Development of Clinical Formulation

1Aditya Bangalore Institute of Pharmacy Education and Research29/11/2018
Dr. Basavaraj K. Nanjwade
Principal Scientist
Trroy Life Sciences Pvt Ltd
C-14, New Town Yelhanka
Bangalore-560064, Karnataka, India
DEVELOPMENT OF CLINICAL
DRUG PRODUCT

CONTENT
• All dosage forms
• Clinical Pharmacology
• Clinical Pharmacokinetics
• Clinical Pharmacodynamics
• Clinical dose range,
• Clinical Trials
• Clinical Packaging (Primary)
• Clinical Packaging (Secondary)
• Clinical Storage & Distribution
• Quality by Design (QbD)
• Clinical Design Space

All dosage forms
• Immediate and modified release capsules
• Immediate and modified release tablets
• Fixed dose combination products
• Powder/granule filled sachets
• Multi-particulates (bead/pellets into capsules)
• Minitablets
• MUPS (Multiple Unit Pellet System)

Clinical Pharmacology
• Clinical Pharmacology promotes the rational use of
medications in humans by studying their restorative
effect to amplify the drugs effect and reduce the side
effects.
• Clinical Pharmacology educates healthcare
professionals on a range of topics that involve the
interaction between drugs and humans.

Clinical Pharmacology

Pharmacokinetics
• Drug design, development and formulation strategies
used to optimise binding site interactions of modified
lead compounds were described earlier.
• A compound with optimised binding site interactions
may be susceptible to enzymatic degradation.
• Methods used to improve drug absorption, distribution,
site-specificity, and metabolic stability must be used
alongside strategies used to improve binding site
interactions.
Aditya Bangalore Institute of Pharmacy Education and Research 629/11/2018

Clinical Pharmacokinetics

Drug Formulation for Oral Route
• Log P is less than +5
• Molecular mass is less than 500 Da
• Hydrogen bond acceptors must not be greater than
10
• Hydrogen bond donors must not be greater than 5

Formulation and Development

Clinical Pharmacodynamics
• The drug with tissue receptors located either in cell
membranes or in the intracellular fluid.
• Some drugs acting at the same receptor (or tissue)
differ in the magnitude of the biological responses
that they can achieve (i.e. their 'efficacy') and the
amount of the drug required to achieve a response
(i.e. their 'potency').

Clinical Pharmacodynamics

Clinical dose range
• A typical dose-ranging study may include four
groups: a placebo group, low-dose group, medium-
dose group and a high-dose group.
• The maximum tolerable dose (MTD) information is
necessary to be able to design such groups and
therefore dose-ranging studies are usually designed
after the availability of MTD information.

Clinical dose range

Clinical Trials
• Clinical trials are research studies performed in
people that are aimed at evaluating a medical,
surgical, or behavioral intervention.
• They are the primary way that researchers find out if
a new treatment, like a new drug or diet or medical
device (for example, a pacemaker) is safe and
effective in people.

Phases of Clinical Trials
• Clinical trials advance through four phases to test a
treatment, find the appropriate dosage, and look for
side effects.
• Clinical trials of drugs are usually described based on
their phase.
• The FDA typically requires Phase I, II, and III trials
to be conducted to determine if the drug can be
approved for use.

Clinical Trials

Phase I Clinical Trial
(INITIAL SAFETY TESTING IN A SMALL GROUP OF HEALTHY VOLUNTEERS )
• In Phase I trials the candidate drug is tested in people for the first
time.
• These studies are usually conducted with a small number of healthy
volunteers, generally 100 or less.
• The main goal of a Phase I trial is to assess the safety of the
medicine when used in humans.
• Researchers look at the pharmacokinetics of a drug: How is it
absorbed?
• How is it metabolized and eliminated from the body?
• They also study the drug’s pharmacodynamics: Does it cause side
effects?
• These closely monitored trials are designed to help researchers
determine what the safe dosing range is and if the candidate
medicine should move on to the next stage of development.

Phase I
• Patients: 20 to 100 healthy volunteers or people with
the disease/condition.
• Length of Study: Several months
• Purpose: Safety and dosage
• Percentage of Drugs that Move to the next Phase
70%

Study Types Included
• Safety & Tolerability studies (Single/ multiple dose in
patients or healthy volunteers)
• Oncology studies in patients with tolerability / MTD
as primary endpoint (efficacy might be a secondary
endpoint)
• Drug-Drug interaction & Food Effect
• PK in renal or hepatic impaired patients

Phase II Clinical Trial
(ASSESS SAFETY AND EFFICACY IN A SMALL GROUP OF PATIENTS)
• In Phase II trials researchers evaluate the candidate
drug’s effectiveness in 100 to 500 patient volunteers
with the disease or condition under study.
• Researchers also analyze optimal dose strength and
schedules for using the drug and examine the possible
short-term side effects (adverse events) and risks
associated with the drug.
• If the drug continues to show promise, they prepare
for the much larger Phase III trials.

Phase II
• Phase IIA: Exploratory (non-pivotal) study that has
clinical efficacy, Pharmacodynamics or biological
activity as primary endpoint, conducted in patients or
healthy volunteers.
• Phase IIB: Definite dose range finding study in
patients with efficacy as primary endpoint.

Phase II
• Patients: Up to several hundred people with the
disease/condition.
• Length of Study: Several months to 2 years
• Purpose: Efficacy and side effects
• Percentage of Drugs that Move to the Next Phase
33%

Study Type Included
• Proof of concept, efficacy, or mechanism
• Mechanistic studies
• Dose range exploration
• Pilot studies
• Definite dose finding studies
• Extension studies of Phase IIB studies

Phase III Clinical Trial
(DEMONSTRATE SAFETY AND EFFICACY IN A LARGE GROUP OF PATIENTS)
• Phase III trials generate statistically significant data about
the safety, efficacy and the overall benefit-risk
relationship of the investigational medicine.
• Phase III trials may enroll 100 to 5,000 patients or more
across numerous clinical trials sites around the world.
• This phase of research is essential in determining whether
the drug is safe and effective.
• It also provides the basis for labeling instructions to help
ensure proper use of the drug (e.g., information on
potential interactions with other medicines, specific
dosing instructions, etc.)

Phase III
• Patients: 100 to 5000 volunteers who have the
disease or condition
• Length of Study: 1 to 4 years
• Purpose: Efficacy and monitoring of adverse
reactions
• Percentage of Drugs that Move to the Next Phase
25-30%

Phase III
• Phase IIIA: A Pivotal study that is a trial designed &
executed to get statistically significant evidence of
efficacy and safety as required NDA/ sNDA approval. It
also provides the basis for labeling instructions to help
ensure proper use of the drug (e.g., information on
potential interactions with other medicines, specific
dosing instructions, etc.)
• Phase IIIB: A study started prior to approval and whose
primary intention is support of publications rather than
registration or label changes. The results are not intended
to be included in the submission dossier.

Study Time Included
• Pivotal studies (vs placebo/comparator)
• Long term safety studies for registration
• Local registration studies
• Post marketing study commitments
• Phase IIIA extension studies
• Studies intended to support publication, claims or
to prepare launch, which start before approval but
are not intended for Regulatory submissions

Phase IV
• Phase IV: A study started after approval with primary
intention to support publications rather than
registration or label changes.
• The results are not intended to be included in a
submission dossier.

Phase IV Clinical Trial
• Patients: Several thousand volunteers who have the
disease/condition
• Purpose: Safety and efficacy

Clinical Packaging (Primary)
• Blistering
• Wallet Cards
• Bottling
• Enhanced Containment and Potent Products

Blistering

Wallet Cards

Bottling

Enhanced Containment and
Potent Products

Clinical Packaging (Secondary)
• Secondary Labelling and Kitting of Clinical Supplies
• Flexible Clinical Supply Solutions
• Label Generation, Printing and Checking
• Biological Products

Clinical Storage & Distribution
• Storage
• Distribution
• Global Depot Network
• Direct-to-patient

Steps in Pharmaceutical Products

Quality by Design (QbD)
• QbD became the answer to assisting both the industry
and FDA to move toward a more scientific, risk-
based, holistic and proactive approach to
pharmaceutical development.
• In the QbD paradigm, a product is designed so that it
will meet its desired clinical performance.

Medicines research

Clinical Design Space
• The concept of clinical design space can be used to
quantify the clinical experience with a product.
• The size of the clinical design space for a given
product will depend on the number of manufactured
lots put in the clinic.

THANK YOUE-mail: nanjwadebk @gmail.com

Development of Clinical Formulation

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