- Pharmaceutical Equivalence Study KFDA drug approval system - Pharmaceutical Equivalence Study 2013 We are dedicated to professional, individualized and market-specific solutions to make our clients’ expansions into Korea and success in the global market

Purpose and Definition - Verify the pharmaceutical equivalence between two products with same API, strength and dosage form Bioequivalence test Comparative dissolution test Comparative disintegration test

Purpose and Definition Subjects of application Prescription pharmaceutical drug (ETC drug) : tablets, capsules and suppositories Non-prescription pharmaceutical drug (OTC drug) : tablets, capsules and suppositories as single active ingredient Changes of the followings; - raw materials and their quantities - manufacturing method - manufacturing site

Purpose and Definition 1. Bioequivalence test - in vivo study to verify the statistical equivalence in bioavailability between two drug products with the same active ingredient and route of administration that are absorbed into the systemic circulation and become available at the site of action. <Subjects > Approved after Jan.1.1989, prescription pharmaceuticals falling into new drug (including same route of administration, but in different dosage form) Pharmaceuticals notified by MFDS’s Commissioner which are needed for equivalence test

Purpose and Definition 2. Comparative dissolution test - verity the similarity to dissolution profile between two drug products <Subjects > Prescription pharmaceuticals with the exclusion of bioequivalence test product tablets, capsules and suppositories as single OTC preparation 3. Comparative disintegration test - verity the similarity to disintegration profile between two drug products such as Herbal medicine, Lactobacillus and Enzyme preparations

Reference drug (Positive Control) Reference drug in case of NDA Approved drug product which safety and efficacy were established Recognized as a reference drug product by MFDS Reference drug in case of change of approval Principle : Pre-manufactured drug according to the current license Exception ; can use the notified reference drug Not verified for equivalence No manufacturing history or exceed expirary date so that there is not suitable product for equivalence test

Test drug Test drug Should be a final form and meet the following criteria; final product the quality and content should meet its “in-house specification and test method” batch size: at least 100,000 units. If the commercial batch size is smaller than 100, 000 units, the batch size of final product can be acceptable. either the total content/potency of the active drug substance according to “in-house specification and test method” is within 5% of labeled content(100%) of reference , or the difference in content/potency between test and reference drug is within 5%.

Bioequivalence test Criteria for waivers of BE test An oral solution such as syrups, elixirs, tinctures (except emulsion and suspension) and topical solutions same API , concentration and dosage form with an approved product & do not contain any excipient that affects drug absorption Injections, ophthalmic solutions, and otic solutions - same API and concentration with an approved product It should be assured that following excipients do not affect the action of active ingredient Injections : preservative, buffering agent, antioxidant Ophthalmic solutions and otic solutions : preservative, buffering agent, isotonizing agent, viscosity adjustive

Bioequivalence test Criteria for waivers of BE test Topical drug product with non-systemic effect Inhalation product as gas or vapor with local effect Fluids, blood volume expanders, and artificial perfusion agents Digestive enzyme preparation Blood product Herbal medicinal product Vaccine Lactobacillus preparation

Comparative dissolution test Test condition Water soluble product Poorly water soluble product ; in the water soluble product condition (1)~(4), mean dissolution rate within the set time < 85% Apparatus Test solution (pH) Time Additional test Apparatus 2 (50rpm) 1.2 4.0 6.8 Water pH 1.2: 2hr Others: 6hr In the condition (1)~(3), mean dissolution rate of reference drug < 85% (100rpm) Apparatus Test solution (pH) Apparatus 2 (50rpm) 1.2 4.0 6.8 Water (1)~(4) all test solution + solubilizer

Comparative dissolution test Test condition Enteric coated product Poorly water soluble, enteric coated product Apparatus Test solution (pH) Time Additional test Apparatus 2 (50rpm) 1.2 6.0 6.8 pH 1.2: 2hr Others: 6hr In the pH 6.0 solution, mean dissolution rate of reference drug < 85% (100rpm) Apparatus Test solution (pH) Time Additional test Apparatus 2 (50rpm) 1.2 6.0 6.8 (2)&(3) + solubilizer pH 1.2: 2hr Others: 6hr In the pH 6.0 and 6.8 solution, mean dissolution rate of reference drug < 85%

Comparative dissolution test Test condition Controlled release product Apparatus Test solution (pH) Time Additional test Apparatus 2 (50rpm) 1.2 4.0 6.8 Water (3) + polysorbate80 etc. 1.0 w/v% pH 1.2: 2hr Others: 24hr In the pH 6.8 solution, mean dissolution rate of reference drug < 85% Apparatus 1 (100rpm)

Comparative dissolution test Test solution pH 1.2: “solution 1” of “Disintegration test” in KP pH 4.0: Acetate buffered solution pH 6.0: sodium phosphate · citric acid buffered solution in KP reagent section pH 6.8: “solution 2” for “Disintegration test” in KP Volume of Solution: in principle, 900mL Temperature of Solution: 37 ± 0.5 ℃

Comparative dissolution test Result report - Including followings Title, object, test period and summary of result CoA of quality control (content or potency; more than 3 times) CoA of active ingredient Description of the manufacturing process of the test drug product Information of test institution (name, address, equipments etc.) Manufacturing (import) manager’s name Test method test condition validation data of dissolution test comparison of the dissolution profile in reference drug and test drug Conclusion of manufacturing (import) manager

Interpretation of equivalence Immediate release & Controlled release product category Mean dissolution rate (reference drug) Point of comparison standard Immediate release & Enteric coated product 85% within 15min around 85% mean dissolution rate ± 15% 85% within 15~30min around 60%, 85% mean dissolution rate ± 15% or similarity factor(f2) ≥50 85% after 30min around 40%, 85% < 85% In the point of interpretation, 50%<dissolution rate<85% In the point of interpretation, dissolution rate<50% mean dissolution rate ± 8% or similarity factor(f2) ≥55 Controlled release product < 50% around 30,50, 80% (if below 80%, final point) ± 10% or similarity factor(f2) ≥55 50~85% (if below 80%, final point) ± 10% or similarity factor(f2) ≥50 ≥ 85% ± 10% or similarity factor(f2) ≥40

Interpretation of equivalence In case of formulation changes, category Mean dissolution rate (reference drug) Point of comparison standard Mean dissolution rate 85% within 15min around 85% mean dissolution rate ± 10% 85% within 15~30min around 60%, 85% mean dissolution rate ± 10% or similarity factor(f2) ≥50 not reach 85% within 30min Final dissolution rate <50% around 1/2dissolution rate, the set time mean dissolution rate ± 6% or similarity factor(f2) ≥60 50~85% mean dissolution rate ± 8% or similarity factor(f2) ≥55 ≥ 85% around 40%, 85% individual dissolution rate < 50% at final point mean dissolution rate of test product > ± 9% ; max. 1 product, but not > ± 15% 50~85% at final point mean dissolution rate of test product > ± 12% ; max. 1 product, but not > ± 20% ≥ 85% at final point mean dissolution rate of test product > ± 15% ; max. 1 product, but not > ± 25%

Comparative disintegration test This test can be performed when the comparative dissolution test is impossible because of product property. Should be based on a scientific basis such as preliminary experimentation . Examples ; - such as Herbal medicine, Lactobacillus and Enzyme preparations - can not get the reasonable analysis method - can not analyze because of microanalysis

Revision of approval (formulation change) Level of formulation changes According to table I & II, determine the level of change - equal to or less than the range of level B  level B - the change in excipients in the range between B and C  level C - the change in excipients in the range between C and D  level D - any change in coloring or flavoring agent  level A Among the changes, the highest level of change is defined as the level of formulation change.

Revision of approval (formulation change) [Table I] Level of change in excipients for uncoated product Excipient category and component Percent excipient (w/w) compared to total dosage form weight (%) B C D Disintegrant Starch Other 3.0 1.0 6.0 2.0 9.0 Binder 0.50 1.5 Lubricant․Polisher Stearate and its salt 0.25 0.75 Glidant 5.0 10 15 Other (except coloring and flavoring agents) The total additive effect of all excipient changes

Revision of approval (formulation change) [Table II] Level of change in excipients for coated product Core / coated layer Excipient category and component Percent excipient (w/w) compared to total dosage form weight (%) B C D Core Disintegrant Starch Other 3.0 1.0 6.0 2.0 9.0 Binder 0.50 1.5 Lubricant․Polisher Stearate and its salt 0.25 0.75 Glidant 5.0 10 15 Other (except coloring and flavoring agents) The total additive effect of all excipient changes in core Film-coated layer The total additive effect of all excipient changes in film coated layer Sugar-coated layer The total additive effect of all excipient changes in sugarcoated layer

Revision of approval (manufacturing process change) Level of change in the manufacturing process & kind of test Level Range Kind of test A Addition/change of a volatile solvent used as coating agents Change the weighing process or packaging process Chang the description of the product Change the size of the capsule No effect on the product equivalence no need to equivalence test B Addition/change of API manufacturer Not A, C or D level Change of batch size Comparative dissolution test or Comparative disintegration test C Change of the assembling method Change of the combination solution (organic solvent, water etc.) Change of the manufacturing process condition ( time, rate etc.) D Change of the manufacturing process that effects on the product quality Bioequivalence test

Revision of approval (manufacturing site change) Level of change in the manufacturing site & kind of test Level Range Kind of test A Change to the site that manufacture the product approved by bioequivalence test Change the site of weighing process or packaging process No effect on the product equivalence no need to equivalence test B Change the manufacturing site of same manufacturer & no change the formulation and manufacturing process Comparative dissolution test or Comparative disintegration test C Change the manufacturing site of same manufacturer & change the formulation and manufacturing process Not A or B level