Drug Patents

When a pharmaceutical company first markets a drug, it is usually under a patent that allows only the pharmaceutical company that developed the drug to sell it.The expiration of a patent removes the monopoly of the patent holder on drug sales licensing.


Patent lifetime differs from country to country,and typically there is no way to renew a patent after it expires.In US drug patents gives 20 years of protection from the date of filling.The standard life time of a European patent is 20 years,calculated from the date of filling.The term for a patent in Japan, China, Korea, and India, is 20 years.In Japan and Korea, in certain circumstances, this period can be extended.


In US patent extension can be granted if changes are made.A new version of the drug with significant changes to the compound could be patented, but this requires new clinical trials.In addition, a patent on a changed compound does not prevent sales of the generic versions of the original drug unless regulators take the original drug off the market. 

What is FDA's Orange Book (Approved Drug Products With Therapeutic Equivalence Equations)

 

FDA ORANGE BOOK (Approved Drug Products with Therapeutic Equivalence Evaluations)

 
“The Orange Book" is actually the U.S. Food and Drug Administration's (FDA) official listing of Approved Drug Products with Therapeutic Equivalences.

 

“Orange book” is published by the FDA's Centre for Drug Evaluation and Research (CDER).The List contains therapeutic equivalence evaluations for approved multisource prescription drug products. Generic drug evaluations contained in the list are designed to serve as public education and advice to physicians, pharmacists and state health agencies, and to help promote access to lower priced medicines.

The Orange Book is divided into four parts: Part one includes approved prescription drug products with therapeutic equivalence evaluations. Part two lists approved over-the-counter (OTC) drug products for those drugs that may not be marketed without NDAs or ANDAs because they are not covered under existing OTC monographs. Part three includes drug products administered by the Center for Biologics Evaluation and Research. Part four includes a list of approved products that have never been marketed, are for export only, are intended for military use, have been discontinued from marketing, or have had their approvals withdrawn for reasons other than safety or efficacy.

The therapeutic equivalence evaluations contained in the list refer to the FDA's criteria for approved multi-source prescription drug products. The evaluations are presented in code letters corresponding to the type of evaluation used. An explanation of the code appears in the introduction to the list. The main criteria for the inclusion of a drug product on the list are that the product has received an effective approval that has not been withdrawn for efficacy or safety or efficacy causes. Inclusion of products on the list is independent of any current regulatory action through administrative or judicial means against a drug product.

Why Generic Drugs are termed "Abbreviated"?

 

Why Generic Drugs are termed "Abbreviated"?

 Generic drug applications are termed "abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the innovator drug). One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream in 24 to 36 healthy, volunteers. This gives them the rate of absorption, or bioavailability, of the generic drug, which they can then compare to that of the innovator drug. The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the innovator drug.

For  articles related to ANDA Filing, log on to pharmatreasures.blogspot.com

Quality Assurance (pharma) frequently asked interview questions

    


Interview is the way for an employer to see what he or she will get if they hire you.It is crucial that you are well prepared. Good interviewer always have a hidden agenda behind their questions.Questions are more or less designed around the specific position you are interested in,however you should expect some common questions irrespective of the job description.BFS





Your first impression during the interview can make a world of difference to your job prospects. First and foremost is dressing up appropriately for the interview. Do not wear  jeans and funky accessories just to prove you are in sync with fashion, neither should to dress up in such a way to suggest you have no dressing sense.Dress up smartly and your body language should reflect confidence.

Everyone is nervous on interviews,but those who are able to display confidence along with the correct attitude are always able to create the right first impression.In general, be upbeat and positive. Never be negative. Rehearse your answers and time them.Don't try to memorize answers word for word.   

Sr.No.	Questions & Answers
1.	Q. Why water for pharmaceutical use is always kept in close loop in continuous circulation ?
	A. Water is a best medium for many microorganisms, microorganism can be a highly pathogenic which causes serious diseases(many diseases are  water born), these pathogens infect after consumption of contaminated water, microorganisms tend to settle on a surface if water is allowed to stand in a stagnant position for few hours, these settled microorganism form a film over the surface of vessel and piping, such film formed by microorganisms is also called as biofilm, biofilms are very difficult of remove, once a biofilm is formed at a particular point then that point may form a biofilm again even after cleaning very easily as seed from this point is may not completely get removed effectively. Biofilms then can become a source of microbial contaminations; therefore purified water after collection in a distribution system is always kept in a closed loop in a continuous circulation. A continuous circulation is also not enough at some points, therefore it is aided with high temperature range from 65 °C to 80°C, a minimum temperature of 65 °C is considered a self sanitizing, but better assurance is obtained with a temperature of 80°C . Purified water collected should be stored in a stainless still vessel which must facilitate distribution to the point of use in a closed loop of continuous circulation, tank should be made of corrosion free material of construction, and must facilitate sanitization and easy cleaning.
2.	Q. Water for pharmaceutical use shall be free cations,anions and other impurities why ?
	A.Water for pharmaceutical must be free from inorganic as well as organic impurities, minerals, and heavy metals. Some impurities like calcium, magnesium, ferrous are responsible for degradation of drug molecule, many cations like ferrous and calcium magnesium act as catalysts in degradation reaction of drug molecule, anions like chloride are highly active they participate in nucliophylic substitution reactions, where in they break a double bond between -C=C- in to a single bond as CL –CH-CH2- , which a reason why we observe that color dies tend to fed in presence of chlorine as most of the dies used are diazo compounds which has plenty of places for nucliophylic substitution reactions, which is also a reason why stability of drug is drastically affected in presence of cations and anions from mineral origin present in water.
3.	Q. Water for pharmaceutical use shall be free heavy metals why ?
	A. Heavy metals like lead and arsenic are highly cumulative neurotoxic metals, heavy metals are not eliminated out of our body easily like other drugs and molecules but heavy metals bind with proteins and tend to get accumulated in fatty tissues, nerve tissue is most likely to get damaged by heavy metals, heavy metal causes nervous tissue damage there for water must be free from heavy metals.
4.	Q. Brazil falls under which climatic zone ?
	A. Zone IVB (30 degree celsius and  75% relative humidity)
5.	Q. Change in the size or shape of the original container requires any stability study?
	A. Change in the size or shape of the original container may not necessitate the initiation of new stability study.
6.	Q. Forced degradation(stress testing) and accelerated stability testing are same?
	A. Forced degradation and stress testing are not same. Stress testing is likely to be carried out on a single batch of the drug substance. The testing should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C) above that for accelerated testing), humidity (e.g., 75 percent relative humidity or greater) where appropriate, oxidation, and photolysis on the drug substance. The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension. Photo stability testing should be an integral part of stress testing.
7.	Q. According to WHO guidelines what is the storage condition of climatic zone IVa and zone IVb?
	A. Zone IV a: 30°C and 65% RH (hot and humid countries) Zone IV b: 30°C and 75% RH (hot and very humid countries
8.	Q. Countries comes under climatic zone IVb?
	A. Brazil,Cuba,China,Brunei,Cambodia,Indonesia,Malaysia,Myanmar,Philippines,Singapore,Thailand
9.	Q. What is the purpose of stress testing in stability studies?
	A. Stress testing of the drug substance can help identify the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved.
10.	Q. What is the formula for calculating number of air changes in an area?
	A. Number of air changes/hour in an area is                     = Total Room Airflow In CFM x 60                     Total Volume of room in cubic feet For calculating Total Room Airflow in CFM, first calculate air flow of individual filter. Formula is given below. Air flow (in cfm) = Avg.air velocity in feet/Minute x Effective area of filter                                                   Then find Total air flow. Formula is Total Air flow = Sum of air flow of individual filter. Air flow Velocity can be measured with the help of Anemometer.
11.	Q. What is dead leg?
	A. A dead leg is defined as an area in a piping system where liquid can become stagnant and not be exchanged during flushing.
12.	Q. What is the recommended bio burden limits of purified water & WFI?
	A. Purified water has a recommended bioburden limit of 100 CFU/mL, and water for injection (WFI) has a recommended bio burden limit of 10 CFU/100 mL.
13.	Q. Brief about ICH stabilty guidelines?
	A. Q1A- Stability testing of new drug substance & products Q1B- Photo stability testing of new drug substances & products Q1C-Stability testing of new dosage forms Q1D-Bracketing & Matrixing designs for testing of new drug substances and products Q1E-Evaluation of stability data Q1F-Stability data package for registration applications in climatic zone III & IV (Withdrawed)
14.	Q. What is significant changes in stability testing?
	A. 1. A 5% change in assay for initial value. 2. Any degradation products exceeds its acceptance     criterion. 3. Failure to meet acceptance criterion for     appearance,physical artributes and functionality      test. 4. Failure to meet acceptance criteria for dissolution     for 12 units.
15.	Q. If leak test fail during in process checks what needs to be done ?
	A. Immediately stop packing process and check for 1.Sealing temperature                  2.Verify for any possible changes like foil width,knurling etc. 3.Check & quarantine the isolated quantity of packed goods from last passed inprocess. 4.Collect random samples & do retest. 5.Blisters from the leak test passed containers shall allow to go further and rest must be deblistered/defoiled accordingly.
16.	Q. How many Tablets shall be taken for checking friability?
	A. For tablets with unit mass equal or less than 650 mg, take  sample of whole tablets corresponding to 6.5g.For tablets with unit mass more than 650mg,take a sample of 10 whole tablets.
17.	Q. What is the formula for calculating weight loss during friability test?
	A. %Weight loss =  Initial Weight - Final Weight  X 100                                                 Initial  Weight
18.	Q. What is the pass or fail criteria for friability test?
	A. Generally the test is run for once.If any cracked,cleaved or broken tablets present in the tablet sample after tumbling,the tablets fails the test.If the results are doubtful,or weight loss is grater than the targeted value,the test should be repeated twice and the mean of the three tests determined.A  mean weight loss from the three samples of not more than 1.0% is considered acceptable for most of the products.
19.	Q. What is the standard number of rotations used for friability test?
	A. 100 rotations
20.	Q. What is the fall height of the tablets in the friabilator during friability testing?
	A. 6 inches.Tablets falls from 6 inches eight in each turn within the apparatus.
21.	Q. Why do we check hardness during inprocess checks?
	A. To determine need for the pressure adjustments on the tableting machine. Hardness can affect the disintegration time.If tablet is too hard, it may not disintegrate in the required period of time. And if tablet is too soft it will not withstand handling and subsequent processing such as coating,packing etc.
22.	Q. What are the factors which influence tablet hardness?
	A.         1.compression force         2.Binder quantity(More binder more hardness)         3.Moisture content
23.	Q. Which type of tablets are exempted from Disintegration testing?
	A. Chewable Tablets
24.	Q. Which capsule is bigger in size - size '0' or size '1'?
	A. '0' size
25.	Q. What is the recommended temperature for checking DT of a dispersible tablet?
	A. 25 ±10C (IP) & 15 – 250C (BP)
26.	Q. What is mesh aperture of DT apparatus ?
	A. 1.8 -2.2mm (#10)
27.	Q. What is the pass/fail criteria for disintegration test?
	A. If one or two tablets/capsules fails to disintegrate completely, repeat the test on another 12 additional dosage units. The requirement is meet if not fewer than 16 out of 18 tablets/capsules tested are disintegrated completely.
28.	Q. What is the recommended storage conditions for empty hard gelatin capsules?
	A. 15 - 250C & 35 -55% RH
29.	Q. Which method is employed for checking “Uniformity of dosage unit”?
	A. A.)Content uniformity B.)    Weight Variation Weight variation is applicable for following dosage forms;Hard gelatin capsules,uncoated or film coated tablets,containing 25mg or more of a drug substance comprising 25% or more by weight of dosage unit.
30.	Q. What is the recommended upward and downward movement frequency of a basket-rack assembly in a DT apparatus?
	A.  28 – 32 cycles per minute.
31.	Q. When performing the ‘uniformity of weight’ of the dosage unit, how many tablet/capsule can deviate the established limit?
	A. Not more than two of the individual weights can deviates from the average weight by more than the percentage given in the pharmacopeia,and none can deviates more than twice that percentage. Weight Variation limits for Tablets        IP/BP Limit       USP 80 mg or less 10% 130mg or less More than 80mg or Less than 250mg 7.5% 130mg to 324mg 250mg or more 5% More than 324mg Weight Variation limits for Capsules IP Limit Less than 300mg 10% 300mg or More 7.5%
32.	Q. What needs to be checked during inprocess QA checks?
	A. a.) Environmental Monitoring b.) Measured values obtained from the process equipment  (ex:temperature,RPM etc.) c.) Measured values obtained from persons (ex:timmings,entries etc.) d.) Process attributes (Ex:weight,hardness,friability etc.)
33.	Q. What precautions shall be taken while collecting  inprocess samples ?
	A. While collecting inprocess samples, avoid contamination of the product being sampled (Don’t collect samples with bare hands) & avoid  contamination of sample taken.
34.	Q. In a tablet manufacturing facility ‘positive’ pressure is maintained in processing area or service corridors?
	A. In tablet manufacturing facilities, pressure gradients are maintained to avoid cross contamination of products through air. Usually processing areas are maintained under positive pressure with respect to service corridors.
35.	Q. If sticking observed during tablet compression what may the probable reason for the same?
	A. 1.If the granules are not dried properly sticking can     occur. 2.Too little or improper lubrication can also leads to     sticking. 3.Sticking can  occur because of too much binder or    hygroscopic granular.
36.	Q. What checks shall be carried out, while calibrating  DT apparatus?
	A. While calibrating DT apparatus, following checks shall be performed. 1.)       Number of strokes per minute (Limit:29-32 cycles/min) 2.)       Temperature by probe & standard thermometer            (Limit: 37 ± 1 OC).     3).   Distance travelled by basket (Limit:53 -57mm)
37.	Q. What is In process checks?
	A. In process checks are  checks performed during an activity,In order to monitor and,if necessary,to adjust the process to ensure that product confirms to its specification.
38.	Q. What is the difference between disintegration and dissolution?
	A. Disintegration is a disaggregation process, in which an oral dosage form falls apart in to smaller aggregates.(Disintegration time is the ‘break up’ time of a solid dosage form). Where as dissolution is a process by which solid substance enters in the solvent to yield a solution.It is controlled by the affinity between the solid substance and the solvent. In other word disintegration is a subset of dissolution.
39.	Q. Why do we calibrate a qualified equipment/instrument on definite intervals?
	A. An equipment or instrument can ‘drift’ out of accuracy between the time of qualification and actual use.So it is recommended to calibrate and recalibrate the measuring devices and instruments on predetermined time intervals, to gain confidence on the accuracy of the data.
40.	Q. Why do we consider three consecutive runs/batches for process validation? Why not two or four?
	A. The number of batches produced in the validation exercise should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation and reproducibility. ·       First batch quality is accidental (co-incidental), ·       Second batch quality is regular (accidental), ·       Third batch quality is validation(conformation). In 2 batch we cannot assure the reproducibility of data,4 batches can be taken but the time and cost are involved.
41	Q. Explain about revalidation criteria of AHU system?
	A. AHU system shall be revalidated periodically as mentioned in the regulatory standards. AHU shall be revalidated in following cases also. ·       When basic design of AHU is changed, ·       When clean room volume is changed, ·       When new equipment is installed ·       When a construction is carried out, that calls for reconstruction of AHU system.
42.	Q. What needs to be checked during AHU validation?
	A. During AHU validation, following tests shall be carried out ·       Filter efficiency test, ·       Air velocity & number of air changes, ·       Air flow pattern (visualization) ·       Differential pressure, temperature and RH ·       Static condition area qualification ·       Dynamic condition qualification ·       Non-viable count ·       Microbial monitoring ·       Area recovery and power failure study.
43.	Q. Position of oblong tablets to be placed in hardness tester to determine the hardness? Lengthwise / widthwise?
	A. Position of oblong tablets should be length wise because the probability of breakage is more in this position.
44.	Q. Explain in detail about qualification of pharmaceutical water system?
	A. Qualification of pharmaceutical water system involves three phases ·       Phase -1 ·       Phase -2 ·       Phase -3 Phase -1 A test period of 2-4 weeks should be spent for monitoring the system intensively. During this period the system should operate continuously without failure or performance deviation.Water cannot be used for pharmaceutical manufacturing in this phase.The following should be included in testing approach. ·       Under take chemical & microbiological testing in accordance with a defined plan. ·       Sample incoming feed water daily to verify its quality. ·       Sample each step of purification process daily. ·       Sample each point of use daily. ·       Develop appropriate operating ranges. ·       Demonstrate production and delivery of product water of required quantity and quality. ·       Use and refine the SOP’s for operation,maintenance,sanitization and trouble shooting. ·       Verify provisional alert and action levels. ·       Develop and refine test failure procedure. Phase -2 A further test period of 2-4 weeks. Sampling scheme will be same as  Phase – 1.Water can be used for manufacturing process in this phase. Approach should also ·       Demonstrate consistent operation within established ranges. ·       Demonstrate consistent production & delivery of water of required quality and quantity. Phase - 3 Phase 3 runs for one year after satisfactory completion of phase-2.Water can be used for manufacturing process during this process. Objectives & Features of Phase -3 ·       Demonstrate extensive reliable performance. ·       Ensure that seasonal variations are evaluated. ·       The sample locations, sampling frequencies and test should be reduced to the normal routine pattern based on established procedures proven during Phase -1 & phase - 2.
45.	Q. What are the recommended environmental monitoring limits for microbial contamination?
46.	Q. What is the difference between calibration and Validation?
	A. Calibration is a demonstration that, a particular Instrument or device produces results with in specified limits by comparisons with those produced by a reference or traceable standard over an appropriate range of measurements. Where as Validation is a documented program that provides high degree of assurance that a specific process, method or system consistently produces a result meeting pre-determined acceptance criteria. In calibration performance of an instrument or device is comparing against a reference standard. But in validation such reference standard is not using. Calibration ensures that instrument or measuring devices producing accurate results. Whereas validation demonstrates that a process, equipment, method or system produces consistent results (in other words, it ensures that uniforms batches are produced).
47.	Q. Briefly explain about ICH climatic zones for stability testing & long term storage conditions?
	A.ICH STABILITY ZONES Zone Type of Climate Zone I Temperate zone Zone II Mediterranean/subtropical zone Zone III Hot dry zone Zone IVa Hot humid/tropical zone Zone IVb ASEAN testing conditions hot/higher humidity             Long term Storage condition Climatic Zone Temperature Humidity Minimum Duration Zone I 21ºC ± 2ºC 45% rH ± 5% rH 12 Months Zone II 25ºC ± 2ºC 60% rH ± 5% rH 12 Months Zone III 30ºC ± 2ºC 35% rH ± 5% rH 12 Months Zone IV 30ºC ± 2ºC 65% rH ± 5% rH 12 Months Zone IVb 30ºC ± 2ºC 75% rH ± 5% rH 12 Months Refrigerated 5ºC ± 3ºC No Humidity 12 Months Frozen -15ºC ± 5ºC No Humidity 12 Months
48.	Q. What is bracketing & matrixing in  stability testing?
	A.Both Matrixing & Bracketing’s are reduced stability testing designs Bracketing The design of a stability schedule, such that only samples of extremes of certain design factors (ex:strength,package size) are tested at all time points as in full design.The designs assumes that the stability of any intermediate level is represented by the stability of extremes tested. Matrixing The design of a stability schedule, such that a selected subset of possible samples for all factor combinations is tested at a specified time point.At a subsequent time point another subset of samples for all factor combination is tested.The design assumes that the stability of each subset samples tested represents the stability of all samples at a given time point. There for a given time point other than initial & final ones not every batch on stability needs to be tested.
49.	Q.What are the common variables in the manufacturing of tablets?
	A. ·       Particle size of the drug substance ·       Bulk density of drug substance/excipients ·       Powder load in granulator ·       Amount & concentration of binder ·       Mixer speed & mixing timings ·       Granulation moisture content ·       Milling conditions ·       Lubricant blending times ·       Tablet hardness ·       Coating solution spray rate
50.	Q. Whether bracketing & validation concept can be applied in process validation?
	A.Both Matrixing & Bracketing’s can be applied in validation studies. Matrixing Different strength of same product Different size of same equipment Bracketting - Evaluating extremes    Largest and smallest fill volumes Fastest and slowest operating speeds