Unit I 10Hours New Drug Discovery and development
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Stages of drug discovery,
Drug development process,
pre-clinical studies, non-clinical activities,
clinical studies,
Innovator and generics,
Concept of generics,
Generic drug product development.
Introduction
Developing a new drug for a disease from original idea to the launch of a finished product is
a complex process which can take 12–15 years of efforts and a cost in excess of $1 billion. It
includes several steps of preliminary research, understanding the disease, finding target
tissues and target drugs which have potential to control the disease, selecting best drugs with
maximum safety and efficacy, testing them in vitro, in vivo, ex vivo, and finally in humans to
ensure that the selected drug is safe and effective in humans. Finally getting approval of FDA
for marketing the drug. All these stages of development involve various regulatory Guidances
which must be strictly followed to ensure compliance to law.
STEPS INVOLVED FROM DISCOVERY TO DRUG LAUNCHING:
Usually following steps are involved in this journey of marketing a new drug.
Step I: drug discovery
Step II: Drug Development
Step III: non- clinical trials and pre-clinical trials
Step IV: filing IND and clinical trials stage 0, stage1, stage2, stage 3
Step V: filing NDA and getting marketing authorization.
Step VI: stage 4 of clinical trial, post marketing surveillance.
Time line and expenses in drug regulatory process
s. no
1
2
3
4
Activity
Drug discovery
Drug development and
preclinical trials
IND application and
Clinical trials
NDA application and
approval
Total
Time required
2-3 years
2-3 years
Investment required
200-300 million dollars
200-300 million dollars
3-5 years
300-500 million dollars
2-3 years
200-300 million dollars
9 - 14 years
900-1400 million dollars
STEP I DRUG DISCOVERY
Target Discovery: The target discovery involves in vitro research to identify targets
involved in specific diseases. It can be cellular or modular structures that appear to play an
important role in pathogenicity, such as a nucleic acid sequence or protein. The target should
be "druggable" i.e., it should be manageable by the external drug molecule. It should have a
definite role in the pathophysiology of the disease or can modify the disease. The target
should capable of being assayed easily.
Target Validation: After identifying a potential target, researchers must demonstrate that it
is involved in the progression of a given disease and that its activity can be managed by drug
molecules. The validation must establish that the target is real and can be proved repeatedly.
Any mistake at this stage may lead to failure of the whole research efforts.
Hit identification:
Once a target has been selected, the next stage of the drug discovery process is hit
identification. Hit molecules are those compounds which are identified to affect the
pathological targets discovered above. The obvious next step is to identify whether the
identified molecules have the desired effect against the identified targets. There are a number
of approaches by which hits can be identified, including high-throughput screening and
virtual screening. Selection of all the possible Hit compounds is carried out which have
potential to be a drug. Around 5000 to 10000 Hit compounds are required to be selected to
find out few effective and safe drug candidates.
High throughput screening (HTS) is the use of automated equipment to rapidly test
thousands to millions of samples for biological activity at the model organism, cellular,
pathway. In its most common form, HTS is an experimental process in which 1000s of
molecules of known structure are screened in parallel. in recent times, HTS is largely enabled
by the modern advances in robotics, liquid handling, plate reader detection as well as highspeed computers. Nevertheless, to run effectively, high-throughput screening still requires a
highly specialized and expensive screening facility
A typical HTS system is equipped with automatic weighing devices, a set of
reactors for making solutions as per predefined recipe, withdrawing multiple samples
by robotic arms and injecting the desired dose to the variety of bacterial cultures and
observing the effects and observing and recording the data in computers and showing
graphical images of the drug effects.
HTS machine
Virtual Screening: virtual screening is computational technique used in drug
discovery to identify such small molecules (ligand molecules) which are most likely to bind
to the target cells (docking) identified for drug discovery. Whether used in conjunction with
HTS or stand alone, VS techniques provide a quick and economical method for the discovery
of novel actives. PyRX is a well-known software used for this purpose. there are many other
software based on Structure Activity Relationship and are capable to identify the HITS which
will bind to the identified target tissues.
for doing Virtual screening the target cell protein molecule three-dimensional
molecular structure is displayed on the computer screen. the ligand molecule structure is also
superimposed on the large protein molecule. now the computer program is run to find out
binding potential. The results are available in the output file.
The following steps are to be tried to arrive at appropriate drug molecules.
Lead Molecule Identification: A chemical compound, which has potential to treat a disease
and can lead to the development of a new drug is called Lead molecule. It is selected from
among thousands of chemical compounds listed as ‘hits’ and which can act on genes, or
cellular proteins involved in the disease. The chemical structure of the lead molecule is used
as a skeleton to develop a drug having maximum efficacy and minimum side effects.
Researchers have to conduct screening experiments on “Hits” to identify possible naturallyoccurring or synthetic compounds that can be utilized as lead-molecules.
Lead molecule Optimization: Once a compound has been identified as lead molecule, they
need to be modified and optimized for maximum efficacy and safety. The design of synthetic
molecules can be altered to obtained desired efficacy and safety, and suitability for
formulation. These tests are performed on animal models such as mice and rats at this stage.
The discovery ends when few lead molecule are finalised and the process of drug
development is initiated.
STEP II DRUG DEVELOPMENT AND NON-CLINICAL STUDIES.
The drug development involves extensive testing in animal models to find out safety and
efficacy and any side effects and adverse drug reactions. In order to progress from this stage
to clinical trials extensive testing and data are to be recorded in order to file IND application.
Animal models that mimic human conditions, such as genetically modified mice, are used
during this stage to study the behaviour of lead molecules. Assay methods are developed in
vivo, in vitro or ex-vivo. Ex-vivo means animal tissues from non-living animals. In silico
assay methods are also performed which involves use of computer models in place of animal
tissues.
Preclinical studies must provide detailed information on dosing and toxicity levels, efficacy,
pharmacological response, dose for men, women, children, elderly people. After preclinical
testing, researchers review their findings and decide whether the drug should be tested in
people. Usually following types of studies may be involved during nonclinical trials.
Types of non-clinical studies which are usually performed on lead molecules.
1. Pharmacodynamics (PD): to determine effects of the molecule on various tissues.
2. Mechanism of action of the lead molecules.
3. Safety: To identify undesirable effects on key physiological functions within the
therapeutic dose range and higher. Usual studies evaluate respiratory, central nervous
system (CNS), and cardiovascular functions, hepatotoxicity, drug-drug interactions,
drug food interactions, immunogenicity, bone marrow toxicity, reactive metabolite
formation, hypersensitivity etc.
4. Pharmacokinetics (PK): ADME: A (absorption), D (distribution), M (metabolism), E
(excretion)
5. Toxicology: Toxicology studies aim to address the toxicity of the compound:
a. Genotoxicity (damage within a cell causing genetic mutations)
b. Carcinogenicity (can it cause cancer?): 2 years mouse and rats.
c. Development and reproductive toxicity: can it affect reproduction capability of
the animals.
d. Immunotoxicity: can it affect natural immunity of the animals.
e. Paediatric toxicity: study of toxic effects on children
f. The standard duration for these tests : Sub-chronic: 7, 14 and 28 days and 3
months, Chronic: 6, 9 and 12 months
6. Genotoxicity studies: The objective is to detect potential interactions with DNA or
chromosomes that lead to the induction of gene mutations and/or chromosomal
damage.
7. Fertility (typically rat): the objective is to find effect on fertility of typically rat and
rabbit.
8. Interaction with other treatments: impact of using new drugs simultaneously with
other drugs
9. Effect on immunity system: to evaluate effects on the natural immunity on the basis
of animal trials.
10. Effectiveness compared to similar drugs: comparison with existing similar products
efficacy and safety to establish superiority of the new product.
11. Formulation development trials: to develop best mode of delivery of the drug.
12. Formulation optimisation: developing the best formulation which is capable of
providing easy od administration and best bioavailability performance and drug
stability.
13. Safety study in paediatric and geriatric patients: the drug should be safe and
effective to children and geriatric population
All preclinical trials should be done in laboratories which are GLP (Good Laboratories
Practices) complied. The GLP regulations are found in 21 CFR part 58. These regulations set
the minimum basic requirements for:
STEP III PRECLINICAL TRIALS
Usually, the terms preclinical studies and non-clinical studies are used interchangeably but
some authors use them differently. Preclinical studies are the last phase of the nonclinical
studies just before starting clinicals trials. During preclinical studies expected dose are
determined for human beings on the basis of animal study data.
Preclinical studies are not very large. However, these studies must provide detailed
information on dosing and toxicity levels. After preclinical testing, researchers review their
findings and decide whether the drug should be tested in people.
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First dose estimation in humans: Estimation of the first dose in humans is an
important element to protect subjects participating in first-in-human studies (Phase I).
All relevant non-clinical data should be considered, but NOAEL gives the most
important information.
Estimation of Human Equivalent Dose (HED) on the basis of animal doses.
Estimation of best dosage, and administration route, gender, race, ethnicity groups.
Estimation of potential Side effects/adverse events
Estimation of Effects on gender, race, or ethnicity groups
(No-observed-adverse-effect level (NOAEL): greatest concentration or amount of a
substance, found by experiment or observation, that causes no detectable adverse
alteration on the target organism under defined conditions of exposure.)
Preclinical trials and drug development stages are merged with each other and difficult to
separate.
STEP IV CLINICAL RESEARCH
Clinical research refers to trials of the drugs selected for safety, efficacy, adverse effects in
human beings. Before conducting clinical research, FDA permission is required. The
permission is obtained by applying IND (Investigational New Drugs) in prescribed format
giving details of previous studies from pre-clinical stage. Getting IND approval is the first
step in starting clinical research.
Scope of clinical trials:
Clinical trials are studies to test new drugs, devices, or already approved drugs for new
indications. Some clinical trials focus at new ways to detect, diagnose, or measure the extent
of disease. Researchers still use human volunteers to test these methods, and the same rules
apply.
Purpose of clinical trials: clinical trials are done in human for following purpose:
1. To find out that the investigational new drug is safe in human beings , and has less
side effects and risk of adverse reactions than the existing drug.
2. That the Investigational new drug is more effective and better in any other aspect than
the existing drug,
3. To find out if any existing drug can be used effectively and safety for other
indications.
4. To determine safe dose of new drugs in human beings.
Clinical Research is done in following steps.
A. Investigational New Drug application, review and approval process (will be discussed
with unit ii regulatory process)
B. Design of clinical trials
C. Conducting Clinical research stage wise
D. Follow Good Clinical Practices at every step.
A.. The Investigational New Drug Application Process
Before a clinical trial can be started, the research must be approved. An investigational new
drug application or IND application must be submitted with the FDA when researchers want
to study a drug in humans. The IND application must contain certain information, such as:
•Results from studies so that the FDA can decide whether the treatment is safe for testing in
people.
•Details of the drug, chemistry, manufacturing, testing procedures, and stability.
•Detailed outlines for the planned clinical studies, called study protocols, are reviewed to see
if people might not be exposed to undue risk.
•Details about the clinical trial team to see if they have the knowledge and skill to run clinical
trials.
•The research sponsor must commit to getting informed consent from everyone on the
clinical trial. They must also commit to having the study reviewed by an institutional review
board (IRB) and following all the rules required for studying investigational new drugs
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Submission of application to FDA with preclinical data in CTD format
Application review by FDA
IND Approval by FDA
B. Designing Clinical Trials
Researchers design clinical trials to answer specific research questions related to a medical
product. These trials follow a specific study plan, called a protocol, that is developed by the
researcher or manufacturer. In clinical research, the aim is to design a study which would be
able to derive a valid and meaningful conclusion by using suitable statistical methods. The
researcher has to decide
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Who qualifies to participate (selection-criteria)?
How many people will be part of the study?
How long the study will last
Whether there will be a control group and other ways to limit research bias
How the drug will be given to patients and at what dosage
What assessments will be conducted, when, and what data will be collected
How the data will be reviewed and analysed
Various types study designs include
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Cohort design
Cross-Over Studies
Double-Blind Method
Single-Blind Method
Randomized Controlled Trial
Non randomised trials
Placebo-controlled:
A Latin square design:
C.. Conducting of clinical trials
Clinical trials are usually conducted in five phases that build on one another. Each phase is
designed to answer certain questions. Knowing the phase of the clinical trial is important
because it gives some idea about how much is known about the treatment being studied.
There are benefits and risks to taking part in each phase of a clinical trial.
Phase 0: (exploratory clinical trail, micro dose trials.)
Phase 0 of a clinical trial is done with a very small number of people, usually fewer than 10,
to find out if the drug is safe and really effective and worth to move for clinical trials which
are highly costly and time consuming.
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Main Purpose: to check safety and pharmacokinetics and pharmacodynamics in people at
micro dose.
Number of subjects. 5-10 subjects.
Type of subjects: healthy subjects
Duration: 3-4 months.
Very small dose: 1/ 100 th of therapeutic dose.
Success rate: the findings of phase 0 help in deciding whether to move ahead for phase I or
return back to preclinical trials or to drop the studies if the results are not as expected.
Phase I study
 Study Participants: 20 to 100 healthy volunteers or people with the healthy
volunteers.
 Type of partcipants: Healthy volunteers.
 Length of Study: Several months
 Purpose of study: to determine patient safety and dosage (maximum tolerated dose)
 Success rate: Approximately 70% of drugs move to the next phase
 Studies conducted: pharmacokinetics, pharmacodynamics, Route of administration.
Maximum tolerable dose (MTD dose with acceptable side effects) determination,
Food effect.
 Although usually conducted with healthy volunteers, Phase I trials are sometimes
conducted with severely or terminally ill patients, for example those with AIDS or
cancer with special permission from regulatory authority.
Phase II study
 Study Participants: Up to several hundred people with the disease/condition.
 Type of participants: diseased people with the related condition
 Length of Study: Several months to 2 years
 Purpose: actual dose and dose frequency determination, , efficacy and side effects.
 Success rate: Approximately 33% of drugs move to the next phase.
 Study design: Most Phase II studies are randomized, which means that subjects are
assigned randomly (by chance not by choice) to receive either the experimental drug,
a standard treatment or a placebo (harmless, inactive substance). Those who receive
the standard treatment or placebo are called a control group.
Phase III study:
 Design: Randomized, controlled and multi center trials
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Study Participants: 300 to 3,000 volunteers who have the disease or condition
Type of participants: diseased participants or condition.
Length of Study: 1 to 4 years
Purpose: efficacy and monitoring adverse reactions
Success rate: Approximately 25-30% of drugs move to the next phase
Once a Phase III study is completed, a pharmaceutical company can request FDA
approval to market the drug. This is called a New Drug Application (NDA). The NDA
contains all the scientific data that the company has gathered throughout the phases in
all trials.
Phase IV study
 Study Participants: Several thousand volunteers who have the disease/condition
 Types of participants: actual patients.
 Length of study: several years
 Purpose: to monitor safety and efficacy in large group after marketing of the drug.
This is also known as post marketing surveillance
 Success rate: Approximately 60-80 % of drugs continue in the market rest may be
withdrawn due to safety or efficacy failure.
D.. follow Good Clinical Practices:
GCP includes various systems and principles which must be followed during clinical trials
and provides a framework which aim to ensure the safety of research participants and the
integrity and validity of data. This will be discussed with clinical trials chapter in details.
 management system for the studies with defined responsibility
 Systematic documentation and data management
 Responsibilities of investigators
 handling of IND in controlled manner
 Responsibility of sponsor
 Proper design of research trials
 Preparation of clinical trial protocols
 investigators brochure preparation
 development of product formulation with GMP norms
 appointment of Institutional Review Board IRB for monitoring
 Recruitment of subjects and informed consent letters, compensation.
 Reporting adverse drug reactions to FDA
 system of external audits by regulatory bodies.
 calculations and reporting of results.
Innovator Product:
An innovator drug is the drug made for first time as a research product and containing its
specific active ingredient approved by regulatory authority. The product has undergone
complete set of preclinical and clinical studies including efficacy, safety and quality. The
product is usually patented for a duration of 20 years or depending upon the rules of the
country. During the patent period, other companies cannot make or sell the same drug until
the patent expires. Innovator products are also known as Reference Listed Drug (RLD) since
these are used as reference for development of the generic product and are listed as Innovator
product in the orange book.
Generic Drugs and ANDA:
Generic Drug
In simple words a Generic Drug is a perfect copy of the Patented Drug (or branded
drug or RLD Reference Listed Drug or Comparator Drug), and sold at much lower
price.
A generic drug is a medication created to be the same as an already marketed brand-name
drug (RLD) in respect of dosage form, safety, strength, route of administration, quality,
performance characteristics, and intended use. These similarities help to demonstrate
bioequivalence between the two similar products, which means that a generic medicine works
in the same way and provides the same clinical benefit as the brand-name medicine.
In applications for generic medicinal products according the concept of bioequivalence is
fundamental. The purpose of establishing bioequivalence is to demonstrate equivalence in
biopharmaceutics quality between the generic medicinal product and a reference medicinal
product in order to allow replacement of preclinical tests and of clinical trials with
Bioequivalence test.
In 1980, The government of USA decided to reduce drug prices for public. the government
passed a bill named " Drug Price Competition and Patent Term Restoration Act 1984,"
(DPC&PTRA act) also known as Hatch-Waxman Act (HWA), In the year 1984. As per this
act generic drug manufacturing was permitted and the bioequivalence became the basis for
approving ANDA applications for generic drugs marketing authorisation, in place of costly
branded drugs. In order to compensate the losses, the patent holders were given 5 years patent
term extension. Today, In the United States about 80 % prescriptions filled are for generic
drugs. Increasing the availability of generic drugs helps to create competition in the
marketplace and reduce drug price.
For getting marketing authorisation of a generic drug in US market ANDA application has to
be submitted. “An Abbreviated New Drug Application (ANDA) contains data which is
submitted to FDA for approval of a generic drug product. Once approved, the holder of
ANDA may manufacture and market the generic drug product to US market. Generic drug
applications are termed "abbreviated" because they are generally not required to conduct
preclinical studies and clinical studies and related data is not required for submission to
establish safety and effectiveness. Only bioequivalence data is to be submitted in place of
preclinical and clinical trials data. This reduces cost of product drastically.
The ANDA applicants is required to demonstrate that their product performs in the same
manner as the innovator drug. To demonstrate this bioequivalence of the generic drug is
compared with the innovator product under identical conditions, to prove the Bioequivalence
of the two products. Once, the bioequivalence is established the data can be submitted in
ANDA format to FDA for approval.
Myths about Generic Drugs
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Generics…are not as safe
Generics…are not as potent
Generics…take longer to act in the body
Generics…are made in sub-standard manufacturing facilities
Generic Drug Product development
Introduction: generic drugs should be developed as per the ICH guidelines Q8
(Pharmaceutical development) and should be documented as per the prescribed format. The
aim of pharmaceutical development is to design a quality product and its manufacturing
process to consistently manufacture good quality product. The information and knowledge
gained from pharmaceutical development studies provide scientific understanding for
establishment of the design space. The design space data is helpful in the product risk
management. The product development should be done in a manner so that quality of the
product is maintained consistently.
To achieve this objective the quality parameters for drug substances, excipients, and drug
product and process parameters, and container-closure systems, must be strictly controlled
and documented.
As discussed above, a generic drug product is essentially identical to the patented drug or
RLD drug product in terms of active ingredient(s), strength, dosage form, route of
administration, quality, safety, efficacy and performance characteristics, and therapeutic
indication.
In order to copy the innovator product and create generic product, usually following steps
will be followed.
Step-1: Selection of a product for generic development. FDA updated
quarterly, “List of Authorised Generic Products” in the Orange-book which includes the drug
trade name, the brand company manufacturer, and the date the authorized generic drug
entered the market etc. One can select suitable product from this resource on the basis of
feasibility and profitability.
Step 2: Arranging Active Pharmaceutical Ingredient same as
Innovator
Discover the source of API local or global market. The API must be same in following
aspects
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the API must have same chemical entity as RLD
The impurity profile of the API must be same and within specified limits of ICH
guidelines.
must have same physical form i.e., same polymorphs and particle size and crystal
type.
should meet all the specifications as per USP or ICH or FDA guidelines which ever
available.
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The physicochemical and biological properties of the drug substance that can
influence the performance of the drug product, should be identified and matched.
Examples of physicochemical and biological properties that might need to be
examined include solubility, water content, particle size, crystal properties, biological
activity, and permeability. These properties could be interrelated and might need to be
considered in combination.
Some variation in crystal forms is allowed if “Suitability Petition” is filed in advance
and accepted by FDA, and proved to have no adverse effect on bioavailability.
The specifications of API should be same as RLD. If a supplier for API should be
DMF holder approved by FDA. The supplier can be found from the DMF data base of
FDA.
The manufacturing plants of API must comply cGMP guidelines. The drug product
manufacturer should inspect the API plant and include as approved manufacturer if
GMP complied.
There should be a technical partnership between the API manufacturer and drug
product manufacturer and s there should be a harmony and cooperation.
Selection of excipients: The excipients chosen, their concentration, and the characteristics
that can influence the drug product performance should be considered. Compatibility of
excipients with other excipients should be established. The ability of excipients to provide
their intended functionality till shelf life, should also be established.
Analytical method Development: Development of a generic drug product is not possible
without proper analytical testing methods for API and the drug product. The DMF provided
by the API manufacturer contains details of the synthetic process, assurance of cGMP
compliance, and information on the drug substance form and purity, along with identity of
impurities listed in the API specifications and methods of analysis. These methods are to be
validated for accuracy and precision.
Next step is to develop Analytical method for drug product has to be developed and
validated by the manufacturer. Analytical method development and its validation is very
important to ensure accuracy of quality control of the developed product. Effect of excipients
on analysis has to be understood. Placebo dosage forms are prepared to nullify the effect of
excipients on the final analysis. Analytical methods are essential at every step of product
development right from R&D stage, then technology transfer and scale up activity of the
product to the manufacturing batch level.
Analytical methods are developed for stability testing and impurity analysis also which are
slightly different from the methods used for API testing or drug product testing. The FDA
recommends that all assay procedures for stability should be stability indicating. The main
objective of a stability indicating method is to monitor results during stability studies in order
to guarantee safety, efficacy and quality.
Analytical method validation: analytical methods are to be validated for following
parameters
1. accuracy, (results closeness to true value)
2. precision (repeatability),
3. specificity (should be specific for the target molecule only)
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detection limit, (ability to test low concentrations)
quantitation limit, (ability to quantify low concentrations)
linearity, (linearity at all concentrations)
range, (ability to measure accurately in the desired concentration)
robustness, (ability to withstand changes of equipment, person, place)
solution stability (stability of test solutions during analysis)
experimental formulation development:
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The formulation scientist in the generic industry has to develop dosage forms which
will match innovator products within acceptable limits of all parameters and should
not violate restrictive formulation patents.
The NDA copy of expired patent can be obtained from FDA to help in product
development.
Orange book also provides sufficient information to help product. A thorough analysis
of the RLD for physical parameters and chemical parameters must be done which will
provide a basis for developing a similar generic product.
Selection of excipients should be done carefully to get a bioequivalent product.
During product development every parameter should be properly documented so that
the results will be reproducible at the time of technology transfer and scale up.
The critical process parameters (CPP) should be carefully recorded to get
reproducible product later. Once the satisfactory product is developed it should be
critically tested at quality control and the test results are documented. Tablet hardness,
DT, and Dissolution parameters are most important hence must be matched with the
RLD. Process parameters like sieve size, batch size, mixing time, mixing speed, etc
must be validated and fixed in the manufacturing records, to ensure reproducible
batches every time.
During development stage the equipments should be selected which are similar in
principle to the scale up plant and manufacturing plant so that the scale-up process
becomes easy and results can be easily reproduced.
Assessment of quality as per written specification must be done for every batch and
the results should be within accepted limits.
The product should be kept on stability studied and documented. for 3 months testing
at desired conditions just to know the inherent stability of the product. Proper
overages should be added to match with the innovator product.
Design Space: design space is the scientific knowledge and data which is generated
during the research on product development. This includes various experiments by
changing excipients, proportions of excipients, process parameters, and related
experimental data. Working within the design space is not considered as a change
hence does not need regulatory permissions for doing small changes in the product
after approval.
Container Closure System: The choice and rationale for selection of the container
closure system for the Product should be considered. Consideration should be given to
the intended use of the drug product and the suitability of the container closure system
for storage and transportation. The choice of materials for primary packaging should
be justified. A possible interaction between product and container or label should be
studied and discussed.
Microbiological Attributes: Where appropriate, the microbiological attributes of the
drug product should be Considered including, for example: The rationale for
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performing microbial limits testing for non-sterile drug products. The selection and
effectiveness of preservative systems.
Product development report PDR: It is an important document to conclude the
stage of laboratory scale batch development and is required at the time of FDA
inspections. This report contains 1) details of innovator product characteristics 2)
detailed specifications of the API used. 3) dissolution methods used for testing 4)
details of experiments conducted to arrive at final formulation. 5) process details 6)
details of complete product analysis.
Master Manufacturing Documents MMD: this document is prepared jointly by
R&D scientist and exhibit batch incharge (Pilot Batch in-charge) using the data from
product development report PDR. The MMD is reviewed by manufacturing head also
to ensure easy scale up to manufacturing batch size. Based on MMD Batch
Manufacturing Record (BMR) is created for doing process validation on exhibit
batches (process validation batches).
Exhibit batches production (Process Validation batches): Manufacture of the exhibit batch
is the responsibility of the formulation scientist team associated with the with the scale-up or
‘‘technology transfer team”. The formulation and process should be tested by manufacturing
a optimisation batch using similar equipment as the scale-up equipment and using the same
raw materials intended for exhibit-batch manufacture to optimise the process parameters
which will be used in actual exhibit batch. Once parameters are satisfactory then three exhibit
batches are taken with identical method. All batches will be taken under cGMP conditions.
Samples will be sent at every logical stage to QC for analysis. Once released by QC the
batches are taken for packaging validation. The packed product is kept for stability testing at
desired temperature and humidity conditions for stability testing.
Cleaning validation: cleaning of process assembly should be done and cleaning method
should be validated at this stage and SOP should be finalised.
Formal stability studies: the exhibit batches (process validation batches) will be subjected to
stability studies as per the guidelines of ICH. Samples will be kept in stability chambers
maintained at 25 C, 30C, 40C at 60 % and 75 % humidity or as per product nature. The
samples will be tested for defined parameters at different time intervals and stability will be
predicted. Based on this data expiry date of the product will be determined. The data will be
part of ANDA submission.
Quality control of the exhibit batches: the exhibit batches shall be tested for quality testing
as per the approved testing methods and specifications. The data will be documented in
proper formats and will be part of submission document for ANDA. The data of the three
batches shall be reviewed for consistent results. The results of the three batches must be lying
within acceptable limits. Other designs are also used if justified.
conducting Bioequivalence studies: Two drug products containing the same drug substances
are considered bioequivalent if their relative bioavailability (BA) (rate and extent of drug
absorption) after administration in the same Molar dose lies within acceptable limits. the
studies are conducted on human volunteers in CRO clinical research organisations under
supervision of Principle Investigator. the BE study details are given below.
Submission of ANDA: based on the data obtained from the three exhibit batches
manufacturing and quality control, and bioequivalence studies, ANDA is submitted to FDA
for approval. After review ANDA documents are approved by FDA then they may ask for
plant inspection. Once plant is also approved then ANDA is granted for marketing of the
product. ANDA submission will be discussed in details in unit 3 of the syllabus.
DETERMINATION OF BIOEQUIVALENCE OF GENERIC VS RLD
Bioequivalence (BE) introduction:
For immediate release oral products, BE studies are done in -vitro by comparing the
dissolution profiles of the generic product with innovator product. Most of the other products
are compared by clinical pharmacokinetics. Furthermore, be studies are used by innovator
and generic product developers for supporting post-approval changes in the formulations.
Two drug products containing the same drug substances are considered bioequivalent if their
relative bioavailability (BA) (rate and extent of drug absorption) after administration in the
same Molar dose lies within acceptable limits.
Some products which are in category a of the biopharmaceutics classification system (bcs)
may get biowaiver from fda. This means that the comparison can be done in-vitro by
comparing dissolution profiles of the two products, and costly clinical studies can be waived
off.
GENERAL PRINCIPLES IN ESTABLISHING BIOEQUIVALENCE:
study design and conduct of BE studies:
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Study population considerations: appropriate subject population for be studies
should be selected so that the difference of bioavailability between the products can
be accurately detected. The studies should normally be performed in healthy subjects
if feasible.
Study design considerations: a randomised, single-dose, two-period, two-sequence
crossover study design is recommended when comparing two formulations, as singledose studies provide the most sensitive conditions to detect differences in the rate and
extent of absorption. Treatment periods should be separated by a sufficiently long
washout period, e.g., at least 5 elimination half-lives. In general, the highest strength
should be used in a be study. Other study designs can be used if above design is not
suitable.
Sample size considerations: the number of subjects to be included in the be study
should be based on an appropriate sample size calculation to achieve desired accuracy
level. the number of subjects in a be study should not be less than 12 for a crossover
design or 12 per treatment group for a parallel design.
Comparator and test products considerations: a comparator product is the drug
product accepted by regulatory agencies that an applicant can use to compare against
the test product in conducting a be study. The test product used in the be study should
be representative of the product to be marketed and this should be discussed in the
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documents. The test product batch size should not be less than 1/10th of proposed
commercial batch size.
Fasting and fed study conditions: be studies should be conducted under standardised
conditions that minimise variability to better detect potential pk differences between
drug products. For ir solid oral dosage forms, single-dose be studies conducted under
fasting conditions typically provide greater discrimination between the pk profiles of
two products. Therefore, for the majority of these drug products, be may be
demonstrated in a single study conducted under fasting conditions. However, if
fasting condition is not feasible than fed conditions can be used.
Dose or strength to be studied: the strength to be used in the be study depends on
the dose proportionality in pk and solubility of the drug. Generally, the highest to-be
marketed strength can be administered as a single unit. Selection of a lower strength
may also be permitted if necessary.
Moieties to be measured/ parent versus metabolite moiety: demonstration of be
should be based on the analysis of the parent drug due to better accuracy to detect a
difference between formulations than metabolite data. However, some prodrugs are
rapidly eliminated, in this situation, it is acceptable to demonstrate be based on a
primary metabolite.
Sampling: the sampling schedule in a be study should cover the concentration-time
curve, including a pre dose sample, samples in the absorption phase, frequent samples
around the expected tmax, and sufficient samples after tmax to ensure a reliable
estimate of the extent of exposure, which is achieved when auc(0-t) covers at least
80% of auc(0-inf). To permit calculation of the relevant pk parameters, a sufficient
number of samples should be collected per subject per period, distributed across all
phases of disposition.
Removal of data due to low exposure: be studies are studies with a smaller number
of subjects compared to other clinical trials. An extreme value in the dataset can have
a large impact on the outcome of the be study. Such data may be eliminated by using
statistical basis.
Concentration time data: for both the test and comparator products, the drug
concentration in a suitable biological fluid, e.g., plasma, serum or blood, determined
at each sampling time point should be tabulated for each subject participating in the
study, along with descriptive statistics. These data should be presented on the original
scale, i.e., as unadjusted, measured drug concentrations.
Pharmacokinetic analysis: for single-dose studies, the following pk parameters
should be tabulated for each subject auc(0-t), cmax, and, where applicable, pauc, and
auc(0-inf), tmax, kel, and t1/2. For single-dose studies, auc(0-t) should cover at least
80% of auc(0-inf). Summary statistics to be reported include geometric mean, median,
arithmetic mean, standard deviation, coefficient of variation, number of observations,
minimum, and maximum. Each variable should be computed using the actual time of
sampling for each concentration data point.
Bioequivalence criteria : for the majority of drug products, the pk parameters to
demonstrate be include cmax and auc(0--t). For drugs with a long elimination halflife, auc(0‐72h) may be used in place of auc(0-t). The 90% confidence interval for the
geometric mean ratio of these pk parameters used to establish be should lie within a
range of 80.00 - 125.00%.
DOCUMENTATION:
The report of the be study should include the complete documentation of its protocol, conduct
of studies and testing. It should be written in accordance with ich guidelines, including
names and affiliations of the responsible investigator(s), the site of the study, and the period
of its execution should be stated.
 Comparator product name, strength, pharmaceutical form, batch number,
manufacturer, expiration
 Date, and country of purchase should be stated.
 Certificates of analysis, or equivalent documents, of comparator and test batches used
in the study should be included in an appendix to the study report.
 The identity of the of the test product(s) used in the study should be provided, i.e.,
pharmaceutical form, strength, batch number, and measured content (% of label
claim).
 The batch size, manufacturing date (and, if available, the expiry date) as well as the
qualitative and quantitative composition of the test product should also be indicated
in the ctd format.
 Concentrations and PK data and statistical analyses should be presented in the level of
detail
 the reporting format should include tabular and graphical presentations showing
individual and mean results and summary statistics.
 Information on bioanalytical method validation and study sample analysis should be
included in the appropriate section of module 5 of the ctd.
Glossary
Applicant: the entity submitting the application for marketing authorisation to the relevant
regulatory authority.
Auc: area under the concentration vs. Time curve
auc (0-inf): area under the concentration vs. Time curve extrapolated to infinity auc (0-t):
Area under the concentration vs. Time curve from time zero to the time of last quantifiable
concentration
Auc (0-tauss): area under the concentration vs. Time curve for one dosing interval at steady
state
Auc(0-72h): area under the concentration vs. Time curve from time 0 to 72 hours
Comparator (product): a comparator product is the drug product accepted by regulatory
agencies that an applicant can use to compare against the test product in conducting a be
study.
Enantiomers: compounds with the same molecular formula as the drug substance, which
differ in the spatial arrangement of atoms within the molecule and are nonsuperimposable
mirror images.
Immediate-release: allows the drug to dissolve in the gi contents, with no intention of
delaying or prolonging the dissolution or absorption of the drug.
Protocol: a document that describes the objective(s), design, methodology, statistical
considerations, and organisation of a trial. The protocol usually also gives the background
and rationale for the trial.
Sponsor: an individual, company, institution, or organisation which takes responsibility for
the initiation, management, and/or financing of a clinical trial.
Tmax: time to maximum observed concentration
T1/2: half-life
QUESTIONS:
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Write a note on various steps involved in new drug discovery.
Write notes on drug development process
Write notes on preclinical / non clinical studies in drug development.
Write detailed note on clinical studies process.
Write a note on generic products and differentiate with innovator product
write a note on the process of generic development with types of ANDA applications
with time lines for various steps
write detailed note on bioequivalence studies
Write a note on Drug price Competition and Patent Term Restoration Act.
Write a note on Hatch Waxman Amendments 1984.
Discuss phase III of clinical trials in detail.
Write a note on preclinical evaluation process.
Give different types of Toxicity Studies. Give a note on Immunotoxicity and
Genotoxicity
Write a note on Phase 0.
outline the main components of an IND application.
write a note on various stages of drug discovery.
write a time line and cost involved in New drug discovery and development.
write short note on: hit molecules, lead molecules, high throughput screening, virtual
screening, lead molecule optimisation, pharmacodynamics, pharmacokinetics,
carcinogenicity, genotoxicity, reproductive toxicity, safety, efficacy, GLP, NOAEL, IND,
placebo controlled studies, single blind studies, double blind studies, RLD, innovator product,
comparator product, FDA, ANDA, NDA, Generic Drugs, CPP, stability study, PDR, MMD,
exhibit batch, process validation, cleaning validation, bioequivalence, AUC, Cmax, T max,
half life.