NOR

TH

Depar
tment

Bioeq
uivale

Submitted by –
I. SM Sabuj Afridi (1912379049)
II. Melita Mehjabin (2011196049)
III. Hasibur Rahman (1512278046)
IV. Shamama Siddiqua (2011159649)
V. Ishrak Ahmed (2013975049)

Date: 08th May, 2023

 List of Contents

Serial No Topic Page

1. Introduction 5
1.1 Definition 5
1.2 Importance of Bioequivalence 5
1.3 Types of Bioequivalence in Studies 6
2. Pharmacokinetics 7
2.1 Definition 7
3. How Pharmacokinetic Parameters Implications for 7
Bioequivalence
4. Biopharmaceutical Factors Affecting 9
Bioequivalence
Statistical Methods for Assessing Bioequivalence 9
5.
Two one-sided tests (TOST) 10
5.1
Confidence interval approach (CI) 11
5.2
Population bioequivalence (PBE) 11
5.3
Average bioequivalence (ABE) 11
5.4
6. Regulatory Requirements for Bioequivalence 11
Studies
6.1 FDA Guidance for Industry 12
6.2 European Medicines Agency Guidelines 14

7. 16
Bioequivalance study of different drug products
8. Bioequivalance study of oral drug product: 16

9. Reference 22

2
 List of Figures

Figure No Topic Page

1. Bioequivalence According to the Curve 8
Statistical methods for assessing
2. bioequivalence 10

3. Two one-sided tests (TOST) 10

4. Figure no 4 12

Figure no 5 12
5.
6. Figure no 6 13

Figure no 7 13
7.
8. Figure no 8 14

9. Figure no 9 14

10. Figure no 10 14

11. Figure no 11 15

12. Figure no 12 15
13. Figure no 13
21

3
 List of Tables

Table No Topic Page

4
 1) Introduction

1. Definition

Bioequivalence is the comparison of two pharmaceutical products that contain the same active
ingredient or therapeutic moiety, in terms of their bioavailability and pharmacokinetic properties,
to determine whether they have equivalent therapeutic effects in humans. In simpler terms, it
refers to how two drug products produce the same therapeutic effect when administered at the
same dosage regimen under similar conditions. Bioequivalence is an important factor in drug
development, as it allows for the approval of generic versions of a drug based on their similarity
to the innovator's product.

2. Importance of Bioequivalence

Bioequivalence studies are critical in ensuring that patients have access to safe, effective, and
affordable drugs. The importance of Bioequivalence is given below.

1. Safety and Efficacy: Bioequivalence studies ensure that generic drugs have similar
safety and efficacy profiles as their brand-name counterparts. This means that patients
can expect the same therapeutic benefits from a generic drug as they would from the
original branded drug but at a lower cost.

2. Interchangeability: Bioequivalence data is used to determine whether a generic drug can

be substituted for a brand-name drug, which can improve patient access to affordable
medication.

3. Regulatory Approval: Bioequivalence studies are required for the approval of generic
drugs by regulatory agencies such as the FDA, Health Canada, and the EMA. These
studies provide the scientific evidence necessary to demonstrate that a generic drug is
therapeutically equivalent to the innovator's product.

4. Quality Assurance: Bioequivalence studies are an important part of quality assurance for
drug products, as they ensure that the drug product is manufactured consistently from
batch to batch and that its performance is consistent with the innovator product.

5
 3. Types of Bioequivalence in Studies

Depending on the study's goals, there are many bioequivalence studies that can be carried out.
The individual drug product and its intended use and the regulatory requirements are being
undertaken regarding the studies of different Bioequivalence. Here are some common types,

1. Single-Dose Bioequivalence: In this type of study, the pharmacokinetic parameters of a

test product are compared to those of a reference product after a single-dose
administration. This study is typically used to demonstrate bioequivalence for immediate-
release solid oral dosage forms.

2. Multiple-Dose Bioequivalence: This study is similar to the single-dose bioequivalence

study, but involves the administration of multiple doses of the test and reference products.
This study is typically used for drugs that are administered over an extended period of
time.

3. Food Effect Bioequivalence: Food can affect the bioavailability of certain drugs. In this
study, the bioavailability of the test and reference products are compared under fed and
fasted conditions.

4. Topical Bioequivalence: This study is used to determine the bioequivalence of topical

drug products, such as creams or ointments.

5. Formulation bioequivalence: This type of study compares the pharmacokinetics of two

different formulations of the same drug. For example, a formulation bioequivalence study
may compare the pharmacokinetics of a tablet formulation to a capsule formulation of the
same drug.

6. In vitro Bioequivalence: This type of study compares the dissolution characteristics of a

test product to a reference product in simulated gastric and intestinal fluids. In vitro,
bioequivalence studies are typically conducted as a preliminary step before conducting
clinical bioequivalence studies.

Pharmacodynamic Bioequivalence: This type of study compares the therapeutic effects of the
test and reference products, rather than just their pharmacokinetics. This study is particularly
useful for drugs that have a narrow therapeutic window.

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 2) Pharmacokinetics

1. Definition

Pharmacokinetics is the study of how drugs are absorbed, distributed, metabolized, and
eliminated by the body. It involves the quantitative analysis of the time course of drug
absorption, distribution, metabolism, and excretion in the body, as well as the factors that affect
these processes, such as age, gender, genetics, disease, and drug-drug interactions.
Pharmacokinetics is a crucial aspect of drug development and helps to determine the appropriate
dosing regimen for a given drug to achieve the desired therapeutic effect while minimizing the
risk of toxicity or side effects.

3) How Pharmacokinetic Parameters Implications for Bioequivalence

Pharmacokinetic parameters are an essential aspect of establishing bioequivalence between two

drug products. Here are some of the key pharmacokinetic parameters related to bioequivalence.

1. Maximum Concentration (Cmax): Cmax is the highest drug concentration achieved in

the bloodstream after administration. Cmax is a critical parameter in determining the rate
and extent of drug absorption.

2. Time to Maximum Concentration (Tmax): Tmax is the time taken to reach the
maximum drug concentration in the bloodstream. Tmax is used to evaluate the rate of
absorption of the drug.

3. Area Under the Concentration-Time Curve (AUC): AUC is the total amount of drug
that enters the bloodstream over time. AUC is a measure of both the rate and extent of
drug absorption.

4. Elimination Half-Life (t1/2): t1/2 is the time taken for the drug concentration to
decrease by half in the bloodstream. t1/2 is used to evaluate the drug's elimination rate
and its overall duration of action.

5. Rate of Absorption (Ka): Ka is the rate at which the drug is absorbed into the
bloodstream. Ka is an essential parameter in determining the drug's bioavailability.

7
 6. Bioavailability (F): Bioavailability is the fraction of the administered drug that reaches
the systemic circulation. Bioavailability is used to determine the extent of drug
absorption and the dose needed to achieve therapeutic efficacy.

7. Variability: Variability is the natural variation in pharmacokinetic parameters between

individuals. Variability is an essential consideration in establishing bioequivalence, as it
can affect the interpretation of pharmacokinetic data.

Pharmacokinetic parameters play a critical role in establishing bioequivalence between drug

products. These parameters provide valuable information on the rate and extent of drug
absorption, distribution, metabolism, and elimination, allowing for a comprehensive comparison
of the drug's performance in the body

Figure 1: Bioequivalence According to the Curve

The Bioequivalence throughout the curve refers to the similarity in the concentration-time
profiles of two drug products over a period. In bioequivalence studies, the concentration-time
curve represents the amount of drug in the body over time, which is typically measured through
blood samples or other body fluids. The comparison of the concentration-time curves of a test
drug product and a reference drug product can provide information on the rate and extent of
drug absorption, distribution, metabolism, and elimination.
8
Bioequivalence throughout the curve is typically assessed using pharmacokinetic parameters
such as the area under the concentration-time curve (AUC) and maximum concentration
(Cmax). The AUC and Cmax of the test drug product are compared to those of the reference
drug product to determine if they are equivalent. It ensures that the test drug product has a
similar concentration-time profile to the reference drug product. This means that the two
products will have similar pharmacokinetic and pharmacodynamic properties and will
produce similar therapeutic effects. If the two products are not bioequivalent throughout
the curve, the test drug product may not be as effective or safe as the reference drug
product.

4) Biopharmaceutical Factors Affecting Bioequivalence

 The process of creating a drug product by combining several chemicals into a dosage
form is known as drug formulation.
 The formulation can considerably influence a drug product's pharmacokinetics,
bioavailability, and bioequivalence drug product's pharmacokinetics, bioavailability, and
bioequivalence can all be considerably influenced by the formulation.
 The kind and quantity of excipients employed in the formulation can have an impact on
the bioavailability and absorption of the medicine.
 Excipients are non-active components that are included in pharmaceutical products to
enhance their physical characteristics, stability, and bioavailability.
 The formulation and bioequivalence of a drug product might also be impacted by
variations in the manufacturing process.
 The manufacturing process can impact the drug's particle size and shape, which might
affect how well it dissolves and absorbs.
 The bioequivalence of the drug product might be impacted by variations in its
formulation.
Thus, the formulation of the generic and innovator/reference drug products should be similar to
establish bioequivalence.

5) Statistical Methods for Assessing Bioequivalence

 The idea of bioequivalence is crucial for regulatory approval and drug development since
it guarantees that generic medications are therapeutically comparable to their
innovator/reference products.
 In determining whether two medication items are bioequivalent, statistical techniques are
crucial.

9
 Figure 2 : Statistical methods for assessing bioequivalence

The most popular statistical techniques for determining bioequivalence include:

1) Two one-sided tests (TOST)
2) Confidence interval approach (CI)
3) Population bioequivalence (PBE)
4) Average bioequivalence (ABE)

1. Two one-sided tests (TOST)

A statistical technique called two one-sided tests (TOST) is used to assess whether the means of
two different samples are equal within a given margin of error. It includes doing two one-sided
hypothesis tests, and the means are regarded as statistically comparable if both reject the null
hypothesis. Clinical trials and measuring technique evaluation both use TOST.

Figure 3 : Two one-sided

tests (TOST)

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 2. Confidence interval approach (CI)
The confidence interval approach (CI) uses statistics to determine a range of values that, with a
certain level of confidence, are likely to include the true population parameter. In order to present
a range of tenable values rather than a single point estimate, it is utilized in research and
decision-making.

3. Population bioequivalence (PBE)

A statistical technique called population bioequivalence (PBE) is used in drug development to
compare the bioavailability of two different medicinal formulations. Given the variation among
people, it compares the pharmacokinetic parameters to see if they are equivalent in the target
population. The findings are used to back up modifications to a drug's formulation or the
approval of generic drug goods.

4. Average bioequivalence (ABE)

ABE is a statistical technique that is frequently used in the approval of generic medications to
assess the bioavailability of two pharmacological formulations. It examines if, assuming normal
distribution, the difference between the two products' average pharmacokinetic measurements
falls within a predetermined margin of equivalence.

6) Regulatory Requirements for Bioequivalence Studies

What do Regulatory Requirements for Bioequivalence Studies mean?

The Regulatory Requirements for Bioequivalence Studies are a number of guidelines and
standards that pharmaceutical companies must follow when conducting to demonstrate a generic
drug product is Bioequivalent to a reference drug product. These regulatory requirements are
established by Regulatory Agencies such as the FDA (Food and Drug Administration) in the
United States or the EMA (European Medicines Agency) in Europe, and Health Canada
Regulations in Canada.

These requirements cover aspects of the drug design, analytical methods, pharmacokinetic
measurements, statistical analysis, and reporting of results. These Agencies aim to ensure that
generic drugs are safe, effective, and of high quality and provide the same therapeutic effect as
the reference drug.

1. FDA Guidance for Industry

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The FDA (Food and Drug Administration) is a regulatory agency in the United States that
oversees and regulates the
safety and efficacy of various
products, including drugs,
medical devices, food,
cosmetics, and tobacco
products. Figure 4

The FDA has established regulations that the industry must follow in order to ensure safety and
quality of these products. Some of the key FDA regulations for the industry include:

Pharmaceutical Manufacturing:
I) The FDA's Current Good Manufacturing Practice (CGMP) regulations apply to the
manufacturing of pharmaceutical products, including prescription drugs, over-the-counter drugs,
and biologics.

II) These establish requirements for drug

design, monitoring, and control of
manufacturing processes and facilities to
ensure that drugs are safe, effective, and of
high quality.

Figure 5

New Drug Application (NDA):

I) FDA requires drug manufacturers to submit an NDA for approval before marketing a
new drug in the United States.
II) II) The NDA must provide data on the safety and efficacy of the drug, including
results from clinical trials.

Medical Device Regulations:

I) FDA's Quality System Regulation (QSR) applies to
maintain standards for device design, development,
manufacturing, labelling, and post-market surveillance of
medical devices. These regulations ensure the safety and
effectiveness of medical devices.

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 Figure 6
Food Labeling:
I) Food labelling is an important sector, before the
launch of a Food product; manufacturers must provide
certain information on food labels, such as ingredients,
nutrition information, and allergen warnings. The
product must pass all Clinical testing.

Figure 7
Adverse Event Reporting:
The FDA requisites manufacturers to report adverse events associated with products, such as
serious side effects or product defects. These reports ensure safety and efficacy of products on
the market and identify potential health hazard issues.

These are just a few examples of the FDA regulations that the industry must follow. The FDA
regulatory requirements change or new additions are made with new up-to-date technology and
needs.

2. European Medicines Agency

Guidelines
The European Medicines Agency (EMA) issues a
large number of guidelines on different aspects
for development, evaluation, and regulation of
medicinal products. Here are some examples of
the specific guidelines issued by the EMA:
Figure 8

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1. Clinical Trials:
- Clinical Investigation of drug products for treatment of
Alzheimer's disease, multiple sclerosis and dementias

- Clinical investigation of recombinant and human

plasma-derived factor VIII products and clinical
development of fixed combination medicinal products.

Figure 9
2. Quality of Medicines:
- The chemistry of active pharmaceutical substances and manufacture of the finished dosage
form

- The quality of water for pharmaceutical use

- Environmental risk assessment of medicinal

products for human use

3. Pharmacovigilance: Figure 10
- Maintenance of guidelines on Good Pharmacovigilance Practices (GVP)

- Management of safety information from clinical trials

- Conduct pharmacovigilance for medicines used by the pediatric population

4. Pediatric Medicines:
- Investigation of drug products for use in treatment of neonatal conditions

- Clinical assurance of drug products in treatment of lipid disorders in pediatric patients

- Role of pharmacokinetics in the development of pediatric medications

5. Biosimilars:

14
- Guideline on similar biological drug
products

- Immunogenicity assessment of
monoclonal antibodies intended for in vivo clinical
use

- Non-clinical and clinical development of similar

biological drug products containing
recombinant human insulin and insulin
analogues
Figure 11

6. Herbal Medicines:
- Quality of Herbal Medicinal products/traditional
herbal medicinal products

- The use of Herbal medicinal products containing

toxic, unsaturated pyrrolizidine alkaloids (PAs)

- Use of the common technical document (CTD)

format for the registration of herbal medicinal
products
Figure 12

Why the Guidelines provided by these agencies are so important?

Compliance with FDA and EMA guidelines is crucial for obtaining regulatory approval for new
product, maintenance, compliance throughout the product lifecycle.

Failure to comply with these guidelines can result in regulatory action, including delays in
product approval or suspension or revocation of marketing authorization. Compliance with these
guidelines helps to ensure public trust in the safety and efficacy of pharmaceutical and medical
device products, which is essential for the continued success of these industries.

7) Bioequivalance study of different drug products:

Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological

equivalence of two proprietary preparations of a drug. If two products are said to be
bioequivalent it means that they would be expected to be, for all intents and purposes, the same.

15
One article defined bioequivalence by stating that, "two pharmaceutical products are
bioequivalent if they are pharmaceutically equivalent and their bioavailabilities (rate and extent
of availability) after administration in the same molar dose are similar to such a degree that their
effects, with respect to both efficacy and safety, can be expected to be essentially the same.
Pharmaceutical equivalence implies the same amount of the same active substance(s), in the
same dosage form, for the same route of administration and meeting the same or comparable
standards.

In determining bioequivalence between two products such as a commercially available Branded

product and a potential to-be-marketed Generic product, pharmacokinetic studies are conducted
whereby each of the preparations are administered in a cross-over study to volunteer subjects,
generally healthy individuals but occasionally in patients. Serum/plasma samples are obtained at
regular intervals and assayed for parent drug (or occasionally metabolite) concentration.
Occasionally, blood concentration levels are neither feasible or possible to compare the two
products (e.g. inhaled corticosteroids), then pharmacodynamic endpoints rather than
pharmacokinetic endpoints (see below) are used for comparison. For a pharmacokinetic
comparison, the plasma concentration data are used to assess key pharmacokinetic parameters
such as area under the curve (AUC), peak concentration (Cmax), time to peak concentration
(Tmax), and absorption lag time (tlag). Testing should be conducted at several different doses,
especially when the drug displays non-linear pharmacokinetics.

8) Bioequivalance study of oral drug product:

In order to assess and predict the bioequivalence (BE) of oral drug products, a new in vitro
system “BE checker” was developed, which reproduced the environmental changes in the
gastrointestinal (GI) tract by changing the pH, composition, and volume of the medium in a
single chamber. The dissolution and membrane permeation profiles of drugs from marketed
products were observed in the BE checker under various conditions reflecting the inter-patient
variations of the GI physiology. As variable factors, initial gastric pH, gastric emptying time, and
GI agitation strength were varied in vitro. Dipyridamole, a basic drug, showed rapid and
supersaturated dissolution when the paddle speed in the donor chamber was 200 rpm, which
corresponds to the high agitation strength in the stomach. In contrast, supersaturated dissolution
disappeared, and the permeated amount decreased under the conditions with a slow paddle speed
(100 and 50 rpm) and short gastric emptying time (10 min). In those conditions, disintegration of
the formulation was delayed, and the subsequent dissolution of dipyridamole was not completed
before the fluid pH was changed to neutral. Similar results were obtained when the initial gastric
pH was increased to 3.0, 5.0, and 6.5. To investigate that those factors also affect the BE of oral
drug products, dissolution and permeation of naftopidil from its ordinary and orally
disintegrating (OD) tablets were observed in the BE checker. Both products showed the similar
dissolution profiles when the paddle speed and gastric emptying time were set to 100 rpm and 10
or 20 min, respectively. However, at a low paddle speed (50 rpm), the dissolution of naftopidil
from ordinary tablets was slower than that from the OD tablets, and the permeation profiles
became dissimilar. These results indicated the possibility of the bioinequivalence of some oral

16
formulations in special patients whose GI physiologies are different from those in the healthy
subjects. The BE checker can be a highly capable in vitro tool to assess the BE of oral drug
products in various populations.

Challenges and limitation of bioequivalence study:

A generic drug is the same as a brand-name drug in dosage,safety,strength,quality,route of
administration safety strength,quality route of administration ,indication and to be bioequivalent
with the innovator.When a generic drug is claimed bioeqivalent to a brand name drug, it is
assumed that they are therapeutically equivalent.
Bioequivalence testing is very important for regulatory filling. This data forms the important
component for abbreviated new drug application submissions.Bioequivalence plays a vital role in
generic drug development.

Bioavailability of drugs is the concentration of the drug compound that reaches the systemic
circulation or the site of action.

Most of the medicines or pharmaceuticals consumed orally reach the systemic circulation
through the gastrointestinal tract. These drug compounds then enter the site of action through the
systemic circulation. Bioavailability of drugs is measured by assessing the active ingredient
(API) concentration of the drug and any metabolites in plasma or serum. The API concentration
also helps in determining the active ingredient release from the drug compounds along with its
absorption, distribution, metabolism, and excretion.

The three primary variables of pharmacokinetic studies used in assessing the bioavailability of
drugs are i) maximum concentration of the drug in the systemic circulation (Cmax), ii) time to
reach this concentration (Tmax), and iii) time-drug concentration area under the curve (AUC).

Bioequivalence testing of transdermal drug :

The pharmacokinetic method for assessing the bioavailability of drugs is an indirect method
which traces the path of medication from absorption in the body until its excretion. The final
assessment reveals the therapeutic index and the optimal dose of the drug. The two methods used
under pharmacokinetic evaluation are plasma-level and urine-level studies. In plasma-level
studies, the relation between the concentration of drug at the site of action and in the plasma is
established. In urine-level studies, the urine is analyzed to assess if the drug has not been
metabolized and excreted unchanged. It is necessary to analyze urinary drug levels to measure
bioequivalence especially when the drug concentration in plasma or serum cannot be reliably
measured.

17
Bioequivalance testing of transdermal drug:
For the majority of topical drug products, comparative clinical end-point studies are used to
demonstrate bioequivalence to a reference drug. While this provides a direct in vivo assessment,
it is also associated with a number of challenges. Clinical end points are associated with high
variability (intra-subject) and low sensitivity (drug-related), which makes such studies less
reliable and less efficient. The other clinical alternative is to use pharmacokinetic studies to
demonstrate bioequivalence for topical products, but this is limited to particular cases where
significant systemic absorption of the drug occurs. Recently, the use of techniques including in
vitro permeation testing (IVPT), in vivo tape stripping, or dermatopharmacokinetics, and in vivo
microdialysis or microperfusion, has been advocated for testing bioequivalence.

IVPT using human dermatomed skin mounted in diffusion cells is increasingly seen as a suitable
tool for demonstrating bioequivalence of topical dosage forms. Indeed, the generation of such
data has been encouraged by regulatory agencies, such as the European Medicines Agency, the
US Environmental Protection Agency, and the US Food and Drug Administration (FDA). Their
utility is grounded on substantial evidence that 1) there is a good correlation between the in vitro
and in vivo rates and extents of human skin absorption of a number of different substances and 2)
there is good agreement on the bioequivalence of topical products seen with IVPT and in vivo
clinical studies.

Currently, however, there are no approved protocols for carrying out IVPT studies. Franz et al
pointed out that the demonstration of valid IVIVC is greatly dependent upon the protocols used,
and they recommended that the in vitro and in vivo protocols followed should be as closely
harmonized as possible to maximize the chance of achieving a good correlation. The work on
which this conclusion was based was an analysis of historical literature data that was available to
the researchers, and despite the wide variation in the way in which it was collected, their
conclusion was that there was compelling evidence that it was possible to correlate IVPT data
with human in vivo skin-absorption data. Others who have demonstrated good IVIVC include
Hadgraft et al, who compared in vitro and in vivo delivery from nitroglycerin patches,and more
recently Yang et al, who compared their own IVPT data with literature reports of in vivo
estradiol delivery from patches.

While the use of IVPT for bioequivalence has only recently been formalized, the design of in
vitro permeation tests has been subject to consideration and validation for many years. In 1987,
the FDA published a report on the important factors to be considered, which included the
membrane type (dermatomed skin or heat-separated epidermis?), the receptor fluid, the cell
design (static or flow-through?), application (finite or infinite dose?), and temperature.

18
The in vivo dermatopharmacokinetic (DPK) method uses tape stripping to remove SC layers.
The FDA has investigated the possibility of introducing a DPK method for evaluating
bioavailability and/or bioequivalence of topical dermatological drug products. In the DPK
method, it is assumed that 1) in normal circumstances, the SC is the rate-determining barrier to
percutaneous absorption, 2) the SC concentration of the drug is related to the amount that
diffuses into the underlying viable epidermis, and 3) SC drug levels are more useful and relevant
for assessing local, dermatological efficacy than plasma concentrations. It is also possible to
deduce partitioning and diffusion parameters that characterize the absorption process and which
can subsequently be used to predict an entire absorption profile from a single short-contact-
duration experiment. The technique is very operator-dependent, and care needs to be taken to
apply and remove the tapes reproducibly. The success of the method is equally dependent on the
development of sensitive analytical methods to quantify the amount of drug in the tapes.

Microdialysis involves the insertion of an ultrathin hollow fiber as a probe into the dermis. The
probe is semipermeable and perfused with sterile buffer using a microdialysis pump. This
involves the exchange of the small diffusible molecules from the extracellular fluid into the
probe and vice versa. This method is used to determine the concentration of the unbound drug or
biomarkers at the site to establish the concentration-versus-time profile of the applied compound.
There are several issues associated with microdialysis. Probe insertion in the skin can lead to
inflammatory responses, as may interactions of the perfusing buffer with the tissue. Recovery is
low for highly lipophilic molecules, which may be resolved to some extent by using albumin,
cyclodextrins, and cosolvents such as ethanol and dimethyl sulfoxide in the buffer, while highly
protein-bound molecules may be difficult to detect, due to binding to the probe material. A major
disadvantage of the method is the intrasubject variability. The newer technique of dermal open-
flow microperfusion differs from microdialysis, in that it gives continuous, membrane-free (ie,
unfiltered) access to dermal fluid. Like microdialysis, differs from microdialysis provides a
direct estimate of the time course of delivery of the permeant near its site of application. Because
of the lack of interaction with a membrane in different form of microdialysis, it can be used for a
wider range of compounds than microdialysis. The technical difficulty of microdialysis and
differs from microdialysis means that significant operator expertise is required, and as such they
are generally only available in a research setting.

Bioequivalance testing of transdermal drug:The increasing complexity of drug formulations is

driving the application of in vitro bioequivalence (IVBE) testing - the process of using in
vitro techniques to assess a test product’s bioavailability and bioequivalence to the reference listed
drug (RLD) product - to help optimize and accelerate drug development. Underlying this trend is a
recognition of the importance of formulation microstructure in controlling drug delivery and
release.

A number of physicochemical properties are key to understanding a pharmaceutical formulation’s

microstructure. These include globule and particle size distribution, particle charge, polymorphic

19
form, phase behavior, particle morphology and molecular structure. Characterizing, controlling and
optimizing these parameters helps drive development success by enabling detailed understanding
of how the structure and properties of the formulation affect the processing and performance of the
drug product.

Malvern Panalytical’s toolkit of physicochemical analysis techniques and expertise enables

assessment of the properties of active pharmaceutical ingredients (API), excipients and drug
product formulations. This toolkit encompasses solutions for composition analysis, morphological
characterization and determination of the structure and interaction between components. All have a
critical role, not only in enabling successful IVBE studies but also in gaining the essential
understanding of a formulation’s stability and performance that provides the basis for more
focused optimization.

(A) Generic medicines work the same way as brand-name medicines, but there are some
differences.

Every medicine has 2 names:

•A brand name, from the pharmaceutical company that markets the medicine.
•A generic name, which is the medicine’s active ingredient that
makes it work.
(B) Biosimilars: Biosimilars are a class of drugs designed to increase access for patients who
need treatment with a biologic medicine.

Biologic:Biologic medicines contain substances that have been created by using living cells or
organisms.
••Biosimilars VS Biologic:Biosimilars are follow-on biologics which have been approved via the
PHS Act. They consist of those which are "highly similar" to the reference drug and those which
are "expected" to produce the same clinical result as the reference drug.
(C) Modified Release Formulations:
THE MOST DELIVERY SOLUTIONS FROM THE INDUSTRY’S LEADING INNOVATOR.
•Method development and validation
•Stability testing
•Assay and impurities

20
•Dissolution profile

Figure 13

(D) Non-inferiority trails: A study that tests whether a new treatment is not worse than an
active treatment it is being compared to. Non-inferiority trials are sometimes done when a
placebo (an inactive treatment) cannot be used.

References –

● Center for Drug Evaluation and Research. (2019). Bioequivalence Studies With
Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug
Application. Retrieved from https://www.fda.gov/media/70945/download

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● European Medicines Agency. (2010). Guideline on the Investigation of Bioequivalence.
Retrieved from https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-
investigation-bioequivalence-rev1_en.pdf
● Health Canada. (2019). Guidance Document: Conduct and Analysis of Bioavailability
and Bioequivalence Studies. Retrieved from
https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-health-products/
drug-products/applications-submissions/guidance-documents/bioequivalence-guidance/
document.pdf
● Smith, J. (2021). Pharmacokinetic parameters related to bioequivalence. Pharmacy
Times. https://www.pharmacytimes.com/view/pharmacokinetic-parameters-related-to-
bioequivalence
● Shah, V. P., Midha, K. K., Dighe, S., McGilveray, I. J., Skelly, J. P., Yacobi, A., ... &
Layloff, T. (1992). Analytical methods validation: bioavailability, bioequivalence and
pharmacokinetic studies. Journal of pharmaceutical sciences, 81(3), 309-312.
● U.S. Food and Drug Administration. (2018). Bioequivalence studies with
pharmacokinetic endpoints for drugs submitted under an ANDA. Guidance for industry.
● Wu, C. Y., & Benet, L. Z. (2005). Predicting drug disposition via application of BCS:
transport/absorption/elimination interplay and development of a biopharmaceutics drug
disposition classification system. Pharmaceutical research, 22(1), 11-23.
● FDA. (2013). Statistical Approaches to Establishing Bioequivalence. Guidance for
Industry.
● Snyder, J. W. (2010). Bioequivalence and Statistics in Clinical Pharmacology. CRC Press.
● Center for Drug Evaluation and Research. (2001). Guidance for Industry: Statistical
Approaches to Establishing Bioequivalence. US Department of Health and Human
Services, Food and Drug Administration, Center for Drug Evaluation and Research.
● Schuirmann, D. J. (1987). 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(6), 657-680.
● Hauschke, D., Steinijans, V. W., & Pigeot, I. (1990). Bioequivalence studies in drug
development: methods and applications. John Wiley & Sons.

22
● Chow, S. C., & Liu, J. P. (2000). Design and analysis of bioavailability and
bioequivalence studies. CRC press.
● FDA. (2018). Guidance for Industry: Waiver of In Vivo Bioavailability and
Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a
Biopharmaceutics Classification System. US Department of Health and Human Services,
Food and Drug Administration, Center for Drug Evaluation and Research.
● Shah, V. P., Tsong, Y., Sathe, P., Liu, J. P., & Zamek-Gliszczynski, M. J. (2014).
Overview of biopharmaceutics classification system (BCS) and BCS-based biowaivers.
Biopharmaceutics & drug disposition, 35(7), 401-406.
● https://onlinelearning.hms.harvard.edu/hmx/hmx-pro-pharmacology-courses/?
utm_source=google&utm_medium=cpc&utm_campaign=DrugDelivery&utm_term=drug
%20delivery
%20program&utm_content=645345978384&gad=1&gclid=Cj0KCQjwmN2iBhCrARIs
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VW6AmJzLTQ83eC96Xu4q6BepzkaAkLFEALw_wcB
● https://www.nps.org.au/consumers/finding-good-information-about-medicines
● https://www.pfizer.com/news/articles/
biologics_vs_biosimilars_understanding_the_differences

● Anissimov YG, Roberts MS. Diffusion modeling of percutaneous absorption kinetics: 3.

Variable diffusion and partition coefficients, consequences for stratum corneum depth
profiles and desorption kinetics. J Pharm Sci. 2004;93(2):470–487. [ PubMed ] [ Google
Scholar ]
● Anissimov YG, Roberts MS. Diffusion modelling of percutaneous absorption kinetics: 4.
Effects of a slow equilibration process within stratum corneum on absorption and
desorption kinetics. J Pharm Sci. 2009;98(2):772–781. [ PubMed ] [ Google Scholar ]

● Zhang Q, Li P, Liu D, Roberts MS. Effect of vehicles on the maximum transepidermal

flux of similar size phenolic compounds. Pharm Res. 2013;30(1):32–
40. [ PubMed ] [ Google Scholar ]
● Raney SG, Franz TJ, Lehman PA, Lionberger R, Chen ML. Pharmacokinetics-based
approaches for bioequivalence evaluation of topical dermatological drug products. Clin
Pharmacokinet. 2015;54(11):1095–1106. [ PubMed ] [ Google Scholar ]

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● https://www.nps.org.au/consumers/finding-good-information-about-medicines
● https://www.pfizer.com/news/articles/
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