PDDS 211 - Pharmaceutical Dosage Form, Drug Delivery System & Medical Devices

Prelims Lecture
Topic 2: • Additional clinical studies
➤ Phase V
New Drug Development Process
• performed to special population, pediatrics or
geriatrics

Source of New Drug

- Plant kingdom
- Animal sources
- Microbiological world
- Biological source
Plant Source
Reserpine
3 Major Steps - Rauwolfia serpentina
1. Molecule Discovery & - (reserpine) tranquilizer and hypotensive
Characterization agent
• Reserpine and Vinca – indole alkaloids
Ex. Vincristine- Indole Alkaloids; anticancer
Vinca rosea (Periwinkle)
2. Pre-clinical
- Vinca rosea
– performed in the laboratory using test animals.
- Vinblastin and Vincristine
IND (Investigational new Drug) – should be
- For cancer
approved first
➤ Phase I (70%investig. drugs survive) Pacific Yew Tree
• safety of the new drug; performed to healthy - Taxus brevifolia
individuals; this phase takes 6-9 months - For ovarian cancer
• 20 – 100 healthy volunteer • Pacific – paclitaxel – ovarian cancer
• Tolerance and safety
• Toxicological studies Animal Source
➤ Phase II • Endocrine glands of cattle, sheep and swine
• participants with disease; dosage strength, ▫ Thyroid extract, insulin and pituitary hormone
correct dosage form; this phase takes 6 months (replacement therapy)
to 3 years • Pregnant mares
• SB – single blinded – test to which participants ▫ Source of estrogens
don’t know their group • Embryo - vaccines
• DB – double blinded – both of the researchers
and participant don’t know who was Microbiological Source
administered with placebo and active drug - penicillin, cephalosphorin, tetracyclines,
• 100 – 300 first controlled studies on patients aminoglycosides, lovastatin (aspergillus
• Efficacy and therapeutic index terreus)
➤ Phase III (10% investing. drugs survive)
• assess the efficacy and ADR (Adverse Drug Genetic engineering
Reaction);this phase takes 1-5 years
● Recombinant DNA – performed by joining
• The longest among all the phases takes (5
DNA, manufactured of insulin and vaccine,
years)
somatostatin – human growth hormone
• submit NDA – should not be approved
● Monoclonal Antibody production –
• 1000 – 3000 extended clinical trials
performed in lab using human tissue cultures,
• dose, efficacy, toxicity and side effects
employed in treatment of cancer
• Performed with the final dosage form
developed in phase II
• Side effects are monitored
➤ Phase IV
• “real use” of molecule;product recall (100 -
1000 people’s)
• Post marketing studies
• Drug product may be improved
▫ Modification on drug formulation as obtained
from manufacturing scale-up and validation
process may be done

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 PDDS 211 - Pharmaceutical Dosage Form, Drug Delivery System & Medical Devices
Prelims Lecture
Goal Drug
• Produce specifically the desired effect
• Administered by the most desired route
• Minimal dosage and dosage frequency
• Have optimal onset and duration of activity
• Exhibit no side effects
• Would be eliminated completely and
without residual effect
• Goal drug – not possible
• Prodrug – inactive after metabolized it
will exert TE
• Lead compound – AI/Prototype
Methods of Discover
• Choosing a disease – focus is on the financial
return
• Choosing a drug target – receptor, enzymes
and nucleic acid
• Molecular modification – SAR/ structure
activity relationship Studies
Types of bioassay
•In vivo test – inducing a clinical condition and
treated with the test drug
•In vitro test – drugs activity is tested on
isolated tissues, cells or enzymes
• In Silico – perform using computer software
Lead Compound
– A prototype chemical compound that has a
fundamental desired biologic or pharmacologic
activity
Prodrugs
– A compound that requires metabolic
biotransformation after administration to
produce the desired pharmacologically active
compound
Preclinical Studies
• Chemical and physical characterization –
solubility, partition coefficient, chirality of the
molecule, protein binding
• Pharmacology - the science of the properties
of the drugs and its effects in the body
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• Pharmacodynamics – the study of the
interaction of drugs with cells (MOA)
Mechanism of action.
• Pharmacokinetics – the handling of a drug
within the body, it includes the ADME processes
• Analytical studies
• Toxicology - the study of the A/E of the
chemical agents on living organisms
• Pharmaceutics - the general area of study
concerned with the formulation, manufacturing
stability and effectiveness of a pharmaceutical
dosage form
Preformulation
– The characterization of the physical and
chemical properties of the active drug
substance in relation to the desired
dosage form
• Solubility
• Partition coefficient
• Dissolution rate
• Physical form
• Stability
File IND Application
Patent the drug – an exclusive rights to the use
and profits of a novel pharmaceutical for a
limited term
• special consideration is given on Orphan drugs
and Treatment IND
• patent – maximum of 5 years
• orphan drugs – tx of rare disease
Submission of a new drug application
– Submitted to the FDA for review and
approval
– Products is effective by all parameters
• Performed during phase 3
Scale-up activities
Scaleup – increase in the batch size from the
clinical batch, submission batch, or to the
full-scale production batch size, using the
finished, marketed product.
• Performed during phase 4
Related Terms
1. SNDA - Supplemental New Drug
Application: filed if you want to add some
changes such as method of manufacturing,
extend expiration date, and some important
labeling changes (change AI)
2. ANDA - Abbreviated New Drug
Application: generic equivalents
3. BLA - Biologics License Application:
manufacturing of vaccines and toxins
 PDDS 211 - Pharmaceutical Dosage Form, Drug Delivery System & Medical Devices
Prelims Lecture
4. ADA - Animal Drug Application: frugs
exclusive for animal use
5. Medical devices
Controlled Studies
- The effects of the IND are compared with
another agent - placebo or active drug
- Single blinded
- Double blinded
• Phase 2
Dosage Regimen
• Dosage Regimen –schedule of dosage
• Usual dose – the amount that may be expected
to produce, in adults, the medicinal effect for
which it is intended
• Usual dosage range – amounts of drug that
may be prescribed within the work of usual
medical practice
• Pediatric dose – dose administered to children
• Initial dose – also the priming or loading dose,
is the amount required to attain the desired
concentration of the drug in the blood or tissues
• Prophylactic dose – (before exposure ex.
vitamins) the amount administered to a patient
before exposure or contraction of the illness
• Therapeutic dose – the amount which is
administered to a patient after the exposure or
contraction of an illness
Therapeutic Index/Range
– The relationship between the desired and
undesired effects of a drug
– TD50/ ED50
• Ratio of safety narrower therapeutic index, less
safer the drug becomes TD/Toxic response to the
50% of population, ED/Therapeutic Effective to
the 50% of population
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Factors affecting the Dose
• Age
• Pharmacogenetics – genetic polymorphism
• Body Weight – inc fat, dec metabolism
absorption
• Body Surface Area – nomogram – inc BSA,
slow distribution
• Sex – male has slower absorption
• Pathologic State – myocardial infraction: low
albumin levels, albumin: floating binding acidic
drugs
• Tolerance
• Concomitant Drug therapy – polypharmacy
– take many drugs
• Time and conditions of administration
• Dosage Form and Route of Administration
- liberation
Current Good Manufacturing practice
• Guidelines and protocols that must be followed
in a manufacturing settings
• AO 220 –CGMP
cGMP
– Current Good Manufacturing Practice
– a term that is recognized worldwide for the
control and management of manufacturing and
quality control testing of foods and
pharmaceutical products.
– "c" in cGMP stands for "current," requiring
companies to use technologies and systems that
are up-to-date in order to comply with the
provide for systems that assure proper design,
monitoring, and control of manufacturing
processes and facilities
– This formal system of controls at a
pharmaceutical company, if adequately put into
practice, helps to prevent instances of
contamination, mix-ups, deviations, failures, and
errors regulations
cGMP and Documentation
- This assures that drug products meet their
quality standards.
- An extremely important part of GMP is
documentation of every aspect of the process,
activities, and operations involved with drug and
medical device manufacture
- The documentation shows how the product was
made and tested which enables traceability and,
in the event of future problems, recall from the
market
GMP and Validation
- GMP requires that all manufacturing and
testing equipment has been qualified as suitable
for use, and that all operational methodologies
and procedures (such as manufacturing,
cleaning, and analytical testing) utilized in the
drug manufacturing process have been validated
 PDDS 211 - Pharmaceutical Dosage Form, Drug Delivery System & Medical Devices
Prelims Lecture
(according to predetermined specifications), to Buildings and Facilities
demonstrate that they can perform their 🡪 Designed for easy cleaning, maintenance and
purported function(s). freedom from congestion and traffic
cGMPs 🡪 Adequate space for operations
● GMPs are enforced 🡪 Adequate lighting, ventilation
– in the United States by the FDA 🡪 Adequate facilities
– in the United Kingdom by the Medicines and 🡪 Adequate supply of water
Healthcare products Regulatory Agency 🡪 suitable housing and space for animal care
(MHRA) 🡪 safe and sanitary waste disposal
– In Australia by the Therapeutical Goods Equipment
Administration (TGA) 🡪 Involve in the manufacture, processing,
– In India by the Ministry of Health packaging, storing, testing, or control of
– Philippines by FDA products and its components
● cGMP 🡪 Quality 🡪 Designed to be non-reactive, additive or
● CGMP is everyone’s responsibility absorptive. It should facilitated disassembly,
● QC function is to audit or inspect periodically adjustment, cleaning and maintenance
the procedures, equipment, facilities; to detect ● Affixed with standard operating procedures
NON-COMPLIANCE and to CORRECT the ● With own logbook and ID tags containing
said deviation – Date used
● Non-compliance may result to quality – Name of product where it was used
variation 🡪 contamination, mix-ups and – Date cleaned
errors 🡪 product recall – Personnel in charge
● Recalls result to the ff disadvantages: – Date of validation
– Lost of money Components
– Bad publicity 🡪 Shall be withheld from such use until they
– Low sales have been identified, sampled, and tested for
– Negative effect on employees conformance with the specifications
Objectives 🡪 raw materials, packaging materials
● Safe Production and Process Control
● Pure 🡪 Includes all reasonable precautions that will
● Effective ensure that the products have the safety, identity,
cGMP as a Law strength, quality, purity they claim to possess.
● Administrative Order No. 220, s. 1974 🡪 Follows a written procedures
-SCOPE 🡪 In –process inspection
- Organization and Personnel Packaging and Labeling Control
- Buildings and Facilities 🡪 Assures that only those products that have
- Equipment met the standards established in the master
- Components formula records shall be distributed
- Production and Process Control 🡪 Assures that correct labels and labeling are
Scope cont. used
● Packaging and Labeling Control 🡪 Assures that correct lot no. and control of the
● Holding and Distribution batch are used
● Laboratory Controls ● Assures that labels used meet the legal
● Records and Reports requirements for content
● Returned and Salvaged products ● Assure that each label contains the
Terminologies expiration date
● Active pharmaceutical ingredient (API) ● Assures that OTC preparations are contained
● Inactive ingredient QA, QC in tamper-evident package
● Component Drug product Laboratory Control
● Batch Strength 🡪 Include the scientifically sound, appropriate
● Lot, Lot number Validation specifications, standards and test procedures
● Master Record 🡪 Include master formula record, reserve
Personnel samples
● Qualified
🡪 healthy with an awareness of the importance
of good hygiene

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