Friday, January 27, 2017

Difference between Incidence and Deviation

 Differentiation between an incidence and deviation 

when it occurs in pharmaceutical GMP manufacturing facility. It causes a big confusion to understand the occurrence of incidence and deviation in pharmaceuticals. A huge number of pharmaceutical professionals difficulties to differentiate the incidence and deviation when they occur in real.
                                     When we have any written procedure like standard operating procedure, protocol, standard test procedure, BMR etc. and someone works against this, then it is called deviation. It means deviation from any written procedure that we have implemented. Now deviation can be of two different types:

  1.  Planned Deviation 
  2.  Unplanned Deviation

                  Planned deviations are those deviations from the procedure that are planned and we know before they occur. For example: calibration or validation is not carried out as per schedule due to delay for various reasons. In this case, we have to fill CAPA for the same. In case of unplanned deviation, the failure of procedure, utility, material, equipment or any system is occurred. We can consider it as any change from the previous or our written procedure. Unplanned deviations may be critical, major or minor.
               These can be categorised on their impact of product quality.

Critical deviations: Manufacturing instructions are not followed, wrong batch details are printed, SOPs or methods of testing not followed during analysis, etc.

Major deviations: Line clearance is not taken from QA, physician sample wrongly printed with price, etc.

Minor deviations: Raw material is received in a damaged container, manometer readings in the sampling booth are crossed the action limits, etc.

 Incidence is any event that can affect our product quality or not but that is against the cGMP. For example: Someone is found without gowning in the production area or any insect is found in granulation area.

These may have impact on product quality but not every time, sometime it will not impact. These are the deviations from GMP but difference is that these are not related to our manufacturing process. So, these will not be categorized as deviations.

Some other examples of incidence: Eating food in production area, spillage of material on floor, break down in any machine during processing, mix-up of two batches, wrong material added in batch etc.

Monday, January 23, 2017

" 21 CFR 11 " related Interview Question

Q: What are the requirements of 21 CFR 11?
A: 21 CFR 11 requires that closed computer systems must have a collection of technological and procedural controls to protect data within the system. Open computer systems must also include controls to ensure that all records are authentic, incorruptible, and (where applicable) confidential.

Q: What computer systems must be compliant with 21 CFR 11?
A: All computer systems which store data which is used to make Quality decisions or data which will be reported to the FDA must be compliant with 21 CFR 11. In laboratory situations, this includes any laboratory results used to determine quality, safety, strength, efficacy, or purity. In clinical environments, this includes all data to be reported as part of the clinical trial used to determine quality, safety, or efficacy. In manufacturing environments, this includes all decisions related to product release and product quality.

Q: What is computer system validation?
A: Validation is a systematic documentation of system requirements, combined with documented testing, demonstrating that the computer system meets the documented requirements. It is the first requirement identified in 21 CFR 11 for compliance. Validation requires that the System Owner maintain the collection of validation documents, including Requirement Specifications and Testing Protocols.

Q: What is accurate record generation?
A: Accurate record generation means that records entered into the system must be completely retrievable without unexpected alteration or unrecorded changes. This is generally tested by verifying that records entered into the system must be accurately displayed and accurately exported from the system.

Q: How must records be protected?
A: Electronic records must not be corrupted and must be readily accessible throughout the record retention period. This is usually performed through a combination of technological and procedural controls.

Q: What is limited system access?
A: System owners must demonstrate that they know who is accessing and altering their system data. When controlled technologically, this is commonly demonstrated by requiring all users have unique user IDs along with passwords to enter the system.

Q: What is an audit trail?
A: An audit trail is an internal log in a program that records all changes to system data. This is tested by demonstrating that all changes made to data are recorded to the audit trail.

Q: What are operational system checks?
A: Operational system checks enforce sequencing of critical system functionality. This is demonstrated by showing that business-defined workflows must be followed. For example, data must be entered before it can be reviewed.

Q: What are device checks?
A: Device checks are tests to ensure the validity of data inputs and operational instructions. Generally speaking, Ofni Systems does not suggest testing keyboards, mice, etc., because these input devices are implicitly tested throughout other testing. However, if particular input devices (optical scanners, laboratory equipment, etc.) these devices should be tested to ensure the accuracy of system inputs.

Q: What training requirements are required for 21 CFR 11 compliant programs?
A: Users must be documented to have the education, training, and experience to use the computer system. Typically training can be covered by your company training procedures.

Q: What is a policy of responsibility for using electronic signatures?
A: Users must state that they are aware that they are responsible for all data they enter or edit in a system. This can be accomplished technologically through accepting conditions upon signing into the system or procedurally by documenting this responsibility as part of training.

Q: What documentation requirements are required for 21 CFR 11 compliant programs?
A: Documentation must exist which defines system operations and maintenance. Typically these requirements are met by company document control procedures.

Q: What are the requirements for electronic signatures?
A: All electronic signatures must:

> Include the printed name of the signer, the date/time the signature was applied, and the meaning of the electronic signature.

> Be included in human readable form of the record. Electronic signatures must not be separable from their record.
> Must be unique to a single user and not used by anyone else.
> Can use biometrics to uniquely identify the user. If biometrics are not used, they need at least two distinct identifiers (for example, the user ID and a secret password).

Q: Does 21 CFR 11 have any requirements for passwords or identification codes?
A: Yes. Procedural controls should exists to ensure that:

> No two individuals have the same user ID and password.
> Passwords are periodically checked and expire.
> Loss management procedures exists to deauthorize lost, stolen, or missing passwords.

IPQA Interview Questions

Q. What are the factors which influence tablet hardness?
Ans: 1.compression force
        2.Binder quantity(More binder more hardness)
        3.Moisture content

Q. Which type of tablets are exempted from Disintegration testing?
Ans: Chewable Tablets

Q. What is the recommended temperature for checking DT of a dispersible tablet?
Ans: 25 ±10C (IP) & 15 – 250C (BP)

Q. What is mesh aperture of DT apparatus ?
Ans: 1.8 -2.2mm (#10)

Q. What is the pass/fail criteria for disintegration test?
Ans: 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.

Q. What is the recommended storage conditions for empty hard gelatin capsules?
Ans: 15 - 250C & 35 -55% RH

Q. Which method is employed for checking “Uniformity of dosage unit”?
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.

Q. What is the recommended upward and downward movement frequency of a basket-rack assembly in a DT apparatus?
Ans: 28 – 32 cycles per minute.

Q. When performing the ‘uniformity of weight’ of the dosage unit, how many tablet/capsule can deviate the established limit?
Ans: 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
80 mg or less
130mg or less
More than 80mg or Less than 250mg
130mg to 324mg
250mg or more
More than 324mg

Weight Variation limits for Capsules
Less than 300mg
300mg or More
Q. How many Tablets shall be taken for checking friability?
Ans: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.

Q. What is the formula for calculating weight loss during friability test?
Ans: %Weight loss =  Initial Weight - Final Weight  X 100
                                                Initial  Weight

Q. What is the pass or fail criteria for friability test?
Ans: 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.

Q. What is the fall height of the tablets in the friabilator during friability testing?
Ans: 6 inches.Tablets falls from 6 inches height in each turn within the apparatus.

Q. Why do we check hardness during inprocess checks?
Ans: 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.

Q. What needs to be checked during inprocess QA checks?
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.)

Q. What precautions shall be taken while collecting  inprocess samples ?
Ans: While collecting inprocess samples, avoid contamination of the product being sampled (Don’t collect samples with bare hands) & avoid  contamination of sample taken.

Q. In a tablet manufacturing facility ‘positive’ pressure is maintained in processing area or service corridors?
Ans: In tablet manufacturing facilities, pressure gradients are maintained to avoid cross contamination of products through air. Usually service corridors are maintained under positive pressure with respect to processing areas.

Q. If sticking observed during tablet compression what may the probable reason for the same?
1.If the granules are not dried properly sticking can occur.
2.Too little or improper lubrication.
3.Too much binder
4.Hygroscopic granular

Q. What checks shall be carried out, while calibrating  DT apparatus?
Ans: 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)

Q. What is In process checks?
Ans: 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.

Q. What is the difference between disintegration and dissolution?
Ans: 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.
Q. What is the difference between calibration and Validation?
Ans: 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).
Q. Why do we calibrate a qualified equipment/instrument on definite intervals?
Ans: 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.

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

Q. Position of oblong tablets to be placed in hardness tester to determine the hardness? Lengthwise / widthwise?
Ans: Position of oblong tablets should be length wise because the probability of breakage is more in this position.

Q. Which type of tablets are exempted from Disintegration testing?
A. Chewable Tablets

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

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

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, FoodsThe 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.

A.  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.  


Capping:- ‘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:- ‘Lamination’ 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:- ‘ Chipping’ is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operation.
Mottling:‘ Mottling’ is the term used to describe an unequal distribution of colour on a tablet.
Double Impression: ‘ Double impression’ involves only those punches,which have a monogram or other engraving on them.

Q What is the fall height of the tablets in the friabilator during friability testing? 
A. 6 inches.Tablets falls from 6 inches height in each turn within the apparatus.

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

Q What is the standard number of rotations used for friability test?
A. 100 rotations

Flame photometric detector

Flame Photometric Detector or GC-FPD is a technique used to analyse sulphur or phosphorous containing compounds and metals such as tin, boron, arsenic and chromium. An FPD uses a Hydrogen/Air flame into which the sample is passed. Phosphorous and sulphur containing hydrocarbons generate chemiluminescene at specific wavelengths which when passed into a photo-multiplier gives an electrical signal which can then be measured

Differences between HPLC & GC

  1. HPLC is useful for analysis of samples which are liable to decompose at higher temperatures. GC involves high temperatures so compounds are stable at such temperatures.
  2. In HPLC the mobile phase is a liquid whereas in GC the mobile phase or carrier is a gas.
  3. GC cannot be used for analysis of high molecular weight molecules whereas HPLC has applications for separation and identification of very high molecular weight compounds
  4. Columns are different
  5. GC is applied for analysis of volatile compounds whereas non volatile compounds can be easily analyzed on HPLC