B.pharma/M.pharma-Technical Questions-Answers Department: QA/QC/Production Area

B.pharma/M.pharma-Technical Questions-

Answers  Department: QA/QC/Production 

Area

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What is dead leg?

A dead leg is defined as an area in a piping system where liquid can become stagnant and not be exchanged during flushing.

What is the recommended bio burden limits of purified water & WFI?

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.

What is significant changes in stability testing?

• A 5% change in assay for initial value.
• Any degradation products exceeds its acceptance criterion.
• Failure to meet acceptance criterion for appearance,physical artributes and functionality test.
• Failure to meet acceptance criteria for dissolution for 12 units.

If leak test fail during in process checks what needs to be done ?

Immediately stop packing process and check for

• Sealing temperature                 
• Verify for any possible changes like foil width,knurling etc.
• Check & quarantine the isolated quantity of packed goods from last passed inprocess.
• Collect random samples & do retest.
• Blisters from the leak test passed containers shall allow to go further and rest must be deblistered/defoiled accordingly.

Which type of tablets are exempted from Disintegration testing?

Chewable Tablets

What are the common variables in the manufacturing of tablets?
 

• Particle size of the drug substance
• Bulk density of drug substance/excipients
• Powder load in granulator
• Amount & concentration of binder

Mixer speed & mixing timings

1. Granulation moisture content
   Milling conditions
   Lubricant blending times
2. Tablet hardness
3. Coating solution spray rate

Whether Bracketing & Validation concept can be applied in process validation?

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

What is the difference between calibration and Validation?

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.

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.

WHAT ARE GOOD MANUFACTURING PRACTICES (GMP)?

A.  Good Manufacturing Practices are a set of regulations, codes, and guidelines for the manufacture of: Drug substances and drug products, Medical devices, In vivo and in vitro diagnostic products, Foods

The term "cGMP" is used by the federal government as current good manufacturing practices. By definition, "cGMP" indicates that the current GMP - which is "state of the art" - can change. "GMP" and "cGMP" are often used interchangeably and essentially they have the same meaning.

Who Enforces Good Manufacturing Practices (GMP)?

Good Manufacturing Practices are enforced in the United States by the FDA (Food   and Drug Administration)

Good Manufacturing Practices are enforced in the United Kingdom by the Medicines and Healthcare Products Regulatory Agency (MHRA)

Good Manufacturing Practices are enforced in Australia by the Therapeutical Goods Administration (TGA)

Good Manufacturing Practices are enforced in India by the Ministry of Health, multinational and/or foreign enterprises and those individuals in the following positions:

Each of the inspectorates carry out routine GMP inspections to ensure that drug products are produced safely and correctly.

Appearance Defects of Tablets During Compression Activity ?

Capping: is the term used, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling.

Laminating:  is the separation of a tablet into two or more distinct horizontal layers.
    
Sticking/filming: Sticking’ refers to the tablet material adhering to the die wall. Filming is a slow form of sticking and is largely due to excess moisture in the granulation.

Cracking: Small fine cracks observed on the upper and lower center surface of the tablets, or very rarely on the side wall are referred to as cracks.
    
Chipping: is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operation.
    
Mottling: is the term used to describe an unequal distribution of colour on a tablet.
    
Double Impression:  involves only those punches,which have a monogram or other engraving on them.

 

What is the standard number of rotations used for friability test?

100 rotations

What is the fall height of the tablets in the friabilator during friability testing? 

 6 inches.Tablets falls from 6 inches height in each turn within the apparatus.

 
Which capsule is bigger in size - size '0' or size '1'? 

 '0' size  

Water for pharmaceutical use shall be free heavy metals why ?

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.

Change in the size or shape of the original container requires any stability study?

Change in the size or shape of the original container may not necessitate the initiation of new stability study.

Forced degradation (stress testing) Vs accelerated stability testing 

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.

According to WHO guidelines what is the storage condition of climatic zone IVa and zone IVb?

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.

What is the main objective of stress testing in stability studies?

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.

What is the formula for calculating number of air changes in an area?

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 as follow-

Total Air flow = Sum of air flow of individual filter.

Air flow Velocity can be measured with the help of Anemometer.

How many Tablets shall be taken for checking friability?

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.

What is the formula for calculating weight loss during friability test?

%Weight loss =  Initial Weight - Final Weight  X 100/Initial  Weight

What is the pass or fail criteria for friability test?

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.

What is the standard number of rotations used for friability test?

100 rotations  

   

What is the fall height of the tablets in the friabilator during friability testing?

6 inches.Tablets falls from 6 inches eight in each turn within the apparatus.

Why do we check hardness during inprocess checks?

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.

What are the factors which influence tablet hardness?

        1.compression force

        2.Binder quantity(More binder more hardness)

        3.Moisture content

What is the recommended temperature for checking DT of a dispersible tablet?

25 ±10C (IP) & 15 – 250C (BP)

What is mesh aperture of DT apparatus ?

1.8 -2.2mm (#10)

What is the pass/fail criteria for disintegration test?

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.

What is the recommended storage conditions for empty hard gelatin capsules?

15 - 250C & 35 -55% RH

What is the recommended upward and downward movement frequency of a basket-rack assembly in a DT apparatus?

28 – 32 cycles/minute

In a tablet manufacturing facility ‘positive’ pressure is maintained in processing area or service corridors?

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.

What checks shall be carried out, while calibrating  DT apparatus?

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)

What is the difference between disintegration and dissolution?

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.

That is why it is said that disintegration is a subset of dissolution.

Why do we calibrate a qualified equipment/instrument on definite intervals?

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.

Why do we consider three consecutive runs/batches for process validation? Why not two or four?

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.

Explain about revalidation criteria of AHU system?

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.

What needs to be checked during AHU validation?

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

What is the difference between calibration and Validation?

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.

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).