Pharmaceutics Midterm Flashcards
(100 cards)
1
Q
What can go wrong?
A
- Drug Recalls
- Impurity
- Labeling error - Drug Shortages
- Ex. Doxil
2
Q
Drug Recalls: Impurity
A
- Mitoxantrone injection USP because “product may not support the specification results for known impurity prior to expiry”
- Piperacillin and Tazobactram for injection because “potential presence of particulate matter”
3
Q
Drug Recalls: Labeling Error
A
- SteriMax-Vancomycin Hal Injection USP because “a typographical error was identified on one lot. Although unlikely, there is a potential for a dosing error to occur if the reconstitution information on the secondary cares of the French text is used” (not actually a recall, just a letter of notice)
- Atropine sulfate injection because “inaccurate dosing information on inner and outer labels”
4
Q
Glaxo Whistle Blower Lawsuit
A
- 2002
- CHERYL ECKARD was assigned to lead a quality assurance team toe ablate a GSK plant in Cidra, Puerto Rico
- Found that “all systems were broken, the facility was broken, the equipment was broken, the processes were broken.” It was the worst thing she had ever seen.
- GSK pleaded guilty to a felony and admitted to distributing adulterated drugs (Paxil CR, Avandamet, Kytril and Bactroban)
- GSK paid $750 million in settlement
5
Q
Drug Shortages
A
- Primary cause: Quality problems at the manufacturing facility
- Increasing in frequency and severity due to fewer companies making drugs
- 80% of drug shortages reported in 2010-2011 were sterile injectable products, with 28% of those being for oncology drugs
6
Q
Drug Shortages: Common Manufacturing Issues
A
- Sterility of product
- Presence of foreign matter and impurities
- Crystallization of active ingredient
- Formation of precipitate
- Breakdown of equiment
7
Q
Drug Shortages: Doxil
A
- Doxil is an anti-cancer medication
- 2011: FDA found major issues in the third party manufacturer’s facility and shut it down, leading to a shortage of Doxil for a year
- This drug is so important that there was even a push to approve a drug from Korea for the time being
- FDA ended up letting Jannsen rehab a small part of the facility in order to help deal with the shortage
8
Q
Drug Shortages: Dynamics of Sterile Injectable Drug Shortages
A
Supply Distribution –> Drug Shortage
-Contributing Factors
+Manufacturing Issues: few producers, specialized facilities and dedicated lines
+Supply Chain Issues: Just-in-time inventory (prevents surplus and reduces expenses)
9
Q
Drug Manufacturing and Pharmaceutical Analysis
A
- Arrival of starting and packaging material
- Sampling of starting materials
- Manufacturing
- Filling
- Labeling
- Packaging
- Documentation and control of finished product and product release
Pharmaceutical Analysis occurs at steps 1, 3 and 7
- Raw materials arrive and are stored in a separate area; samples are taken for analysis to ensure identity and purity of the material
- Following manufacture of the drug product, it is held in quarantine and samples are analyzed prior to filling in the designated containers
- Following release of finished product, samples are retained for evaluation
10
Q
Roles of Pharmaceutical Analysis
A
- Assurance of raw material and drug product quality and stability
- Evaluation of the PK of a drug
- Therapeutic drug monitoring
- Clinical and forensic toxicology analysis
- Analysis of blood and urine samples for professional athletes
11
Q
Pharmaceutical Analysis Terms: Identity Test
A
Identification of a drug or substance that does not involve quantitation
12
Q
Pharmaceutical Analysis Terms: Assay
A
A quantitative analysis of a drug or substance
13
Q
Pharmaceutical Analysis Terms: Analyte
A
The drug or substance being analyzed
14
Q
Pharmaceutical Analysis Terms: Standard
A
A solution of a drug or substance of known concentration
15
Q
Pharmaceutical Analysis Terms: Calibration Curve
A
A plot of the analytical signal versus concentration for a series of standards
16
Q
UV-Vis Spectroscopy in Drug Analysis: UV-Vis Spectrum
A
UV: 200-380 nm
Visible: 380-750 nm
IR: >750 nm
Most drugs absorb in UV region, but some are colored and absorb in visible region
17
Q
UV-Vis Spectroscopy in Drug Analysis: Absorbance of Radiation
A
- Atoms are held together by covalent bonds formed by electron sharing
- Electronic ground state: Energy of their electrons are at a minimum
- Radiation is absorbed through excitation of electrons involved in the bonds between atoms
- Electrons in weaker bonds can be excited by radiation in >200 nm range (lower wavelengths)
18
Q
UV-Vis Spectroscopy in Drug Analysis: Chromophores and their Absorbance Maxima
A
- Carbonyl, ketone –> 271 nm
- Carbonyl, aldehyde –> 293 nm
- Carboxyl –> 204
- Amide –> 208
19
Q
UV-Vis Spectroscopy in Drug Analysis: Qualitative Analysis
A
- Useful for identifying the drug based on wavelength max values
- Not an absolute identification technique because many drugs with similar structures have similar values
20
Q
UV-Vis Spectroscopy in Drug Analysis: Quantitative Analysis
A
- Compares absorbance to a standard of the drug of known concentrations
- Can also calibrate curve obtained by analysis of several standards
21
Q
UV-Vis Spectroscopy in Drug Analysis: Absorption Measurements
A
- Typically operate 200-800 nm
- Light passes through cuvette and amount of absorbed light is measured
- Cuvettes are Quartz or UV transparent
22
Q
UV-Vis Spectroscopy in Drug Analysis: Beer-Lambert Law
A
Absorbance = a x b x c
a: molar absorptivity or extinction coefficient
b: path length
c: concentration
A = log (I0,I)
23
Q
UV-Vis Spectroscopy in Drug Analysis: Drug Quantitation
A
-Using the Beer-Lambert Lab, a and b are constants, so we can solve for concentration
C(unknown) = A(unknown) x C(standard) / A(standard)
24
Q
UV-Vis Spectroscopy in Drug Analysis: Example - Furosemide Standard Curve Method
A
Asked to determine if a lot of furosemide tablets contain the indicated amount of active pharmaceutical ingredient per tablet
- Assay a concentration in the middle of the calibration curve (about 0.025 mg/mL)
- Dilute 400 mg in 250 mL and then dilute 5 mL of that to 250 mL to get desired concentration (0.032 mg/mL)
- Measure absorption (A = 0.80)
- Using calibration curve equation (A = 26.67*C), C = 0.030 mg/mL
- Obtain % of expected concentration
0.030/0.032 = 93.8%
25
UV-Vis Spectroscopy in Drug Analysis: Example - Furosemide Single Point Determination
Asked to determine if a lot of furosemide tablets contain the indicated amount of active pharmaceutical ingredient per tablet
1. Dilute 400 mg in 250 mL and then dilute 5 mL of that to 250 mL to obtain desired concentration (0.032 mg/mL)
2. Measure absorption (A = 0.80)
3. Using the Reference Table, the standard with a concentration of 0.030 mg/mL had an average absorbance of 0.81
C(u) = A(u) x C(s) / A(s)
C(u) = 0.030 mg/mL
4. Obtain % of expected concentration
0.030/0.032 = 93.8%
26
Fluorescence Spectroscopy in Drug Analysis
- Identification of a compound/drug
- Measurement of concentration of drug in a sample to determine amount of drug in dosage form, assess dissolution rate, or measure drug in biological sample
- Can use a bench top spectrofluorometer or HPLC with fluorescence detector
- Ex: Chlorpromazine, doxorubicin, quinine, tetracycline, ethinyl estradiol
27
Fluorescence Spectroscopy in Drug Analysis: Advantages
- Fluorescence is proportional to the intensity of light used to excite the molecules
- Background fluorescence is theoretically "zero"
- Approximately 10,000 times more sensitive than UV-vis
- Highly specific for molecule of interest since only certain molecules fluoresce
28
Chromatography in Drug Analysis
- Physical method of separating two or more components based on their distribution between two phases (stationary and mobile)
- Most commonly used analytical technique for drug analysis
29
Chromatography in Drug Analysis: Chromatographic Separations
1. Column or Liquid Chromatography
- Adsorption
- Ion-exchange
- HPLC
- Size-exclusion
- Affinity
2. Thin Layer Chromatography
3. Gas Chromatography
30
Chromatography in Drug Analysis: HPLC
High Performance Liquid Chromatography
-High resolution column chromatography that separates drugs based on their partitioning between a stationary phase and a mobile phase
31
Chromatography in Drug Analysis: HPLC - Columns
- Made of stainless steel to withstand high pressures
- Sometimes made of resilient polymeric material (PEEK - polyether ether ketone)
- Packed with different types of resins that allow for separation
- Dimensions: 0.5 cm x 25 cm
32
Chromatography in Drug Analysis: HPLC - Basis of Separation
- Drug molecule with high affinity for stationary phase will have longer residence time in the column and move more slowly
- Drug molecules with low affinity for stationary phase will have shorter residence time in the column and move more quickly
33
Chromatography in Drug Analysis: HPLC - Applications
Qualitative
-Identification of a drug substance by its chromatographic characteristics in a specific system
Quantitative
- Assay of the concentration of a drug based on the area under the peak relative to that for a standard of the drug
- Assay of a drug substance in the presence of other drugs or impurities
34
Chromatography in Drug Analysis: HPLC - Retention Time
- Time taken for an analyte to elute from the column and be detected by a monitor
- Depends on nature of compound, nature of column packing material, the nature of the solvent, and the flow rate
35
Chromatography in Drug Analysis: HPLC - Void Volume
Empty space not occupied by the stationary phase material
V(0) = t(0) x flow rate
36
Chromatography in Drug Analysis: HPLC - t(0)
Time taken for an unretained molecule to pass through the void volume
37
Chromatography in Drug Analysis: HPLC - Types
1. Normal Phase - polar/hydrophilic
2. Reverse Phase - nonpolar/hydrophobic
3. Ion-Exchange - ionic charge
4. Size-Exclusion - molecular size
5. Chiral - optical isomers
38
Chromatography in Drug Analysis: HPLC - Normal Phase
-Forms hydrogen bonds with functional groups on drug molecules (e.g., OH, NH, etc.)
-Column matrix: Silica gel
+OH groups on silica gel H bond to polar groups on molecule (e.g., hydroxyl, amine, carboxylic acid)
-Order of elution: Less polar elutes first
-Common Solvents: Hexane > DCM > Isopropanol > Methanol
-Improve separation by increasing polarity of solvent in order to elute more polar compound more quickly
39
Chromatography in Drug Analysis: HPLC - Reverse Phase
- Forms hydrophobic interactions with non-polar functional groups on drug molecules
- Column matrix: silica derivatized with hydrocarbon chains C18, C8 or C2
- Order of elution: More polar elutes first
- Common Solvents: Water > Methanol > Acetonitrile > THF
- Improve separation by decreasing polarity of the solvent in order to elute less polar more quickly
40
Need for Health Canada and FDA
Agencies, policies and regulations have been established and developed largely in response to crises and adverse events
41
Sulfanilamide Crisis
1937
- Tablets and capsules were available, but no liquid because they could not find a good solvent
- S.E. Massengil Co. of Bristol, TN's chief chemist HAROLD CATKINS selected diethylene glycol but did no toxicity studies
- Raspberry-tasking pink elixir containing 10% sulfanilamide, 72% diethlyene glycol, 16% water and flavours
- 107 deaths (34 children) due to renal failure and coma
- Led to formation of FDA and need for products to be tested for safety and approved
42
Drug Approval and Manufacturing
- 1906: Pure Food and Drug Act (US)
- 1920: Health Canada - Food and Drug Act
- 1938: FDA instituted and said drugs need to be shown to be safe
- 1962: Kefauver-Harris Drug Amendments said drugs need to be safe and effective
43
Thalidomide Crisis
- Morning sickness medication found to be teratogenic
- FRANCES KELSEY, FDA employee, did not approve of the toxicology profile of drug and stalled approval in the US
- About 80,000 kids were born with severe birth defects (pharcomelia - flipper-like limbs)
- Demonstrated need for reporting and registration system for adverse events
- Led to FDA requiring at least 3 phases of research for innovator products
1. First in human, dose ranging
2. Short-term safety and efficacy
3. Long-term safety and efficacy
44
Regulation of Drugs in Canada
- Health Canada is responsible for assuring the quality, safety and efficacy of drugs before and after they are marketed in Canada
- 2011: Reported that there were 13,000 drugs on the market and estimated that Canadians were expected to spend $31 billion on them
- Canadian retail pharmacies dispensed 505 million prescriptions in 2010
- 2009-2010: Health Canada spent about $80 million on drug regulation (with $33 million received in fees from industry)
45
Health Canada's Responsibilities
1. Reviewing clinical trial applications, for clinical trials conducted in Canada
2. Reviewing drug submissions from manufacturers for market authorization and for post-market changes
3. Monitoring the safety of drugs in the Canadian market and communicating safety risks to health care professionals and the public, in collaboration with industry
4. Enforcing pharmaceutical industry's compliance with regulations, including those related to clinical trials, drug manufacturing, and the reporting of adverse drug reactions
46
Regulatory Process for Drugs
Pre-Clinical --> Clinical Trials --> New Drug Submission (regulatory product submission, submission review, market authorization decision) --> Marketing (Public Access) --> Surveillance, inspection, and investigation
47
Pre-Clinical Studies
- Not regulated by government
- Conducted to gather necessary preclinical data to demonstrate safety and efficacy in animal models
- Provides indication that it is safe to conduct clinical trials in humans and of potential therapeutic uses in humans
- Sponsor files a Clinical Trial Application (CTA) to the Therapeutic Products Directorate of Health Canada
- CTA includes summary of preclinical data and must be approved before pursuing clinical trials
48
Clinical Trials
Phase 1
- Safety and toxicity
- Small cohort (20-80)
- Healthy volunteers
- Determines how drug is absorbed, metabolized and eliminated
Phase 2
- Optimal and safe dose
- Large cohort (100-300)
- Patients with disease the drug is intended to treat
Phase 3
- RCT
- Large cohort (1000-3000)
- Patients who are to receive the new drug or the standard therapy currently being used to treat the disease
49
Parts of New Drug Submission
1. Master volume
2. Chemistry and manufacturing
3. Comprehensive summary
4. Sectional reports
5. Raw data
50
Parts of New Drug Submission: Master Volume
- Submission certification
- Application form
- Table on contents
- Brief summary
- Product monograph
- Draft labeling
- List of prior related submissions
- Non-Canadian package inserts
51
Parts of New Drug Submission: Chemistry and Manufacturing
- Drug substance
- Drug product
- Addendum for biologics
52
Parts of New Drug Submission: Comprehensive Summary
- Investigational studies
- Clinical studies
- Status of research and development of drug
53
Parts of New Drug Submission: Sectional Reports
- Investigational studies
- Clinical studies
- CV of each investigator
54
Parts of New Drug Submission: Raw Data
- Pre-clinical studies
| - Clinical studies
55
Drug Quality at Different Stages of Development
- Stringency increases as drug gets closer to market
- Initially, need to confirm identity and structure of drug and set broad limits for purity and potency
- As drug is developed, narrower limits for purity and potency are implemented and assays for drug and its impurities are finalized and validated
56
Pharmaceutical Analysis: Preformulation
1. Crystals and Other Properties
2. Physiochemical Properties
3. Stability/Degradation
57
Pharmaceutical Analysis: Preformulation - Crystals and Other Properties
- Polymorhs
- Psuedopolymorphs/solvates
- Crystal habits
- Crystal defects
- Optical isomers
- Chirality/isomer/racemic
58
Pharmaceutical Analysis: Preformulation - Polymorphs
-May differ in terms of solubility, hardness, mp, density and rate of dissolution
-Ex. Ritonavir
+Protease inhibitor indicated for treatment of HIV
+1996: Marketed as Norvir oral liquid and semi-solid capsules (ethanol/water based solutions) since it is not bioavailable in solid state --> no crystal form controls were required
+Originally, one crystal form was identified and produced with no stability issues, but over time there were several lots that failed dissolution tests and so capsules were analyzed by microscopy and x-ray powder diffraction --> found a second polymer
+Form II revealed to have reduced solubility
59
Pharmaceutical Analysis: Preformulation - Physiochemical Properties
- Particle size
- Melting point
- Water/solvent/pH solubility
- Kow
- pKa
- Surface area
- Wetting
- Hygroscopicity/water sorption
- Powder flow
- Compression
- Excipients including solvents
Solubility
- helps to guide selection of an appropriate formulation strategy including excipients
- can vary for different polymorphs
- influence bioavailability
60
Pharmaceutical Analysis: Preformulation - Stability/Degradation
- Hydrolysis
- Temperature
- Oxidation
- Photolysis
- Excipient stability
- Microbial degradation
Stability influences formulation strategy, excipient selection, shelf-life and storage conditions
61
Pharmaceutical Analysis: Formulation - Tablets/Capsules
- Compatibility with excipients (lubricants, binders, disintegrants, diluents)
- Microbial bioburden
- Container closure compatibility
- Stability
62
Pharmaceutical Analysis: Formulation - Parenterals
- Tonicity
- Aqueous solubility
- Sterilization and stability
- Particulate matter
- Preservative effectiveness
- Container closure compatibility/integrity
63
Pharmaceutical Analysis: Phases I-III - Drug Substance (Stability)
Phase I
-Preliminary stability data and test methods used
Phase II
- Stability-indicating analytical procedure to detect changes in quality of drug substance
- Preliminary stability data including stability data for Phase 1 clinical materials
Phase III
-Complete stability protocol, including tests, analytical procedures, expected duration, sampling points, storage conditions
64
Pharmaceutical Analysis: Phases I-III - Drug Product (Stability)
Phase I
-Stability data in proposed container closure, test methods
Phase II
- Stability - Degradation profiles, stability data for the clinical material in Phase I; stress testing including photo stability should be conducted
- Stability protocol with tests, analytical procedures, sampling points, expected duration
Phase III
-Stability protocol with tests, and sampling point for each tests, temperature and humidity conditions, dissolution profiling in physiologically relevant media
65
Quality Assurance
Wide ranging concept that covers all matters that individually or collectively influence the quality of a drug
66
Good Manufacturing Process
Part of QA that ensure that drugs are consistently produced and controlled in such a way to meet the quality standards appropriate to their intended use, as required by the market authorization
67
Quality Control
Part of GMP that is concerned with sampling, specifications testing, documentation and release procedures. Ensures that the necessary and relevant tests are carried out and that raw materials, packaging materials, and products are released for use or sale, only if their quality if satisfactory.
68
Specifications
- Detailed description of a drug, the raw material used in a drug, or the packaging material for a drug
- Standards and acceptable limits for quality
- Assure safety and efficacy of drug product
69
Acetaminophen USP Specifications: Raw Material
1. Identify the drug substance
2. Assay the potency of the drug substance
3. Determine the level of impurities
70
Acetaminophen USP Specifications: Raw Material - Identification (Reference Standards)
- Extremely pure (100.0%) standards of a drug, which are kept in a a secure, controlled area under stable long-term storage conditions
- Used to confirm the identity of a drug substance by comparing it to the standard
- Primary from USP, secondary is in-house
71
Acetaminophen USP Specifications: Raw Material - Identification Tests
-H or C NMR
-Mass spec
-IR
-Melting point
-Colour tests for functional groups
-UV-vis
-Chromatographic parameters
+tR in HPLC and GC
+Rf in TLC
+Mol wt determination in SE-HPLC
-Amino acid analysis
-Electrophoresis by SDS-PAGE and Western blot
72
Acetaminophen USP Specifications: Raw Material - Impurity (Assays and Tests)
- HPLC, GC, TLC, SE-HPLC
- SDS-PAGE
- UV-Vis
- Capillary electrophoresis
- Isoelectric focusing
73
Acetaminophen USP Specifications: Raw Material
1. Purity: 98.0-101.0% of acetaminophen (UV-vis at 244 nm)
2. Identification
- IR
- UV-Vis
- TLC
- mp 168-172 C
3. Impurities
- Water content
74
Acetaminophen USP Specifications: Tablets
1. Potency: Tablets contain 90.0-110.0% of labeled amount of acetaminophen (HPLC)
2. Identification: retention tie corresponds to reference standard in HPLC analysis on C-18 column eluted with 25% methanol/75% water at a flow rate of 1.0 mL/min
3. Dissolution: Not less than 80% of drug dissolved in pH 5.8 phosphate buffer in 30 minutes
75
Acetaminophen USP Specifications: Final Product
-Potency: Assay product for expected amounts of active drug substance and other key components
-Techniques
+Aqueous or non-aqueous titration
+UV-vis
+HPLC or SE-HPLC
+GC but not TLC
+Immunoassays
+Biological assays
+Radioactive assays
76
General Tests in USP
General testing procedures that apply to drugs in a similar class or a similar product category
1. Sterility test
2. Pyrogen test
3. Bacterial endotoxins test
4. Spectrophotometric identification tests
5. TLC test
6. Limit tests for heavy metals and other impurities
7. Antibiotic-microbial assays
8. Disintegration tests
9. Dissolution tests
77
General Tests in USP: Tests for Minor Impurities
1. Residual solvents - GC
2. Inorganic compounds - residue on ignition
3. Heavy metals (Pb, Hg, Bi, As, Sb, Sn, Cd, Ag, Cu, Mo) - colourmetric assay using thioacetamide-glycerine test solution
78
General Tests in USP: Water Content
Karl Fisher titration
| -For drug products that are lyophilized (freeze-dried) to improve stability and extend expiry
79
General Tests in USP: Sterile Products
- Isotonic
- pH range 5.0-8.0
- Clear, no particulate matter
- Sterile: Absence of viable bacteria or fungi or other microorganisms
- Apyrogenic: Does not cause fever
- Very low bacterial endotoxin levels
- Packaged in a way that maintains these properties as well as drug potency
80
General Tests in USP: USP Sterility Test
-Detect presence of viable bacteria/fungi
-14-day incubation on two media (soybean casein medium, fluid thioglycholate broth)
-Injectables are terminally sterilized
+Aseptic filtration through 0.22 um filter
+Autoclaving
81
General Tests in USP: USP Pyrogen Tests
- Detects all types of pyrogens
1. Inject 3 rabbits
2. Measure rectal temperatures every 0.5 h for 3 h
- If one rabbit has an increase of more than 0.5 C, test 5 more rabbits
- If not more than 3/8 rabbits show individual rises of 0.5 C and the sum of all 8 individual rises is not > 3.3 C, then material meets requirements
82
General Tests in USP: USP Bacterial Endotoxins Test
- Official test for gram-negative bacterial endotoxin, which is one of the major pyrogens which can contaminate parenteral drug products
- In vitro tests that relies on the formation of a clot in a test tube when sample of drug product is incubated with lysate from horseshoe crab for 1 hour at 37 C
83
General Tests in USP: Packaging Materials (Stability Testing and Expiry)
Packaging materials should not decrease drug quality - adsorption, contamination, physiochemical degradation, bacterial contamination
- Drug product tested against specifications over time in packaging stored under recommended conditions
- Can also test under extreme conditions
- Based on testing, expiry times are established
84
Bioavailability
Rate and extent of absorption of a drug systemically
85
Bioequivalence: Major Players
- Sponsor: Drug company making the test product
- Innovator: Drug company with the current marketed reference product
- Regulatory Body: Protecting the public from ineffective and/or harmful drugs
- Contract Research Organization: Provides facility and expertise to run clinical trials if sponsor does not have infrastructure or resources
86
Bioequivalence: Regulatory Definitions - Canada
- Bioequivalent when profiles of drug are similar
- Implies that the test product can be expected to have the same therapeutic effects and safety profile as the reference product
87
Bioequivalence: Regulatory Definitions - USA
The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study
88
Generic Drug
-Drug product that compares to the reference drug product in dosage form, strength, route of administration, quality and performance characteristics, and in intended use
89
Generic Drug Setbacks: Chloramphenicol
- 1966: Patent expired and a bunch of generics approved
- Broad spectrum antibiotic for ophthalmic use
- Innovator (Parke-Davis) runs clinical tests and found that adequate blood levels were not reached
- By 1968, all generics were off the market
90
Generic Drug Setbacks: Digoxin
- 1969: Radioimmunoassay developed for digoxin and found that one marketed formulation was producing 7c potency, associated with toxicity (progressive cardiac disease)
- 1974: FDA Drug Bulletin saying that the bioavailability problems are not due to the manufacturing companies, but rather that they were present from the beginning and we didn't have the science to find it
91
Generic Drug: US Hatch-Waxman Act
1984 - Drug Price Competition and Patent Restoration Act
1. Sponsor must establish BE between generic and reference product, and adhere to FDA-approved manufacturing process
- Safety and efficacy clinical trials not required
2. Sponsor may conduct BE trials before patent expires without worry of being sued
3. A process was outlined for the resolution of new patent disputes
- First to File: First generic to file ANDA that successfully challenges the innovated gets 180 days of exclusivity
- Non-infringement claim: Sponsors must claim that their product will not infringe on any existing patients
- If a patent-infringement action is initiated by the innovator within 45 days of non-infringement claim, FDA cannot approve generic for 30 months or until litigation is resolved
92
NDA vs ANDA Review Process
- Both require chemistry, manufacturing, controls, labeling, and testing
- NDA requires animal studies, clinical studies and BA
- ANDA requires BE
93
Required PK Data - Clinical Trials
ANDA
-Single dose fasted BE, sometimes fed
NDA
- Single dose fasted BA, usually fed as well
- Multiple-dose
94
PK Parmaters
-Cmax: First occurring max plasma conc
-tmax: Time of Cmax
-AUC: Total amount of drug absorbed by body
-AUCt: Trapezoidal rule
-AUCinf = AUCt + residual (=Clast/lambda)
-F: Fraction of drug absorbed
F = dose normalized oral/IV ratio of AUCinf
95
Demonstrate BE (PK)
Three Ratios
- Cmax
- AUCt
- AUCinf
96
Bioequivalence Trials: Confidence Interval
- 90%
- Mean Ratio (Cmax) = 95.6%
- Lower 90% CI = 89.2%
- Upper 90% CI = 110.4%
- Goal posts: 80-125%
- Increase sample size, smaller CI, more confident about true mean
97
Bioequivalence Trials: Standards - Single Oral Dose
```
80-125%
-Cmax and AUCt
-AUCinf in USA
-Quirks
+USA: Re-dosing studies allowed
+Canada: Group sequential, adaptive study design permitted
```
98
Bioequivalence Trials: Standards - Long Half-Life Drugs
80-125%
- Cmax and AUCt
- AUCt truncated at 72 hours
99
Bioequivalence Trials: Standards - Special Cases in Canada
Critical Dose Drugs
-AUCt 90% CI 90-112%
-Cmax 90% CI 80-125%
Fasted and Fed
If the rate of release or onset is important, also need AUCref to be within 80-125%
100
Critical Dose Drugs
- Cyclosporine
- Digoxin
- Flecainide
- Lithium
- Phenytoin
- Sirolimus
- Tacrolimus
- Theophylline
- Warfarin
