Lecture 1

Quality control, assurance and management of various parameters for achieving quality
pharmaceutical products.

This course deals with the basic need of quality in the manufacturing of Pharmaceutical
products and it's build up with the help of quality control and quality assurance management.

Various current Good Manufacturing Practices (cGMP) to be followed in a pharmaceutical

organization and its validation procedure are part of the course.

This course also covers the regulatory procedures applicable in clinical trials and approval of
new drug products

Understanding the regulations, requirements, procedures and applications of new drug approval
process

New Drug Approval Process

Pre-clinical studies
Brochure preparation for IND & ANDA
Management of clinical studies

Overview of quality control and validation process in a pharmaceutical industry

Introduction

Interrelation of factors influencing quality and customer acceptability of Pharmaceutical products

Quality & factors affecting Quality

Quality improvement techniques

Quality Control and Quality Assurance

Application of statistical approaches for quality control

Quality Control Charts

Concepts and tools for effective implementation of TQM

Total Quality Management (TQM)

Understanding the significance and implementation of Good Laboratory Practices

QC laboratory- Rules & Regulations

Points to cover
Concepts and tools in the planning, implementation and control of current Good Manufacturing
Practices in the Pharmaceutical industry

Good Manufacturing Practices

Organization & Personnel
Buildings & Facilities
Equipment
Components, Containers & Closures
Production & Process control
Packaging & Labeling control
Laboratory controls- Reports & Records
Return Goods & Relabeling

Points to cover
Quality audit (means and mechanism) as a tool for manufacturing and quality control system
development

Quality Audit

Process and significance of ISO certification

ISO certification

Points to cover
Concepts, tools, methods and statistical application in validation of various areas in a Pharmaceutical
industry

Pharmaceutical Process Validation

Organization

Pharmaceutical Products (Solid dosage forms and Sterile products)

Prospective validation

Retrospective validation & Analysis

Raw material validation

Analytical method validation

Drug Discovery and Development

A drug is any substance that alters normal bodily function.

OR

A chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to
otherwise enhance physical or mental well-being.

What is Drug Discovery?

The process by which new chemicals that might have specific biological activity are
developed.
The chemicals are examined to see if they are active using some assay or biological
marker to determine if they might be useful clinically.
Goals of Drug Discovery
To develop a drug that will benefit patients, satisfy prescribers and earn profits for the
company.
Drug development is not always successful, but when it does lead to a new drug
available to patients and doctors, it is a very satisfying endeavor.
Reasons for Medication Use
Prevention
Vaccines
Antimalaria agents
Antibiotic prophylaxis
Curative
Antibacterial
 Oncology drugs
Antifungal
Control of Disease Process
Antihypertensives
Antidiabetics
Thyroid agents
Palliation
Analgesics
Oncology drugs
Life Cycle of a Drug:

Life Cycle of a Drug

The Pyramid of Uncertainty

For every 10000 chemicals screened, only 1000 show some biological activity

Of these 1000, only 10 will/may advance so far as to be administered to humans

Only 1 may reach the market place

The approximate cost of developing a new drug, from the concept to the market is
approx. US$1000+ million
Therefore the process of drug discovery is fraught with great uncertainty and financial
burden
For every 10000 chemicals screened, only 1000 show some biological activity

Of these 1000, only 10 will/may advance so far as to be administered to humans

Only 1 may reach the market place

The approximate cost of developing a new drug, from the concept to the market is
approx. US$1000+ million
 Therefore the process of drug discovery is fraught with great uncertainty and financial
burden
Ensuring Drugs Are Safe and Effective
The path a drug travels from a lab to your medicine cabinet is usually long, and every drug
takes a unique route.
Often, a drug is developed to treat a specific disease.
An important use of a drug may also be discovered by accident- Penicillin.
Retrovir (zidovudine, also known as AZT) was first studied as an anti-cancer drug in the
1960s with disappointing results.
Twenty years later, researchers discovered the drug could treat AIDS, and Food and Drug
Administration approved the drug, manufactured by GlaxoSmithKline, for that purpose in
1987.
Most drugs that undergo preclinical (animal) testing never even make it to human testing and
review by the FDA.
Drugs must undergo the agency's rigorous evaluation process
which scrutinizes everything about the drug--from the design of clinical trials
to the severity of side effects to the conditions under which the drug is
manufactured.
Stages of Drug Development and Review
Sponsors--companies, research institutions, and other organizations that take responsibility
for developing a drug- Target Identification.
They must show the FDA results of preclinical testing in laboratory animals and what they
propose to do for human testing.
At this stage, the FDA decides whether it is reasonably safe for the company to move forward
with testing the drug in humans.
Pre-clinical Studies
Extensive Toxicological Tests and Animal Experiments are conducted to determine
efficacy and safety of the compound to predict its efficacy and safety in Humans.
They are conducted to ascertain that the drug may be tested safely in Human and may
be effective in specific Human Disease state.
Objectives of Pre-clinical Studies
Predict Human Efficacy

Predict Toxicity in Human

Predict Availability of Drug Concentration in Human Blood

Deciding New Dosage Forms and Formulation

Pre-clinical Studies help to

Pharmacodynamics (PD)
 Primary Pharmacodynamics: studies on mode of action and/or effects of a
substance to its desired therapeutic effects
Secondary Pharmacodynamics: effects of a substance not related to its desired
therapeutic target
Safety pharmacology (S7A and S7B ICH guideline)

Pharmacokinetics and metabolism (S3A and S3B ICH guideline)

Toxicology (S4 ICH guideline)
Secondary pharmacology data
Secondary pharmacology studies evaluate compounds for pharmacodynamic activity against
a broad range of targets that are related to or distinct from the intended therapeutic target.
Information on the potency of a drug for a given biological target can be used to assess
potential liability for off-target effects, and influence early clinical trial design, dose selection
and patient monitoring.
Although secondary pharmacology data are often included early in the drug submission
process as part of a standard safety pharmacology screen:
there is variability in the timing,
type,
extent and format of secondary pharmacology data submitted to regulatory
agencies
Regulatory assessment of in vitro secondary pharmacology data
Various protocols for secondary pharmacology studies are commonly available and generally
consist of binding assays, functional assays and enzyme assays, all of which provide
important information regarding the pharmacological activity of a drug and possible
unanticipated side effects that may be seen in humans.
Regulatory assessment of in vitro secondary pharmacology data
The panels of targets that are employed vary widely and are often selected without
justification or a description of their relevance to human safety.
In such cases, a repeat of the study may be recommended using a more appropriate selection
of clinically relevant targets.
It is useful to determine whether a drug shares similar off-target activity with other drugs in
the class for example, the sedative and anticholinergic properties of certain histamine H1
receptor antagonists so that such side effects in humans can be better anticipated and
monitored.
Regulatory assessment of in vitro secondary pharmacology data
Correlations between positive secondary pharmacology results and results seen in animals
may be used to determine whether in vitro activity translates to possible human risk under
therapeutic conditions.
It is important to note that in vitro panels generally use human-specific targets, and in vitro
results may not always correlate with those observed in animals.
Regulatory assessment of in vitro secondary pharmacology data
Correlations between in vitro half-maximal inhibitory concentration (IC50) or inhibition
constant (Ki) values with in vivo plasma drug levels are also used to assess possible effects at
therapeutic exposures.
The closer the IC50 or Ki values are to plasma drug levels, the more likely the clinical effect.
Use of focused profiling may be recommended to address specific issues of concern, such as
the safety of active drug metabolites or unique major human metabolites not formed in
animals but found during subsequent clinical testing.
Drug Assay
Chemical: estimation of the active constituents by means of the chemical method
Biological Assays: estimation of the active constituents in biological samples
Radioimmunoassay
ELISA
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of localizing proteins in cells of a
tissue section exploiting the principle of antibodies binding specifically to antigens in
biological tissues
Immunohistochemical staining is widely used in the diagnosis of cancer

Specific molecular markers are characteristic of particular cancer types. IHC is also
widely used in basic research to understand the distribution and localization of
biomarkers in different parts of a tissue
Visualizing an antibody-antigen interaction can be accomplished in a number of ways

In the most common instance, an antibody is conjugated to an enzyme, such as

peroxidase, that can catalyse a colour-producing reaction (immunoperoxidase
staining)
Alternatively, the antibody can also be tagged to a fluorophore, such as FITC,
rhodamine, or Texas Red, (immunofluorescence)
The latter method is of great use in confocal laser scanning microscopy, which is
highly sensitive and can also be used to visualise the interactions between multiple
proteins
ELISA
The Enzyme-Linked ImmunoSorbent Assay, or ELISA, is a biochemical technique
used mainly in immunology to detect the presence of an antibody or an antigen in a
sample. It uses two antibodies.
One antibody is specific to the antigen. The other reacts to antigen-antibody
complexes, and is coupled to an enzyme. This second antibody, which accounts for
"enzyme-linked" in the test's name, can also cause a chromogenic or fluorogenic
substrate to produce a signal.
Because the ELISA can be performed to evaluate either the presence of antigen or the
presence of antibody in a sample, it is a useful tool both for determining serum
antibody concentrations (such as with the Human Immunodeficiency Virus, HIV test)
and also for detecting the presence of antigen.
Western Blotting
A western blot (immunoblot) is a method in molecular
biology/biochemistry/immunogenetics to detect protein in a given sample of tissue
homogenate or extract.
It uses gel electrophoresis to separate denatured proteins by mass.

The proteins are then transferred out of the gel and onto a membrane (typically
nitrocellulose), where they are "probed" using antibodies specific to the protein.
As a result, researchers can examine the amount of protein in a given sample and
compare levels between several groups
Animal Toxicity Studies
Immunotoxicity (S8 ICH guideline)
Systemic Toxicity Studies (S4 ICH guideline)
Single Dose
Repeated Dose
Local Toxicity Studies (S4 ICH guideline)
Specialized toxicity studies
Male fertility Studies (S5 ICH guideline)
Female reproduction and fetal development (Teratogenecity) (S5)
Carcinogenicity (S1A-S1C ICH guideline)
Genotoxicity (S2 ICH guideline)
Safety Evaluation Information
Starting dose

Parameters for potential A.D.R (adverse drug reaction)

Ethical and scientific justification to expose human to new drug and helps to plan the
clinical trials
Preclinical trial data is one of the requirements used for Investigational New drug
application submission
Basic process for a new drug approval

Investigational New Drug (IND) Application

Its an application filed to the FDA in order to start clinical trials in humans if the drug was
found to be safe from the reports of Preclinical trials. A firm or institution, called a Sponsor,
is responsible for submitting the IND application.

New Drug Application (NDA)

If clinical studies confirm that a new drug is relatively safe and effective, and will not pose
unreasonable risks to patients, the manufacturer files a New Drug Application (NDA), the
actual request to manufacture and sell the drug.
Abbreviated New Drug Application (ANDA)

Its an application made for approval of Generic Drugs. Generic drug manufacturers must
demonstrate that their product is the same as, and bioequivalent to, a previously approved
brand name product.

Investigational New Drug (IND) Application

Its an application filed to the FDA in order to start clinical trials in humans if the drug was
found to be safe from the reports of Preclinical trials. A firm or institution, called a Sponsor,
is responsible for submitting the IND application.

Stages of Drug Development and Review

Clinical Trials

Drug studies in humans can begin only after an IND is reviewed by the FDA and a local
institutional review board (IRB).

The board is a panel of scientists and non-scientists in hospitals and research institutions that
oversees clinical research.

IRBs approve the clinical trial protocols, which describe the type of people who may
participate in the clinical trial, the schedule of tests and procedures, the medications and
dosages to be studied, the length of the study, the study's objectives, and other details.

During a new drug's early preclinical development, the sponsor's primary goal is to:

determine if the product is reasonably safe for initial use in humans,

and if the compound exhibits pharmacological activity that justifies

commercial development.

When a product is identified as a viable candidate for further development:

the sponsor then focuses on collecting the data and information necessary to
establish that the product will not expose humans to unreasonable risks when
used in limited, early-stage clinical studies.

FDA's role in the development of a new drug begins when the drug's sponsor (usually
the manufacturer or potential marketer), having screened the new molecule for
pharmacological activity and acute toxicity potential in animals, wants to test its
diagnostic or therapeutic potential in humans.

At that point, the molecule changes in legal status under the Federal Food, Drug, and
Cosmetic Act and becomes a new drug subject to specific requirements of the drug
regulatory system.

Who Can Apply for an IND?

IND applicant is called: Sponsor

Person/Organization who takes responsibility for and initiates a clinical

investigation

IND Sponsor may be a company, institution, or individual

 Investigator conducts the clinical study

Sponsor-Investigator both initiates and conducts the clinical investigation

Must be an individual

Types of IND

An Investigator IND:

is submitted by a physician who both initiates and conducts an investigation,

and under whose immediate direction the investigational drug is administered
or dispensed.

A physician might submit a research IND to propose studying an unapproved

drug, or an approved product for a new indication or in a new patient
population.

Emergency Use IND:

allows the FDA to authorize use of an experimental drug in an emergency

situation that does not allow time for submission of an IND in accordance with
21CFR , Sec. 312.23 or Sec. 312.34.

It is also used for patients who do not meet the criteria of an existing study
protocol, or if an approved study protocol does not exist.

Classification of IND

Commercial

o Permits sponsor to collect data on clinical safety and effectiveness needed for
application for marketing in the form of NDA

Research (non-commercial)

o Permits the sponsor to use drug in research to obtain advanced scientific

knowledge of new drug

o No plan to market the product

The IND application must contain information in three broad areas:

1. Animal Pharmacology and Toxicology Studies -

Preclinical data to permit an assessment as to whether the product is reasonably safe

for initial testing in humans.

Also included are any previous experience with the drug in humans

2. Manufacturing Information -

Information pertaining to the composition, manufacturer, stability, and

controls used for manufacturing the drug substance and the drug product.

This information is assessed to ensure that the company can adequately

produce and supply consistent batches of the drug.
3. Clinical Protocols and Investigator Information

Detailed protocols for proposed clinical studies to assess whether the initial-
phase trials will expose subjects to unnecessary risks.

Information on the qualifications of clinical investigators-generally physicians

who oversee the administration of the experimental compound--to assess
whether they are qualified to fulfill their clinical trial duties.

Finally, commitments to obtain informed consent from the research subjects,

to obtain review of the study by an institutional review board (IRB), and to
adhere to the investigational new drug regulations

IND Application

Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any
clinical trials.

During this time, FDA has an opportunity to review the IND for safety to assure that research
subjects will not be subjected to unreasonable risk.

Format of IND

A. Cover sheet (Form FDA-1571)

o Name, address, telephone of sponsor

o Identification of phases

o Commitment not to begin CT until IND approval

o Commitment by IRB- Form 56

o Commitment for conducting CT- accordance with regulations

o Name, title Monitor

o Name, title person(s) for reviewing

o Name, Address of CRO, if any

o Signature of sponsor

B. Table of contents

C. Introductory statement & general investigational plan

D. Investigators brochure

E. Study protocol

F. Investigator facilities & IRB data

G. Chemistry manufacturing & control data

H. Pharmacology & toxicology data

I. Previous human experience

 IND Review Process

IND Review Process

Code of Federal Regulations (CFR)

The final regulations published in the Federal Register (daily published record of proposed
rules, final rules, meeting notices, etc.) are collected in the Code Of Federal Regulations
(CFR).
The CFR is divided into 50 titles that represent broad areas subject to Federal regulations.
The FDA's portion of the CFR interprets the The Federal Food, Drug, and Cosmetic Act and
related statutes. Section 21 of the CFR contains most regulations pertaining to food and
drugs.
The regulations document all actions of all drug sponsors that are required under Federal law
Subpart AGeneral Provisions
312.1 Scope.

312.2 Applicability.
 312.3 Definitions and interpretations.

312.6 Labeling of an investigational new drug.

312.7 Promotion and charging for investigational drugs.

312.10 Waivers.

312.1 Scope
This part contains procedures and requirements governing the use of investigational new
drugs, including procedures and requirements for the submission to, and review by, the Food
and Drug Administration of investigational new drug applications (INDs).
An investigational new drug for which an IND is in effect in accordance with this part is
exempt from the premarketing approval requirements that are otherwise applicable and may
be shipped lawfully for the purpose of conducting clinical investigations of that drug
312.3 Definitions and interpretations.
Contract research organization:
means a person that assumes, as an independent contractor with the sponsor,
one or more of the obligations of a sponsor, e.g., design of a protocol,
selection or monitoring of investigations, evaluation of reports, and
preparation of materials to be submitted to the Food and Drug Administration.
Clinical investigation:
means any experiment in which a drug is administered or dispensed to, or used
involving, one or more human subjects.
312.3 Definitions and interpretations.
Investigator:
Investigator means an individual who actually conducts a clinical investigation
(i.e., under whose immediate direction the drug is administered or dispensed to
a subject).
In the event an investigation is conducted by a team of individuals, the
investigator is the responsible leader of the team.
Subinvestigator includes any other individual member of that team., or used
involving, one or more human subjects.
312.3 Definitions and interpretations.
Subject:
Subject means a human who participates in an investigation, either as a
recipient of the investigational new drug or as a control.
A subject may be a healthy human or a patient with a disease.
312.3 Definitions and interpretations.
Sponsor:
Sponsor means a person who takes responsibility for and initiates a clinical
investigation.
 The sponsor may be an individual or pharmaceutical company, governmental
agency, academic institution, private organization, or other organization.
The sponsor does not actually conduct the investigation unless the sponsor is a
sponsor-investigator.
Subpart BInvestigational New Drug
Application (IND)
312.20 Requirement for an IND.

312.21 Phases of an investigation.

312.22 General principles of the IND submission.

312.23 IND content and format.

312.30 Protocol amendments.

312.31 Information amendments.

312.32 IND safety reports.

312.33 Annual reports.

312.34 Treatment use of an investigational new drug.

312.35 Submissions for treatment use.

312.36 Emergency use of an investigational new drug.

312.38 Withdrawal of an IND.

312.20 Requirement for an IND.

(a) A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical
investigation with an investigational new drug
(b) A sponsor shall not begin a clinical investigation subject to 312.2(a) until the
investigation is subject to an IND which is in effect in accordance with 312.40.
Such a clinical investigation is not permitted to proceed without the prior written
authorization from FDA.
FDA shall provide a written determination 30 days after FDA receives the IND or
earlier.
Elements of an IND Application
Form FDA 1571 21 CFR 312.23(a)(1)
Table of Contents 21 CFR 312.23(a)(2)
Introductory statement and general investigational plan
21 CFR 312.23(a)(3)
Investigators Brochure 21 CFR 312.23(a)(5)
Protocols 21 CFR 312.23(a)(6)
Product/CMC information 21 CFR 312.23(a)(7)
Pharmacology/Toxicology information 21 CFR 312.23(a)(8)
 Previous human experience 21 CFR 312.23(a)(9)
Additional Information 21 CFR 312.23(a)(10)
Form FDA-1571
Cover sheet containing information about the Sponsor and submission components
Required for original submission
Recommended but not required for amendments
Available at:

http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.h
tm
Subpart AGeneral Provisions
312.1 Scope.

312.2 Applicability.

312.3 Definitions and interpretations.

312.6 Labeling of an investigational new drug.

312.7 Promotion and charging for investigational drugs.

312.10 Waivers.

312.1 Scope
This part contains procedures and requirements governing the use of investigational new
drugs, including procedures and requirements for the submission to, and review by, the Food
and Drug Administration of investigational new drug applications (INDs).
An investigational new drug for which an IND is in effect in accordance with this part is
exempt from the premarketing approval requirements that are otherwise applicable and may
be shipped lawfully for the purpose of conducting clinical investigations of that drug
312.3 Definitions and interpretations.
Contract research organization:
means a person that assumes, as an independent contractor with the sponsor,
one or more of the obligations of a sponsor, e.g., design of a protocol,
selection or monitoring of investigations, evaluation of reports, and
preparation of materials to be submitted to the Food and Drug Administration.
Clinical investigation:
means any experiment in which a drug is administered or dispensed to, or used
involving, one or more human subjects.
312.3 Definitions and interpretations.
Investigator:
Investigator means an individual who actually conducts a clinical investigation
(i.e., under whose immediate direction the drug is administered or dispensed to
a subject).
 In the event an investigation is conducted by a team of individuals, the
investigator is the responsible leader of the team.
Subinvestigator includes any other individual member of that team., or used
involving, one or more human subjects.
312.3 Definitions and interpretations.
Subject:
Subject means a human who participates in an investigation, either as a
recipient of the investigational new drug or as a control.
A subject may be a healthy human or a patient with a disease.
312.3 Definitions and interpretations.
Sponsor:
Sponsor means a person who takes responsibility for and initiates a clinical
investigation.
The sponsor may be an individual or pharmaceutical company, governmental
agency, academic institution, private organization, or other organization.
The sponsor does not actually conduct the investigation unless the sponsor is a
sponsor-investigator.
Subpart BInvestigational New Drug
Application (IND)
312.20 Requirement for an IND.

312.21 Phases of an investigation.

312.22 General principles of the IND submission.

312.23 IND content and format.

312.30 Protocol amendments.

312.31 Information amendments.

312.32 IND safety reports.

312.33 Annual reports.

312.34 Treatment use of an investigational new drug.

312.35 Submissions for treatment use.

312.36 Emergency use of an investigational new drug.

312.38 Withdrawal of an IND.

312.20 Requirement for an IND.

(a) A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical
investigation with an investigational new drug
(b) A sponsor shall not begin a clinical investigation subject to 312.2(a) until the
investigation is subject to an IND which is in effect in accordance with 312.40.
 Such a clinical investigation is not permitted to proceed without the prior written
authorization from FDA.
FDA shall provide a written determination 30 days after FDA receives the IND or
earlier.
Elements of an IND Application
Form FDA 1571 21 CFR 312.23(a)(1)
Table of Contents 21 CFR 312.23(a)(2)
Introductory statement and general investigational plan
21 CFR 312.23(a)(3)
Investigators Brochure 21 CFR 312.23(a)(5)
Protocols 21 CFR 312.23(a)(6)
Product/CMC information 21 CFR 312.23(a)(7)
Pharmacology/Toxicology information 21 CFR 312.23(a)(8)
Previous human experience 21 CFR 312.23(a)(9)
Additional Information 21 CFR 312.23(a)(10)
Form FDA-1571
Cover sheet containing information about the Sponsor and submission components
Required for original submission
Recommended but not required for amendments
Available at:

http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.h
tm