Month: March 2020

Static Charges in Pharmaceuticals Manufacturing

Static charge is a small variable which affects the quality of the product indirectly, so we should understand how it can be avoided. Static charges can also have a major impact on human safety and is a health hazard.

Static charges is a major cause of fire and explosions in many industries handling flammable liquid and many incidents have been reported around the world in pharmaceuticals also due to static charges.

What is Static Electricity  :

Static electricity is an imbalance of electric charges within or on the surface of a material. The charge remains until it is able to move away by means of an electric current or electrical discharge. Static electricity is named in contrast with current electricity, which flows through wires or other conductors and transmits energy.

A static electric charge is created whenever two surfaces contact and separate, and at least one of the surfaces has a high resistance to electrical current (an electrical insulator). The effects of static electricity can be demonstrated by the spark as the excess charge is neutralised when brought close to an electrical conductor (e.g. a path to ground), or a region with an excess charge of the opposite polarity (positive or negative). The familiar phenomenon of a static shock, more specifically, an electrostatic discharge–is caused by the neutralisation of charge.

Static electricity is generated when  two or more objects rub with each other charge does not generates due to friction it rather generates due to increase in surface area when we rub two things.

Generation of Static Charges in Pharmaceuticals:

Pharma  manufacturing  have come across many operations in line with the above categories wherein it is prone to generate static electricity for e.g.

  1. Solvent dispensing
  2. Vibro-sifters
  3. Fluidised bed drier
  4. Powder transmission

Solvent Dispensing:

Electric charges can build up on an object or liquid when certain liquids (e.g., petroleum solvents, fuels) move in contact with other materials. This charge can occur when liquids are poured, pumped, filtered, agitated, stirred or flow through pipes. This buildup of electrical charge is called static electricity. Even when liquids are transported or handled in non-conductive containers, something rubbing the outside surface of the container may cause a static charge to build up in the liquid. The amount of charge that develops depends, in part, on how much liquid is involved and how fast is it flowing or is being agitated or stirred.

Transferring a liquid from one metal container to another may result in static electrical sparks. To prevent the generation of static electricity and prevent sparks from causing a fire, it is important to bond metal dispensing and receiving containers together before pouring. Bonding is done by making an electrical connection from one metal container to the other which ensures that there will be no difference in electrical potential between the two containers and, therefore, no sparks will be formed.

In pharmaceuticals because in pharmaceuticals we deal with Volatile and Flammable substances like Iso propyl alcohol , Methylene chloride which tends to burn even at single spark and could create accident  in industry as well as a risk to persons working in area.

The chances of static build-up may lead spark explosions, fires, property damage and injury to workers. Occupational Safety and Health Administration (OSHA) has regulation for these liquid dispensing systems to ensure the processes being safe enough for men at work and the environment.

Vibro sifter (during the sifting of materials):

Vibratory Sifter

Vibro sifter consists of specially designed motor mounted vertically at the center of the base plate of the screen. The screen is in between feeding hopper and bowl. The material is fed on to the centre of top screen. The undersize material passes rapidly through the screen during its travel to the periphery. The oversize material gets continuously discharged through a tangential outlet.

Due to the vibration the friction between the screen and the product material static current is being generated in the body of the sifter. Unless the product is flammable in nature then it will not lead to an explosion but it has a great impact on the operator around it, once the operator gets in contact with any conductive part of the sifter he/ she gets the electric shock. To avoid such situation it has to be properly grounded and on real time it should be monitored and controlled before starting the operation. The static current grounding device should be integrated for monitoring and control of the process.

It can be eliminated by providing earthing to the sifter or static electricity clamp can be used.

Fluidised bed Drier :

Drying is a process of removal of liquid from solid products with the help of heat. Various process of drying is being implemented. Drying is a function of contact area, between the drying media and the product.

In fluid bed drying, heat is supplied by the fluidisation gas, in some cases the heat also being supplied by heating plates or tubes which are immersed in the fluidised layer.

These fluid beds are designed to dry powder particles where the residual moisture content is higher than what is wanted in the final powder. Hot drying air is distributed through specially designed perforated plates on which the powder particles/ agglomerates are resting.

Static charge will generate due to rubbing of materials and if binding of IPA or MDC.

Static charge generated due to the powder or granules which gets fluidised inside the dryer unit should be degenerated with proper grounding system otherwise it will may cause damage to the material  or may affect the personnel working in the area.

Powder transmission:

Powder transmissions are being done by any of the following methods like conveyors, gravitational flow or flow through a pipeline with dry air. In case of gravitational flow and pneumatic conveying the friction caused between the powder and wall generates the static electricity at both ends i.e. at pipeline and the product. So the pipeline and the collecting bin should be properly grounded so that the static current generated is dissipated properly. Same grounding system (used in case of Vibro sifter) can be deployed to control the static charge generated in the system.

Conclusion :

Static Charges Clamp

Static charge generation is a common remarkable occurrence for any flowing or vibrating mechanism. Where there is friction between two independent surfaces there is static charge generated and generation of static charge can’t be fully eliminated but can be controlled.

Below are the precautions which can be taken to prevent and control the generation of Static charge in pharmaceuticals.

  1. Earthing or Static Charges Clamp to be provided to all manufacturing equipment’s to avoid static charges and persons working in manufacturing area should wear cotton clothes.
  2. The conductance of equipment wheels and footwear should be increased to prevent the development of static charges.
  3. We can increase the conductance of the nonconductor materials by using conductor film.
  4. We know that maximum Indian pharmaceuticals are not taking safety precautions to avoid static charges in the equipment’s but  prevention is better than cure so everybody should take care of it to avoid any damage to the Product as well as personnel.
  5. Earthing should be checked and verified before starting of operation of the particular equipment’s and if necessary it shall be included as a checkpoint in Line clearance checklist of all equipment’s.

Pharmaceutical Warehouse Interview Questions and Answers

1. What is the role of Warehouse in Pharmaceuticals :

Warehouse in pharmaceutical plays an important role which includes Receiving of Raw material, Packing material, Finished products, Storage of materials in required storage condition (Temperature and RH), Dispensing of Raw and Packing materials which are required for manufacturing of the batches , Dispatch of Finished (the products which completed all stages i.e. manufacturing and Final packing) products.

2. What is Good Warehouse Practices (GWP):

Good Warehouse Practices (GWP) includes Entry and Exit to warehouse with proper gowning, Receiving and storage of materials in required storage condition, Proper Labeling of Raw and packing materials, Systematic arrangement of materials in warehouse, Use of required personnel protective equipment during dispensing of materials, Storage of controlled drug substances, Training of persons working in warehouse, Verification of Incoming materials with respect to Quantity and damage, Sampling and testing of materials, Handling of Returned and expiry materials and dispatch of Finished goods to market.

3. What are to be checked Before Receipt of Raw and Primary Packing Materials :

Before  and receipt of materials below details to be checked:

  • Check the documents for correct company address which is mentioned on the Delivery challan or Excise Invoice.
  • Check the Purchase Order provided by purchase department and verifies that the material received is as per order. Quantity supplied as per challan is confirmed against the ordered quantity.
  • Check whether vendor is approved or not from the Approved vendor list or Provisionally Approved Vendor list provided by Quality Assurance Department.
  • Check availability of Vendors Certificate of Analysis. If not available, inform to Purchase Department and Department Head and hold the vehicle till further decision.
  • Checklist for Receipt of Materials to be filled by Warehouse person & allow for unloading.
  • After unloading verify whole consignment against the provided document (challan copy ,Invoice Copy ,Vendor COA .) for its vendor batch/Lot number ,manufacturing Date ,Expiry Date, Retest Date ,manufacturer name ,manufacturer address ,Gross weight ,Tare Weight and net weight .
  • If any damage or deshaped or defaced container or any other discrepancies noted, same shall be reported to QA department through Damage Report.
  • Deface the Manufacturer Approved label if any by permanent marker pen by doing cross mark and De-dusting of material containers shall be done with the help of De-Dusting machine.
  • 100 % weight verification shall be done for Active Ingredients, Excipients, Aluminium foils, PVC films, PVC / PVDC, films, cotton, rayon coil, ploybags etc.
  • After Physical Weight Verification transfer clean material containers on HDPE pallet and affix status label on each pallet as Awaiting for GRN and and transfer these material pallets to Staging Area.
  • Then Prepare Goods Receipt Note (GRN).

4.  What  Goods Receipt Note (GRN) Contains :

  • Goods Receipt Note (GRN) Contains GRN Number, GRN Date, Purchase Order Number, Purchase order date, Challan / Invoice Number, Challan / Invoice date, Material Code, Material Description, Manufacturer Batch / Lot Number, Manufacture name, Manufacturing date, Expiry date, Qty. Received, Number of containers or boxes and A.R Number.
  • Warehouse person fill the GRN and Submit copies to QC along with vendor COA, then Quality control will assign Analytical reference number and sign on the GRN copies and retain original copy of GRN along with COA and keep the duplicate copy  with Him/Her.
  • Quality control has to perform sampling after receipt of GRN copy.

5. How materials are destroyed in Warehouse :

  • All raw materials shall be dissolved as per Material safety Data Sheet Bulk container shall be deshaped /crushed and collect in double layered poly bag  and sent it to scrap yard.
  • Aluminium, shrink wrap roll and PVC/ PVDC foil shall be defoiled and cut into the  piece and collect in a double layer poly bag and send it to scrap yard.
  • Carton, Leaflet, printed sticker lable, shipper, silica gel bag etc. shall be destroyed by manually torn / shredding and send it to scrap yard.
  • All destruction activities shall be performed after approval from quality assurance and plant head and in the presence of Quality assurance person. Stores person shall prepare Destroyed material handover to Environmental Health Safety Department and handover the rejected material to EHS department for disposal.

6. What  are the reasons of Materials rejection in warehouse :

  • Rejects due to damage at the time of receipt or damaged during handling.
  • Material rejects during Quality Control testing.
  • Online Rejection
  • Material rejects during retesting
  • Approved material expired during storage.
  • Obsolete materials (No longer appropriate for the purpose of use either due to the availability of better alternatives) .

7. How to Handle the Approved Expired Materials:

  • Every first (1st) week of month Stores person shall prepare a list of materials which are going to expire in next 60 days. Warehouse person has Inform to Head Production, Head QA and Purchase Department about near expiry materials.
  • Stores person shall affix Expired label on the container of Expired material by doing cross mark on present status label, on the day of expiry date and then transfer expired materials from approved storage location to reject room.
  • After getting approval for destruction on “Destruction Approval Form” Material shall be destroyed in presence of Quality Assurance.

8. How to Handle Spillage of Solid Materials in warehouse:

  • If any spillage observed, Raw Material Store person shall segregate the damage container from other containers to avoid contamination and immediately inform to Department Head and Head Quality Assurance.
  • With the help of vacuum cleaner or dry mop collect the spilled material by taking sufficient safety precautions i.e. wear safety goggles, nose mask, hand gloves etc.
  • As per instructions from Head Quality Assurance and Department Head transfer the content of damaged container or bag to another good container or bag then Weigh and note the quantity of the spilled material and destroyed as per MSDS. Fill the destruction note and destroyed the spilled material in presence of Quality Assurance person and sign on the destruction note.

9. Checkpoints during dispensing of Raw and Primary Packing material:

  • Switch “ON” the Reverse Laminar Air Flow Unit at least 20 minutes prior to start of dispensing / sampling activity and take the line clearance of the area from Quality Assurance person.
  • Update the area status board and ensure the cleanliness of the area, Pressure differential, Temperature and Relative Humidity of the area is within limit and ensure that all the materials are approved.
  • Ensure the calibration status of Weighing Balances and respective logbook of the area to be checked for completeness of all entries.
  • Transfer Material containers to dispensing room through “Material Entry” of respective dispensing area.
  • Check material details like material code, Material description, A. R. No., Mfg. Date, Expiry Date, Retest Date, Manufacturer Name etc. from the container label.
  • Take tare weight of double polythene bags, double cable tie and dispensing label and dispense the required quantity (net weight) of materials as per Material Requisition Note under RLAF by using clean scoops / spatulas.
  • After completion of dispensing activity, affix loose label to loose container and transfer loose containers to raw material store through material entry of respective dispensing area.
  • Aluminum foil, PVC foil, PVC/PVDC shall be weight individual under RLAF on weighing balance and issue the quantity equal or more than the quantity mentioned in the batch record and affix dispensing label to individual roll.

10. Checkpoints during Dispatch of Finished Goods:

  • Finished Goods Store person shall prepare packing list for finished goods to be dispatch and Send packing list to commercial department and marketing department for completion of dispatch related documentation activity.
  • Thorough inspection on arrival of container / vehicle, before & after loading of goods shall be done. Ensure cleanliness of container / vehicle, absence of any other materials or corrosive items , abnormal odour, dirt & holes etc. which can contaminate the goods.
  • If palletization requires to be done, arrange the finished product shippers on plastic pallet or Certified heat treated wooden pallets and after completion of wrapping and strapping put identification labels on each pallet.
  • Load the palletized finished goods inside the container/vehicle with the help of pallet trolley, by taking one by one palletized finished goods through loading bay and dispatch approved finished goods as per dispatch order.
  • Place activated data loggers in loose shipper and if loose shipper not available, place activated data logger in fully filled shipper and ensure that two data loggers shall be kept in each container / vehicle.
  • Close the door and seal the container and ensure that the thermostat on the refer container is get to run between 18-20 °C.
  • Take photograph of sealed container / vehicle and Collect Finished Goods Certificate of Analysis (COA) from QA and Handover dispatch documents along with finished product COA to lorry driver.

66 Pharmaceutical Production Interview Questions & Answers

Below are some Interview Questions and answers which can help the freshers as well as experience personnel for interview preparation so please Read and share if you think it useful.

1.What is Production :

All operations involved in the preparation of a pharmaceutical product, from receipt of raw materials through the completion of a finished product i.e from Raw material Receipt to Finished product dispatch. It also includes the handling of manpower and recording the manufacturing and the packing activity performed.

2. What is Batch Processing or Batch Manufacturing Record : 

Documentation that provides the history of a batch from the raw material dispensing stage to completion of the batch or lot which include Dispensing of raw material, Granulation, Blending Compression, Capsule Filling, Coating, Inspection and yield at different stages. It also includes the details of the activity performed by whom, checked by whom, at what time activity was performed, at what date activity was performed and signature of the personnel involved in the batch or activity.

3. What is Batch Packaging Record :

Documentation that provides the history of a batch from packaging material  dispensing, Blister packing, Bottle packing, Jar packing, Dry syrup Filling, labeling, Carton packing and shipper packing up to  Dispatch of a Batch or Lot.

It also includes the details of the activity performed by whom, checked by whom, at what time activity was performed, at what date activity was performed and signature of the personnel involved in the batch or activity.

4. Active Pharmaceutical Ingredient :

A substance or a bulk pharmaceutical chemical that is intended to furnish pharmacological  activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of  the disease or to effect the structure or any function of the body of man or other animals.

5. What is Standard Operating Procedure (SOP):

It is an authorized written document which describes the step by step instructions requirements for performing operations or any activity and non-specific to any product, process or material. It provides detailed procedure about systems applicable to various operation e.g. Equipment’s / Instrument’s / System’s Operation / Cleaning / Maintenance etc.

Everybody working in organization has to follow the instruction which are written in SOP and perform their activities accordingly.

6. What is GMP and CGMP :

Good manufacturing practices (GMP) are the practices required in order to conform the guidelines recommended by agencies that control the authorization and licensing of the manufacture and sale of food and beverages, pharmaceutical products, dietary supplements,  and  medical devices. 

These guidelines provide minimum requirements that a manufacturer must meet or follow to assure that their products are consistently high in quality, from batch to batch, for their intended use.

CGMP is Current Good manufacturing practices (GMP) and we have to follow the current practices as there are the changes in regulations so always you have to follow the current practices so it is called current.

7. What are the In processes checks parameters during Tablet compression:

Appearance, Group weight, Individual weight variation, Uniformity of weight, Thickness, Diameter, Hardness, friability, Speed of machine, compaction force, die fill depth and Disintegration time.

8. What are the In processes checks parameters during Capsule Filling:

Appearance, Group weight of filled capsule, Individual weight of filled capsule, Net fill content of the powder, locking length and Disintegration time.

9. What are the In processes checks parameters during Tablet coating:

Appearance, Inlet temperature, out let temperature, pan RPM, Gun distance from tablet bed, spray rate, weight gain, Group weight of Coated tablets, Individual weight of Coated tablets, and Thickness.

10. What are the defects in Compressed tablets :

Picking, sticking, capping, laminating, weight variation, Broken, chipped, Rough Surface, Double compressed, Rough edges, Powdery, Incorrect Description, Black spot, Oil spot, Foreign Product  and Debossing/ Embossing.

11. What are the defects in Capsules :

Empty, Cracked, Dented, Telescopic, Unlocked, Partially locked, Improper polishing, Powdery, Long or Short caps, Printing defects, Improper locking length and Weight variation.

12. What is Water For Injection (WFI) :

Water for injection It is the water of extra high quality without significant contamination and Water for injection is generally made by distillation or reverse osmosis.

13. What is Aerosol in Pharmaceuticals :

Aerosol is a pressurized dosage forms containing one or more therapeutic active ingredients which will produce a fine dispersion of liquid and/or solid materials in a gaseous medium during operation.

14. Tell about  wet   granulation :

It involves Sifting of API & Excipients, Wet mixing, drying, Sifting, Blending and then Blend shall be compressed or Filled in Capsule and then compressed tablets are coated with coating solution.

Sifting of API and Excipients through Sifter, Mixing of API & Excipients then addition of binder solution to form a wet mass in Fluid Bed Processor or Rapid Mixer Granulator, then dried the wet mass in Fluid Bed Processor or Fluid Bed dryer. Dried granules are again screened through a sieve which helps it to break down the granule then it should be lubricated or mixed in Blender. These same size Blend are then compressed or can be filled in capsule.

15. Tell  about   Dry  granulation :

Dry granulation involves mixing, pre-mixing, milling, compression or Capsule Filling. API and Excipients are sifted, milled in roll compactor to product slugs then slug size  is reduced in multi mill or Oscillating granulator. Then these granules are Mixed or lubricated in Blended and then blend shall be compressed in compression machine or can be filled in capsule filling machine to form tablets or capsules.

16. What is tablet :

Tablets is defined as the solid unit dosage form of medicines with suitable Excipients and prepared either by molding or by compression. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose.

17. Name any four tablet processing problems :

Mottling, Capping, lamination, picking and sticking

Mottling– unequal colour distribution of a tablet.

Capping– Partial or complete separation of a tablet top or bottom crowns.

Lamination– Separation of tablets into two or more layers.

Picking– Because of adhesion to the punch faces, Localized portion missing on the surface of the tablet.

Sticking– Adhesion of tablet localized portion to the punch faces resulting in rough and dull appearance.

18. What is Disintegration Test :

It is the time required for the Tablet / Capsule to break into particles, the disintegration test is a measure of the time required under a given set of conditions (Temperature) for a group of tablets/capsules to disintegrate into particles.

Cycle of shaft holding the tube basket limit is 29-32 cycles per minutes and distance covered by shaft basket is 50-60 mm and beaker temperature is 35 to 39 º C. Disintegration is to be Performed to determine whether tablets or capsules disintegrate within the prescribed time when placed in a liquid medium at the experimental conditions.

19. What are the Disintegration Time of tablets :

  • Uncoated Tablet 15 min as per BP & 30 min as per USP
  • Sugar Coated Tablet 60 min as per BP
  • Film Coated Tablet 30 min as per BP
  • Plain Coated Tablets DT in specific medium for 30 min as per USP
  • Enteric Coated Tablets DT in  simulated gastric fluid (0.1 M HCl) for 1 hr and then in simulated intestinal fluid (Phosphate buffer 6.8 pH) until disintegrate as per USP.
  • Dispersible Tablets 3 min ( 15- 25º C ) as per BP.
  • Effervescent Tablets 1 tablet in 200 mL water  for 5 min ( 15- 25º C )
    as per BP
  • Buccal Tablets 4 hrs as per USP.
  • Soluble Tablets 3 min ( 15- 25º C ) as per BP.
  • Chewable Tablets are not require to comply with test

20. What is Disintegration Time of capsules :

  • Gastro resistant capsule DT 2 hrs without disk in 0.1 M HCl  and phosphate buffer pH 6.8 for further  60 min as per BP.
  • Hard and Soft gelatin capsule DT 30 min as per BP & USP.

21. What is Friability Test of Tablet & friability Calculation :

Friability is defined as the percentage of weight loss of powder from the surface of the tablets due to mechanical action and the test is performed to measure the weight loss during transportation.

Friability (%)  =W1– W2/W1X100

Where,
W1 = Weight of Tablets (Initial / Before Tumbling) &
W2 = Weight of Tablets (After Tumbling or friability)

Limit : Friability (%) = Not More Than 1.0 %

Tablets with individual weight equal to or less than 650 mg then take the sample of whole corresponding to as near as 6.5 gram equivalent and tablets with individual weight more than 650 mg then take sample of 10 whole tablets to perform friability test. Tablets must be de-dusted prior to and after use.

22. Weight Variation limit for Tablets and Uniformity of Mass Variation:

23. What is Validation :

Documented program or evidence, that provides a high degree of assurance that a specific process method or system consistently produce a result indicating predetermined accepted criteria.

24. What is Calibration :

The demonstration that a particular instrument or device produces results within specified limits  by comparison with those produced by a traceable standard over an appropriate range of  measurements.

25. What is Qualification :

The action of proving that any equipment or process work correctly and consistently and  produces the expected result. Qualification is part of, but not limited to a validation process, i.e. Installation Qualification (IQ), Operation Qualification(OQ) and Performance Qualification (PQ).

The act of planning, carrying out and recording the results of tests on equipment to confirm its capabilities and to demonstrate that it will perform consistently as intended use and against predefined specification.

26. Design Qualification : 

Documented verification that equipment, instrument, facility and system are of suitable design against the URS and all key aspects of design meet user requirements.

27. Installation Qualification (IQ) :

The documented verification that all components of the equipment and associated utilities are properly installed or modified in accordance with the approved design and manufacturer’s recommendations.

28. Operational Qualification : 

Operational qualification consists of verification and documentation, of the parameters of the subjected equipment. The documented verification that the equipment, instrument, facility and system as installed or modified, perform as intended throughout the installed operating range.

29. Performance Qualification :

Performance Qualification is designed to prove the process, can consistently produce a product that meets the stated requirements and specifications. It is a documented verification that the equipment, instrument, facility and system as connected together, can perform effectively and reproducibly, based on the approved process method and product specification.

30. Why Three consecutive batches taken for Validation :

Consecutive meaning following closely with no gap or following one after another without interruption.

  • The number of batches to be taken under validation depends upon the risk involved in the manufacturing Critical process parameters & critical Quality Attribute so  depends upon that manufacturer have to choose the number of batches to be validated.
  • If we will consider less than two batches then the data will not be sufficient for evaluation of and to prove reproducibility of data  between batch to batch variation & if we consider more than three batches it can increase the time & cost of manufacturer which usually not preferred.
  • Generally if we will require quality in the First batch, then it is accidental (co-incidental), Second batch quality is regular & third batch quality is Validation or Confirmation.

Statistical evaluation cannot be done by considering two points, because two points always draw a straight line so minimum three points required for comparison of data.

31. What is Airlock :

An enclosed space with two or more doors, which is interposed
between two or more rooms, e.g. of differing classes of cleanliness, for the
purpose of controlling the airflow between those rooms when they need to be entered.
An airlock is designed for use either by people or for goods and/or equipment.

32. What is Clean Area :

An area with defined environmental control of particulate and microbial
contamination, constructed and used in such a way as to reduce the
introduction, generation, and retention of contaminants within the area

33. What is yield reconciliation :

A comparison between the theoretical quantity of the material and the actual quantity.
Yield Reconciliation can be done in manufacturing and packing stages . i.e Blending, Compression, Capsule filling, Coating, Inspection and packing etc.

34. What is in-process control or checks :

Checks performed during production in order to monitor whether it is meeting the required specification or not and, if necessary, to adjust the process to ensure that the product conforms to its specifications. The control of the environment or equipment may also be regarded as a part of in-process control.

35. What is Finished Products :

A finished dosage form that has undergone all stages of manufacturing
including packaging in its final container with labelling and which is ready for sale or release to market.

36. What is intermediate Product :

Partly or Partially processed product that must undergo further manufacturing steps which includes Blend, Filled capsule, Compressed tablets, coated tablets etc.

37. What are the defects of Coated  tablets :

Twins, Cracking, Partially coated, Incomplete drying, Edge broken, Peeling, Print defects, Shade Variation, Weight variation, Debossing/ Embossing fill

38. What is SMF and how it works :

When the product is under drying in FBD, the product loss often occurs due to a puncture or broken filter bag. Solid flow monitor (SFM ) or broken bag detector (BBD) provides good detection of  filled filter bag failure or tear in FBD, thus prevent product loss. SFM or BBD located in the exhaust duct of FBD.

39. What is Tolling in compression machine :

In tablet compression machines Punches and dies are used to compressed powder to form table. The dies and punches and their setup on compression machine is called tooling.

40. Tolling are  how many Types :

There are four types of tolling in compression machine B Tolling, BB tolling, D tolling and DB tolling. D tolling punch and die diameter is greater than B tolling punch and die diameter. D tolling punch diameter  is 25.4 mm and Die diameter is 38.10 mm where as B tolling punch diameter is 19.00 mm and die diameter is 30.15 mm

41. What is Dual time in Compression Machine :

In tablet compression, dwell time is the time that the punch head remains in contact with the compression roller and it is defined as the amount of time that the compression force applied when forming the tablet is above 90% of its peak value.

42. What is the work of Pre compression Rollers in Compression Machine :

These are the very first rollers in rotary tablet press. Basically, these rollers apply a small amount of force on the upper and lower punches.

This gives the initial compression force. The aim of this process is to remove air that could be in the die or powder particles.

43. What is the work of Main compression Rollers in Compression Machine :

Main compression rollers exert a predetermined amount of force (final compression force) for the formation of tablets. The compression force at this stage is higher than the pre-compression force.

It is important that the rollers remain stable with no vibration during the entire process. This is to ensure consistency of the tablets’ thickness and size.

44. What are the units of Hardness in tablets :

Kilogram (kg), Newton (N), Pound (lb), Kilopond (kp) and Strong-Cobb (SC)

45. What is Leak test in Packing :

The test which is used to check the integrity of packed strips, blisters, Bottles and small sachets containing tablets, Capsules and Dry Powders is called leak test.

Leak test Apparatus is used to test the quality of the packaging process and to check that the seals enclosing the product are perfectly intact and no water should go inside the pack. It is designed to find the smallest holes or Puncture and imperfections in packed Products .

46. What is FMD in Packing :

The FMD (Falsified Medicines Directive) is a legal framework introduced by the European Commission to improve the protection of Public health within the European Union. The directive applies since 2 January 2013 & the European Commission Delegated Regulation, (EU) 2016/161, supplements Directive 2001/83/EC with rules regarding safety features for the packaging of medicinal products for human use. The regulation was adopted in October 2015 to counteract to fake medicines include stricter record-keeping of wholesale distributors, pharmaceutical producers, an EU-wide quality mark to identify online pharmacies and mandatory safety features on packages.

47. Which indicator is used in Leak test Apparatus :

In order to identify the leakage in Blister or stripes methylene blue colour is used and the solution in the desiccators required to be changed every day or whenever required.

48. What is NFD & how it works :

Non Fill Detection is an system incorporated into the machine which enables the machine to automatically detect and reject those strips or Blisters that have missing tablets or capsules in cavity. This arrangement involves a sensing system, a control system consisting of a Programmable Logic Controller (PLC) and an HMI (Human Machine Interface), and an electro pneumatically activated auto-rejection system. Both – the Strip & blister Packing Machine as well as the NFD system are designed and built by us at our works and are therefore fully integrated with each other.

49. What is Hold time Study:

Hold Time studies establish the time limits for holding the materials at different stages of production to ensure that the quality of the product does not degrade significantly during the hold time at a required temperature and Relative Humidity.

Hold time can be considered as the established time period for which materials (dispensed raw materials, intermediates and bulk dosage form awaiting final packaging) may be held under specified conditions and will remain within the defined specifications. Hold-time studies establish the time limits for holding the materials at different stages of production to ensure that the quality of the product does not produce results outside the acceptance criteria during the hold time.

50. What is Deviation:

Any unwanted event that represents a departure from approved processes or procedures or instruction or specification or established standard or from what is required. Deviations can occur during manufacturing, packing, sampling and testing of drug products.

Examples of Deviations: Temperature and RH of area goes out of limit during manufacturing, Typographical error observed in approved documents, Standard operating procedure not followed, Breakdown of equipment, Spillage of material during unloading, Instrument calibration results goes out of limit etc. Deviations are of three types Minor, Major and Critical.

51. What is Change Control :

It is a Approved Procedure which is taken to change in any documents, Standard operating procedures, Specification, Process parameters and change in batch size etc. Change control is raised by user department as per requirement and finally the change control is approved by Quality assurance. Change control can be raised through software or through manually.

After Final approval of change control the changes can be made in documents  and change control can be closed after completion of required action plan which is mentioned in the Change control form. Change controls are of two types i.e Major and Minor.

52. Corrective action  and preventive action :

An action taken to eliminate the cause of the existing deviation , incident or problem in order to prevent its recurrence (occurring again).

An action taken to eliminate the cause of potential deviation, incident or problem in order to prevent its occurrence (an incident or event) is called preventive action.

53. What is the Principle of Coating process:

The basic principle of tablet coating involves the application of coating solution to a moving bed of tablets with the concurrent use of heated air to facilitate evaporation of the solvent. The distribution of coating is achieved by the movement of the tablets either perpendicular (coating pan) or vertical (air suspension).

54. What are the Coating equipments which are being used : 

For the coating process use of one of the 3 types of following equipments.

  1. Conventional coating pan. 2) The perforated coating pan. 3) The fluidized bed coater.

55.What is Conventional Coating Pan:

The Conventional Coating Pan is simple unit, which employs the principle of rolling a batch of tablets in an oval shape pan, spraying the coating solution on it and passing hot air across the tablet bed. An exhaust blower may be used to carry away the excess fumes generated during the coating and drying process.

Improvements in conventional pan are pellegrini system which has a baffled pan and diffuser which improves the drying efficiency and can be suitable for sugar coating process.

The immersion sword system which includes a metal sword that will immerse in the tablet bed and during drying process it will introduce drying air which flows through perforated metal sword then upwards towards bed.

The immersion tube system which includes a tube that will immerse in the tablet bed and this tube has a spray nozzle that delivers both the hot air and coating solution. This is suitable for both sugar coating and film coating.

56. What is perforated coating Pan:

The coating drum is an enclosed housing with various spray nozzles and these spray nozzles atomize the coating solution. This coater have an dry inlet air flows from the upper section of the drum, passing in between the tablets which leaves the drum through the perforations.

There are different type of coating systems which are Accela-cota system, Hi-Coater system, Dria coater and the Glatt coater.

57.What is fluidized bed Coater:

The fluidized bed coaters have enhanced drying efficiency fluidization of tablet mass is achieved by columnar chamber by the upward movement of the drying air. The movement of the tablets is upward through the center of the camber. Then they fall toward the chamber wall and move downward to re-enter into air stream at the bottom of the chamber. It has a basically two spray application systems they are (1) high pressure airless (2) low pressure air atomized.

58. What are the Process parameters which are to be checked during Coating:

Inlet temperature, Outlet temperature, Spray rate, Automizing air pressure, Pan Rpm, Gun distance from tablet bed, weight gain of tablets, Peristaltic pump RPM, tablets thickness, tablet hardness, Group weight of tablets and Appearance.

59. What are the reasons for Twin of tablets in Coating:

The possible causes are If coating solution are sticky, If spray guns are too close to the tablet bed, Inappropriate tablet shape, If pan speed is low  & if spray rate is too high.

60. What are the reasons for Picking or Sticking of  tablets in Coating: The possible causes are if  spray rate is too high, Poor distribution of coating solution, If pan speed is low, Inadequate drying conditions and Inadequate atomizing air pressure.

61. What are the reasons for Edge Chipping of  tablets in Coating:

The possible causes are if  tablet hardness is low, If tablet friability is low, If tablets edges are sharp, If spray rate is low, Low mechanical strength and if solid contents is low in coating solution.

62. What are the reasons for Color variation of  tablets in Coating:

The possible causes are Inadequate mixing of tablets during coating, If spray Patten is poor, If pan speed is too low, If little coating solution is applied, if solid contents is too high in coating solution and if number of spray gun is not sufficient.

63. What are the methods used in tablet coating :

Generally three methods are used for tablet coating A) Sugar coating. B) Film coating. C) Enteric coating.

64. Which polymers are used in enteric coating :

Polymers used in enteric coating are Cellulose acetate phthalate, Acrylate polymers, Hydroxypropyl methyl cellulose Phthalate, Polyvinyl acetate phthalate and Shellac.

65. Which solvents are used in film Coating:

IPA and Methylene chloride are mainly used in film coating as a solvents.

Titanium dioxide, talc and aluminum silicate are mainly used as opacifiers in film coating

66. Which colorants are used in film coating :

FD and C colors, D and C colors, iron oxides, Carmel, and turmeric are mainly used as colorants in film coating

You can also read the Interview Questions and Answers for Quality Assurance https://pharmaceuticalupdates.com/2020/03/06/pharmaceutical-interview-questions-answers/

Top 10 Tips for a FDA Inspection

Following tips can be useful for a Organization during regulatory Audit

1. Arrange the Required documents as per the Audit Agenda in the near by location of auditor room before one day to avoid delay in showing the required document to the auditor and arrange all the documents with proper labeling and keep all the documents in lock & key. The audit compliance person of the organization along with quality Assurance should lead the team and should communicate with all departments before start of audit or during audit.

2. Retrieve all the required documents from document cell or from the respective places and follow the document retrieval procedure and after completion of audit submit the required documents to Quality Assurance or keep the documents in their respective places.

3. Review all the documents which are requested by the auditor before sending it to auditor and the documents required to be checked for any missing entry or sign or date, availability of all the pages, completeness etc.

4. The Subject matter Expert (SME) of the particular department should explain about the system or procedure which are asked by the auditor or the auditor may ask question to the person who has perform the activity or the doer so be ready for that.

5. If a person is not able to understand the language of auditor then the other persons who are guided the auditor or who are present along with auditor shall translate the same in to the regional language and help him or her to understand the question. If required translate the same to English

6. Answer all questions honestly which are asked by the auditor and never give false data and always tell the truth. If you don’t know the answer then you tell I don’t know or let me check and call the Subject matter Expert to answer the query and don’t guess if you are not sure.

7. Listen the question carefully and answer only what asked and clarify what you don’t understand before answering the question during audit.

8. Auditor may read your body language so be aware of your body language so don’t stand around the auditor in worried face which may make people nervous and may alert auditor that something may wrong.

9. Don’t argue with the auditor when answering a question asked and don’t challenge the auditor and if something misunderstood then explain it in professional manner.

10. Each person should know the system and the procedure of their respective areas where they are working and every body should understand their job role and responsibility.

11. The team along with the auditor shall note down the observation findings during the audit and shall compile the observation or shall raise the necessary deviation or CAPA on the same day which are observed by the auditor.

Leak test of Blisters / Strips / Containers /Dry Syrup bottles/Vials

Leak Test Apparatus

What is Leak Test and Leak test Apparatus:

The test which is used to check the integrity of packed strips, blisters, Bottles and small sachets containing tablets, Capsules and Dry Powders is called leak test.

Leak test Apparatus is used to test the quality of the packaging process and to check that the seals enclosing the product are perfectly intact and no water should go inside the pack. It is designed to find the smallest holes or Puncture and imperfections in packed Products .

General requirements :

Leak test shall be performed by Production and Quality assurance during packing operation. Leak test shall be performed Before starting of packing operation, every 3 to 4 hours interval, after Break, End of Operation and after change in Foil roll.

Take 4 litter of fresh potable water in Vacuum desiccator and add 10 to 12 drops of methylene blue solution and ensure complete mixing of methylene blue.

In order to identify the leakage in Blister or stripes methylene blue colour is used and Change the solution in the desiccator everyday or whenever required.

Procedure of Leak test Apparatus :

Collect sufficient no. of consecutive strips or blisters from the sealing station so as to cover all the blisters/stripes sealed in one cycle and Place the required number of strips or blisters in desiccator and put the disk on desiccator.

Place blister / strips / containers / vials in the vacuum desiccators containing purified water coloured with 2 – 3 drops of 2% w/v solution of Methylene blue and covers it with the perforated disc to hold the sample submerged. Ensure that water level is above the perforated plate.

In case of Dry Syrup bottles, place number of bottles in desiccator after induction sealing equivalent to the No. of capping heads while in case of screw capping place number of bottles equivalent to the No. of capping heads.

In case of Bottle Packing (Tablets/Capsules ) collect  empty bottles by crossing it with permanent marker pen & pass it through Cap sealing & induction sealing machine  while in case of Screw capping collect  empty bottles equivalent to the No. of capping heads.

Close the desicator and switch on the power supply then apply 305 mm of Hg or 12 inch of Hg  vacuum by adjusting vacuum gauge and hold vacuum for 2 minutes.

Then slowly release the vacuum and remove the samples from the desicator and Wipe the samples with tissue paper or lint free cloth then Examine for leakage of water into the pockets by defoiling, removing the seal of the vials or container.

Any tablet or capsules etc. found in blue colour on the surface of tablet or capsules it means sample fail in the leak test and discard all the tablets/capsules/Bottles taken for leak test.

What Happen if Leak test is Failed :

If one tablet / capsule of even one blisters / strips / vials fails repeat the test with further blisters / strips / containers / vials. No blisters / strips / containers / vials should show leakage then stop the  machine and rectify the problem and if required investigation shall be performed.

If leakage is through surface of Strip then check the foils used for the pinholes.

Remove 2 – 3 meters foil and visually examine for the pinholes, raise an online rejection form for the foil if pinholes are observed, return it and get new foil & proceed and check the sealing, foil or cap with wad for any damage.

If leakage is from sides (For strips / blister):

  • Check for the heater temperature by using thermometer
  • Check for knurling and pressure of Pressure Sealing Roller.
  • Check for any damage to the Counter Sealing Roller.
  • Adjust the temperature if it is low.
  • If knurling on the roller is not good, clean the roller by using soft wire brush and with cleaning liquid.
  • If sealing is not proper adjust the pressure of the roller and If powder in channel, clean the channel, if necessary dedust the uncoated tablets.

If leakage is from sides (For containers):

  • Check for the powder level of induction sealer and check for the distance between the sealer and container.
  • Check for powder on neck of the container, if uncoated tablets / powder are being packed or rayon on container if rayon is used for packing.
  • Adjust the power level by increasing or decreasing the power level by pressing the up and down arrows on control panel.

For vials (if the leakage is in vials):

  • Check, adjust the pressure on chuck and sealing rollers and repeat the test till it complies.
  • If leak test fails, quarantine the shippers between the previous acceptable test and failed test collect five blisters / strips / containers / vials for leak test from each layer of the packed shipper starting from the first, and perform the leak test

Calibration of Leak test Apparatus :

Calibration shall be performed Once in three months or Calibration should be performed after     any maintenance job.

Adjust the set time to 2 minutes. Press the start button and simultaneously start the calibrated stopwatch.

Check the time on the stopwatch and record the observations in calibration report at the end of the test.

Acceptance Criteria: Time on the stopwatch should be in the limit of 2 min ± 2 seconds.

If results are out of acceptance criteria, then affix “DO NOT USE-BREAKDOWN” label on the instrument.

AQL (Acceptable Quality Levels) for all Lyophilized injectable Products

What is Acceptable Quality Level (AQL) :

Acceptable Quality Level (AQL) is a percent defective that is the base line requirement for the quality of the product. The sampling plan required to be prepared or design in such a way that there is high probability of accepting a lot that has a defect level less than or equal to the AQL.

Procedure :

  • After completion of Visual inspection, all the inspected vials shall be re-inspected for its physical defects and shall be evaluated for AQL prior to batch packing operation.
  • Clean the unlabelled vials with lint free cloth to remove any adhering particles or oily substance.
  • Check the vials for different type of rejects as per following sequence but not limited to:
  1. Volume rejects

                           a) Low fill.

                           b) High fill.

.                     2. Broken vial rejects.

                      3. Sealing rejects                       

                      4. Melt back rejects.

                      5. Glass particles

                      6. Particulate matter rejects

                           a) Black particles.

                          b) Fiber particles

                           c) White particles in lyophilized vials (in case of colored cake)

                           d)  Fiber particles (in case of colored cake)

                           e) Red particles

                      7. Abnormal Spots of filled and sealed vial

                      8. Others

Reference Vial selection (Dry Powder & Lyophilized vial):  

Randomly select 20 vials and place all the vials on plane surface and check the powder height. In case of Lyophilized vial check the cake height. Select the vial as reference having a height in maximum no of vials. Label the vial as reference vial.

Description of Rejects :

Sealing rejection : Check visually the vials for any type of sealing reject.  If found, separate the vials  as sealing rejects.

 Broken vial rejection : Check the vials for any type of breakages on the vial surface. If found, separate them as broken vial rejects.

Low fill rejection: Compare the vials for cake height with the reference vial. If the height is found to be lower than the reference vial separate those as low fill rejects.

 High fill rejection:  Compare the vials for cake height with the reference vial. If the height is found to be higher than the reference vial separate those as high fill reject.

Melt back rejects : Check the vials for any type of change in cake shape and size, any shrinkage in cake or cake collapsing. Check the vials for presence of moisture and water also. If found, separate vials as melt back rejects.

Black particle rejection : Check the vials on the cake peripheral surface and vial surface from inside for black particles against white back ground. If found, separate the vials as black particle rejects.

White particle rejection : Check the vials on the powder peripheral surface and vial surface from inside for white particle against black back ground. If found, separate them as white particle rejects.

Red particle rejection : Check the vials on the cake peripheral surface and vial surface from inside for red particles against white background. If found, separate them as red particle rejects

Fibers (colored cake) : Check the vials on the cake peripheral surface and vials surface from inside for fibers against black back ground (for colored cake) If found separate them as fiber rejects

Keep the rejected vials with respect to the rejection type in designated place provided on the table and the operator shall collect the rejected vials separately in different crates / trays showing the status label as “REJECTED” and all the rejects shall be placed in Quarantine area.

During inspection process collect representative samples of required quantity in a separate crate / shipper as mentioned in the below table to cover entire inspection process i.e from Initial, Middle & End of the process and required quantity of samples shall be drawn for AQL inspection as per the below table and shall write all the details of AQL inspection.

The inspected vials shall be finally verified by QA person for critical, major and minor defects as per the below mentioned AQL level.

Acceptance criteria: 

AQL 0.01% for critical defects, 0.1% for major defects and 1.0 % for minor defects

Examples of Defects :

  • Critical Defects: Safety risk may cause permanent injury to patient.       

Examples of a Critical defect (Mentioned below but not limited to):

1. Cracks on glass / leakage of product from vial

2. Hidden cracks under the crimp

3. Particulate matter (glass particles)

4. Sealing defect

5. Incorrect product

6. Incorrect color

7. Presence of more than one product ( mix-up)

8. Empty vial ( with out product)

  • Major Defects: Functional risk, product impossible or difficult to use. Result in the patient being unable to obtain the dose of a non-life saving medicine.

Examples of a Major defect (Mentioned below but not limited to)

1. Crack in primary container of a sterile product.

2. Gross over or under fill of liquid injection or lyophilized injection.

3. Black particles, white particles, fibers

4. Molding defects

5. Powder spillage on the surface of the vial

Minor Defects: A defect which is cosmetic in nature:

1. Molding defects

2. Scratches          

3. Abnormal spots on filled and sealed vials

If any non conformity observed against the  specified AQL limits in any batch / lot , such entire batch  / lot shall be appropriately stored and affix “ Quarantine “ label until re-work plan for re inspection initiated and In case of any abnormality,” Under Hold” label shall be pasted on to the containers and the container shifted to the Quarantine area till further decision.

Investigation shall be initiated for the batches / lots those exceeds AQL limits before proceeding to  next processing stage and based on the investigation made the batch / lot  shall be re inspected for the whole batch / lot and the appropriate corrective actions shall be implemented.

In case the percentage of defects are found to be within the specified AQL levels, the IPQA executive shall  verify the AQL results and release the entire lot for next process stage.

The quantity withdrawn for the AQL check shall be added to a good vials of particular batch / lot and the approved good vials should be shifted to the approved quarantine area or to the labeling and packing area as per the requirement after pasting the proper status label.

You can also Read the AQL in Pharmaceuticals for Oral solid dosage form https://pharmaceuticalupdates.com/2020/02/23/acceptable-quality-level-aql-in-pharmaceuticals/

Handling of Laboratory Incidents

What is Incident :

Any unplanned or uncontrolled event in the form of non-compliance to the designed systems or procedures at any stage of testing, and storage of drug product due to system failure or equipment breakdown or manual error.

A laboratory Incident is an event in the laboratory that occurs for two primary reasons either due to analyst error or instrument error.

Responsibilities of the Personnel in case incidents:

Analyst :

Reporting of an incident to Head QC/ Designee Immediately, to initiate the incident report and to provide complete details associated with the incident to investigator, to preserve and store all the solutions, standards and reagents used in the analysis until investigation is completed and to implement Corrective Action Preventive Action proposed as per incident report.

Quality Control Head/ Designee :

To ensure that incident is reported to QA, to evaluate, investigate and conclude the incident, to conclude the incident with effective Corrective and preventive action (CAPA),to review and approve the incident investigation report and to check the effectiveness of CAPA proposed.

Analytical Quality Assurance Head/ Designee :

To register incident and assign a sequential number to each incident in log book in case of manual system, to monitor investigation,to approve root cause investigation, Corrective Actions and Preventive actions and to share incident report with CQA for review if required.

Requirements:

The analyst should be trained and aware of potential problems that could occur during the testing process.

The analyst should ensure the use of valid specification and control procedures/ method of analysis.

For the incident, where the root cause is clearly known or identified along with incident, then the investigation is not mandatory. Record the root cause for the incident in the incident form and proceed further after taking necessary corrective action. (E.g. Sequence interruption due to leak detection, vial missing, Pressure fluctuation, SST failure, data transcription error, etc.)

If the incident noticed after completion of test or observed during review and final results if come out as OOS results then the incident should be handled as per Procedure of Out of Specification.

All sample and standard solutions to be preserved as it is until completion of investigation of incident.

Laboratory investigations will be initiated within one working day of the discovery of the incident /atypical result, and will be completed within 15 working days.

Types of analyst and instrument errors (But not Limited to) :

1. Incorrect Sample

2. Incorrect Standard Preparation

3. Incorrect Sample Weighing

4. Wrong Diluent Used and Wrong Diluent Volume

5. Bracketing standard failing during chromatographic analysis

6. Mobile Phase Preparation Error or Improper Mixing of Mobile Phase

7. Improper Baseline observed, running the sample set and Improper integration observed, before release of product / Material

8. Incorrect pH Adjustment

9. Incorrect HPLC/GC Set up and Run

10. Wrong Injection Volume

11. Wrong Detector Wavelength

12. Incorrect Injection Sequence

13. Uncalibrated Instrument Used

14. HPLC/GC Auto Injector Malfunction

15. Lamp Intensity Failure

16. Column Leak, Poor Plate Count, Poor Resolution

17. Power Failure

18. Connectivity failure between software and Instrument.

19. Wrong specification selected in LIMS observed , while register the Product / material before release of product/ Material.

20. Chromatographic peaks are not eluted in between the sample set .

21. Improper separation (merging the components) observed in chromatograms, during the chromatographic analysis.

22. System failure observed during the analysis due to column high pressure/ Instrument.

23. In case of calculation errors or wrong reporting observed after release of materials/products, which effect the end value.

24. In case of bracketing of standards in assay, content uniformity, dissolution, dissolution profile any deviation from specified limits.

25. Calibration failure during quarterly/daily calibration procedure

Incident Procedure :

When an analyst obtains atypical results, or when the analyst becomes aware of laboratory errors that were committed during testing, he or she will annotate the atypical results or known laboratory error in the appropriate analytical protocol and notify section in-charge immediately.

Analyst shall preserve all starting materials, solvents, intermediate and final solutions, and standards used in the testing. These materials will be retained and preserved until completion of the investigation or until it has been determined that they are no longer useful.

The analyst shall fill all details into incident report and based on review of incident, section in-charge shall intimate to QA for login of incident report.

Based on the request of section in-charge, QA person shall enter the details of incident in laboratory Incident Register, assign a sequential number to the incident report in case of manual system.

The QC Head/Designee will review the results, the analytical protocol, the starting materials and all solutions, the raw data, and the calculations used to generate the final results.

The checklist will be completed by the QC Head/Designee and analyst together. The QC Head/Designee will interview the analyst, and will check relevant documents, in order to answer questions which will help identify whether common or obvious laboratory errors were the root cause of the Incident/atypical result.

If an assignable cause has been found, and the original result is invalidated and the analyst repeats the test. The investigation findings are documented in the incident Report and the investigation is closed.

If no assignable cause is found, a full investigation will be completed involving both manufacturing as well as the QC laboratory, since the origin of the incident /atypical result is unknown. These will be handled as full investigations since those types of results may be attributed to product quality and a full investigation is needed to determine if the result is valid or not.

If the original test solution is suspected, re-dilution of the stock or intermediate sample preparations can be re-analyzed.

a. If all re-analyzed, re-diluted results do not confirm the original result, and meets acceptance criteria, then dilution error may be the assignable cause. If this is found to be the case, then the re-dilution results from the re-analysis are accepted. The original result is invalidated and the investigation is closed.

b. If the re-dilution results do not confirm the atypical results, other factors such as insufficient mixing, sonication, shaking, etc., may be suspected as the assignable cause. The results are recorded in the investigation. The original atypical result is invalidated. Re-test the sample according to the method .

c. If any of the re-dilution results confirm the original atypical result, a full investigation is required to determine if the original results are valid or not.

If new results from the investigation are within acceptance criteria, and assignable cause is determined, the new results are accepted and reported, and the Laboratory Investigation is concluded.

When an assignable cause is found for a laboratory error, an appropriate corrective and preventative action plan (CAPA) must be taken.

Flow chart of Incident :

Incident Check list :


In-Process Checks during Manufacturing Operation

What is In-Process Checks :

It is an acceptance quality tool to verify and check that the product physical parameters are been checked in accordance to predefined frequency given in respective documents, to assure that the products produced the results which are well within specified limit.

Production and QA personnel shall check following before commencing In-process start up checks :

Ensure that the Differential Pressure, Relative Humidity and Temperature of the respective manufacturing areas are within limit.
Ensure Line Clearance of equipment, instrument and area prior to start of activity.
Ensure that the Batch Manufacturing Record (BMR) is available and completed up to the previous stage.
Ensure all instruments / balance used for measuring purpose are cleaned, calibrated and have not exceed their calibration due date.
Ensure that the status labels of equipments affixed and room’s status shall be updated prior to start of the activity.
Ensure that the all details are correct on status label of HDPE container, IPC bin and Bin Blender etc. of respective product at respective stage.
Prior to start of the tablet compression and capsule filling operation, ensure that the Blender bin containing bulk material is affixed with Approved label.
Verify that all start-up parameters has been checked by production department and Quality Assurance and recorded in Batch Manufacturing Record of respective product.
Ensure that all parameters are within the acceptance limit as mentioned in manufacturing instructions.

In-process checks during Granulation :

At Granulation stage, Frequency of In process checks and in process sample size shall be specified in respective Batch Manufacturing Record (BMR). For Example: If 5 gm sample required for LOD or Water content Checking then withdrawn approx. Quantity of sample and use 5 gm sample for LOD or Water Content destroy the remaining quantity of sample along with tested sample after completion of in-process checks.

In-Process checks during Tablet Compression Operation:

Ensure correct tooling / spares are set on machine before loading of the product.
Ensure the metal detector sensitivity challenge test is performed and recorded as specified in Batch Manufacturing Record (BMR).
Production person shall follow Frequency of In process checks and in process sample size as specified in respective Batch Manufacturing Record (BMR)
For Example: If required 20 Tablets for in-process checks then collect approx. sample of compressed tablets and use 20 tablets for In-process; destroy the remaining quantity of sample along with tested sample after completion of in-process checks.                           
In case of double rotary Tablet compression machine the sample size shall be collected from Right Hand Side (RHS) & Left Hand Side (LHS) of compression machine.
Ensure all in process checks are within acceptable limit as specified in Batch Manufacturing Record (BMR) of respective product.
If all in process parameters are found within acceptable limit at Pre-Compression stage as specified in Batch Manufacturing Record (BMR) allow for the tablet compression operation.
If parameters are not being met the predetermined specifications, inform to production personal to reset the parameters.
QA person shall be perform all in-process checks at start up of batch and as specified in BMR, Every after two or three or four hour & after break.
During in-process checks at compression stage, Tablets shall be checked visually for any physical defects. If any defects observed then stop the machine immediately and inform to concern supervisor and same shall be noted into BMR as a remark. Refer Table A

In-Process checks during Capsule Filling operation:

Production person shall follow Frequency of In process checks and in process sample size as specified in respective Batch Manufacturing Record (BMR).                           Collect approx. sample for in-process checks as per respective BMR for different test and record in-process checks in BMR.
For Example: If required 20 Capsules for in-process checks then collect approx. sample of Filled Capsules and use 20 capsules for In-process; Destroy the remaining quantity of sample along with tested sample after completion of in-process checks.
Ensure the Metal detector sensitivity challenge test is performed and recorded as specified in Batch Manufacturing Record (BMR).
At Pre-Encapsulation stage in process checks sample size shall be considered as specified in respective Batch Manufacturing Record (BMR) for different test.
In process checks of different test shall be performed as specified in respective Batch Manufacturing Record (BMR).
If all parameters are found within acceptable limit at Pre-Encapsulation stage as specified in Batch Manufacturing Record (BMR) allow for the Encapsulation operation.
During in-process checks by QA person, If parameters are not being met the predetermined specification as specified in BMR, inform to production personnel to reset the parameters.
QA person shall be perform all in-process checks as specified in BMR, at start up of batch, every after two or three or four hour & after break .
For ongoing Encapsulation operation in process sample size as mentioned in respective BMR shall be considered for different test.
During in-process checks at Encapsulation stage, capsule shall be checked visually for any physical defects. If any defects observed then machine shall be stop immediately and inform to concern supervisor and same shall be noted into BMR as a remark.  Refer Table B

In-Process checks during Tablet Coating operation:

Production person shall follow Frequency of In process checks and in process sample size as specified in respective Batch Manufacturing Record (BMR). Collect approx. Sample for in-process checks as per respective BMR for different test and record in-process checks in BMR.
For Example: If required 20 Tablets for in-process checks then collect approx. Sample of compressed tablets and use 20 tablets for In-process and destroy the withdrawn quantity of sample along with tested sample after completion of in-process checks.                            
During in-process checks for coating stage, defected coated tablets/caplets as mention below shall be checked visually for any physical defects. If any defects observed then machine shall be stop & shall be informed to concern supervisor and same shall be noted into BMR as a remark. Refer Table C
QA person shall perform in-process checks as per instruction given in BMR

General Instruction to be followed by both Production and Quality Assurance during In-process checks :

Collect the in-process sample in sample bag with labelled as ‘Sample for In-Process Checks prior to carry the sample out of area.
Collected Sample for in-process checks shall not carried back to same area or any other area except the IPQA area.
After completion of in-process checks tested / left over sample shall be destroyed.
Prior to start of test, ensure the product name, batch no. / Lot no., date, time and other details are set correct on the report / instrument / equipment.
In case of any discrepancy observed during in-process check, follow the SOP “Handling of non compliance during in process checks”:
Immediately stop the activity and inform to department head and QA. Segregate the container(s) from initial / previous good tablet / capsule container(s), labelled it as HOLD & keep it aside till further decision.
Reset the machine and test the samples for the process parameter. On observing that process parameters are found within limit, get them counter checked by QA personals before restarting the production.
If still does not meet the test within acceptance limit, fill deviation approval form and investigate.
Affix the printout (where ever applicable) of in-process checks / tests performed in BMR or respective documents.
In case during in process checks, printer gets problem such as page gets stuck or hanged up or not working then perform additional test with available sample or record the data manually in BMR.
During In process checks Quality Assurance person shall collect the Required sample for Analysis from Start, Middle & End of operation and same shall be recorded in respective batch record yield reconciliation stage. Sample collection date, time and signature shall be written in the batch record
TABLE A for Compressed Tablets
TABLE B for Capsules
TABLE A for Coated Tablets

46 Pharmaceutical Quality Assurance Interview Questions & Answers

1.What is Quality Assurance :

Quality Assurance is a deep concept covering all matters that individually or collectively influence the quality of a product. It is the complete & whole of the arrangements made with the object of ensuring that the manufactured products are of the quality required for their intended use.

2. Responsibility of Quality Assurance:

In process checks during manufacturing & packing activities, Providing Line clearance in Manufacturing, Packaging and Warehouse, Sampling of products in manufacturing and packing, Reviewing the manufacturing and packing batch record, Issuance of  documents to other departments, calibration of Instruments, Providing training to other department, Ensuring online documentation and compliance throughout the plant,Review & approve Standard operating procedure, change controls and deviations.

3. What is tablet :

Tablets is defined as the solid unit dosage form of medicines with suitable excipients and prepared either by molding or by compression. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose.

4. Name any three tablet processing problems :

Mottling, Capping, lamination, picking and sticking

Mottling- unequal colour distribution of a tablet.

Capping- Partial or complete separation of a tablet top or bottom crowns.

Lamination- Separation of tablets into two or more layers.

picking- Because of adhesion to the punch faces, Localized portion missing on the surface of the tablet.

Sticking- Adhesion of tablet localized portion to the punch faces resulting in rough and dull appearance.

5. What is Disintegration Test :

It is the time required for the Tablet / Capsule to break into particles, the disintegration test is a measure of the time required under a given set of conditions (Temperature) for a group of tablets/capsules to disintegrate into particles.

Cycle of shaft holding the tube basket limit is 29-32 cycles per minutes and distance covered by shaft basket is 50-60 mm and beaker temperature is 35 to 39 º C.

Disintegration is to be Performed to determine whether tablets or capsules disintegrate within the prescribed time when placed in a liquid medium at the experimental conditions.

6. What are the Disintegration Time of tablets :

  • Uncoated Tablet 15 min as per BP
  • Uncoated Tablet 30 min as per USP
  • Sugar Coated Tablet 60 min as per BP
  • Film Coated Tablet 30 min as per BP
  • Plain Coated Tablets DT in specific medium for 30 min as per USP
  • Enteric Coated Tablets DT in  simulated gastric fluid (0.1 M HCl) for 1 hr and then in simulated intestinal fluid (Phosphate buffer 6.8 pH) until disintegrate as per USP.
  • Dispersible Tablets 3 min ( 15- 25º C ) as per BP.
  • Effervescent Tablets 1 tablet in 200 mL water  for 5 min ( 15- 25º C )
  • as per BP
  • Buccal Tablets 4 hrs as per USP.
  • Soluble Tablets 3 min ( 15- 25º C ) as per BP.
  • Chewable Tablets are not require to comply with test

7. What are the Disintegration Time of capsules:

  • Gastro resistant capsule DT 2 hrs without disk in 0.1 M HCl  and phosphate buffer pH 6.8 for further  60 min as per BP.
  • Hard and Soft gelatin capsule DT 30 min as per BP & USP.

8. What is Friability Test of Tablet & friability calculation :

Friability is defined as the percentage of weight loss of powder from the surface of the tablets due to mechanical action and the test is performed to measure the weight loss during transportation.

Friability (%)  =W1– W2/W1X100

Where,
W1 = Weight of Tablets (Initial / Before Tumbling) &
W2 = Weight of Tablets (After Tumbling or friability)

Limit : Friability (%) = Not More Than 1.0 %

Tablets with individual weight equal to or less than 650 mg then take the sample of whole corresponding to as near as 6.5 gram equivalent and tablets with individual weight more than 650 mg then take sample of 10 whole tablets to perform friability test. Tablets must be de-dusted prior to and after use.

9. Weight Variation limit for Tablets and Uniformity of Mass Variation:

10. What is Validation :

Documented program or evidence, that provides a high degree of assurance that a specific process method or system consistently produce a result indicating predetermined accepted criteria.

11. What is Validation Protocol :

A written plan starting how validation will be conducted and identifying specific acceptance criteria.  For example the protocol for a typical manufacturing process identifies processing equipment’s, critical process parameters/ operating ranges, Critical Quality attributes and product characteristics. Sampling and test data to be collected, number of validation runs and acceptable test results.

12. Prospective Validation :

Establishing documented evidence that a system dos what it  suppose to do prior to the commercial distribution of the new product or an existing product made by  a new  or modified process.

13. Retrospective Validation :

Establishing documented evidence that a system does what it purports to do based on a review and analysis of historic information. It is normally conducted on the drug material already being commercially distributed and is based on accumulated production, testing and control data.

14. What is Calibration :

The demonstration that a particular instrument or device produces results within specified limits  by comparison with those produced by a traceable standard over an appropriate range of  measurements.

15. What is Qualification :

The action of proving that any equipment or process work correctly and consistently and  produces the expected result. Qualification is part of, but not limited to a validation process, i.e. Installation Qualification (IQ), Operation Qualification(OQ) and Performance Qualification (PQ).

The act of planning, carrying out and recording the results of tests on equipment to confirm its capabilities and to demonstrate that it will perform consistently as intended use and against predefined specification.

16. What is User Requirement Specification :

A requirement specification that describes what the equipment or the system is supposed to do, thus containing at least a set of criteria or condition that have to meet.

Detailed design & functional specifications shall be taken from the supplier for a particular piece of equipment / instrument / system / facility. The same shall be prepared by User & reviewed by Engineering & Quality Assurance. Based on the specifications, URS document shall be prepared

17. What is Factory Acceptance Test :

A Factory Acceptance Test is usually preformed at the vendor prior to shipping to a client. The vendor tests the system in accordance with the clients approved test plans and specifications to show that system is at a point to be installed and tested on site.

18. What is Site Acceptance Test :

A  Site Acceptance Test the system is tested in accordance to client approved test plans and specifications to show the system is installed properly and interfaces with other systems and peripherals in its working environment.

19. Design Qualification : 

Documented verification that equipment, instrument, facility and system are of suitable design against the URS and all key aspects of design meet user requirements.

20. Installation Qualification (IQ) :

The documented verification that all components of the equipment and associated utilities are properly installed or modified in accordance with the approved design and manufacturer’s recommendations.

21. Operational Qualification : 

Operational qualification consists of verification and documentation, of the parameters of the subjected equipment. The documented verification that the equipment, instrument, facility and system as installed or modified, perform as intended throughout the installed operating range.

22. Performance Qualification :

Performance Qualification is designed to prove the process, can consistently produce a product that meets the stated requirements and specifications. It is a documented verification that the equipment, instrument, facility and system as connected together, can perform effectively and reproducibly, based on the approved process method and product specification.

23. Why Three consecutive batches taken for Validation :

Consecutive meaning following closely with no gap or following one after another without interruption.

  • The number of batches to be taken under validation depends upon the risk involved in the manufacturing Critical process parameters & critical Quality Attribute so  depends upon that manufacturer have to choose the number of batches to be validated.
  • If we will consider less than two batches then the data will not be sufficient for evaluation of and to prove reproducibility of data  between batch to batch variation & if we consider more than three batches it can increase the time & cost of manufacturer which usually not preferred.
  • Generally if we will require quality in the First batch, then it is accidental (co-incidental), Second batch quality is regular & third batch quality is Validation or Confirmation.
  • Statistical evaluation cannot be done by considering two points, because two points always draw a straight line so minimum three points required for comparison of data.

24. In A Oral solid dosage 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.

25. What is Positive Pressure :

Atmospheric pressure which is higher than the immediate surrounding areas usually measured in inches of water or Pascal.

26.What is Cross Contamination :

Contamination of a material or product with another material or product is called cross contamination.

27. What is Schedule -M :

Good manufacturing practice and requirements of the Premises of the plant, Waste disposal and equipment’s. GMP has two parts Part I and Part II

Part I is GMP for Factory Premises and Part II is GMP for Plant & equipment’s.

28. What is Quarantine in pharmaceuticals :

The status of the materials isolated physically or by other effective means, pending for a decision on their subsequent use. Materials are kept in Quarantine area with proper status labeling.

29. What is Relative Humidity :

It is the ratio between the actual amount of water vapour present in certain volume of air at a given temperature and the maximum amount of water vapour that the air can retain at that temperature.

30. Expiry/Expiration Date :

The date usually placed on the containers /labels of material designating the time during which the material is expected to remain within the established self  life specifications if stored under defined conditions and after which it should not be used.

31. What is Deviation:

Any unwanted event that represents a departure from approved processes or procedures or instruction or specification or established standard or from what is required. Deviations can occur during manufacturing, packing, sampling and testing of drug products.

Examples of Deviations: Temperature and RH of area goes out of limit during manufacturing, Typographical error observed in approved documents, Standard operating procedure not followed, Breakdown of equipment, Spillage of material during unloading, Instrument calibration results goes out of limit etc. Deviations are of three types Minor, Major and Critical

32. What is Change Control :

It is a Approved Procedure which is taken to change in any documents, Standard operating procedures, Specification, Process parameters and change in batch size etc. Change control is raised by user department as per requirement and finally the change control is approved by Quality assurance. Change control can be raised through software or through manually.

After Final approval of change control the changes can be made in documents  and change control can be closed after completion of required action plan which is mentioned in the Change control form.

Change controls are of two types i.e Major and Minor.

33. Corrective action :

An action taken to eliminate the cause of the existing deviation , incident or problem in order to prevent its recurrence (occurring again).

34. Preventive action:

An action taken to eliminate the cause of potential deviation, incident or problem in order to prevent its occurrence (an incident or event).

35. What is Hold Time Study :

Hold Time studies establish the time limits for holding the materials at different stages of production to ensure that the quality of the product does not degrade significantly during the hold time at a required temperature and Relative Humidity.

36. What is Site Master File :

A Site Master File (SMF) is a document that describes the structure of the organization which includes the site, the manufacturing activities carried out, the facility and premises, number of employee with their Qualification, Production system, Quality Control System and also details of the quality management system which are in place.

It contains General information about the plant, Quality System, Personnel, Premises and Equipments, Production system, Documentation, Quality Control system, Self Inspection and site inspection history etc.

37. What is VMP :

A Validation Master Plan is a document that summarizes the firm’s/organizations overall philosophy, intentions and approach to be used for establishing performance adequacy. It provides information on the firms/organizations validation work programme and defines details of and timescales for the validation work to be performed, including a statement of the responsibilities of those implementing the plan.

It contains the validation policy, Process & Cleaning validation, Qualification & Requalification, Computer validation, Utility validation & Qualification, Vendor Qualification , Temperature mapping, Change control, Deviation, Risk Assessment, Standard Operating procedure, Training, Area Qualification, calibration and Preventive maintenance & closure of VMP etc. VMP Shall be updated yearly.

38. What is Control Sample :

An appropriately identified sample that is representative of each batch that shall be retained is known as control sample. These are also referred as retention or reference sample.

The control sample shall be collected at the initial, middle and at the end of packing operation of the batch and the details of the total pooled quantity collected shall be entered in the respective Batch Packing Records with sign, date & sample collection time.

39. How much sample to be collected for Control or Reference Sample :

The control sample should consist of twice the quantity required for complete analysis and Sample quantity shall be decided on the basis of specifications given by Quality Control.

Control sample shall be collected for Raw material, Packing Material and Finished Products

40. What are the tools used for Investigation in Pharmaceuticals :

The tools are Brain Storming,Fish Bone diagram, 5 Why, Affinity Diagram or Chart, Root cause analysis, Failure Mode Effect Analysis etc.

41.What is Cleaning Validation :

It is a  documented evidence which provides us the assurance that a cleaning procedure is consistently removing product residue from equipment.

Three batches shall be taken for Cleaning validation After the Cleaning procedure for the equipment’s are validated, periodic monitoring / Cleaning verification shall be done once in year on worst case product

42. What is Worst case in cleaning validation :

The product selected from a group of products that represents a greater risk of carry over the residue of previous product to next product manufactured using the same equipment by virtue of its solubility, Cleanability, Permitted daily dosage exposure, toxicity or a combination of these factors, therapeutic dose, etc.

It is the case or condition where there is a chances of Product failure.

43. What is Line clearance :

Line clearance is a process which provides a high degree of confidence or assurance that the said line or area is free from any unwanted residue or left over of previous processing’s before proceeding for next process. Quality assurance has to provide Line clearance before the start of any activity whether it is batch to batch change over and Product to product change over.

Line clearance shall be given by Quality Assurance at Raw material Dispensing stage, Manufacturing stage, Packing stage and in Quality Control before start of any activity.

44. Water Validation Phases :

Water system validation has been categorized into 3 phases: Phase I, Phase II and Phase III.

Phase I  Requires a 2 – 4 weeks (14 days minimum) testing period in order to monitor the system deeply.

Phase II  is continuity of previous phase i-e phase I, it carries the sampling plan same as previous phase plan & it also facilitates the monitoring of system for 2 – 4 weeks (30 days) period.

In phase III sampling locations and frequency reduced as compared to previous phases. Phase III represents that the water system shows reliable under control attainment over such a long time period & Phase III typically runs for one year after the satisfactory completion of phase II.

45. What is Concurrent Validation :

Concurrent validation is used to establish documented evidence that a facility and process will perform as they are intended, based on information generated during actual use of the process.

46. What is Product Recall & Mock Recall :

A product recall is a request from a manufacturer to return or removal of a  marketed product after the discovery of safety issues or product defects that might endanger the consumer or put the maker/seller/ manufacturer at risk of legal action.

Mock means Make a Duplicate or exact copy of something.

Mock recalls are routine exercises conducted by manufacturers, processors, distributors and other various trading partners in the supply chain to assess or verify their recall procedures and responsiveness and to train the recall team.