Chapter 8:

Manufacturing Process:

A comprehensive understanding of all steps in the manufacturing process for the proposed bio similar product should be established

Which of the following about generic substitution is NOT True

A generic product may be marketed before the patent expiration, as long as demonstrating therapeutic equivalency of the generic to the brand

Functional activities:

A quality measure of the function of the protein product

Which of the following bioequivalency studies is/are required for modified-release or extended-release products to demonstrate bioequivalency?

Fasting study, Food Intervention Study, and Multiple-Dose Study

A drug substance is considered highly soluble when:

The highest dose strength is soluble in 250 mL or less of aqueous medium over the pH range 1-8

Bioequivalent Drug Products

The pharmaceutical equivalent or pharmaceutical alternative products that display comparable bioavailability when studied under similar experimental conditions.

Pharmaceutical Substitution

The process of dispensing a pharmaceutical alternative for the prescribed drug product

Drug Product Performance, in vivo, may be defined as:

The release of the drug substance from the drug product leading to bioavailability of the drug substance

Drug Product Performance

The release of the drug substance from the drug product, leading to bioavailability of the drug substance and leading to a pharmacodynamic response. Bioequivalence studies are drug product performance tests

Expression System:

Therapeutic protein products can be produced by microbial cells, cell lines of human or animal origin. A proposed Biosimilar product will encode the same primary amino acid sequence as its reference product

Receptor binding and immunochemical properties:

When applicable, analytical tests should be performed to characterize the product in these properties

Therapeutic Substitution

process of dispensing a therapeutic alternative in place of the prescribed drug product

Relative Bioavailability Equation

(AUC)A/DoseA / (AUC)B /Dose B

Degree of fluctuation

(Cmax-Cmin)/Cmax

Swing =

(Cmax-Cmin)/Cmin

FDA Orange Book

Annual list of approved drug products with therapeutic equivalence evaluations

The formulation and method of manufacture of a generic drug product may be

Different from the brand drug product

Which of the following factors will have the least effect on the absolute Bioavailability after an oral dose?

Dose administered

Which of the following in vitro characteristics of a drug product is most closely related to the rate and extent of oral drug absorption?

Drug Dissolution Profile

Cmin

Drug concentration at the end of a dosing interval

Bioequivalence Studies are:

Drug product performance tests that compare the bioavailability of the same active pharmaceutical ingredient from one drug product (test) to a second drug product (reference)

Pharmaceutical Equivalents

Drug products containing the same active ingredient(s), same dosage form and route of administration and identical in strength or concentration.

What is listed on Negative formularies?

Drug products that are not therapeutically equivalent

Absolute Bioavailability Equation

F(abs)= (AUC)PO/DosePO /(AUC)IV/DoseIV

Orange Book

FDA's Approved Drug products with therapeutic equivalence evaluations

T/F: Increase the dose will cause the AB to increase

False

T/F: The RB of a drug product cannot be determined if an IV formulation of the drug is not available

False

T/F:Relative Bioavailability (RB) may exceed 100% and Absolute Bioavailability (AB) also may exceed 100%

False. AB can NOT exceed 100%

T/F: Intravenous is relevant to determination of Relative Bioavailability (RB)

False. RB=Oral

Subjects participating in a bioequivalency study are usually:

Fasted overnight prior to drug administration

Which of the following statements regarding Relative Bioavailability is TRUE

If relative bioavailability is less than 100% the reference drug product has a higher absolute bioavailability than the test drug product

Bioavailability Studies are:

In vivo drug product performance studies that relate the physicochemcial properties of the drug substance, the formulation of the drug and the manufacture process, to the expected clinical efficacy and safety of the drug product

Assessment of physiochemical properties:

Includes the primary, secondary, tertiary, and quaternary structure, post-translational modifications, and functional activity[ies]

Negative Formulary

List of drug products that are NOT therapeutically equivalent (assume BE if not on the list)

Positive Formulary (Texas)

List of therapeutically equivalent products (interchangeable)

BCS Class 4

Low Solubility, Low Permeability

BCS Class 2

Low solubility, High permeability

Cmax

Maximum drug concentration during dosing interval

A generic drug product is a

Multisource drug product that has been approved by the FDA as a therapeutic equivalent to the reference listed drug (RLD) product (usually the brand) that has proven equivalent drug product performance

Biopharmaceutics Classification System (BCS)

- Used to classify Solubility and Permeability

All of the above are methods off assessing bioavailability:

-Clinical observation -Pharmacologic Effect -Plasma Concentration -Urinary Drug Excretion

Oral Bioavailability of a drug may be affected by all of the following:

-Dosage Formulation of the Drug -Hepatic Metabolic Enzyme Activity -Stability of the Drug in the GI Tract -Permeability of the Drug in the GI Tract

Bioequivalence Studies are Used to Compare:

-Early and Late Clinical Trial Formulations -Formulations used in clinical trials & stability studies, if different -Clinical trial formulations and to-be-marketed products, if different -Product strength equivalence, as appropriate -New formulations of previously approved products, such as new fixed-dose combination version of two products approved for coadministration -Modified-release (MR) versions of immediate-release products -For post approval with respect to any major changes in formulation, manufacturing, or site, in comparison to reference formulation (usually the pre-change formulation)

SATA: When CYP3A4 activity is inhibited by inhibitors such as Cimetidine?

-Hepatic Clearance Decrease -Hepatic Metabolism Decrease -Bioavailability Increase

Which of the following is associated with low bioavailability of a drug? SATA

-Low Water Solubility (<5 mg/mL) -Low permeability through intestinal membrane -Rapid Hepatic or GI drug metabolism -Substrate of GI transporters

In vivo BE studies are required when:

-No comparable therapeutic effect from various products in clinical trials is available -Narrow Therapeutic Index Drugs -Physiochemcial Evidence -Pharmacokinetic Evidence

Fasting Study (2-way crossover design)

-Overnight fasting (10-12 h) til 2-4 h post dose -Healthy subjects N=12-24; or 48 for high CV drugs -Single dose -Washout period: >10 t1/2 between treatments -Required for all immediate release products and modified-release products

Multiple-Dose (Steady-State) Study

-Required for extended-release products -2-way crossover -2 treatments, T & R -3 Cmin (trough) to assure S.S. -Last dose/fasting to get complete profile

Food Intervention Study (2-way crossover)

-Required for: All modified release products, Immediate release products, but known to be affected by food in absorption -Single Dose -2 periods -2 sequences -2 treatments

Pharmaceutic Substitution:

-Same ingredient, different chemical (salt, ester, or complex)(i.e. Tetracycline phosphate vs Tetracycline HCl) -Within a product line, different dosage forms (i.e. Immediate-release vs Extended-release; Ampicillin Suspension vs Capsules)

Bioavailability Studies: Required for all NDA Applications:

-Therapeutic moieties not yet approved for marketing by FDA -New formulations of an approved drug -New salt/ester form of an approved drug

Bioequivalent drug products (generic and its brand products) usually possess all of the following characteristics:

-They are pharmaceutical equivalents -They have the same rate of absorption -They have the same extent of absorption -They are therapeutically equivalent

Pharmacokinetic Parameters used to asses bioavailability include all of the following:

-Tmax -Cmax -AUC (0->infinity) -Du

Regulatory Recommendations for Optimizing Bioavailability Study Design:

-Use of randomized crossover design whenever possible -Enrolling both male and female subjects whenever possible -Administering single doses rather than multiple doses -Conducting the studies under fasting and fed conditions -Measuring the parent drug rather than the metabolites, unless the parent can't be reliably measured

What are the three types of In Vivo BE Study Designs?

1. Fasting Study 2. Food Intervention Study (2-way crossover) 3. Multiple-dose (Steady-state) Study

Which of the following 90% confidence intervals, for the ratio of log-transformed means for AUC and Cmax of the test product to that of the reference product, is acceptable range by FDA for bioequivalency?

80%-125%

BE acceptance criteria

90% Cl of the geometric mean ratios of Cmax and AUC between test and reference fall within 80%-125%

To be classified as highly permeable:

A test drug should have an extent of absorption >90% in humans

Reference product and reference standards:

A thorough physiochemical and biological assessment of the reference product should provide a base

Bioequivalence is the:

Absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

Which of the following is NOT associated with low bioavailability of a drug?

Amount of a dose

Stability:

An appropriate accelerated and stress stability studies, or forced degradation studies

What pair defines a "pharmaceutical equivalent"

Apixaban 5-mg tablets (Bristal-Myers Squibb Company) and Apixaban 5-mg (Mylan Pharmaceuticals)

What does the FDA Orange Book Contain

Approved drug products with therapeutic equivalence evaluations

AUC0-tau

Area under the curve during a dosing interval

Which of the following drug categories of the Biopharmaceutical Classification System (BCS) would FDA grant biowaver in a process of marketing a generic drug product

BCS Class 1 Drug

Oral bioavailability of a drug may be affected by all of the following EXCEPT

Binding of the drug in tissue

Drug product performance is measured by

Bioequivalence studies in normal healthy adult subjects under fasted and fed conditions. Drug product performance comparisons in vitro may also include comparative drug dissolution profiles

A therapeutically generic product is interchangeable to its:

Brand Product

All of the above are methods of assessing bioavailability EXCEPT:

Cell or urine culture

Pharmacokinetic Parameters used to asses bioavailability include all of the following EXCEPT:

Clearance

Name three parameters are usually determined when assessing Bioequivalence of drug products

Cmax, Tmax, AUC

Which of the following pharmacokinetic parameters are usually determined when assessing the bioequivalency using plasma drug concentration data?

Cmax, Tmax, AUC

A drug that has been prepared at the same dosage level in three formulations. A, B, and C. These formulations are given to a group of volunteers using a three-way, randomized crossover design. Pharmacokinetics profiles are shown. Which of the following is TRUE about these formulations

Formulation B has slower rate of drug absorption as compared with formulation C

Which of the following additional factors is/are taken into consideration in defining Biopharmaceutics Drug Disposition Classification System (BDDCS) as compared to the original Biopharmaceutics Classification System (BCS)?

Hepatic Metabolism and GI Transporters

BCS Class 3

High Solubility, Low Permeability

BCS Class 1

High solubility, High Permeability

Which of the following route of administration is NOT relevant to the determination of relative bioavailability?

Intravenous

Which of the following is the primary reason that crossover study design is often used in bioequivalency studies?

It is to minimize inter-subject pharmacokinetic variations

In a relative bioavailability study for oral drug, the reference standard is:

Oral Solution

A generic product must demonstrate:

Pharmaceutically equivalent, bioequivalent, and therapeutically equivalent (i.e. has the same drug product performance) to the comparator brand-name drug product

Finished Drug product:

Product characterization studies should be performed on the most downstream intermediate best suited for the analytical procedures used

Bioavailability is the:

Rate (Cmax & tmax) and extent (AUC) to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action

Generic Substitution:

Same active ingredient, Same dosage form, different manufacturers. (For example: Motrin vs Advil)

Therapeutic Substitution:

Same therapeutic objective, different active ingredients and/or dosage forms (i.e. Amoxicillin vs Ampicillin)

Biopharmaceutics Drug Disposition Classification System (BDDCS)

Takes into account drug metabolism (Hepatic Clearance) and transporters in the GI tract for drugs that are orally administered

Which State has a positive formulary?

Texas

Impurities

The applicant should characterize, identify, and quantity impurities in the proposed biosimilar product and reference product

Cav

The average drug concentration during a dosing interval

Biosimilar or Biosimilarity

The biological product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.

Bioequivalent drug products (generic and its brand products) usually possess all of the following characteristics EXCEPT:

They contain the same inactive ingredients

Tmax

Time to Cmax during a dosing interval

What is the objective of BE Studies

To evaluate the rate (Cmax and tmax) and extent (AUC) of absorption of drug from a test formulation (vs reference formulation)

For BCS 2 Drugs (Low Solubility and High Permeability)

Transporter effects are more important

For BCS 1 drugs (i.e. high solubility and high permeability):

Transporter effects will be minimal

T/F: RB may be determined without parenteral drug administration whereas the determination of AB required parenteral drug administration

True

T/F: Urinary drug excretion data may be used to determine RB and AB

True

Relative bioavailability studies compare:

Two or more drug product formulations. A Bioequivalence study is a relative bioavailability study

Bioequivalence Requirement

a requirement imposed by the FDA for in vitro and/or in vivo testing of specified drug products , which must be satisfied as a condition of marketing

Therapeutic Equivalents

chemical equivalents which when administered in the same amounts will provide the same therapeutic effect as measured by the control of a symptom or disease

Therapeutic Alternatives

drug products containing different therapeutic moieties but of the same pharmacological or therapeutic class can be expected to have similar therapeutic effects when administered in therapeutically equivalent doses

Pharmaceutical Alternatives

drug products that have the same therapeutic effect and strength but differ in the salt, ester or dosage form and are administered by the same rout

Generic Substitution

the process of dispensing a different brand or unbranded drug product in place of the prescribed drug product