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

U. RONALYN
 PDDS 211 - Pharmaceutical Dosage Form, Drug Delivery System & Medical Devices
Prelims Lecture
• 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
Goal Drug stability and effectiveness of a pharmaceutical
• Produce specifically the desired effect dosage form
• Administered by the most desired route
• Minimal dosage and dosage frequency Preformulation
• Have optimal onset and duration of activity – The characterization of the physical and
• Exhibit no side effects chemical properties of the active drug
• Would be eliminated completely and substance in relation to the desired
without residual effect dosage form
• Goal drug – not possible • Solubility
• Prodrug – inactive after metabolized it • Partition coefficient
will exert TE • Dissolution rate
• Lead compound – AI/Prototype • Physical form
• Stability
Methods of Discover
• Choosing a disease – focus is on the financial File IND Application
return
Patent the drug – an exclusive rights to the use
• Choosing a drug target – receptor, enzymes
and profits of a novel pharmaceutical for a
and nucleic acid
limited term
• Molecular modification – SAR/ structure
• special consideration is given on Orphan drugs
activity relationship Studies
and Treatment IND
• patent – maximum of 5 years
Types of bioassay
• orphan drugs – tx of rare disease
•In vivo test – inducing a clinical condition and
treated with the test drug
Submission of a new drug application
•In vitro test – drugs activity is tested on
– Submitted to the FDA for review and
isolated tissues, cells or enzymes
approval
• In Silico – perform using computer software
– Products is effective by all parameters
• Performed during phase 3
Lead Compound
– A prototype chemical compound that has a
Scale-up activities
fundamental desired biologic or pharmacologic
Scaleup – increase in the batch size from the
activity
clinical batch, submission batch, or to the
full-scale production batch size, using the
Prodrugs finished, marketed product.
– A compound that requires metabolic • Performed during phase 4
biotransformation after administration to
produce the desired pharmacologically active Related Terms
compound 1. SNDA - Supplemental New Drug
Application: filed if you want to add some
Preclinical Studies changes such as method of manufacturing,
• Chemical and physical characterization – extend expiration date, and some important
solubility, partition coefficient, chirality of the labeling changes (change AI)
molecule, protein binding 2. ANDA - Abbreviated New Drug
• Pharmacology - the science of the properties Application: generic equivalents
of the drugs and its effects in the body 3. BLA - Biologics License Application:
manufacturing of vaccines and toxins

U. RONALYN
 PDDS 211 - Pharmaceutical Dosage Form, Drug Delivery System & Medical Devices
Prelims Lecture
4. ADA - Animal Drug Application: frugs Factors affecting the Dose
exclusive for animal use • Age
5. Medical devices • Pharmacogenetics – genetic polymorphism
Controlled Studies • Body Weight – inc fat, dec metabolism
- The effects of the IND are compared with absorption
another agent - placebo or active drug • Body Surface Area – nomogram – inc BSA,
- Single blinded slow distribution
- Double blinded • Sex – male has slower absorption
• Phase 2 • 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
Dosage Regimen in a manufacturing settings
• Dosage Regimen –schedule of dosage • AO 220 –CGMP
• Usual dose – the amount that may be expected cGMP
to produce, in adults, the medicinal effect for – Current Good Manufacturing Practice
which it is intended – a term that is recognized worldwide for the
• Usual dosage range – amounts of drug that control and management of manufacturing and
may be prescribed within the work of usual quality control testing of foods and
medical practice pharmaceutical products.
• Pediatric dose – dose administered to children – "c" in cGMP stands for "current," requiring
• Initial dose – also the priming or loading dose, companies to use technologies and systems that
is the amount required to attain the desired are up-to-date in order to comply with the
concentration of the drug in the blood or tissues provide for systems that assure proper design,
• Prophylactic dose – (before exposure ex. monitoring, and control of manufacturing
vitamins) the amount administered to a patient processes and facilities
before exposure or contraction of the illness – This formal system of controls at a
• Therapeutic dose – the amount which is pharmaceutical company, if adequately put into
administered to a patient after the exposure or practice, helps to prevent instances of
contraction of an illness 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
Therapeutic Index/Range market
– The relationship between the desired and GMP and Validation
undesired effects of a drug
- GMP requires that all manufacturing and
– TD50/ ED50
testing equipment has been qualified as suitable
• Ratio of safety narrower therapeutic index, less
for use, and that all operational methodologies
safer the drug becomes TD/Toxic response to the
and procedures (such as manufacturing,
50% of population, ED/Therapeutic Effective to
cleaning, and analytical testing) utilized in the
the 50% of population
drug manufacturing process have been validated

U. RONALYN
 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

U. RONALYN