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Demonstration of bioequivalence for TB medicines . Milan Smid, MD, PhD. Tutorial: Quality of Pharmaceutical Ingredients, TB medicines, Beijing, 31 March, 2010.

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Demonstration of bioequivalence for TB medicines

Milan Smid, MD, PhD

Tutorial: Quality of Pharmaceutical Ingredients, TB medicines, Beijing, 31 March, 2010

Although medicines may contain same active ingredient in the same strength and dosage form, after administration to the organism due to pharmaceutical differences the release and absorption of active moiety may be different. Therapeutic effect is different.
  • In vitro tests provide valuable information but are not necessarily a reliable guide to the bioavailability or therapeutic performance of the product.
  • The same principles valid for TB medicines

Pharmaceutical Equivalent




Possible Differences

Drug particle size, ..


Manufacturing process


Site of manufacture

Batch size ….

Documented Bioequivalence

= Therapeutic Equivalence

(Note: Generally, same dissolution specifications)

demonstration of bioequivalence
Demonstration of bioequivalence

Bioequivalence study


PD studies



In vitro



general requirements for tested product
General requirements for tested product
  • GMP
  • batch size
    • pilot batch
    • commercial batch
  • not smaller than 100 000 units or 10 % of industrial batch size (whichever is higher)
  • difference regarding the content of the investigative products (T and R) should preferably not be more than 5 %
  • strength with the largest sensitivity to detect differences in the two products
pq recommended comparator products for selected tb medicines
PQ recommended comparator products for selected TB medicines
  • Market selection
    • Purchased from a well regulated market with stringent regulatory authority
  • Information requirements
    • Labelling, invoice from distributor, shipment, authenticity statement
  • Dose equivalence
  • Fixed dose combination products
    • Testing also possible with corresponding mono-component comparators
  • Suitability of a comparator products for BCS-based biowaiver applications
  • Other comparators must be justified. Recommended to consult WHO
bioequivalence study design
Bioequivalence study design
  • Single dose
  • Two period
  • Crossover
  • Healthy volunteers
  • WHO can provide advice on planned design
  • Specific guidance on conduct of BE for TB medicines is under preparation
analytical methods
Analytical methods
  • FDA Guidance for Industry
    • Bioanalytical method validation, May 2001
  • ICH Guidance for industry
    • Validation of analytical methods: definitions and terminology, June 1995
    • Validation of analytical procedures: methodology, November 1996
quality of bioequivalence studies
Quality of Bioequivalence Studies

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trials subjects are

protected, consistent with the principles

that have their origin in the Declaration

of Helsinki, and that the

clinical trial data are credible.

btif bioequivalence trial information form
BTIFBioequivalence Trial Information Form

Information for Applicants

Generics, ANNEX 7:

Presentation of Bioequivalence Trial Information

possibility of biowaiver
Possibility of biowaiver
  • General notes on biowaiver applications
  • "Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability". In: Fortieth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. Geneva, World Health Organization. WHO Technical Report Series, No. 937, 2006, Annex 7.
    • FDA - Guidance for Industry: “Waiver of in vivo bio-equivalence studies for immediate release solid oral dosage forms containing certain active moieties/active ingredients based on a Biopharmaceutics Classification System” (2000)
    • EU-guidance:“Note for Guidance on the Investigation of Bioavailability andBioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1
biowaivers for tb medicines 1
Biowaivers for TB medicines /1
  • Biopharmaceutics Classification System (BCS)-based biowaiver applications: anti-tuberculosis medicines
  • Eligible for biowaiving:
  • Biowaivers possible only under specified circumstances

Ethambutol (BCS 3), Isoniazid (BCS 3/1), Pyrazinamide (BCS 3/1)

Levofloxacin (BCS 1), Ofloxacin (BCS 1)

biowaivers for tb medicines 2
Biowaivers for TB medicines /2
  • Only for mono-component formulations
  • Highest strength acceptable:
    • Ethambutol 400mg
    • Isoniazid 300mg
    • Pyrazinamid 400mg
  • Same excipients as comparator
  • The test product formulation is quantitatively very similar to that of the comparator product
    • ‘very similar’ is defined as per ‘Level 1 Changes’ according to the SUPAC (Scale-Up and Postapproval Changes, US FDA) guidance
    • Lactose and other 'reducing sugars' should be avoided, unless in the same amount as in the comparator
biowaivers for tb medicines 3
Biowaivers for TB medicines /3
  • In vitro dissolution is at least 85% within 15 minutes for both the test and comparator products. At least 85% dissolution up to 30 minutes is acceptable, if the dissolution profiles are similar and composition of test product is very similar to comparator.
  • Rifampicin products are not acceptable for biowaiver
    • BCS class 2
    • Problematic physicochemical properties
  • Recommended comparator must be suitable
    • Dissolution at least 85% in 15, respectively 30 minutes
    • Unsuitable comparator for biowaiver may still be acceptable for BE study
bcs based biowaiver application form
BCS-based Biowaiver Application Form

Designed to facilitate information exchange between the Applicant and the WHO Prequalification of Medicines Programme if the Applicant seeks to waive bioequivalence studies, based on the Biopharmaceutics Classification System (BCS).

For further information, please study the respective WHO biowaiver guidance documents. This form is not to be used, if a biowaiver is applied for additional strength(s) of the submitted product(s), in which situation a separate "Biowaiver Application Form: Additional Strengths" should be used.