Transcript Basic Principles of GMP - World Health Organization

Pharmaceutical Development with Focus
on Paediatric formulations
WHO/FIP Training Workshop
Hyatt Regency Hotel
Sahar Airport Road
Andheri East, Mumbai, India
28 April 2008 – 2 May 2008
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Slide 1 of 25
Dr Rägo
28 April – 2 May 2008
Biopharmaceutical Classification System
(BCS)
Presented by:
Lembit Rägo MD, PhD
Contact details:
Dr Lembit Rägo
Coordinator,
Quality Assurance and Safety: Medicines
Medicines Policy and Standards
World Health Organization
Geneva
Switzerland
E-Mail: [email protected]
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Slide 2 of 25
Dr Rägo
28 April – 2 May 2008
Biopharmaceutical Classification System (BCS)
 Background
 What is a problem?
 What is WHO doing and planning to do?
 What resources are available?
 Conclusions
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Slide 3 of 25
Dr Rägo
28 April – 2 May 2008
What is the key for multisource (generic)
pharmaceutical products?
 New medicines – applicant has to prove quality, safety
and efficacy
 Multisource (generic) pharmaceutical products – applicant
has to prove quality, in case of safety and efficacy it refers
to the originator product
 The key is THERAPEUTIC INTERCHANGEABILITY
– It is assumed that if the concentration pattern in the blood is
essentially the same then the safety and efficacy profile must
be essentially the same
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Dr Rägo
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Therapeutic interchangeability: prerequisites
 Constant and reproducible quality of MPPs
– Manufactured under GMP
– Compliance with all quality specifications
 Variations control
 No constant and reproducible quality, no need for proving
interchangeability as it is meaningless (all batches
different anyhow…)
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Slide 5 of 25
Dr Rägo
28 April – 2 May 2008
Options to show therapeutic interchangeability of
multisource pharmaceutical products (MPP)
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Sensitivity/use
Experimental setting
Generally regarded as most sensitive
Comparative pharmacokinetic studies in
humans – evaluation of systemic exposure by
means of pharmacokinetic measures like e.g.
AUC and Cmax (and Tmax)
Prerequisites should be noted
Comparative in vitro tests – BCS-based
biowaiver
Sensitivity may not be optimal, rarely
used
Comparative pharmacodynamic studies in
humans – evaluation of relevant
pharmacodynamic endpoints like e.g., lowered
blood pressure in mm Hg
Rarely used for oral MPP formulations
with systemic actions
comparative clinical trials – evaluation of e.g.,
non-inferiority trials
Slide 6 of 25
Dr Rägo
28 April – 2 May 2008
The in vitro approach refers to the Biopharmaceutics
Classification System (BCS)
Drug substance classification according to the BCS. Active
pharmaceutical ingredients (APIs) are classified into classes based on
their aqueous solubility and permeability characteristics
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BCS classification
Solubility
Permeability
BCS class I
High
High
BCS class II
Low
High
BCS class III
High
Low
BCS class IV
Low
Low
Slide 7 of 25
Dr Rägo
28 April – 2 May 2008
In Vitro Approaches/Biowaiver options
 The possibility of ‘in vitro documentation of bioequivalence’ for
‘certain medicines and dosage forms’ is specified in Section 9 of
the WHO guidance document [1].
 If the drug substance in question is highly soluble and highly
permeable (BCS class I) and is manufactured as an immediate
release dosage form, exemption from an in vivo pharmacokinetic
bioequivalence study may be considered provided that relevant
dissolution requirements are fulfilled.
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Slide 8 of 25
Dr Rägo
28 April – 2 May 2008
Principles
 The solubility is not meant to be the absolute solubility here. In
contrast high solubility refers to the highest single unit dose to be
completely soluble in 250 ml aqueous buffer medium within the pH
range of 1.2 to 6.8 without any stability problems.
 As another related physicochemical characteristic high permeability
should be demonstrated for the particular API demonstrating that
the fraction dose absorbed amounts to at least 85 %. Accordingly,
high permeability would stand for almost complete absorption of the
compound in humans.
 Physicochemical measures needed for BCS classification purposes
may be taken from sound literature. The WHO Model List of
Essential Medicines has been reviewed based on the BCS concept
and active compounds are classified accordingly in the appendix of
respective WHO document [1].
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Slide 9 of 25
Dr Rägo
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A theoretical risk assessment is mandatory to minimize risk for
falsely waiving a necessary in vivo study
Situations where BCS-based biowaivers are not applicable
Immediate release dosage forms with
intended systemic action
Formulation related considerations
- critical use medicines (e.g. hormones)
- non-oral, non-parenteral products with
systemic action (e.g. transdermal therapeutic
systems (TTS), suppositories, etc.)
- narrow therapeutic range (steep doseresponse curve) drugs
- modified release products with systemic
action
- where there are documented evidence of
- fixed combination products with at least
bioavailability problems (or bio-inequivalence one API requiring an in vivo study i.e., this
API is not eligible for the BCS based
biowaiver approach
- polymorphs, certain excipients, or a
manufacturing process which may have
implications for bioavailability
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Slide 10 of 25
Dr Rägo
28 April – 2 May 2008
- non-solution products with non-systemic
action (and without systemic absorption*),
e.g., topical, locally acting emulsions
Assessment of risks – practical points
 In practice some of the criteria listed in the table for risk
assessment are difficult to assess e.g., the meaning of
‘critical use’ or ‘bioavailability problems’, and are probably
not easy to be defined.
 However, published literature provides valuable examples
of how to evaluate the applicability of the BCS based
biowaiver approach (see biowaiver monographs on the
following slide).
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Slide 11 of 25
Dr Rägo
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Available resources: Biowaiver Monographs
 Biowaiver monographs are worked
out by group of well established
scientists linked to FIP and published
in Journal of Pharmaceutical
Sciences

These can be useful scientific
material for manufacturers when
considering applications for biowaiver
based on BCS
 The monographs as such have no
"regulatory authority" – decisions will
be made by regulators who may or
may not accept biowaiver depending
on their national legislation and
requirements
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Slide 12 of 25
Dr Rägo
28 April – 2 May 2008
Biowaiver monographs published
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Stosik A.G., Junginger H.E., Kopp S., Midha K.K., Shah V.P., Stavchansky S.,
Dressman J.B., Barends D.M.: Biowaiver monographs for immediate release
solid oral dosage forms: metoclopramide hydrochloride. J Pharm Sci Feb 12
(2008)
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Becker C., Dressman J.B., Amidon G.L, Junginger H.E., Kopp S., Midha K.K.,
Shah V.P., Stavchansky S., Barends D.M.: Biowaiver monographs for
immediate release solid oral dosage forms: Pyrazinamide. J Pharm Sci Feb 12
(2008)
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Becker C., Dressman J.B., Amidon G.L, Junginger H.E., Kopp S., Midha K.K.,
Shah V.P., Stavchansky S., Barends D.M.: Biowaiver monographs for
immediate release solid oral dosage forms: ethambutol dihydrochloride. J
Pharm Sci Aug 21 (2007)
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Becker C., Dressman J.B., Amidon G.L, Junginger H.E., Kopp S., Midha K.K.,
Shah V.P., Stavchansky S., Barends D.M.:Biowaiver monographs for immediate
release solid oral dosage forms: isoniazid. J Pharm Sci 96 (2007) 522-31
Slide 13 of 25
Dr Rägo
28 April – 2 May 2008
WHO Guidance (1)
 The in vitro dissolution investigations including experimental
conditions and characteristics are outlined in Section 9 of the WHO
guideline [1].
 It is of utmost importance to note that it is not sufficient to
demonstrate the in vitro dissolution characteristics for the particular
multisource product, but to ensure ‘the similarity of dissolution
profiles between the test and comparator products’ [1].
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WHO guidance (2)
 The WHO guidance in basic aspects is similar to the US FDA
guidance on the biowaiver approach (August 2000)
 In addition, the current scientific discussions in terms of so called
‘biowaiver extensions’ are also considered. Accordingly, BCS based
biowaivers may be acceptable for drugs containing BCS class 2
and 3 drug substances manufactured as immediate release dosage
forms.
 As an example, a biowaiver may be possible for BCS class 3 drug
products that are ‘very rapidly’ (i.e. at least 85 % dissolution within
15 min in all required media) dissolving. The relevant dissolution
criteria are outlined in section 9.2.1 of the WHO guideline [1].
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Regulators guidance for industry
 US FDA relevant to biowaiver
guidelines:
www.fda.gov/cder/Guidance/3618f
nl.pdf
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Dr Rägo
28 April – 2 May 2008
Conclusions
 Biowaiver concept is a developing concept and new guidance
documents and scientific data are appearing
 Proper comparator products are also crucial for biowaiver
 Regulatory acceptance and practice of biowaivers needs to catch
up the concept development
 WHO will soon issue more practical implementation guidelines for
PQ programme
 WHO PQ programme starts accepting biowaivers, as appropriate
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Slide 17 of 25
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Some useful references
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(1) Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish
interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations,
Fortieth Report. Geneva, World Health Organization, 2006, WHO Technical Report Series, No. 937,
Annex 7: 347-390.
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(2) van Faassen F., Vromans H. et al. Biowaivers for oral immediate-release products: implications of
linear pharmacokinetics. Clin Pharmacokinet 43 (2004) 1117.
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(3) Note to Applicants on the Choice of Comparator Products for the Prequalification Project. Located
on the World Health Organization (WHO) Prequalification of Medicines web site, Guidance on selection
of comparator product. Web page: http://healthtech.who.int/pq/
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(4) Shah, V.P. et al. Bioanalytical method validation – a revisit with a decade of progress.
Pharmaceutical Reseach, 17 (2000) 1551-1557.
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(5) Schuirmann, D.J. A comparison of the two one-sided tests procedure and the power approach for
assessing the equivalence of average bioavailability. Journal of Pharmacokinetics and
Biopharmaceutics, 15 (1987) 657-680.
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(6) Westlake, W.J. Bioavailability and bioequivalence of pharmaceutical formulations. In: Peace, K.E.
ed. Biopharmaceutical statistics for drug development. New York, Marcel Dekker, Inc., 1988: 329-352.
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(7) Guidelines for registration of fixed-dose combination medicinal products. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations, Thirty-ninth report. Geneva, World
Health Organization, 2005 (WHO Technical Report Series, No. 929, Annex 5): 94-142.
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Dr Rägo
28 April – 2 May 2008