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

Cough Medications (Cough Informations & Types of cough medicines)

                             

Cough Medications

                                  
                                                
                


Cough is a forceful release of air from the lungs. Coughing protects the respiratory system by clearing it of irritants and secretions.

 
Basically, there are two kinds of cough: productive and non-productive.

Productive cough (Wet Cough): A productive cough (chesty cough) is typically associated with a viral upper respiratory tract infection (URI), such as the common cold. Infection causes the mucous membrane of the bronchial tubes to become inflamed and produce thick, sticky mucus, so that it is no longer removed by the normal action of the cilia and clogs up the airways. Coughing is a reflex that expels this sticky mucus, also called phlegm. Inflammation and accumulated mucus narrow the airways, restrict respiration, and can promote bacterial infection.

Non-productive cough (Dry cough): A non-productive cough is dry, tickling and irritating - a repeated stimulus in the respiratory tract and usually without expectoration. This cough can for example be caused by cigarette smoke or dust. It can also have an allergic or neurotic origin or can be caused by other perhaps more severe diseases.
 

Cough medications are grouped in to two types - Antitussives and Expectorants.

 
Expectorants (Expels mucus, phlegm) are mediations which promotes or facilitates the secretion or expulsion of phlegm, mucus, or other matter from the respiratory tract Or in other words expectorants make cough up mucus easier and less irritating. Usually expectorants are used to treat productive cough. Ex. Guaifenisin

 

Antitussives (Cough Suppressants) suppress the cough reflex by depressing the medullary cough centre or associated higher centres in the brain and/or peripheral cough receptors - resulting in calming down the cough. Antitussives are used for treating Nonproductive (dry) cough. Cough suppressants simply lessen the urge to cough. They should not be used if the cough is wet sounding and produces mucus. Examples of antitussives are codeine,hydrocodone,dextromethorphan etc.

 

Coughs associated with colds should be treated with an expectorant to clear out mucus.A productive cough is the body's way of clearing out mucus. An expectorant encourages the body to get rid of the phlegm quickly and get over the  coughing. Suppressants, on the other hand, suppress the body's natural desire to healing by blocking the cough reflex.

 

BFS (BLOW FILL SEAL)

                                  

Blow-fill-seal (BFS) Technology

 
BFS is an automated aseptic filling process in which containers are formed, filled and sealed in a continuous operation. BFS systems can reduce the risk of product contamination by reducing operator interventions. The systems are typically used for filling sterile ophthalmic and respiratory care products.

 
Blow fill seal technology is now widely considered to be superior form of aseptic processing by various medicine regulatory authorities including FDA.This type of system combines the blow molding of container with the filling of product and a sealing operation in one piece of equipment.From microbiological point of view,the sequence of forming the container,filling with sterile product and formation and application of the seal are achieved aseptically in an uninterrupted operation with minimal exposure of the environment.This systems have been in existence over 30 years and have demonstrated the capacity of achieving contamination rates below 0.1%.Blow Fill Seal equipment restricts employee contact with the product.

 
The process is multi stepped-in which,first pharmaceutical grade plastic resin is being heated and extruded under pressure through a circular throat,to form a hanging tube called the parison.The mold that forms the body of the container is in two halves.The lower halt closes to seal the bottom of the open parrison.Filling needles draw the stipulated volume of sterile product in to the container and after withdrawal of the needles the upper part of the mold closes to form the upper part of the container.All the actions takes place in a sterile chamber inside the machine.The forming,filling and sealing steps are thus carried out in one unit operation,taking just 10-12 seconds.Throughout this process sterile air is used.
 

BFS machinery and its surrounding barriers should be designed to prevent the potential for extraneous contamination. The classified environment surrounding BFS machinery should generally meet Class 100,000 (ISO 8), or better, standards, depending on the design of the BFS machinery and the surrounding room. HEPA-filtered or sterile air provided by membrane filters should be used during the steps when sterile products or materials are exposed (e.g., parison formation, container molding or filling steps). Air in the critical area should meet Class 100 (ISO 5) microbiological standards during operations. A well-designed BFS system should also normally achieve Class 100 (ISO 5) airborne particle levels. Only personnel who have been qualified and appropriately gowned should enter the classified environment surrounding the BFS machinery.

 

BFS technology reduces personnel intervention making it a more robust method for the aseptic preparation of sterile pharmaceuticals. By its nature,the BFS process offers high levels of quality assurance. By integrating container manufacture with product filling,BFS removes a major step from the production process,together with its associated risks.

In Process Checks and its importance in Pharmaceuticals

                                                  

                               

In-Process Control refers to the checks performed during an activity (it can be manufacturing or packing) in order to monitor and if necessary to adjust the process and/or to ensure that the intermediate or finished product conforms to its specification. The control of equipment and environment may also be regarded as the part of in process control.

In process checks are vital as manufacturing activity itself and the same shall be performed at regular intervals. Frequency of the in process checks need to be realistic. By carrying out in process checks one can assure the product quality.

In process quality check is designed to provide early warning for quality or other problems arising during production. In Other words it is intended to provide a snap shot of the quality of the product manufactured at the factory. The objective of in process checks are both quality control and process control.

In process checks shall include following process controls.

l  Measured values obtained from process equipment. e.g. Inlet & outlet temperature of FBD

l  Measured values obtained from persons e.g. Times

l  Product attributes e.g.Weight,Hardness,friability

l  Measured values obtained from the room environment e.g. Temperature, Humidity.

Note: Rejected in process materials should be identified and controlled under a quarantine system designed to prevent their use in manufacturing.

During process checks following things needs to be checked

l  Verification of the status labels on the area, equipments  & process containers.

l  Online stage wise review of the batch record (Online review).

l  Cleanliness of the area, equipment and line clearance.

l  Confirming material correctness, AR.no, quantity & vendor against the batch record.

l  Product attributes like weight variation, avg.wt, hardness, thickness, D.T, friability.

l  Monitoring environmental conditions.

l  Weight of the blend & other intermediates.

l  Checking the appearance tablet during compression & coating

l  Solution preparation.

l  Film formation and integrity.

l  Ensure machine setting parameters match with batch records.

l  Yield verification of various stages of production

l  Sampling

In Process Checks During Manufacturing

l  Ensure correct materials are brought in for manufacturing activity.

l  Check sieve integrity.

l  Ensure manufacturing is carried out as per the instruction given in the BMR.

l  Ensure operators are wearing hand gloves and nose mask during all stages of manufacturing.

l  Verify the records for online entries.

l  Environmental Monitoring.

l  Check & verify equipment parameters like temperature, drying time etc.

l  Checking process parameters like Appearance, Avg.Weight, Group Weight, Hardness, friability, DT etc.

l  Yield verification.

l  Checking the weights of in process materials.

l  Checking labeling status of the quarantine materials.

l  Ensure doors are closed during processing.

In Process Checks During packing

l  Ensure Name, Strength, Volume & quantity is correct.

l  Check the status labels on equipment, area & in process container.

l  Over printing quality.

l  Batch coding details on primary & secondary pack (B.No.,Mfg.,Exp., M.R.P.etc.).

l  Text matter on the ptd. foil & carton.

l  Verification forming & sealing temperature.

l  Ensure blisters are free from knurling defects.

l  Leak Test.

l  Pharmacopeial status of the material used is correct.

l  Mfg.License number is printed correctly.

l  Preprinted packing materials provide mandatory information & legal status.

l  Storage conditions details available in the packaging materials.

l  Directions for use details available in the packaging materials.

l  Ensure warnings against wrong administration is provided in the pack.

l   Storage condition is same all printed packing Materials.

l  Ensure correct leaflet is used for the product.

l  Verify printed matter on the outer cartons and shippers.

l  Ensure checkers are performing their activity in a proper way.

l  Verify blisters & strips for alignment defects & empty pockets.

l  Ensure doors are closed during processing.

l  Verify the records for online entries.

l  Environmental Monitoring.

l  Sampling

Documentation

Results of the in process checks shall be documented with initials of the person carrying them out and results obtained. If problems or deviations from the manufacturing formula and processing instructions occurred, all relevant information associated to this have to be documented well. 

Biofilms & their associated risks to pharmaceutical industry (Production Equipment’s & Pharmaceutical Water Systems)

                                    
                    
Biofilm

Biofilm is a complex aggregation of microorganisms growing on solid substrate. A biofilm contains about 15% of microbial cells & 85% EPS (Extra polymeric substance).EPS composed of polysaccharides,proteins,and other polymers and water.

Biofilms are characterized by structural heterogeneity, genetic diversity and complex community interactions.

A biofilm formation often initiated by micro colonies from one type of organism. However biofilms quickly become heterogeneous as mixed cultures of bacteria, as well as fungi, algae and protozoa join the established structure and become intermixed. In fact with in a biofilm different types of microorganisms can coexist and form stable communities.

Biofilm formation is a survival strategy against environmental stress. Biofilms are resistant to phagocytic amoebae, and are considered to be 100% phage proof. Biofilms are much more resistant than planktonic cells to antimicrobial agents. For example chlorination of a biofilm is usually unsuccessful because the biocide only kills the bacteria in the outer layers of biofilm. The bacteria within the biofilm remains healthy and the biofilm can regrow. Repeated use of antimicrobial agents on biofilms can cause bacteria within the biofilm to develop an increased resistance to biocides.

In the industrial environments, biofilms can develop on the product contact surfaces of equipment’s and  interiors of water purification and distribution system, which leads to clogs, corrosion and biological contamination of the medicinal products.

Stages of biofilm formation

There are three stages for biofilm formation. They are

1.       Initial adhesion to a surface. The first colonists adhere to the surface initially through weak, reversible Van der Waals forces. If the colonists are not immediately separated from the surface, they can anchor themselves more permanently using cell adhesion molecules such as Pilli. First colonies facilitate the arrival of other cells by providing more diverse adhesion sites and beginning to build matrix that holds the biofilm together.

2.       Cell growth or reproduction and production of EPS.  Once colonization has begun, the biofilm grows through a combination of cell division and recruitment.

3.       Detachment of sessile micro colonies. These cells travel to form new biofilms on other locations.

Quorum Sensing

Quorum sensing plays a major role in the initial stages of biofilm formation and biofilm dispersion. This phenomenon is a type of cell to cell signaling mechanism that enables a bacterium to regulate gene expression in response to population density. This type of intracellular communications occurs both within and between species.

Quorum sensing depends on production of diffusible signal molecules called auto inducers or pheromones. Once these molecules reach a high concentration, they start to interact with regulatory proteins that modulates gene expression. Besides bioluminescence, cell adhesion and cell detachment, a variety of other physiological process is regulated by quorum sensing and those includes swarming, motility sporulation, conjugation and production of virulent molecules. 

Cell Adhesion

The initial cell adhesion surfaces is a process governed by long range forces, primarily van der Waals and electrostatic interactions. Initial stage of biofilm formation is dependent on several factors ,including bacterial cell properties (ex:hydrophobicity),the nature, type, shape and physiochemical properties of substratum as well as chemical composition, hydrodynamics and flow characteristics of liquid environment.

Biofilm Dispersion

Biofilm cells can be dispersed by three main process. Shedding, detachment and by physical process. Dispersion of biofilm cells can have detrimental effects on a process unit operation, a piece of equipment or water system.   Dispersed film often maintain their biofilm phenotype, including antimicrobial resistance and the ability to attach new surfaces, thus posing a risk for systemic microbial colonization and potential product contamination.

Water Systems & Biofilm Formation

Important design features for prevention of biofilm formation in water systems are the material of construction, temperature of the system, and water flow. Usually stainless steel(SS316 or SS316L)piping is the preferred material due to ease of cleanability and suitability for heat sanitization.

WFI systems that are maintained circulating with a turbulent flow and at a high temperature (65–80°C) are deemed self-sanitizing. Purified water systems that are maintained circulating with a turbulent flow and at ambient temperature (25 ± 5°C) or cold WFI systems (0–5°C) are typically steam sanitized once a week, with user points

heat sanitized daily. These practices are often effective in preventing biofilm formation. Maintaining a circulating water system is critical because a one-way water system is basically a dead leg.

In pharmaceuticals, the risk of systemic microbial contamination in a water system is low due to proper purification steps and routine monitoring. Hence pharmaceutical water systems can be contaminated due to a failure in the maintenance or operating procedures designed to prevent introduction of microorganisms into the system. For example, nonsterile air that remains in a pipe, valve, or hose after drainage may be introduced into the system inadvertently. Carbon beds used for pretreatment of feed water can become a breeding ground for biofilms, and these units must be heat sanitized as backwashing does not work and can exacerbate the problem. Perforated heat exchangers can also lead to contamination of a water system. FDA recommends that heat exchangers not be drained of the cooling water when not in use to prevent pinholes from being formed in the tubing after they are drained as a result of corrosion of the stainless steel tubes in the presence of moisture and air.

Dead legs in piping’s can potentiates  biofilm formation. Microbial contamination can also occur if pumps are not continuously in operation, resulting in a static reservoir area where water will become stagnant.

RO systems are used as pretreatment for highly purified waters. However, RO systems, if not of sanitary design, are prone to microbial contamination that often becomes established in the membrane filters and in the ball valves; the center of the valve can collect water when the valve is closed, and the stagnant water can harbor microorganisms and provide a starting point for the development of a biofilm. With the recognition of the dangers of potential biofilm formation in RO units, filter manufacturers recommend installing at least two units in series, and some manufacturers have installed heat exchangers immediately after the RO filters to heat the water to 75–80°C in an attempt to minimize microbial contamination. In addition, an ultraviolet (UV) light is often installed in the system

downstream from the RO units to aid in the control of microbial proliferation.

Although ozone and UV light have been used to control microbial contamination in water systems, both methods have pros and cons. The dissolved residual ozone remains in the system may pose safety concerns not only for employees but also for drugs formulated with the water. Another concern with using ozone is that ozonating

the incoming water breaks up many types of nutrients that otherwise would not be available for uptake by microorganisms. Therefore, for some water systems, ozone makes nutrients available to bacteria, and a biofilm bloom can develop immediately after the ozonater. The effectiveness of UV lights for control of microbial contamination is limited and dependent on where the unit is located, and whether the UV light is on continuously or just turned on when water is needed. UV light penetrates biofilms poorly. Much of the radiation gets trapped in the EPS matrix, so the sessile cells are protected from and resistant to the radiation.

Production Equipment’s & Biofilm Formation

The primary rule for biofilm prevention is to store equipment and materials as dry as possible. So cells cannot form biofilms in the absence of water or moisture. Care should be taken when connecting pipes, gauges, sensor probes, hoses, and other parts of equipment to ensure that connections do not create dead legs or dead zones where liquid can collect.

Product contact surfaces should be maintained smooth, with no imperfections or deterioration that would lead to microbial colonization. Corrosion of metals after exposure to water and chemicals is of great concern in the pharmaceutical industry. Water is the largest component used in pharmaceutical manufacturing and its use can lead to detrimental effects on metal surfaces such as rouging, corrosion, and biofilm formation.

Microbial contamination of pharmaceutical equipment occurs primarily with equipment and materials that do not meet sanitary design standards. The equipment used in pharmaceutical manufacturing should meet good engineering design and principles. Including aspects that relate to sterility and cleanability, dimensions and tolerances, surface finish, material joining, and seals.

Biofilm Control & Prevention

Biofilm control involves one of the following strategies: preventing the initial contamination of the material, attempting to minimize the initial microbial adhesion to the surface, killing of the biofilm cells via chemical or heat treatment, and removing the piece of equipment altogether and replacing it with a new and clean one.

Heat

Heat is very effective in removing biofilms, and it is the first choice for biofilm prevention and remediation. Companies should modify, whenever possible, equipment components so the system can be steamed in place. In order to do so, the equipment must be fitted with steam traps, and should have parts and components that can withstand heat. Another alternative is to disassemble the various equipment parts, autoclave them, and then reassemble the equipment using aseptic technique and under aseptic conditions.

Chemical Treatment

Equipment that cannot undergo steaming in place or autoclaving must be chemically sanitized prior to use. Chemical sanitization of equipment can be accomplished using caustic, acidic, and oxidizing agents such as hydrogen peroxide and sodium hypochlorite solutions. Oxidizing chemicals can actually dissolve the polysaccharide matrix and kill the bacteria. These solutions are very effective in biofilm removal but, unfortunately, not compatible with many materials.

Decongestant

                                                            

A decongestant is a medication that  relieve the stuffy-nose feeling caused by an illness, most commonly the flu, a cold or allergies.In other words decongestant shrinks the swollen membranes in the nose and makes it easier to breath.

Decongestants can be taken orally or by nasal spray. Decongestant nasal sprays should not be used for more than five days without the doctor's advice.Decongestants should not be used by patients with high blood pressure(hypertension) unless under doctor's supervision.

The vast majority of decongestants act via enhancing nor epinephrine or epinephrine or adrenergic activity by stimulating alpha adrenergic receptors.This includes vasoconstriction of blood vessels in the nose, throat,and para nasal sinuses,which results in reduced inflammation (swelling) and mucous formation in these areas.

The active ingredients in most ingested decongestants are Psuedoepedrine or phenylephrine.Pseudoephedrine acts indirectly on the adrenergic receptor system, whereas phenylephrine is a direct agonist.Usage of Pseudoephedrine is banned in diffrent countries including India.

Pharmaceutical Pipes dead legs - 6D Rule

                                       


Purified water is frequently used in the pharmaceutical industry during the manufacture of medicines. This water is distributed throughout the manufacturing facility to points-of-use using high quality process pipework. The installation of a pipe tee in this pipework often creates a stagnant dead-leg zone. This dead-leg can contaminate the entire distribution network resulting in lost production, contaminated product and down time for cleaning.

The formal definition of a pipe dead-leg as given by the Food and Drug Administration (the FDA) is:Pipelines for the distribution of purified water for manufacturing or final rinse should not have an unused portion greater in length than 6 diameters (the 6D rule) of the unused portion of pipe measured from the axis of the pipe in use.

The FDA suggest the 6D rule will help prevent contamination: however industrial experts are designing systems with dead legs limited to 3D or less. Some systems and fittings claim to have zero dead legs.

Brusting Strength

Pressure at which a film or sheet (of paper or plastic, for example) will burst. Used as a measure of resistance to rupture, burst strength depends largely on the tensile strength and extensibility of the material. Determined by procedures such as Mullen burst test, it is expressed commonly in pounds per square inch (psi). Burst strength of packaging material used in shipment of merchandise is usually printed on the package.