual solvents) to be characterised and limits set
  • 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 2 specs compendial apis
2.5.2 Specs: compendial APIs
  • Additional critical specifications not included in monograph e.g.
    • particle size & polymorphic form
    • synthesis related impurities
    • residual solvents
  • Valid CoAs for at least 2 batches

2.5.3 Container-closure system for API 4/33

    • see guideline
2 7 stability testing 6 33
2.7 Stability testing 6/33

2.7.1 Stress testing (forced degradation)

2.7.2 Stability testing (regulatory)

2 7 1 forced degradation
2.7.1 Forced degradation
  • Literature information and/or CEP in support or to replace studies
  • Forced degradation studies
    • To identify possible degradants for stability studies
    • To verify specificity of stability assay method-Diode array detection for API peak purity!!
    • Different stress conditions in solution (guideline)
    • Different stress conditions in solid state (guideline)
2 7 2 stability testing regulatory
2.7.2 Stability testing (regulatory)
  • Only degradants that form under the real-time and accelerated conditions needs to be considered
  • Stability protocol, particulars of batches (3), tabulated results and discussion of data
  • Typical schedule given under FPPs
  • Propose re-test period when stored under defined conditions
some conclusions
Some conclusions
  • Get to know your API by
    • Analysis of literature information
    • Analysis of the structures / functional groups
    • Lab studies, e.g. forced degradation, spectral data and physical data
    • Considering the dossier requirements
  • Decision on API manufacturer should include
    • DMF quality, GMP inspection, CEP availability
  • API manufacturers are encouraged to apply for CEPs for their APIs