Download Bergström_Regulatory Biopharmaceutics 2017

Regulatory Biopharmaceutics
Christel Bergström
Institutionen för farmaci, Uppsala Universitet
Biopharmaceutical input to regulatory
documentation
• Clinical trial submissions
– New pharmaceutical form or excipient
– Changes in dosage form, formulation or manufacturing
process from previous studies
• Submissions for marketing authorisation
– Formulation development
– Absorption characterisation
– Generics: Demonstration of bioequivalence with the
originator is pivotal
• Post approval changes
– E.g. changes in formulation or manufacturing
• Scientific advice during drug development
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BIOPHARMACEUTICAL INPUT TO
NEW APPLICATIONS
Regulatory documentation
• Dossier for a new application should contain
– Module 1: Administrative
– Module 2: Summaries (quality, non-clinical and clinical)
– Module 3: Quality
– Module 4: Non-clinical
– Module 5: Clinical
•
•
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Pharmacokinetics
Pharmacodynamics
Efficacy
Safety
Biopharmaceutics
 Overall benefit/risk evaluation: The drug should be effective, safe
and have adequate labelling!
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Biopharmaceutical documentation – new
application
• A new application may be e.g. a new active substance,
new pharmaceutical form or a generic.
•
Biopharmaceutical documentation:
1. Formulation development
2. Absorption characterisation
a.
b.
c.
d.
Bioavailability, bioequivalence
Permeability and drug transporters
Food effects
Drug-drug interactions affecting absorption
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1. Formulation development
• Overall view of the formulation development from initial
concept to final formulation. Approach and rationale.
• Identify factors that may affect in vivo performance.
– Drug substance (e.g. solubility, particle size, crystal
properties).
– Excipients (e.g. stability, bioavailability).
– Manufacturing process.
• Summarize in vitro and in vivo studies.
• Justification for specification limits; e.g. dissolution
• In vitro in vivo correlation (IVIVC).
• Example moving from IR to ER tablet
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2 a. Absorption; Bioavailability/Bioequivalence
• Absolute bioavailability
– New formulation vs. IV (e.g. tablet vs. IV-solution)
– Useful in characterisation of elimination pathways.
• Important to know how the drug is eliminated to predict
exposure in subgroups of patients (e.g. renal or hepatic
impairment) and DDIs.
– Useful in the BCS-classification
• Relative bioavailability
– New formulation vs standard formulation (e.g. tablet vs.
capsule)
– Evaluate possible differences  are clinical studies
necessary?
• Bioequivalence
– Proof of absence of a significant difference
– Bridge between different formulations
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2 b. Absorption; Permeability & drug transporters
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•
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Evaluation usually in Caco-2 cells.
Is there evidence of active transport?
Which transporters are involved?
Influx vs. efflux?
If active transport is relevant  in vivo DDI studies with
known transport inhibitors.
• Is the drug itself an inhibitor?
• Ex of IR vs ER; no need for studies if same dose
strength is used (knowledge based on IR applies)
 Understand PK and assure adequate labelling. Part of
the puzzle in the BCS-classification.
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2 c. Absorption; Food effects
• Evaluation of effects of food on rate and extent of absorption
in vivo is mandatory for a new drug.
• High-fat, high calorie meal vs fasting.
• If significant food effect  test lighter meals.
• Recommended to be evaluated early  ensure optimal food
recommendations in phase III.
• May be necessary to re-evaluate if the formulation is changed
during development.
• Food effect substance or formulation dependent?
• Risk of formulation dependent food effects for low solubility
drugs.
 Ensure optimal administration in phase III.
 Ensure optimal labelling.
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2 d. Absorption; Drug-drug interactions
• Is solubility, dissolution or absorption affected by other
drugs?
• Effect of increased GI pH?
– In vitro pH-dependent solubility or dissolution?
 In vivo study with e.g. proton pump inhibitor (PPI).
• Risk of complex binding (e.g. Ca)?
• Interaction with inhibitors of uptake or efflux
transporters?
• What happens if the formulation is changed?
 Ensure optimal labelling.
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BIOEQUIVALENCE (BE)
What is bioequivalence?
Two medicinal products containing the same active substance are considered
bioequivalent if they are pharmaceutically equivalent or pharmaceutical
alternatives and their bioavailabilities (rate and extent) after administration in
the same molar dose lie within acceptable predefined limits (EMA guideline).
Similar exposure  Similar efficacy and safety!
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Why bioequivalence studies?
MS4
Phase I
Phase II
Phase III
•
•
•
•
Market
Bridging instead of conducting new efficacy and safety studies.
Bridge between pivotal clinical trial formulation (Phase III) and commercial
formulation.
Bridge between generic and originator.
Post approval changes (formulation, manufacturing).
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Bioequivalence study
• Two-way crossover study
• Single-dose (IR)
Test
– For ER: also multiple-dose
Ref
• Healthy volunteers, n ≥ 12
• Standardised conditions
• Blood sampling  plasma conc time profile
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BE-study: Parameters to be analysed and
acceptance criteria
• AUC and Cmax (and Cmin for PR-formulations)
– 20% difference allowed
– 90% CI for test/reference-ratio within 80.00-125.00%.
• Tmax
– Compared if rapid release important for efficacy or safety.
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What does a 20% difference mean?
• The accepted difference is not expected to lead to a
clinical relevant difference in efficacy or safety.
– Often a flat relationship between plasma concentration
and effect  20% difference in plasma conc  less
difference in effect.
– There is always a natural variability. Plasma conc differ
from e.g. day to day also when the patient use the
same drug product.
– Batch-to-batch variability for all drugs.
• The BE-study is a comparison in a group of subjects.
Individual differences cannot be excluded.
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Consequences of pivotal BE failure
• Reasons for failure
– Study inadequately powered?
– Outliers?
– False negative results (type 2 error)
– True difference between products.
• Generics
– Not approved unless BE is shown.
– Additional BE-studies may be needed. Consider all data. Failed
studies cannot be ignored.
• Commercial vs phase III formulation
– Strict BE not always needed.
– Clinical consequences?
– PK/PD relationship?
– Reformulation?
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IN VITRO STUDIES AS
BIOEQUIVALENCE SURROGATES
Biopharmaceutics Classification System (BCS)
I
II
85% / High
Fraction abs. (%)
/ Permeability
• Gastric emptying
-> absorption
III
. Permeability
-> absorption
• Solubility / Disso
-> absorption
IV
• Perm. / Solu. /Disso
-> absorption
250 ml
Volume to dissolve highest dose strength, pH 1-6.8
• Useful ”tool” that indicates what the rate limiting step in
the overall absorption process is.
 Can be used to get a Biowaiver, i.e. regulatory permission to
perform bioequivalence studies in vitro instead of in vivo.
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BCS-based biowaiver
• Applies for IR, solid pharmaceutical products for oral administration
and systemic action.
• Not allowed for narrow therapeutic index drugs.
• Applicable for BCS-class I and BCS-class III drugs.
• BCS I (high solubility, complete absorption):
– Very rapid (>85% in 15 min) or similarly rapid (85% within 30
min) in vitro dissolution.
– No difference in excipients that may affect bioavailability.
• BCS III (high solubility, limited absorption):
– Very rapid in vitro dissolution (>85% in 15 min).
– No difference in excipients that may affect bioavailability.
– Other excipients qualitatively the same and quantitatively very
similar.
* Biowaiver = exemption of conducting a BE-study in vivo.
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In vitro in vivo correlation (IVIVC)
• A mathematical model describing the relationship between an
in vitro property of a dosage form (e.g. dissolution or drug
release) and a relevant in vivo response (e.g. drug plasma
concentration or amount absorbed).
• Relevant when the formulation controls the rate of
appearance of drug in plasma.
• The most useful level for regulatory purposes is the Level A
correlation (prediction of the entire concentration-time profile)
• May reduce the number of in vivo studies during product
development (e.g., bioequivalence studies), be helpful in
setting specifications and be used to facilitate certain
regulatory decisions (e.g., scale-up and post-approval
variations)
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POST-APPROVAL CHANGES
Post-approval changes
• Post-approval changes may include:
– Composition
– Site of manufacture
– Scale up/Scale down batch size
– Manufacturing process
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EU requirements, post-approval changes
• Three types of procedures (levels) of variations: IA, IB and II
• IA: Unlikely to have impact on formulation quality and
performance
– Example: Change in composition of colouring system
• IB: May have some impact on quality and performance
– Example: Change in break lines intended to divide into equal
doses
• II: May have significant impact on quality and performance
– Example: Change in coating weight of MR dosage form
• Conditions to be fulfilled and documents to be
supplied are clearly defined for each specific
variation.
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EU requirements, Type IA variation
• Example: Increase or reduction in colouring system.
IA
– Conditions, e.g.:
• No change in disintegration/dissolution profile
• Minor adjustment of formulation to maintain total weight
should be made by ingredient which currently makes up
a major part of the formulation
– Documentation, e.g.:
• Declaration that stability studies have been started under
ICH conditions
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EU requirements, Type IB variation
• Example: Replacement of single excipient with
comparable excipient with the same functional
characteristics and at similar level. IB
– Documentation, e.g.:
• Justification for the change
• Comparative dissolution profile data for at least pilot
scale batches
• Justification for not submitting a new BE study according
the guidelines
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EU requirements, Type II variations
• Larger changes
• A Type II variation often need a BE study, unless:
– Biowaiver
– IVIVC
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GUIDANCE FOR INDUSTRY
IR SOLID ORAL DOSAGE FORMS
SUPAC, FDA
Scale Up and Post-Approval Changes
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Purpose of SUPAC guidance
• Changes during postapproval for solid oral IR product:
– Composition
– Site of manufacture
– Scale up/Scale down batch size
– Manufacturing process
• Can also be used as guide during the late stage
development process
– When do we need a Bioequivalence study?
– When is it enough with in vitro dissolution bridging?
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SUPAC. Three levels of changes:
Level 1-3 (Similar to EU)
• Level 1: Changes unlikely to have impact on formulation
quality and performance.
• Example: small changes of colour or printing ink.
• Level 2: Changes that could have significant impact on
formulation quality and performance.
• Example: Change of amount lubricant (e.g. Mg stearate) <
0.5% of total weight.
• Level 3: Changes that are likely to have significant
impact on formulation quality and performance.
• Example: change in amount of lubricant during scale up >
0.75%
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