How to Prove Interchangeability of Generic drugs with Originators
Korean Experience
Sang-Aeh Park
Korea Food and Drug Administration
Outline
KFDA Organization
Milestones in BE on Generics : Korea
Guideline for BE on Generics : Korea
Current Issues
KFDA Organization
Milestones in BE on Generics : Korea
1988, Introduction of BE provision 1994, Mandatory submission of BE data or clinical
trial data on generic drugs for new drugs that had been approved since Jan. 1, 1989
2001, Generic Substitution is limited to approved drugs with BE
2005, Expansion to mandatory objects for BE submission
2010, Expansion to combination drugs for BE submission
Guideline for BE on Generics : Korea
BE submission for Generics
Generic products with New drug substance since ’89.1.1
Generic products with one more out of 507 drug substances including other salts and enantiomers designated by KFDA
Criteria for Biowaiver of BE (1)
1. Oral solutionsQuantitatively & Qualitatively Same Drug substances
Excipients don’t affect the absorbance of DS
2. Injections Excipients are Qualitatively Same
Exception ; Differ from following Excipients
Preservatives
Buffering agents
Antioxidents
Criteria for Biowaiver of BE (2)3. Opthalmic and Otic solutions
Excipients are Qualitatively Same
Exception ; Differ from following Excipients
Preservatives
Buffering agents
Substance to adjust tonicity
Thickening agents
4. Locally acting solutions (Topical)
Criteria for Biowaiver of BE (3)
5. The Additional Strengthsby the Same Manufacturing Process
Compositions of the strengths are Quantitatively proportional
Appropriate in vitro Dissolution data
Linear elimination kinetics over the therapeutic dose
(if only higher strength based on BE of Lower strength)
Criteria for Biowaiver of BE (4)
6. Biopharmaceutical Classification Systems (BCS)
High Solubility on Drug substance
High Permeability on Drug substance
Rapid Dissolution Data on Drug products
ExceptionsNarrow Therapeutic Range Drugs
Extended Release Drugs
Sublingual and Buccal Drugs
Test products
Biobatch for pK evaluationAt least 100,000 units
or
Commercial batch
The difference in the content between RLD & Test
product is not more than 5%
or
The difference from Label Content is not more than
5%
Guideline for BE (1)Study Design
Single dose comparison
Non-replicate crossover study
Fasting condition
☞ Extended Release : Fasting & Fed conditionsHigh Fat Diet (900kcal, Fat 35%)
Number of Subjects
More than 24 subjects (12 for each group)
Add on subjects study if insufficient number
Guideline for BE (2)Selection of Subjects
Healthy adult volunteers (19~55 years)
Non-pregnant females
Exclusion of SubjectsWithin 1 month, Subject with a history of metabolism induction like Barbiturates, Heavy alcohol
Within 3 months, Subject with a history of other BE or Clinical study
For 10 days before BE study, Subject having drugs which affect BE
Guideline for BE (3)
Subject Management
Fasting for at least 10 hours prior to medication
Medication with 240mL water
No water is allowed for 1 hour before and after dose
No food is allowed for at least 4 hours post-dose
Similar position and behavior among subjects for 2 hrs after dose
Guideline for BE (4)Sampling times
More than 12 samples, principally
More than 2 samples prior to Cmax
Sampling schedule is enough to provide a reliable estimate of peak exposure
which is achieved if AUC (0→t) covers at least 80% of AUC (0→∞)
which is more than 3 times of Elimination Half life
which is 72hr • If sampling period is longer than 72hr (Half life is long)
• If Intra-subject variability of Distribution and Elimination is low
Guideline for BE (5)
Analytes to measure (in descending order of priority)
Parent drug, principally
Active Metabolite when appropriate
In whole blood, plasma or serum
Guideline for BE (6)
Measures of Rate and Extent of AbsorptionRate of Absorption : Cmax
Extent of Absorption : AUC
Bioequivalence Criteria
90% confidence interval of difference in the average values of logarithmic AUC and Cmax
: log 0.8 ~ log 1.25
Current Issues
Highly Variable Drugs (HVDs)
KFDA
Ohsong
Seoul
Ohsong Life Science Park
KFDA
KFDA
Thank You for your Attention!