350+ Pharmaceutical Interview Questions and Answers for the year 2021-22

Technical know-how is a must to clear the pharmaceutical interview. Most of the answers are based on basic knowledge and current pharmaceutical guidelines. Here, we have compiled interview questions and answers, most common during the interview for pharmaceutical jobs for working in an oral solid manufacturing facility, sterile manufacturing facility, quality assurance, microbiology, or validation department.

The questions and answers will help pharma freshers, beginners, and experienced individuals. Freshers and beginners can understand what types of questions could be asked and the answers to those questions. Experienced pharma professionals can refresh their basic knowledge, and the questions and answers will help them while interviewing other pharma professionals during the recruitment process.

  1. Top 15 interview tips for Pharma Professionals
  2. Pharmaceutical Interview Questions and Answers on General Topic
  3. Pharmaceutical Interview Questions and Answers on Production System – Oral Solid Dosage Formulation
  4. Pharmaceutical Interview Questions and Answers on Production System – Sterile and Injectable Dosage Formulation
  5. Pharmaceutical Interview Questions and Answers on Validation
  6. Pharmaceutical Interview Questions and Answers on Microbiology
General Pharmaceutical Interview Questions and Answers

Mostly asked 10+ General Pharmaceutical Interview Questions and Answers for 2021-2022

Most commonly asked general questions and answers for the freshers in the pharmaceutical industry. Even though freshers have good knowledge about subjects, following are few general questions which interviewer will expect that candidate must have to know about as it is very basic knowledge and connecting bridge between student life and industry life.

1. What is the Good Manufacturing Practice (GMP) or Current Good Manufacturing Practice (CGMP)? Provide reference to GMP regulations of different countries.

Quality of pharmaceuticals is important for the patient’s safety and are very carefully regulated by respective country regulators.

GMP or CGMP refers to the Current Good Manufacturing Practice regulations enforced by the respective country regulations.

GMP provides systems that assure proper design, monitoring, and control of manufacturing processes and facilities. Adherence to the GMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations.

The US FDA uses terminology CGMP. According to the U.S. FDA, “‘C’ in CGMP stands for “current,” requiring companies to use technologies and systems that are up-to-date in order to comply with the regulations. Systems and equipment that may have been “top-of-the-line” to prevent contamination, mix-ups, and errors 10 or 20 years ago may be less than adequate by today’s standards.

GMP regulations governed by different countries and its reference guidance are detailed as follows. Following table provides reference for most common regulatory bodies. This will provide understanding on how GMP regulations are forced by different regulatory bodies.

CountryRegulatory BodyReference regulations under respective country’s law
United StatesU.S. FDA  Code of Federal Regulations (CFR):21 CFR Part 210.  Current Good Manufacturing Practice in Manufacturing Processing, packing, or Holding of Drugs.21 CFR Part 211.  Current Good Manufacturing Practice for Finished Pharmaceuticals.21 CFR Part 212. Current Good Manufacturing Practice for Positron Emission Tomography Drugs.21 CFR Part 600.  Biological Products: General.21 CFR Part 314. For FDA approval to market a new drug.
European Union (EU) CountriesEuropean Commission – Health and Food Safety    The entire body of EU medicines legislation (EudraLex) is compiled in “The rules governing medicinal products in the European Union”.   Pharmaceutical sector is compiled in Volume 1 and Volume 5 of the publication “The rules governing medicinal products in the European Union”:  Volume 1 – EU pharmaceutical legislation for medicinal products for human useVolume 5 – EU pharmaceutical legislation for medicinal products for veterinary use
Countries following WHO guidanceWorld Health Organization (WHO)WHO good manufacturing practices for pharmaceutical products: main principles, Annex 2, WHO Technical Report Series 986, 2014
IndiaMinistry of health and family welfareThe drugs and cosmetics act, 1940 and The drugs and cosmetics rules, 1945   Schedule M: Good Manufacturing Practices and requirements of premises, plant and equipment for pharmaceutical products
CanadaHealth Canada  Good Manufacturing Practices Guidelines by Health Products and Food Branch Inspectorate   Good Manufacturing Practices (GMP) refer to Division 2, Part C of the Food and Drug Regulations. The guidelines apply to pharmaceutical, radiopharmaceutical, biological, and veterinary drugs and were developed by Health Canada in consultation with their stakeholders.   Division 1A, Part C of the Food and Drug Regulations defines activities for which GMP compliance is to be demonstrated prior to the issuance of an establishment license.   Guidance based on PIC/S
JapanPharmaceuticals and Medical Devices Agency (PMDA)Pharmaceuticals and Medical Devices Agency (PMDA) was established and came into service on April 1, 2004, under the Law for the Pharmaceuticals and Medical Devices Agency, as a consolidation of the services of the Pharmaceuticals and Medical Devices Evaluation Center of the National Institute of Health Sciences (PMDEC), the Organization for Pharmaceutical Safety and Research (OPSR/KIKO), and part of the Japan Association for the Advancement of Medical Equipment (JAAME).   GMP Ministerial Ordinance (Ministerial Ordinance on Standards for Manufacturing Control and Quality Control for Drugs and Quasi-drugs) No. 179, 2004
AustraliaTherapeutic Goods AdministrationAUSTRALIAN CODE OF GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS   Therapeutic Goods Act 1989. This upholds the main objective of the Act, which is to ensure the safety, quality, efficacy and timely supply of therapeutic goods for Australian consumers.   Guidance based on PIC/S
New ZealandMedsafeNew Zealand Code of Good Manufacturing Practice for Manufacture and Distribution of Therapeutic Goods   Part 1: Manufacture of Pharmaceutical Products (2009)   Guidance based on PIC/S

2. What is Standard Operating Procedure (SOP)?

SOPs are documented Standards Operating Procedure, authorized by the Quality Unit or Quality Assurance department having sets of written instructions to be followed by employees on a day to day basis to carry out operations in a consistent manner to achieve predetermined specification and a quality end-result.

Examples of Standard Operating Procedures are as follows:

– SOP for entry and exit in the manufacturing facility

– SOP for operation and cleaning of compression machine

– SOP for preparation of SOP

– SOP for pest control

– SOP for material receipt

– SOP for preventive maintenance program

– SOP for operation of High Performance Liquid Chromatography (HPLC) instrument

3. What is the typical content of Standard Operating Procedure (SOP)?

Objective or Purpose

Scope

Responsibility

Accountability

Definitions

Abbreviations

Reference

Procedure

List of Annexes

Format for recording Revision history

4. What is Master Formula Record, Master Formula, Manufacturing Formula, and Master Production and Control Record?

Master Formula Record, Master Formula, Manufacturing Formula, and Master Production and Control Record mean the same thing. This is an approved master document that describes the full manufacturing process of the drug product. [Reference: 1]

5. What is drug substance?

Drug substance is an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient. [Reference: 2]

6. What is drug product?

Drug product means a finished dosage form, for example, tablet, capsule, solution, etc., that contains an active drug ingredient generally, but not necessarily, in association with inactive ingredients. The term also includes a finished dosage form that does not contain an active ingredient but is intended to be used as a placebo. [Reference:3]

7. What is Active ingredient?

Active ingredient means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect. [Reference:3]

8. Fiber means?

Fiber means any particulate contaminant with a length at least three times greater than its width. [Reference:3]

9. What is inactive ingredient?

Inactive ingredient means any component other than an active ingredient. [Reference:3]

10. What is Gang-printing?

Gang-printed labeling means labeling derived from a sheet of material on which more than one item of labeling is printed. [Reference:3]

11. What is full form of ICH?

Full form of ICH is International Council for Harmonisation (ICH), formerly known as the International Conference on Harmonisation (ICH).

12. ICH Guidelines are divided into how many categories? What are those?

The ICH topics are divided into the four categories below.

Quality Guidelines

Safety Guidelines

Efficacy Guidelines

Multidisciplinary Guidelines

13. How many main topic quality guidelines are published by ICH ?

Q1A – Q1F Stability

Q1A(R2) Stability Testing of New Drug Substances and Products

Q1B Stability Testing : Photostability Testing of New Drug Substances and Products

Q1C Stability Testing for New Dosage Forms

Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products

Q1E Evaluation of Stability Data

Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV

Q2 Analytical Validation

Q2(R1) Validation of Analytical Procedures: Text and Methodology

Q2(R2)/Q14 EWG Analytical Procedure Development and Revision of Q2 (R1) Analytical Validation

Q3A – Q3E Impurities

Q3A(R2) Impurities in New Drug Substances

Q3B(R2) Impurities in New Drug Products

Q3C(R8) Guideline for Residual Solvents

Q3C(R9) Maintenance EWG Maintenance of the Guideline for Residual Solvents

Q3D(R1) Guideline for Elemental Impurities

Q3D(R2) Maintenance EWG Revision of Q3D(R1) for cutaneous and transdermal products

Q3D training Implementation of Guideline for Elemental Impurities

Q3E EWG Impurity: Assessment and Control of Extractables and Leachables for Pharmaceuticals and Biologics

Q4A – Q4B Pharmacopoeias

Q4A Pharmacopoeial Harmonisation

Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions

Q4B Annex 1(R1) Residue on Ignition/Sulphated Ash General Chapter

Q4B Annex 2(R1) Test for Extractable Volume of Parenteral Preparations General Chapter

Q4B Annex 3(R1) Test for Particulate Contamination: Sub-Visible Particles General Chapter

Q4B Annex 4A(R1) Microbiological Examination of Non-Sterile Products: Microbial Enumeration Tests General Chapter

Q4B Annex 4B(R1) Microbiological Examination of Non-Sterile Products: Tests for Specified Micro-Organisms General Chapter

4C(R1) Microbiological Examination of Non-Sterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use General Chapter

Q4B Annex 5(R1) Disintegration Test General Chapter

Q4B Annex 6 Uniformity of Dosage Units General Chapter

Q4B Annex 7(R2) Dissolution Test General Chapter

Q4B Annex 8(R1) Sterility Test General Chapter

Q4B Annex 9(R1) Tablet Friability General Chapter

Q4B Annex 10(R1) Polyacrylamide Gel Electrophoresis General Chapter

Q4B Annex 11 Capillary Electrophoresis General Chapter

Q4B Annex 12 Analytical Sieving General Chapter

Q4B Annex 13 Bulk Density and Tapped Density of Powders General Chapter

Q4B Annex 14 Bacterial Endotoxins Test General Chapter

Q4B FAQs Frequently Asked Question

Q5A – Q5E Quality of Biotechnological Products

Q5A(R1) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin

Q5A(R2) EWG Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin

Q5B Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products

Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products

Q5D Derivation and Characterisation of Cell Substrates Used for Production of Biotechnological/Biological Products

Q5E Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process

Q6A- Q6B Specifications

Q6A Specifications : Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances

Q6B Specifications : Test Procedures and Acceptance Criteria for Biotechnological/Biological Products

Q7 Good Manufacturing Practice

Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

Q7 Q&As Questions and Answers: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

Q8 Pharmaceutical Development

Q8(R2) Pharmaceutical Development

Q8/9/10 Q&As (R4) Q8/Q9/Q10 – Implementation

Q9 Quality Risk Management

Q9 Quality Risk Management

Q9(R1) EWG Quality Risk Management

Q8/9/10 Q&As (R4) Q8/Q9/Q10 – Implementation

Q10 Pharmaceutical Quality System

Q10 Pharmaceutical Quality System

Q8/9/10 Q&As (R4) Q8/Q9/Q10 – Implementation

Q11 Development and Manufacture of Drug Substances

Q11 Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)

Q11 Q&As Questions & Answers: Selection and Justification of Starting Materials for the Manufacture of Drug Substances

Q12 Lifecycle Management

Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

Q12 IWG Training on Regulatory and Technical Considerations for Pharmaceutical Product Lifecycle Management

Q13 Continuous Manufacturing of Drug Substances and Drug Products

Q13 EWG Continuous Manufacturing of Drug Substances and Drug Products

Q14 Analytical Procedure Development Q2(R2)/Q14 EWG Analytical Procedure Development and Revision of Q2 (R1) Analytical Validation

Reference: ICH.org

References:

1. WHO GMP Guidelines: Guide to Master Formulae, WHO/FWC/IVB/QSS/VQR, 2011

EU and PIC GMP guidelines: EudraLex Volume 4, Chapter 4: Documentation

PIC/S guidelines: Chapter 4: Documentation

Health Canada GMP guidelines: Good manufacturing practices guide for drug products (GUI-0001), Manufacturing control, C.02.011

U.S. FDA: CFR 21, Chapter I, Subchapter F: Biologics, Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals; Subpart F–Production and Process Controls, Sec. 211.100 Written procedures; deviations; and Subpart J–Records and Reports; Sec. 211.186 Master production and control records

U.S. FDA: CFR 21, Chapter I, Subchapter F: Biologics; Subchapter C: Drugs General; Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals; Subpart J– Records and Reports; Sec. 211.188 Batch production and control records.

India: The drugs and cosmetics act, 1940 and The drugs and cosmetics rules, 1945, Schedule M, 12. Documentation and records]

2. PART 314 — APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG, Subpart A – General Provisions Sec. 314.3 Definitions.

3. 21 CFR PART 210: CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL Sec. 210.1 Status of current good manufacturing practice regulations.

5. Wet Granulation:

End-Point Determination and Scale-Up, By Michael Levin, Ph. D., Metropolitan Computing Corporation East Hanover, New Jersey, USA

6. Saudi Pharmaceutical Journal

Volume 20, Issue 1, January 2012, Pages 9-19, Saudi Pharmaceutical Journal, Review article, Upgrading wet granulation monitoring from hand squeeze test to mixing torque rheometry Author links open overlay panel Walid F. Sakr Mohamed A. Ibrahim Fars K. Alanazi Adel A. Sakr

7. natoli.com

8. pacifictools.in

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Interview Questions and Answers for Oral Solid Formulations

160+ Pharmaceutical Interview Questions and Answers for Oral Solid Formulations

This page covers most of the interview questions and answers during a technical round in Production Oral Solid Dosage. The interview questions cover questions from basic to advance level of technical aspects. These interview questions and answers will help to crack an interview, enhance your knowledge, and also be helpful for the interviewer who is involved in the recruitment process.

The topics covered here are the Granulation process, the Tablet Compression process, the Coating process, and associated topics. In addition, the interview questions and answers cover various equipment used for the manufacturing process of solid oral formulation such as Compression Machine, Coating Machine, Graduation equipment, and supporting accessories.

You will find it much more enjoyable while going through these interview questions and answers. So enjoy learning, and best of luck with your interview! Happy Learning.

1. What is the granulation end point?

End-point can be defined by the formulator as a target particle size mean or distribution. [Reference: 5]

The agglomerate growth in wet granulation processes depend mainly on rheology of the wet powder mass, as an adequate consistency is necessary for a controllable coalescence and growth of smaller agglomerates into larger agglomerates.[Reference: 6]

2. Method for end point detection for wet granulation process.

i. Banana breaking test or Hand squeeze test

ii. Ampere load method

iii. Measurements of power consumption of the mixer motor

iv. Impeller Torque

v. Binder solution addition and measurement of Loss On Drying (LOD)

vi. Torque value

3. What is the Banana breaking method or Hand squeeze test for determination of granulation end point?

Wear hand gloves, take one handful of wet mass in the palm and press to make a lump. Open the palm and break the lump by pressing the thumb at the center of the lump.

4. What is the principle of metal detectors?

The operation of these metal detectors is based on the principles of electromagnetic induction. Metal detectors contain one or more inductor coils that are used to interact with metallic elements. Metallic contaminant in the product creates a high frequency magnetic field within the detector coil, which in turn activates a reject flap.

5. What is the fail safe mechanism of metal detectors?

When a metal detector gets off because of power failure or inadvertently did not start before the start of the batch, the flap should remain open so that tablets get rejected. It must be challenged at regular intervals (e.g.: start, intermittently and at the end of shift) to make sure they are effective.

6. What are typical standards used for the challenge of metal detectors?

Tablet: Ferrous – 0.3 mm, Non-ferrous – 0.3 mm, Stainless Steel – 0.5 mm, Plain (without metal as a blank)

Capsule: Ferrous – 0.1 mm, Non-ferrous – 0.15 mm, Stainless Steel – 0.2 mm, Plain (without metal as a blank)

7. What is tablet tooling?

Tooling consists of three parts.

i. Upper punch, ii. Lower punch, and iii. Die

8. What is the meaning of one set of tablet tooling?

One set consists of one Upper punch, one Lower punch and a Die.

9. What is a tooling station?

The place where one set accommodates the tablet press.

10. Explain parts of tablet tooling.

Punch terminologies:

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SVCf0Z gVv9R1m zmiSUsqIrAMyCwBqM6MEw2aUDcQLKJGUHnDibis2yw2DjwCLQPQCRIehWHWte4UmUP6ER008QCFiz4 JrghrcWsCCmaia5Yrv jLwW9c1oi QaNEl0sW7i84h

Head: Head is the top part of upper and lower punch which contacts the machine’s cams and the pressure rollers apply the pressure to the head to compress the tablets.

Head flat or Dwell Flat: Top flat area of the head. Compression force applied through the upper punch head flat and ejection pressure applied through the head flat of lower punches. Dwell time for compression is determined based on the Head flat hence, it is also called Dwell Flat.

Outside head angle: The area touches the pressure roller during compression operation.

Inside head angle: The part of the punch head helps the upper punch to lift after compression of tablets and helps in pulling down the lower punches after ejection.

Neck: The part between head and barrel. Allow a clear path to the cam.

Barrel: Allows punch to do vertical up and down movement.

Stem: Area from tip end to barrel edge.

Tip: It is the lowest portion of the punch which is responsible for shape, size and profile of the tablet.

Tip face or cup: Outer part of the tip which gives shape to the tablet. The face also will have embossing depending on the need of the tablet requirement.

Tip length: The straight portion of the stem or tip.

Tip straight: The portion of tip towards the face having a higher diameter of the tip.

Tip relief: Tip part other than the tip straight.

Working length: This is the distance from the head flat to bottom of the cup.

Overall length: Length from punch head flat to the tip.

Key or woodruff key: An elevated portion in the middle of the punch barrel. The key with upper punches for shaped tablets to prevent punch rotation when the punch is out of the die.

Types of heads: Domed head and Flat head

Difference between Flat head and Domed headDomed head punches have smaller flat heads.

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hFBduOfPTsxVV0eEgtKhsxSW5oegE

The extended head flat offers multiple benefits, including a longer dwell time (the time the head flat spends in contact with the pressure roll) at a given press speed to better compact poorly compressible products. The longer dwell time may even reduce the amount of force required to attain specific tablet hardness.

Whereas, round extended head flats don’t require keyed tooling as oval ones do, and that allows them to be used on multiple makes and models of tablet presses.

Dwell time: It is the time the head flat spends in contact with the pressure roller.

Land: The area between the outer part of the punch cup and the outside edge of the punch tip.

Cup depth: Distance between tip edge to the center point of the cup.

Barrel chamfer: Chamfers at the ends of the punch barrel.

Die terminologies:

RF6xkmujKbuBpWL2dmDnIYLBKIaZCD4LC8lRs24kgADEuHWH3pCRz3Z2wCBOVKLuobEXaPg56MpNcGGAkwY4 31OYPPmEp2 CvQ lxGXAzdy J8eULp4wxVdEAtndgoln9 qA6gZ

Clearance: pace between die bore diameter and punch tip diameter

Die Bore: It is the cavity of the die where granules are converted into tablets.

Die height or overall length: The height from top to bottom face of the die.

Die chamfer: This is the angle of the die bore at entry point. It guides the upper punch into the die bore.

Die groove and die lock: The radial groove around the die outer diameter requires locking the die into the turret with the help of die lock.

Die taper: Taper is a feature that increases the bore size at the top of the die then nominal bore size. It helps to release air from the die cavity during the compression. The feature helps to reduce tablet defects, such as capping and lamination.

Annealing: This is a heat treatment process to reduce the hardness to make it more workable. The processing done fragile punch tips to decrease the hardness of the punch cups which helps in reducing punch tip fracturing.

11. Describe tablet tooling standards?

There are two types of standards for tablet tooling:

i. US specification provided by Tableting Specification Manual (TSM) (This is the only tooling specifications are the only published standards for the tablet compression industry). The standard is established by the American Pharmacists Association (APhA),

ii. European standard known as the EU, or “Euronorm” standard.

EU, or Euronorm standard tool configurations are not published or governed by an organization or association. The EU standard is the most common tooling configuration used outside the U.S. [Reference: 7]

12. Differences between TSM and EU Tooling Configurations

Tableting Specification Manual (TSM) Tooling ConfigurationsEU Tooling Configurations
Angled top profileDomed head profile
Inside head angle for “B” punches is 37°Inside head angle for “B” punches is 30°
Overall head thickness is greater in both “B” and “D”Overall head thickness is lesser in both “B” and “D”
Overall punch length of the TSM tool is 0.010 inches shorter than the EUOverall punch length of the EU tool is 0.010 inches longer than the TSM
[Reference: 7]

13. What is the type of tablet tooling for a compression machine with die and punch dimension?

There are the following six types of tablet tooling and its dimensions.


Tooling specification
Nominal punch barrel diameter (mm)Nominal punch die diameter (mm)Maximum tablet diameter for round tablet (mm)Maximum tablet diameter for shaped tablet (mm)
TSM or EU B1930.161616
TSM or EU D25.3538.12525
TSM or EU BB19241314
TSM or EU DB25.3530.161919
TSM or EU  BBS19211213
TSM or EU A12.71788
[Reference: 8]

14. What is the choice for material of construction (MoC) of Die and Punch?

i. OHNS (T) Oil Hardened Non shrinking steel (Tungsten) – AISI 01 (American Iron and Steel Institute)

ii. HCHC – High carbon High chromium steel – AISI D3

15. What is the choice for material of construction (MoC) of Turret?

Three piece turret having the center die table of SS 316 and the Upper and lower piece of Spheroidal Graphite Iron (SG Iron) with ELNP (ELECTROLESS NICKEL PLATING) Coating.

16. What is the chemical composition of OHNS steel?

ElementContent (%)
C0.85-1.00
Si0.15-0.35
Mn1.00-1.20
P0.03 Max
S0.03 Max
Cr0.50-0.70
W0.50-0.70

17. How much is the lifespan of the die and punches?

The life span of punches and dies is purely depending on materials of construction (MoC) as well as usage and handling.

OHNS Punches and HCHC Dies: 4 million tablets

HCHC Punches and HCHC Dies: 8 Million tablets Complete hard chrome plating punches and

HCHC dies: 10 Million tablets

18. How to maintain Punches and Dies?

The maintenance of compression tooling becomes easy by following these mentioned steps:

Step 1: Cleaning during every product change over or on a periodic basis. They can be washed in water and dried using a lint free cloth.

Step 2: Periodic evaluation to increase their shelf life. Industry practice is to

Step 3: The regular visual inspection of the tooling should be done after each cleaning to check for physical damages to head, tip, die, and embossing, debossing using Magnifying glass.

Step 4: Periodic inspection of the punch set should be done using measuring tools. Frequency for die and punch inspection should be such that first inspection after procurement should be done after 3 million tablet compression using each tool set and subsequently after each million.

Step 5: Compression punch set should be lubricated to decrease friction and enhance the operational activity of the tablet compression machine. A non-toxic, FDA approved oils and greases should be used for preservation and lubrication purposes. Storage of tooling should be done in the safe and moisture-free place.

19. What should be available in a punch set/ tablet tooling inspection kit?

1Dial gauge compactor stand with a least count of 0.001 inch
2Micrometer Range from 0.25 mm with least count : 0.01 mm
3Punch holding bushes for B type punch and D type of punch
4Punch height gauge
5Die Outer diameter block for all types of die i.e. D, B, BB, DB etc.
6Magnetic V – block
7GO – NO GO gauges
8Magnifying Glass
9Die Pocket Cleaner

20. Explain about the punch set/ tablet tooling inspection program?

i. Height uniformity of the punches

ii. Punch body to punch tip concentricity

iii. Die bore Go / No go status

iv. Other dimensions as per the drawing

v.  Punch tip to die before clearance

vi. Hollow penetration of the punches

vii. Die outdoor diameter consistency

viii. Die height regularity

ix. Die hole GO and NO GO examination

x. Die internal diameter to outer diameter concentricity

21. Issue that may arise after prolonged use for punch set/ tablet tooling.

i. Tablet weight difference          

ii. Tablet hardness difference    

iii. Powder leakage from lower punch or collar formation

iv. Twisting of small size punch tips

22. Commonly used material of construction in the pharmaceutical industry for equipment manufacturing?

i. Commonly used materials of construction in the pharmaceutical industry for product contact parts are Stainless steel 316, 316 L, Toughened glass, Silicon, Food grade Teflon etc.

ii. Commonly used materials of construction in the pharmaceutical industry for product contact parts are Stainless steel 304, 304 L, Teflon, Anodized or powder coated aluminum, brass etc.

23. Explain characteristics of different grades of stainless steel material.

Following are the different types of types of Stainless and similar material with its characteristics.

Stainless and similar materialApplication for the different types of environment
Hastelloy C276Excellent corrosion resistance in a wide range of severe environments
316, 316LChemical corrosion
304, Custom 450Medium Corrosion
430, 431, Custom 455Industry polluted air
405, 410, 420, 440Clean air

24. Explain most commonly used stainless steel for pharmaceutical industry and its attributes.

Following most commonly used stainless steel for the pharmaceutical industry and its attributes.

Commonly known namesUNSENAttributes
304S304001.4301Good at general corrosion resistance to acidic as well as caustic material
304LS304031.4307Good at general corrosion resistance to acidic as well as caustic material with low carbon and improved performance
316S316001.4401/ 1.4436Improved corrosion resistance to most acidic as well as caustic material with high temperature or chloride present
316LS316031.4404/ 1.4432Improved corrosion resistance to most acidic as well as caustic material with high temperature or chloride present with low carbon and improved performance

25. How to distinguish SS 202, SS 304 and SS 316 grade stainless steel?

Using molybdenum detection electrolyte kit. To know how to perform the test, Click Here.

26. What is the composition of SS 304, SS 304L, SS 316, and SS 316L?

Following are the composition of SS 304, SS 304L, SS 316, and SS 316L

iG1NXz0DKa0RGGWQwJRCgOFuvpKoXeUazXGu96w72kbSrelLi6l6tszG08E7HghqKG7Wlt9oC8TYkqy61fjw3q9rPG0X5UUwhI628GwxQk

27. What is the meaning of Suffix L in SS 316L and SS 304L?

Suffix L for SS 316 and SS 304 represents low carbon content. Standard grade consists of ≤ 0.08 % carbon and low carbon grade consists of ≤ 0.03 % carbon content.

28. What are the different types of stainless steel in terms of material composition?

sTlJ3UXRNoc3TOJcFZvbxBfd XjbdVBOFObWMU8 zVJhcSsMXS qwjazdGleG2bx sHKxXOS0 2r9fY52z8viAhULVFLNy4JXi2023GeWgmRoqYNhi4tRPgVzKAta5tBF4ptWd7B

29. What is Hastelloy?

Hastelloy is a nickel-molybdenum-chromium superalloy with an addition of tungsten designed to have excellent corrosion resistance in a wide range of severe environments. The high nickel and molybdenum contents make the nickel steel alloy especially resistant to pitting and crevice corrosion in reducing environments while chromium conveys resistance to oxidizing media. The low carbon content minimizes carbide precipitation during welding to maintain corrosion resistance in as-welded structures. This nickel alloy is resistant to the formation of grain boundary precipitates in the weld heat-affected zone, thus making it suitable for most chemical process application in an as welded condition.

Source: megamex.com

30. In what applications is Hastelloy used?

i. Pharmaceutical and food processing equipment

ii. Chemical processing components like heat exchangers, reaction vessels, evaporators, and transfer piping

iii. Sour gas wells

iv. Waste treatment

31. Which are typical in-process control tests for tablets?

Dimensions

Hardness

Friability

Thickness

Disintegration

Weight variation

Content uniformity

Dissolution

Leakage testing for strip and blister packaging

Checking printing matter during packaging

Physical appearance of packs

32. Explain Disintegration time (DT) of different types of tablets?

Disintegration time (DT) of different types of tablets is as follows.

Types of tabletsDisintegration time (DT)
Uncoated15 minutes
Plain coated tablet60 minutes
Enteric coated tablet3 hours
Dispersible tablet3 minutes
Effervescent tablet˂ 3 minutes
Sublingual tablet4 hours
Buccal tablet4 hours
Vaginal tablet60 minutes
Chewable tabletnot required

33. What are the types of hardness testers?

Manual hardness tester

Monsanto tester

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Pfizer tester

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Strong-cobb

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Automatic hardness testers

Erweka tester

Dr. Schleuniger tester

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34. Which instruments are used for testing tablet dimension?

A. Vernier caliper

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1. Outside jaws: used to measure external length

2. Inside jaws: used to measure internal length

3. Depth probe: used to measure depth

4. Main scale (cm)

5. Main scale (inch)

6. Vernier (cm)

7. Vernier (inch)

8. Retainer: used to block/release movable part

B. Micrometer screw gauge

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35. Which instruments are used for testing of tablet friability?

Roche friabilator is used for testing of tablet friability.

36. Explain the construction of tablet friability tester, testing process and limit.

i. Plastic chamber that revolves at 25 rpm

ii. For testing it operates for 100 revolutions

iii. Dropping the tablets from a Distance of 6 inches in the tester

iv. The tablets are weighed before and after rotation. De-dust tablets after rotation. Perform calculation in percentage weight loss.

v. Limit of friability testing is NMT 1.0 %

37. What is Disintegration Time (DT) Test?

Disintegration time is time taken to break down the tablets into granules or primary powder particles.

38. Explain the tablet disintegration tester parts.

i. Basket rack assembly

ii. A suitable vessel for the immersion liquid

iii. Heater for fluid heating between 35°C and 39°C

iv. Basket in the immersion in fluid at frequency rate between 28 and 32 cpm (Cycle per minute)

v. Distance of up and down not less than 5 cm and not more than 6 cm

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39. What are the common tablet defects at compression stage?

Weight variation

High friability

High or low hardness (resistance to crushing)

Sticking

Picking

Capping

Laminating

Chipping

Mottling

Double press or impression

Cracking

Binding

Edging or Flashing of tablet

Disintegration time abnormality

Black Spot/ particles/ fiber

Improper embossing or debossing

Layer separation

Improper Layers

40. What are the different types of tablet coating defects?

Blistering

Chipping

Cratering

Sticking or Picking

Pitting

Blooming

Blushing

Color Variation

Infilling

Orange Peel or Roughness

Cracking or Splitting

Twinning Erosion

Bridging

41. Definitions of tablet defects at compression stage.

Weight variation: Individual weight of tablet outside of the accepted criteria.

High friability: The condition of tablets being friable. The tendency of tablets to break into smaller pieces or weight loss of powder from the surface of the tablets due to mechanical action such as transportation conditions. When percentage loss is more than 1%, it is considered as high friability.

To view images of tablet defects and to download high resolution poster, CLICK HERE

High or low hardness (resistance to crushing): Individual hardness of tablets is outside the accepted limit (upper limit or lower limit). Hardness limits are determined during the development phase of the product.

Sticking: Sticking is a defect of the tablet wherein the portion tablet surface sticks to the face of the punch or to the die wall during tablet compression activity.

Picking: Picking is a counter part of the sticking. When part of the tablet surface sticks to the punch or to the die wall, the produced tablets are with a pitted surface instead of a smooth surface.

Capping: Capping (or splitting) is a term used to describe the partial or complete separation of the upper or lower segment of the tablet horizontally from the main body of a tablet during ejection from the tablet press.

Laminating: Laminating of tablets means separation of a tablet into two or more different parallel layers.

Chipping: Chipping of tablets is the breaking of tablet edges during manufacturing or handling.

Mottling: Mottling of tablet refers to unequal or nonuniform distribution of color on the tablet surface.

Double press or impression: Double impression is a tablet defect where an embossing or break or score line appears two times on the tablet surface.

Cracking: Cracking of tablets means small fine cracks on the upper and lower central surface of the tablets and sometimes seen on the side wall.

Binding: The term binding is used when tablets stick to the die and do not eject properly out of the die.

Edging or Flashing of tablet: Edging or Flashing means observation of burrs or sharp edges on the edges of tablet.

Disintegration time abnormality – Too fast or too slow disintegration of tablets.

Black Spot/ particles/ fiber – Observation of black spot or particles or fiber which could be indigenous or foreign matter or contaminant.

Improper embossing or debossing: The defect because of improper embossing or debossing of letter, logo or monogram.

Layer separation: Layer separation is the defect of a tablet where layers of tablet get separated. This is usually seen in tablets such as bilayer tablets.

Improper Layers: Improper Layers mainly appear in layered tablets such as bilayer tablets. In this type of defect, the layer does not distinguish sharply.

42. What are the different types of tablet coating defects?

Blistering: Blistering means blistering of a surface film appears when film becomes detached from the tablet’s substrate.

Chipping: Chipping means dented and chipped film mostly on the edges of the tablet.

Cratering: Cratering means volcanic-like cratering happens exposing the tablet surface.

Sticking or Picking: Sticking or picking means sticking of film with each other or with the coating pan resulting in some of the tablet pieces being detached from the core.

Pitting: Pitting is the deformation of the core of the tablet without any visible signs of disruption of the film coating.

Blooming: Blooming is the fading or dulling of a tablet color after it is stored for a prolonged period at a high temperature.

Blushing: Blushing is described as the appearance of white specks or a haziness in the film.

Color Variation: Color variation of tablet film.

Infilling: This refers to the filling of intagliations – i.e., the distinctive words or symbols formed on the tablet.

Orange Peel or Roughness: When film having a rough surface or having a matt surface rather than glossy texture. It appears the same as an orange.

Cracking or Splitting: The cracking defect is observed when the film coating of the tablet cracks in the crown area or splits around the edges.

Twinning: Twinning is when two tablets stick together.

Erosion: Coating gets removed from the surface due to friction between tablets.

Bridging: When coating material fills in the logo or letter, bridging occurs.

43. Explain the remediation for various types of tablet defects.

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44. What are the different sizes of hard gelatin capsules?

The capsule sizes are 000, 00, 0, 1, 2, 3, 4, and 5 from the largest to the smallest. There are few special sizes of capsules available such as 2el, 1el, 0el, 0el+, 0xel, 00el etc. Details are tabulated below.

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45. What are the US Mesh size and corresponding micron, mm and inch for commonly used sieves, provide a few examples?

U.S. MeshMicronsInchesMillimeters
367300.26506.730
447600.18794.760
540000.15704.000
633600.13203.360
728300.11102.830
823800.09372.380
1020000.07872.000
1216800.06611.680
1414100.05551.410
1611900.04691.190
1810000.03941.000
208400.03110.841
257070.02800.707
305950.02320.595
355000.01970.500
404000.01650.400
453540.01380.354
502970.01170.297
602500.00980.250
702100.00830.210
801770.0070.177
1001490.00590.149
1201250.00490.125
1401050.00410.105
170880.00350.088
200740.00290.074
230630.00240.063
270530.00210.053
325440.00170.044
400370.00150.037
450320.00130.032
500250.00100.025
550250.00090.023
635200.00080.020
800150.00060.015
1250100.00040.010

Reference: ASTM E11

46. Give examples of sieve size and corresponding number of Apertures per Linear inch.

Sr. No.Sieve SizeNumber of Apertures per Linear Inch
110 #9-11
212#11-13
314#13-15
416#15-17
520#19-21
624#23-25
730#28-32
840#38-42
960#57-63
1080#77-83
11100#97-103

47. What is the aperture size of the screen?

The size of a square opening (length of clear space between individual wires) is called the aperture size of the screen.

48. What is the Mesh number of screens?

Mesh number of screens is defined as the number of aperture or opening per linear inch of the screen.  E.g. A screen having 10 square openings per inch is said to have Mesh no. 10. Higher the mesh number, smaller the aperture size of the screen.

49. What is the broad classification of Granulation techniques?

Granulation technique is broadly classified into two types as follows:

(i) Dry granulation

a. Slugging technique

b. Roller compaction

c. Pneumatic dry granulation

(ii) Wet granulation

a. Steam granulation

b. Reverse wet granulation

c. Moisture-Activated Dry Granulation

d. Thermal adhesion granulation

e. Melt granulation

f. Freeze granulation

g. Foam granulation

50. What are the equipment used during the Wet Granulation Process?

Depending on process, batch size and type of process steps, following equipment are used during the Wet Granulation Process.

Low Shear mixer/ granulator

High Shear mixer/ granulator OR Rapid Mixture granulator

Fluid-Bed granulator/ dryer,

Spray Dryer,

Extruders and Spheronizer

Vibratory sifter

Cutting mills such as Multimill, Co-mill, Pin Mill etc.

Hammer mill

51. What are the equipment used during the Dry Granulation Process?

Depending on process, batch size and type of process steps, following equipment are used during the Dry Granulation Process.

Role com

Low Shear mixer/ granulator

High Shear mixer/ granulator OR Rapid Mixture granulator

Vibratory sifter

Cutting mills such as Multimill, Co-mill, Pin Mill etc.

Roller Compactor Granulator

Compression machine to generate slugs

52. What is the most commonly used testing method to determine powder flow?

There are four commonly used methods for testing powder flow:

(1) Angle of repose

(2) Compressibility index or Hausner ratio

(3) Flow rate through an orifice

(4) Shear cell

Reference: General Chapters: <1174> POWDER FLOW

53. What is Angle of Repose?

Definition of Angle of Repose: The angle of repose is a relatively simple technique for estimating the flow properties of a powder. It is determined by allowing a powder to flow through a funnel and fall freely onto a fixed diameter base. The height and diameter of the resulting cone are measured. For further reading on Angle of Repose and download free excel, click on this link.

54. What is the Compressibility index and what is Hausner Ratio?

Definition of Compressibility index: The Compressibility Index (Carr Compressibility Index) is a measure of the tendency of a powder to be compressed. It is a measure of the powder’s ability to settle, and it permits an assessment of the relative importance of interparticulate interactions.

Definition of Hausner Ratio: The Hausner Ratio is measures that can be used to predict the tendency of a given powder sample to be compressed. Hausner Ratio reflects the importance of interparticulate interactions.

For further reading of Simple methods to determine powder flow property -Angle of repose, Compressibility index and Hausner ratio CLICK on this link. Also get a FREE Excel sheet for calculation.

55. What is the disintegration time of Chewable Tablets?

Disintegration time test is not applicable for chewable tablets.

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

100 Revolutions / 4 Minutes, 25 rotations per minute

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

Fall height of the tablets is in the friabilator is 154.0 – 158.0 mm (156.0 ± 2.0 mm)

58. Which capsule is bigger in size – size ‘0’ or size ‘1’?

‘0’ size

59. How many tablets shall be taken for checking friability?

6.5 g for the tablets with unit mass equal or less than 650 mg. For tablets with unit mass more than 650 mg, it requires 10 tablets.

60. What is the mesh aperture of DT apparatus?

Mesh aperture of DT apparatus is #10. That is 1.8 -2.2 mm.

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

28 – 32 cycles/minute

62. What are the parameters tested during the calibrating DT apparatus?

Parameters covered during the DT apparatus calibration are as follows

(1) Number of strokes per minute (Limit: 29-32 cycles/min)

(2) Temperature by probe and standard thermometer (Limit: 37 ± 1 °C). (3) Distance travelled by basket (Limit: 53 -57 mm)

63. What is the Disintegration time for different types of tablets?

Type of TabletsDisintegration time
Uncoated Tablets15 minutes
Film-coated30 minutes
Other coated tablets60 minutes
Enteric-coated Tablets 
0.1M hydrochloric acidShould not disintegrate in 120 minutes
Phosphate buffer pH 6.8,60 minutes.
Dispersible and Soluble Tabletswithin 3 minutes
Effervescent Tablets5 minutes
Chewable tabletsNot applicable

64. What are the different clean room conditions? Explain it.

There are three conditions of clean rooms – as built, at rest and in-operation.

As built:

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Condition where the installation is complete with all services connected and functioning but with no production equipment, materials, or personnel present.

At rest:

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Condition where the installation is complete with equipment installed and operating in a manner agreed upon by the customer and supplier, but with no personnel present.

In operational:

This condition relates to carrying out room  classification tests with the normal production process with equipment in operation, and the normal staff present in the room.

Reference: WHO Working document QAS/02.048/Rev.2

65. What are the different types of air locks? Explain it.

There are three types of air locks, Cascade airlock, Sink airlock and Bubble airlock.

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Cascade airlock: high pressure on one side of the airlock and low pressure on the other side.

Bubble Airlock: high pressure inside the airlock and low pressure on both outer sides.

Sink Airlock: low pressure inside the airlock and high pressure on both outer sides.

Reference: WHO Working document QAS/02.048/Rev.2

66. What should be the differential pressure between two adjacent clean room zones?

The most widely accepted pressure differential to achieve containment between the two adjacent zones is 15 Pa, but pressure differentials of between 5 Pa and 20 Pa could be acceptable.

Where the design pressure differential is too low and tolerances are at opposite extremities, a flow reversal can take place. E.g. where a control tolerance of ±3 Pa is specified, the implications of the upper and lower tolerances on containment should be evaluated.

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67. Comparison of pascals to mm of water?

Pascals to Millimeters of water formula

mm H2O =Pa * 0.10197

Pascals (Pa)

Millimeters of water (mm H2O)

PascalsMillimeters of waterPascalsMillimeters of waterPascalsMillimeters of water
1Pa0.10mm H2O16Pa1.63mm H2O31Pa3.16mm H2O
2Pa0.20mm H2O17Pa1.73mm H2O32Pa3.26mm H2O
3Pa0.31mm H2O18Pa1.84mm H2O33Pa3.37mm H2O
4Pa0.41mm H2O19Pa1.94mm H2O34Pa3.47mm H2O
5Pa0.51mm H2O20Pa2.04mm H2O35Pa3.57mm H2O
6Pa0.61mm H2O21Pa2.14mm H2O36Pa3.67mm H2O
7Pa0.71mm H2O22Pa2.24mm H2O37Pa3.77mm H2O
8Pa0.82mm H2O23Pa2.35mm H2O38Pa3.87mm H2O
9Pa0.92mm H2O24Pa2.45mm H2O39Pa3.98mm H2O
10Pa1.02mm H2O25Pa2.55mm H2O40Pa4.08mm H2O
11Pa1.12mm H2O26Pa2.65mm H2O41Pa4.18mm H2O
12Pa1.22mm H2O27Pa2.75mm H2O42Pa4.28mm H2O
13Pa1.33mm H2O28Pa2.86mm H2O43Pa4.38mm H2O
14Pa1.43mm H2O29Pa2.96mm H2O44Pa4.49mm H2O
15Pa1.53mm H2O30Pa3.06mm H2O45Pa4.59mm H2O

68. What is the difference between disintegration and dissolution?

Disintegration is a process of breaking down of granules into small fragments.

Dissolution is the process in which a substance goes into a solution. It is a measure of bioavailability and therapeutic effectiveness. Dissolution is also called drug release.

69. What is the purpose of maintaining pressure gradients between processing areas and service corridors?

Pressure gradients are maintained to avoid cross contamination of products through air.

70. In oral solid manufacturing facility ‘positive’ pressure is maintained in processing area or in service corridors?

Positive pressure is maintained in service corridors with respect to processing rooms.

71. What should be the characteristic of  Finger Bags used for Fluid Bed Dryer (FBD) or Fluid Bed Processor (FBP)?

Antistatic

Waterproof cloth

Able to handle granulation of highly viscous materials, such as extract powder

Non-stick cloth bag

Good permeability

Good boiling effect

Cost-efficient and durable

72. What is generally used material of construction of Finger Bags used for Fluid Bed Dryer (FBD) or Fluid Bed Processor (FBP)

Finger bags are constructed by a combination of Antistatic polymer, Nylon fabric and Cotton fabric. Following materials are also used for Finger bags’ construction.

Antistatic

Epitropic

Polypropylene

Polyester

Stain

73. What are the typically seen micron ratings of Finger Bags used for Fluid Bed Dryer (FBD) or Fluid Bed Processor (FBP)?

Micron Rating: 1, 5, 10, 15, 25, 50, 100

74. What is the formula for calculating friability test results?

Friability (%) = Weight 1 – Weight 2 / Weight 1 X 100

Where,

Weight 1 = Weight of Tablets (Initial / Before Tumbling) & Weight 2 = Weight of Tablets (After Tumbling or friability)

75. What is the limit of friability test results?

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

76. What is Rheology?

Rheology (Greek words rheos meaning flow and logos meaning science) is the study of the flow under the influence of stress. The principle can be applied to solids, liquids, and gases.

77. Explain the types of excipients.

Organoleptic

o Color

o Flavor

o Sweetener

Stabilizers

o Preservative

o Antioxidant

o Emulsifier

o Suspending Agent

Dose Accuracy

o Diluent

o Bulking agent

o Filler

Process Aids

o Binder

o Lubricant

o Glidant

o Anti-adherent

Drug release

o Disintigrant

o Penetration enhancer

o Coating agent

78 What are the types of tablets? Or Classification of Tablets.

Classification of tablets by route of administration

Oral tablets for ingestion

Implantation tablets

Chewable tablets

Tablets used in the oral cavity

Buccal and sublingual tablets

Dental cones

Vaginal tablets

Tablets used to prepare solutions

Effervescent tablets

Dispensing tablets (DT)

Hypodermic tablets (HT)

Tablet triturates (TT)

Troches and lozenges

Classification of tablets by manufacturing process

Compressed tablets

Layered tablets

Sugar coated tablets

Film-coated tablets

Classification of tablets by onset of action

Immediate release tablets

Repeat-action tablets

Delayed-action and enteric coated tablets Controlled release tablets

79. What are the various types of tablets?

Following are various types of tablets.

  • Compressed Tablet (CT)
  • Sugar-Coated Tablets (SCT)
  • Film-Coated Tablets (FCT)
  • Enteric-Coated Tablets (ECT)
  • Multiple Compressed Tablets (MCT)
  • Layered Tablets
  • Press-Coated Tablets
  • Controlled-Release Tablets (CRT)
  • Tablets for Solution (CTS)
  • Effervescent Tablets
  • Compressed Suppositories or Inserts
  • Buccal and Sublingual Tablets
  • Molded Tablets or Tablet Triturates (TT)
  • Dispensing Tablets (DT)
  • Hypodermic Tablets (BT)
  • Compressed Tablets (CT)

80. What are the ingredients used to formulate or manufacture the various types of tablets?

Following are ingredients used to formulate or manufacture the various types of tablets.

  • Active pharmaceutical ingredient
  • Diluents
  • Binders
  • Lubricants
  • Glidants
  • Disintegrants
  • Coloring Agents
  • Flavoring Agents

81. Explain parts of the compression machine.

  • Machine Hopper
  • Feeder System (force feeder/ gravity feeder)
    • Feeder housing
    • Feed pedals
  •  Punches System
    • Upper punch system
    • Lower punch system
  • Die System
  • Turret
  • Machine Cam Tracks
  • Powder Filling Station and Weight Control
  • Compression Rollers (Pre-compression, main-compression)
  • Tablet Press Ejection Cam
  • Take –off blade
  • Discharge Chute
  • Touch Screen Control Panel (HMI/ MMI)
  • Electric Motors, Gears and Belts
  • Lubrication Systems

82. What are the types of tablet press or compression machines?

Broadly, we there are two main types of tableting machines:

  • Single-station tablet press or compression
  • Multi-station tablet press or compression
    • Single rotary machine
    • Double rotary machine

83. What are the types of tablet Coating Machines available in the market?

• Standard Coating Pan

• Perforated Coating Pan

• Fluidized Bed Coater

84. What are the advantages of the tablet coating process?

Following are the advantages of tablet coating:

• It enhances its appearance

• Easy to consume

• Minimizes the unpleasant colour, odour or taste of drug

• Identification

• Helps to reduces drug degradation by protecting it from environmental factors

• Facilitates the packing process

• Functional coating gives functional advantages like extended release, enteric release, prolonged release etc.

85. What are the disadvantages of the tablet coating process?

Following are the disadvantages of tablet coating:

• Cost of operation, resources and material

• Equipment operation and maintenance cost

• May change tablet properties

• Residual solvent toxicity

• Waiting time between processes

• Increase process lead time

• Increase analysis load

86. Explain parts of tablet coating equipment or machine.

Following are the parts of tablet coating equipment or machine

• Perforated coating pan

• Baffles in coating pan

• Spray gun

• Spray pump e.g. Peristalsis pump, Diaphragm pump

• Electric Motors

• Air Handling unit for inlet air

o Inlet air blower

o Air Handling unit housing

o Primary filter (Washable)

o High temperature HEPA filter

o Inlet air temperature sensor

o Differential air pressure sensors across the above filters

• Ducting to supply air and exhaust air

• Control panel with PLC Control and HMI

• Exhaust air blower

• Dust collector or air Scrubber (Wet or Dry)

• Solution preparation tank

87. Explain parts of Fluid bed dryer and Fluid bed processor?

Following are the parts of Fluid bed dryer and Fluid bed equipment

• Plenum

• Product Container with PU wheel trolley

• Inflatable gasket for connection between plenum and Product Container, and Product Container and expansion chamber

• Product temperature sensor

• Inlet air temperature and RH sensor

• Damper for inlet air

• Sample collection port in Product Container

• Glass view in Product Container

• Silicon molded Dutch Woven sieves

• Conidur mesh for mechanism of vortex formation

• Expansion chamber

• Glass view in Expansion chamber

• Finger bag

• Finger bag mounting assembly

• Finger bag shaking assembly

• Inflatable gasket to seal finger bag assembly

• Broken Bag Detector (BBD) sensor OR Solid Flow Monitor (SFM) sensor

• Exhaust blower

• Exhaust filters (10 and 3 µm porosity)

• Explosion flap and Explosion port

• Inlet Air Handling Unit

o Air Handling unit housing

o Primary filter (Washable)

o High temperature HEPA filter

o Dew point sensor

o Differential air pressure sensors across the above filters

o Damper

• CFM or Air flow sensor

• Inlet air duct

• Clean in place system

• Differential pressure sensors, across filters, across finger bag, across product container

• Exhaust air temperature

• Spraying system (for top spray granulation)

88. What is a Tablet Deduster?

Deduster is an equipment used in the pharmaceutical and nutraceutical industry to remove surface dust from the tablets.

89. What are different types of tablet Deduster?

  • Rotary Vibrating Deduster
  • Uphill Deduster
  • Brush Type Deduster
  • Horizontal Deduster
  • Vertical Deduster
    i. Vertical Downward Conveying Deduster
    ii. Vertical Upward Conveying Deduster

90. Explain in detail about different types of Tablet Deduster.

There are different types of tablet dedusters. Each has its advantages and disadvantages.

a. Rotary Vibrating Tablet Deduster

Rotary Vibrating Tablet Deduster depends on rotation and vibration principles.

It has a vibrated helical path with a perforated sieve. As the tablets vibrate and spin along the helical path with a perforated plate, burrs and dust are wiped from their surface. A dust extraction mechanism extracts the dust and the tablets drop into the collection container.

b. Uphill Tablet Deduster

Uphill tablet Dedusting machine depends on the vibration that removes burr and dust as it elevates the tablets. The deduster elevates and dedusts concurrently.

c. Brush Type Tablet Deduster

It consists of a helically wound brush installed within a stainless steel tube (same as screw conveyor) steered by an adjustable speed motor.

The brush pushes the tablets across the tube till they get to the discharge of the deduster at the top or end.

d. Horizontal Tablet Deduster

These types of tablet dedusters use perforated tubes or perforated stainless steel plates that vibrate from one side to another. It is horizontal but slants downwards that the tablets fall as the vibration conveys them over a distance of around 1 meter.

e. Vertical Tablet Deduster

Vertical tablet dedusters are of two types, Downward Conveying Tablet Dedusters and Upward Conveying Tablet Dedusters. The working principle of both types of dedusters are similar.

The dedusters rely on spiral punctured trays on an anchored central column.

91. Which Material is used to make Tablet Dedusters?

Stainless Steel: Stainless steel forms the largest portion of tablet dedusters.

Acrylic: To make the windows.

92. Which Quality Standards should a Tablet Deduster Comply with?

a. Current good manufacturing practices (cGMP) quality standards

b. ISO certification quality standards

c. CCC compliant

d. CE certification

93. How do you select the tablet deduster?

a. Height of compression machine and containers

b. Tablet Size

c. Output

d. Tablet Hardness and Features of Dust

e. Inclusion of Extra Components such as metal detector

94. Explain parts of multimill?

Material Charging Hopper: To load the material to be milled

Milling chamber: Milling of material happens within the chamber with the help of Cutting blades and desired size of particles are passed through specific size screen

Discharge port: Milled material is discharged from this part

Castor wheels: To move the mill from one place to another place

Operating Panel: To operate the equipment

Screen: To produce desired particle size

Cutting blades: To mill the material

95. What is the Material Of Construction (MOC) of multimill parts?

Product contact parts are made up of SS 316 or SS316L

Non-product contact parts are made up of SS 304 Castor wheels are made up of Polyurethane

96. What is the mechanism of size reduction when using multimill?

a. Impact Milling: Particles are reduced in size by high-speed mechanical impact or impact with other particles; also known as milling, pulverizing, or comminuting.

b. Cutting: Particles are reduced in size by mechanical shearing.

c. Screening: Particles are reduced in size by mechanically induced attrition through a screen. This process commonly is referred to as milling or deagglomeration.

97. What are the typical speeds of multimill?

Fast speed: 2880

Medium fast speed: 2160

Medium speed: 1440

Low speed: 720

Note: Nowadays multimill are available with variable frequency drive where speed can be set as per the requirement (Custom speed).

98. What are the typical settings for milling operation using multimill?

Blade direction: Impact forward or Knife forward

Machine speed: Using V belt adjustment or using VFD as per machine design

99. What is Vibro sifter?

Vibro sifter is equipment used for separating particles based upon particle size alone and without any significant particle size reduction. This process commonly is referred to as screening or bolting. Vibration and Gyratory motion plays an important role to facilitate the screening process.

100. What is the principle of Vibro sifter?

Vibro sifters work on the principle of separation. Particles are segregated based upon particle size alone and without any significant particle size reduction. This process commonly is referred to as screening or bolting. Vibration and Gyratory motion plays an important role to facilitate the screening process.

The mechanism on which Vibro Sifter works is the principle of gyratory vibrations. The material is separated based on its particle size. Once the motor gets energized, vibration is caused in the screen/. This makes material travel across the sieves according to its particle size and sieve/ screen size.

Separator subclasses as per SUPAC: Vibratory/ Shaker and Centrifugal.

101. What is the gyratory motion of a vibro sifter and how does it get generated?

In the vibro sifter gyratory motion is obtained from a specially designed gyro motor, which is fitted underneath the vibrating assembly. A specially designed rugged spring completely isolates this assembly from the base with the help of Gyro-motor.

The motor is fitted with eccentric weights present at its top as well as base to create centrifugal force. This whole assembly is covered by an SS plate.

102. What are other names of vibro sifters?

The vibro sifter machine is also known as:

Vibro Screen

Vibrating Screen

Lab Vibro Sifter

Pharmaceutical Sifter

Vibro Sieve

Vibro Sifter Machine

Powder Sieving Machine

103. What are the salient features or use of vibro sifter?

• Gradation and separation of dry powder, granules, semi solids and liquids

• Main functioning mechanical arrangement is suspended on a spring to prevent vibration on the floor

• Easy assembling and disabling

• Easy to clean

104. What are different parts of vibro sifter?

• Dust cover

• Clamp for assembling of different parts

• Inlet

• Sieve/ screen

• Vibrating motor for Gyratory motion with eccentrically arranged top and bottom hammer

• Caster wheel

• Discharge port

• Spring

105. How to discharge the static electricity which may get generated over the vibro sifter sieve when silicone bonded sieve is used?

Following are the solutions to discharge the static electricity which may get generated over the vibro sifter sieve when silicone bonded screen is used:

i. Using antistatic screen

ii. Use C clamp over the silicone bonded sieve which makes the entire assembly conductive and to provide earthing to the body of the equipment.

106. What is a solution preparation vessel?

The solution preparation vessel is a closed tank used to prepare solution at room temperature or elevated temperature by using electrical heating or steam heating. To mix the solution homogeneously, it consists of stirring to create a vortex inside the solution.

107. What is the use of solution preparation vessels in the pharmaceutical industry?

The solution preparation vessel is used to prepare various types of solutions such as binder solution, coating solution, heating of water, liquid preparations such as syrup, suspension, solutions, etc. The vessel is used to ensure a homogeneous mix.

108. Explain parts of solution preparation vessel and Material of Construction (MOC)?

• Tank – SS316 or SS316L

• Stirrer – SS316 or SS316L

• Thermal Insulation

• Motor

• Variable Frequency Drive

• Control Panel

• Pressure gauge for jacket

• Temperature sensor – Product contact part SS316 or SS316 L

• Discharge valve (Zero dead leg and sanitary type)(Note: Ball valve is not acceptable) – SS316 or SS316L

• Caster wheel for movement (Need based) – Polyurethane

109. What is vortex and how is it helpful for solution preparation?

A circular, spiral, or helical motion in a fluid. A vortex often forms around areas of low pressure and attracts the fluid (and the objects moving within it) toward its center.

Velocity in the vortex is maximum next to the axis and inversely decreases with the radius.

Vortex enhances the desired solubility of pharmaceutical binder solute into the various solvents.

110. What should be characteristics of the solution preparation vessel?

• Zero dead leg and sanitary design components

• Stationary or mobile use

• Capable to handle wide temperature range (design as per requirement)

• The Internal surfaces of our preparation vessels are flush ground and mirror polished to <0.3 Microns Ra and electro-polished

• Easy to clean

• Adjustable speed of stirrer

• Adjustable temperature

• 21 CFR Part 11 compliant and EU Annex 11 Compliant

• Low maintenance and long service

111. What are the different particle size reduction mechanisms?

Particle size reduction mechanismsDescription
ImpactParticle size reduction by applying an instantaneous force perpendicular to the particle/ agglomerate surface. The force can result from particle-to-particle or particle-to-mill surface collision.
AttritionParticle size reduction by applying a force in a direction parallel to the particle surface.
CompressionParticle size reduction by applying a force slowly (as compared to Impact) to the particle surface in a direction toward the center of the particle.
CuttingParticle size reduction by applying a shearing force to a material.

112. What are the types of Equipment used for Particle Size Reduction/ Separation. Explain its Operating Principles.

Types of EquipmentOperating Principles
Fluid Energy MillingParticles are reduced in size as a result of high-speed particle-to-particle impact and/or attrition; also known as micronizing.
Impact MillingParticles are reduced in size by high-speed mechanical impact or impact with other particles; also known as milling, pulverizing, or comminuting.
CuttingParticles are reduced in size by mechanical shearing.
Compression MillingParticles are reduced in size by compression stress and shear between two surfaces.
ScreeningParticles are reduced in size by mechanically induced attrition through a screen. This process commonly is referred to as milling or deagglomeration.
Tumble MillingParticles are reduced in size by attrition utilizing grinding media.
SeparatingParticles are segregated based upon particle size alone and without any significant particle size reduction. This process commonly is referred to as screening or bolting.

113. Explain Equipment Classifications for Particle Size Reduction/ Separation. Give examples of Equipment for each classification.

Equipment typeSub classification descriptionSub classification
Fluid Energy MillsFluid energy mill subclasses have no moving parts and primarily are distinguished from one another by the configuration and/ or shape of their chambers, nozzles, and classifiers.Tangential Jet Loop/ Oval Opposed Jet Opposed Jet with Dynamic Classifier Fluidized Bed Fixed Target Moving Target High Pressure Homogenizer   E.g. Jet mill
Impact MillsImpact mill subclasses primarily are distinguished from one another by the configuration of the grinding heads, chamber grinding liners (if any), and classifiers.Hammer Air Swept Hammer Conventional Pin/ Disc Cage  E.g. Hammer millPin mill Impact millCage millDisk millBall mill
Cutting MillsAlthough cutting mills may differ from one another in whether the knives are movable or fixed and in the classifier configuration, no cutting mill subclasses have been identified.No sub class  E.g. MultimillComill
Compression MillsAlthough compression mills may differ from one another in whether one or both surfaces are moving, no compression mill subclasses have been identified.No sub class  E.g. Roller mill
Screening MillsScreening mill subclasses primarily are distinguished from one another by the rotating element.Rotating Impeller Rotating Screen Oscillating Bar  E.g. MultimillComill
Tumbling MillsTumbling mill subclasses primarily are distinguished from one another by the grinding media used and by whether the mill is vibrated.Ball Media Rod Media Vibrating  E.g. Ball millTubular Rod Mills
SeparatorsSeparator subclasses primarily are distinguished from one another by the mechanical means used to induce particle movement.  Vibratory/ Shaker Centrifugal  E.g. Vibro sifterUltra Centrifugal Mill

Source: fda.gov

114. What is Blending and Mixing?

Blending and Mixing is the process of reorientation of particles relative to one another in order to achieve uniformity.

115. What are the Operating Principles of different equipment for Blending and Mixing?

Types of EquipmentOperating Principles
Diffusion Blending (Tumble blending)Particles are reoriented in relation to one another when they are placed in random motion and interparticular friction is reduced as the result of bed expansion (usually within a rotating container).
Convection Mixing (also known as paddle or plow mixing)Particles are reoriented in relation to one another as a result of mechanical movement.
Pneumatic MixingParticles are reoriented in relation to one another as a result of the expansion of a powder bed by gas.

116. Equipment Classifications used for Blending and Mixing

Equipment typeSub classification descriptionSub classification
Diffusion Mixers (Tumble)Diffusion mixer subclasses primarily are distinguished by geometric shape and the positioning of the axis of rotation.• V-blenders• Double Cone Blenders• Slant Cone Blenders• Cube Blenders• Bin Blenders• Horizontal/ Vertical/ Drum Blenders• Static Continuous Blenders• Dynamic Continuous Blenders
Convection Mixers  Convection blender subclasses primarily are distinguished by vessel shape and impeller geometry.• Ribbon Blenders• Orbiting Screw Blenders• Planetary Blenders• Forberg Blenders• Horizontal Double Arm Blenders• Horizontal High Intensity Mixers• Vertical High Intensity Mixers• Diffusion Mixers (Tumble) with Intensifier/Agitator
Pneumatic Mixers  Although pneumatic mixers may differ from one another in vessel geometry, air nozzle type, and air nozzle configuration, no pneumatic mixer subclasses have been identified.No sub lass

Source: fda.gov

117. What is Granulation

Granulation is the process of creating granules. The powder morphology is modified through the use of either a liquid that causes particles to bind through capillary forces or dry compaction forces.

The process will result in one or more of the following powder properties:

Enhanced flow;

Increased compressibility;

Densification;

Alteration of physical appearance to more spherical, uniform, or larger particles;

And/or enhanced hydrophilic surface properties.

118. What are the Operating Principles of different Granulation?

Types of GranulationOperating Principles
Dry GranulationDry powder densification and/or agglomeration by direct physical compaction.
Wet High-Shear GranulationPowder densification and/or agglomeration by the incorporation of a granulation fluid into the powder with high-power-per-unit mass, through rotating high-shear forces.
Wet Low-Shear GranulationPowder densification and/or agglomeration by the incorporation of a granulation fluid into the powder with low-power-per-unit mass, through rotating low-shear forces.
Low-Shear Tumble GranulationPowder densification and/or agglomeration by the incorporation of a granulation fluid into the powder with low-power-per-unit mass, through rotation of the container vessel and/or intensifier bar.
Extrusion GranulationPlasticization of solids or wetted mass of solids and granulation fluid with linear shear through a sized orifice using a pressure gradient.
Rotary GranulationSpheronization, agglomeration, and/or densification of a wetted or non-wetted powder or extruded material.   This is accomplished by centrifugal or rotational forces from a central rotating disk, rotating walls, or both. The process may include the incorporation and/or drying of a granulation fluid.
Fluid Bed GranulationPowder densification and/or agglomeration with little or no shear by direct granulation fluid atomization and impingement on solids, while suspended by a controlled gas stream, with simultaneous drying.
Spray Dry GranulationA pumpable granulating liquid containing solids (in solution or suspension) is atomized in a drying chamber and rapidly dried by a controlled gas stream, producing a dry powder.
Hot-melt GranulationAn agglomeration process that utilizes a molten liquid as a binder(s) or granulation matrix in which the active pharmaceutical ingredient (API) is mixed and then cooled down followed by milling into powder. This is usually accomplished in a temperature controlled jacketed high shear granulating tank or using a heated nozzle that sprays the molten binders(s) onto the fluidizing bed of the API and other inactive ingredients.
Melt ExtrusionA process that involves melting and mixing API and an excipient (generally a polymer) using low or high shear kneading screws followed by cooling and then milling into granules. Thermal energy for melting is usually supplied by the electric/water heater placed on the barrel. Materials are either premixed or fed into an extruder separately. Melt extruder subclasses primarily are distinguished by the configuration of the screw. • Single screw extruder • Twin screw extruder

119. Equipment Classifications used for granulation.

Equipment typeSub classification descriptionSub classification
Dry GranulatorDry granulator subclasses primarily are distinguished by the densification force application mechanism.• Slugging • Roller Compaction
Wet High-Shear GranulatorWet high-shear granulator subclasses primarily are distinguished by the geometric positioning of the primary impellers; impellers can be top, bottom, or side driven.• Vertical (Top or Bottom Driven) • Horizontal (Side Driven)
Wet Low-Shear GranulatorWet low-shear granulator subclasses primarily are distinguished by the geometry and design of the shear inducing components; shear can be induced by rotating impeller, reciprocal kneading action, or convection screw action.• Planetary • Kneading • Screw
Low-Shear Tumble GranulatorAlthough low-shear tumble granulators may differ from one another in vessel geometry and type of dispersion or intensifier bar, no low-shear tumble granulator subclasses have been identified.• Slant cone • Double cone • V-blender
Extrusion GranulatorExtrusion granulator subclasses primarily are distinguished by the orientation of extrusion surfaces and driving pressure production mechanism.• Radial or Basket • Axial • Ram • Roller, Gear, or Pelletizer
Rotary GranulatorRotary granulator subclasses primarily are distinguished by their structural architecture. They have either open top architecture, such as a vertical centrifugal spheronizer, or closed top architecture, such as a closed top fluid bed dryer.• Open • Closed
Fluid Bed GranulatorAlthough fluid bed granulators may differ from one another in geometry, operating pressures, and other conditions, no fluid bed granulator subclasses have been identified.No subclass
Spray Dry GranulatorAlthough spray dry granulators may differ from one another in geometry, operating pressures, and other conditions, no spray dry granulator subclasses have been identified.No subclass
Hot-melt GranulatorAlthough, hot-melt granulator may differ from one another in primarily melting the 455 inactive ingredient (particularly the binder or other polymeric matrices), no 456 subclasses have been identified at this time.No subclass

120. What is an integrated unit as per SUPAC?

When a single piece of equipment is capable of performing multiple discrete unit operations (i.e. mixing, granulating, drying), the unit was evaluated solely for its ability to granulate. If multifunctional units were incapable of discrete steps (fluid bed granulator/ drier), the unit was evaluated as an integrated unit.

Source: fda.gov

121. What is Drying?

The removal of a liquid from a solid by evaporation.

122. What are the Operating Principles of different equipment for Drying?

Types of Drying principleDetails of Principles
Direct Heating, Static Solids BedHeat transfer is accomplished by direct contact between the wet solids and hot gases. The vaporized liquid is carried away by the drying gases. There is no relative motion among solid particles. The solids bed exists as a dense bed, with the particles resting upon one another.
Direct Heating, Moving Solids BedHeat transfer is accomplished by direct contact between the wet solids and hot gases. The vaporized liquid is carried away by the drying gases. Solids motion is achieved by either mechanical agitation or gravity force, which slightly expands the bed enough to flow one particle over another.
Direct Heating, Fluidized Solids BedHeat transfer is accomplished by direct contact between the wet solids and hot gases. The vaporized liquid is carried away by the drying gases. The solids are in an expanded condition, with the particles supported by drag forces caused by the gas phase. The solids and gases intermix and behave like a boiling liquid. This process commonly is referred to as fluid bed drying.
Direct Heating, Dilute Solids Bed, Spray DryingHeat transfer is accomplished by direct contact between a highly dispersed liquid and hot gases. The feed liquid may be a solution, slurry, emulsion, gel or paste, provided it is pumpable and capable of being atomized. The fluid is dispersed as fine droplets into a moving stream of hot gases, where they evaporate rapidly before reaching the wall of the drying chamber. The vaporized liquid is carried away by the drying gases. The solids are fully expanded and so widely separated that they exert essentially no influence on one another.
Direct Heating, Dilute Solids Bed, Flash DryingHeat transfer is accomplished by direct contact between wet solids and hot gases. The solid mass is suspended in a finely divided state in a high-velocity and high-temperature gas stream. The vaporized liquid is carried away by the drying gases.
Indirect Conduction, Moving Solids BedHeat transfer to the wet solid is through a retaining wall. The vaporized liquid is removed independently from the heating medium. Solids motion is achieved by either mechanical agitation or gravity force, which slightly expands the bed enough to flow one particle over another.
Indirect Conduction, Static Solids BedHeat transfer to the wet solid is through a retaining wall. The vaporized liquid is removed independently from the heating medium. There is no relative motion among solid particles. The solid bed exists as a dense bed, with the particles resting upon one another.
Indirect Conduction, LyophilizationDrying in which the water vapor sublimes from the product after freezing.
Gas StrippingHeat transfer is a combination of direct and indirect heating. The solid motion is achieved by agitation and the bed is partially fluidized.
Indirect Radiant, Moving Solids BedHeat transfer is accomplished with varying wavelengths of energy. Vaporized liquid is removed independently from the solid bed. The solid’s motion is achieved by mechanical agitation, which slightly expands the bed enough to flow one particle over one another. This process commonly is referred to as microwave drying.

123. Equipment Classifications used for drying.

Equipment typeSub classification descriptionSub classification
Direct Heating, Static Solids BedStatic solids bed subclasses primarily are distinguished by the method of moving the solids into the dryer.• Tray and Truck • Belt
Direct Heating, Moving Solids BedMoving solids bed subclasses primarily are distinguished by the method or technology for moving the solid bed.• Rotating Tray • Horizontal Vibrating Conveyor
Direct Heating, Fluidized Solids Bed (Fluid Bed Dryer)Although fluid bed dryers may differ from one another in geometry, operating pressures, and other conditions, no fluidized solids bed dryer subclasses have been identified.No subclass
Direct Heating, Dilute Solids Bed, Spray DryerAlthough spray dryers may differ from one another in geometry, operating pressures, and other conditions, no spray dryer subclasses have been identified.No subclass
Direct Heating, Dilute Solids Bed, Flash DryerAlthough flash dryers may differ from one another in geometry, operating pressures, and other conditions, no flash dryer subclasses have been identified.No subclass
Indirect Conduction Heating, Moving Solids BedMoving solids bed subclasses primarily are distinguished by the method or technology for moving the solids bed.• Paddle • Rotary (Tumble) • Agitation
Indirect Conduction Heating, Static Solids BedsNo indirect heating, static solids bed shelf dryer subclasses have been identified.No subclass
Indirect Conduction, LyophilizationNo lyophilizer subclasses have been identified.No subclass
Gas StrippingAlthough gas stripping dryers may differ from one another in geometry, shape of agitator, and how fluidizing gas is moved through the bed, no gas stripping dryer subclasses have been identified.No subclass
Indirect Radiant Heating, Moving Solids Bed (Microwave Dryer)Although microwave dryers may differ from one another in vessel geometry and the way microwaves are directed into the solids, no indirect radiant heating, moving solids bed dryer subclasses have been identified.No subclass

Source: fda.gov

124. What is Unit Dosing?

The division of a powder blend into uniform single portions for delivery to patients.

125. What are the Operating Principles of different equipment for Unit Dosing?

Types of Unit Dosing principleDetails of Principles
TablettingThe division of a powder blend in which compression force is applied to form a single unit dose.
EncapsulatingThe division of material into a hard gelatin capsule. Encapsulators should all have the following operating principles in common: rectification (orientation of the hard gelatin capsules), separation of capsule caps from bodies, dosing of fill material/formulation, rejoining of caps and bodies, and ejection of filled capsules.
Powder FillingThe division of a powder blend into a container closure system.

126. Equipment Classifications used for Unit Dosing.

Equipment typeSub classification descriptionSub classification
Tablet PressTablet press subclasses primarily are distinguished from one another by the method that the powder blend is delivered to the die cavity. Tablet presses can deliver powders without mechanical assistance (gravity), with mechanical assistance (power assisted), by rotational forces (centrifugal), and in two different locations where a tablet core is formed and subsequently an outer layer of coating material is applied (compression coating).• Gravity• Power Assisted• Centrifugal• Compression Coating
Tablet PressTablet press subclasses are also distinguished from one another for some special types of tablets where more than one hopper and precise powder feeding mechanism might be necessary.• Multi-tablet press for micro/mini tablet • Multi-layer tablet press (bi-layer, tri-layer)
EncapsulatorEncapsulator subclasses primarily are distinguished from one another by the method that is used for introducing material into the capsule. Encapsulators can deliver materials with a rotating auger, vacuum, vibration of perforated plate, tamping into a bored disk (dosing disk), or cylindrical tubes fitted with pistons (dosator).• Auger• Vacuum• Vibratory• Dosing Disk• Dosator
Powder FillerSubclasses of powder fillers primarily are distinguished by the method used to deliver the predetermined amount for container fill.• Vacuum• Auger

Source: fda.gov

127. What is Coating?

The uniform deposition of a layer of material on or around a solid dosage form.

128. Why is the coating done?

Coating is done for the following reasons:

a. Protect the drug from its surrounding environment (air, moisture, and light), with a view to improving stability.

b. Mask unpleasant taste, odor, or color of the drug.

c. Increase the ease of ingesting the product for the patient.

d. Impart a characteristic appearance to the tablets, which facilitates product identification and aids patient compliance.

e. Provide physical protection to facilitate handling. This includes minimizing dust generation in subsequent unit operations.

f. Reduce the risk of interaction between incompatible components. This would be achieved by coating one or more of the offending ingredients.

g. Modify the release of the drug from the dosage form. This includes delaying, extending, and sustaining drug substance release.

h. Modify the dosage form by depositing the API or drug substance on or around a core tablet, which could be a placebo core tablet or a tablet containing another drug or a fractional quantity of the same drug.

129. What are the major techniques used for coating?

The coating material deposition typically is accomplished through one of six major techniques:

a. Sugar Coating – Deposition of coating material onto the substrate from aqueous solution/suspension of coatings, based predominantly upon sucrose as a raw material.

b. Film Coating – The deposition of polymeric film onto the solid dosage form.

c. Core Enrobing – The gelatin coating of gravity or force fed pre- formed tablets or caplets.

d. Microencapsulation – The deposition of a coating material onto a particle, pellet, granule, or bead core. The substrate in this application ranges in size from submicron to several millimeters. It is this size range that differentiates it from the standard coating described in 1 and 2 above.

e. Compression Coating (also addressed in the Unit Dosing section) – A coating process where a dry coatings blend is applied on a previously compressed core tablet using a tablet compression machine.11 Therefore, this process is also known as a dry coating process that does not involve any water or any other solvent in the coating process.

f. Active/ API coating – Deposition of active pharmaceutical ingredient (API or drug substance) on or around a core tablet utilizing any of the above five coating techniques.

Source: fda.gov

130. What are the Operating Principles of different equipment for coating?

Types of coatingDetails of Principles
Pan CoatingThe uniform deposition of coating material onto the surface of a solid dosage form, or component thereof, while being translated via a rotating vessel.
Gas SuspensionThe application of a coating material onto a solid dosage form, or component thereof, while being entrained in a process gas stream. Alternatively, this may be accomplished simultaneously by spraying the coating material and substrate into a process gas stream.
Vacuum Film CoatingThis technique uses a jacketed pan equipped with a baffle system. Tablets are placed into the sealed pan, an inert gas (i.e., nitrogen) is used to displace the air and then a vacuum is drawn.
Dip CoatingCoating is applied to the substrate by dipping it into the coating material. Drying is accomplished using pan coating equipment.
Electrostatic CoatingA strong electrostatic charge is applied to the surface of the substrate. The coating material containing oppositely charged ionic species is sprayed onto the substrate.
Compression CoatingThe division of a powder blend in which compression force is applied to form a single unit dose.

131. Equipment Classifications used for coating.

Equipment typeSub classification descriptionSub classification
Pan CoatingPan coating subclasses primarily are distinguished by the pan configuration, the pan perforations, and/or the perforated device used to introduce process air for drying purposes. Perforated coating systems include both batch and continuous coating processes.• Non-perforated (conventional) Coating System • Perforated Coating System
Gas SuspensionGas suspension subclasses primarily are distinguished by the method by which the coating is applied to the substrate.• Fluidized Bed with bottom spray mechanism • Fluidized Bed with tangential spray mechanism • Fluidized Bed with top spray mechanism • Fluidized Bed with Wurster column • Spray Congealing/Drying
Vacuum Film CoatingAlthough there may be differences in the jacketed pan, baffle system, or vacuum source, no vacuum film coating subclasses have been identified.No sub class
Dip CoatingBecause of the custom design associated with this class of coating, no dip 1013 coating subclasses or examples have been identified.No sub class
Electrostatic CoatingBecause of the custom design associated with this class of coating, no 1018 electrostatic coating subclasses or examples have been identified.No sub class
Compression CoatingRefer tablet press principle Unit Dosing section of previous post.No sub class

Source: fda.gov

132. What is Printing?

The marking of a capsule or tablet surface for the purpose of product identification.

Printing may be accomplished by either the application of a contrasting colored polymer (ink) onto the surface of a capsule or tablet, or by the use of laser etching. The method of application, provided the ink formulation is not altered, is of no consequence to the physical-chemical properties of the product.

133. What is Drilling?

The drilling or ablating of a hole or holes through the polymeric film coating shell on the surfaces of a solid oral dosage form using a laser.

The polymeric film shell is not soluble in vivo. The hole or holes allow for the modified release of the drug from the core of the dosage form.

134. What are the Operating Principles of different equipment for Printing and Drilling?

Types of Printing/ DrillingDetails of Principles
Ink-Based PrintingThe application of contrasting colored polymer (ink) onto the surface of a tablet or capsule.
Laser EtchingThe application of identifying markings onto the surface of a tablet or capsule using laser-based technology.
DrillingA drilling system typically is a custom built unit consisting of a material handling system to orient and hold the solid dosage form, a laser (or lasers), and optics (lenses, mirrors, deflectors, etc.) to ablate the hole or holes, and controls. The drilling unit may include debris extraction and inspection systems as well. The sorting, orienting, and holding equipment commonly is provided by dosage form printing equipment manufacturers, and is considered ancillary in this use.

135. Equipment Classifications used for Printing and Drilling.

Equipment typeSub classification descriptionSub classification
Ink-Based PrintingInk-based printing subclasses primarily are distinguished by the method by which the marking is applied to a capsule or tablet surface.• Offset • Ink Jet
Laser Etching (Printing)Although laser etching systems may differ from one another, no laser etching subclasses have been identified.No sub class
DrillingThe method of producing the laser pulse that ablates the hole(s) is of no consequence to the physical-chemical properties of the product. Therefore, no dosage form drilling equipment subclasses have been identified.No sub class

Source: fda.gov

136. What is excipient?

The word excipient originates from the Latin excipere, which means to receive; hence, the excipient receives the active substance.

As per European Pharmacopoeia (Ph. Eur.) “An excipient is any component, other than the active substance(s), present in a medicinal product or used in the manufacture of the product. The intended function of an excipient is to act as the carrier (vehicle or basis) or as a component of the carrier of the active substance(s) and, in so doing, to contribute to product attributes such as stability, biopharmaceutical profile, appearance and patient acceptability and to the ease with which the product can be manufactured. Usually, more than one excipient is used in the formulation of a medicinal product.”

147. What are the typical functions of excipients?

Excipients play a role in the formulation as Diluent, Binder, Disintegrant, Glidant, Lubricant, Coatings agent, or Coloring agent. It can further classified depending on its functions in the dosage form, which includes:

(i) Modulating solubility and bioavailability of the drug,

(ii) Enhancing stability of the drug in its dosage forms,

(iii) Maintaining a required polymorphic form,

(iv) Maintaining pH and osmolarity of liquid products,

(v)Antioxidants,

(vi) Preventing aggregation or dissociation agent,

(vii) Modulating the immunogenic response of drug,

(viii) Suspending agent,

(ix) Emulsifier,

(x) Aerosol propellants,

(xi) Base or tablet diluent

138. What is role of Diluents as an excipient?

Diluents are the material which provides bulk to the formulation and enable accurate dosing of potent ingredients.

139. Give a few examples of Diluents as an excipient?

Microcrystalline cellulose, Lactose, dextrin, glucose, sucrose, sorbitol, silicates, calcium and magnesium salts, sodium or potassium chloride, starch, lactose

140. What is the role of Binder as an excipient?

Binders, compression aids, granulating agents are the materials which bind the ingredients together giving form and mechanical strength and form granules for tablet, capsule or relevant formualtions

141. Give a few examples of Binder as an excipient?

Polyvinyl pyrrolidone, starch, gelatin, cellulose derivatives, sugars, sugar alcohols and cellulose derivatives

142. What is the role of Disintegrant as an excipient?

Disintegrant aid in dispersion of the tablet in the gastrointestinal tract, releasing the active ingredient and increasing the surface area for dissolution.

143. Give a few examples of Disintegrant as an excipient?

Starch, sodium starch glycollate, cross – linked polyvinyl pyrrolidone super disintegrants, cellulose derivatives and alginates, and crospovidone.

144. What is role of Glidant as an excipient?

Glidant improves the flow of powders during tablet manufacturing by reducing friction and adhesion between particles. It also used as anti-caking agents.

145. Give a few examples of Glidant as an excipient?

Colloidal anhydrous silicon and other silica compounds, talc, magnesium stearate

146. What is the role of Lubricant as an excipient?

Lubricants are used to prevent sticking of granules from die and punch wall during compression.

147. Give a few examples of Lubricant as an excipient?

Stearic acid and its salts (e.g. magnesium stearate), polyethylene glycol, sodium chloride

148. What is the role of coating agents as an excipient?

Coating agents have various functions such as, protect tablets from the environment (air, light and moisture), increase the mechanical strength, mask taste and smell, aid swallowing, assist in product identification.

It also can be used to modify release of the active ingredient.

149. Give a few examples of coating agents as an excipient?

Sugar, cellulose acetate phthalate etc.

150. What is the role of Colouring agent as an excipient?

Coloring agents improves acceptability to patients, aids identification and prevents counterfeiting. It also increases the stability of light-sensitive drugs.

151. Give a few examples of Colouring agents as an excipient?

Iron oxide, natural pigments, and other synthetic dyes.

152. Explain excipient classification based on objective of addition in dosage form.

Type of excipientObjective in dosage form
Improve organoleptic propertyColor Flavor Sweetener Masking of unpleasant test
StabilizersPreservative Antioxidant Emulsifier Suspending agent Isotonicity agent Maintaining pH and osmolarity
Dosage accuracyDiluent Filler Bulking agent
Process aidsBinder Glidant Lubricant Anti-adherent
Drug releaseDisintigrant Permiability enhancer Release rate limiting agent

153. What is immediate – release dosage form?

This is the dosage form intended to release the drug immediately after administration.

154. What is Delayed – release dosage form?

This is the dosage form where drug is not released until a physical event has occurred, e.g., change in pH etc.

155. What is sustained – release dosage form?

This is the dosage form where drug is released slowly over extended time.

156. What is a soluble tablet?

Soluble tablets are those which dissolve in water before administration.

157. What is a Dispersible tablet?

Tablet is added to water to form a suspension to administer.

158. What is an Effervescent tablet?

Tablet which is added into water. Tablet releases carbon dioxide to form an effervescent solution.

159. What is a Chewable tablet?

To administer the dose, the tablet is chewed and swallowed.

160. What is Chewable gum?

The formulation is chewed and removed from the mouth after a directed time as per the label claim.

161. What are Buccal and sublingual tablets?

The tablet which is placed in the oral cavity for local or systemic action is called Buccal and sublingual.

162. What is an Orally disintegrating tablet?

The tablet which gets dissolved or disintegrated in the mouth without the need for water is called an orally disintegrating tablet.

163. What is Lozenge?

Lozenge is a slowly dissolving tablet designed to be sucked in the mouth.

164. What is Pastille?

Pastille is the tablet consisting of gelatin and glycerine that facilitate dissolving tablets slowly in the mouth.

165. What is a Hard gelatin capsule?

Hard gelatin capsule is a two piece capsule shell that is filled with powder, granulate, tablets, semisolid or liquid in it.

166. What is Soft gelatin capsule (softgel)?

Soft gelatin capsule is a one piece capsule that contains a liquid or semisolid filled in it.

References:

1. WHO GMP Guidelines: Guide to Master Formulae, WHO/FWC/IVB/QSS/VQR, 2011

EU and PIC GMP guidelines: EudraLex Volume 4, Chapter 4: Documentation

PIC/S guidelines: Chapter 4: Documentation

Health Canada GMP guidelines: Good manufacturing practices guide for drug products (GUI-0001), Manufacturing control, C.02.011

U.S. FDA: CFR 21, Chapter I, Subchapter F: Biologics, Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals; Subpart F–Production and Process Controls, Sec. 211.100 Written procedures; deviations; and Subpart J–Records and Reports; Sec. 211.186 Master production and control records

U.S. FDA: CFR 21, Chapter I, Subchapter F: Biologics; Subchapter C: Drugs General; Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals; Subpart J– Records and Reports; Sec. 211.188 Batch production and control records.

India: The drugs and cosmetics act, 1940 and The drugs and cosmetics rules, 1945, Schedule M, 12. Documentation and records]

2. PART 314 — APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG, Subpart A – General Provisions Sec. 314.3 Definitions.

3. 21 CFR PART 210: CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL Sec. 210.1 Status of current good manufacturing practice regulations.

5. Wet Granulation:

End-Point Determination and Scale-Up, By Michael Levin, Ph. D., Metropolitan Computing Corporation East Hanover, New Jersey, USA

6. Saudi Pharmaceutical Journal

Volume 20, Issue 1, January 2012, Pages 9-19, Saudi Pharmaceutical Journal, Review article, Upgrading wet granulation monitoring from hand squeeze test to mixing torque rheometry Author links open overlay panel Walid F. Sakr Mohamed A. Ibrahim Fars K. Alanazi Adel A. Sakr

7. natoli.com

8. pacifictools.in

For more interview questions and answers Click Here

Interview Questions and Answers for Sterile Formulations

125+ Pharmaceutical Interview Questions and Answers for Sterile Formulations

This page covers most of the interview questions and answers during a technical round in Production of Sterile Formulations. The interview questions cover questions from basic to advance level of technical aspects. These interview questions and answers will help to crack an interview, enhance your knowledge, and also be helpful for the interviewer who is involved in the recruitment process.

The topics covered here are sterilization process, aseptic processing, media fill, area classification, and associated topics. In addition, the interview questions and answers cover various equipment used for the manufacturing process of sterile formulations.

You will find it much more enjoyable while going through these interview questions and answers. So enjoy learning, and best of luck with your interview! Happy Learning.

1. What is sterilization:

A suitably designed, validated and controlled process that inactivates or removes viable microorganisms in a product until sterility is obtained.

2. What is Sterility:

Sterility is the absence of viable microorganisms, as defined by a sterility assurance level equal to or less than 10−6. The inactivation of microorganisms by physical or chemical means follows an exponential law; thus there is always a finite statistical probability that a micro-organism may survive the sterilizing process. For a given process, the probability of survival is determined by the number, types and resistance of the microorganisms present and by the environment in which the organisms exist during treatment.

3. What is Aseptic processing?

A process performed maintaining the sterility of a product that is assembled from components, each of which has been sterilised by steam, dry heat, ionizing radiation, gas or sterile filtration. This is achieved by using conditions and facilities designed to prevent microbiological contaminants.

4. Bioburden:

The total number of micro-organisms associated with a specific item prior to any sterilisation or bioburden reduction step.

5. Biological indicator:

Biological indicators are test systems containing viable microorganisms (usually spores of bacteria) that provide a defined challenge to verify the required effectiveness of a specified sterilisation process.

6. Colony Forming Unit (CFU):

A microbiological term that describes the formation of a single macroscopic colony after the introduction of one or more micro-organisms to microbiological growth media. One colony forming unit is expressed as 1 CFU.

7. Depyrogenation

A process used to destroy or remove pyrogens (e.g. endotoxins).

8. D-value (decimal reduction value)

The value of a parameter of sterilisation (duration or absorbed dose) required to reduce the number of viable organisms to 10 per cent of the original number. It is only of significance under precisely defined experimental conditions. D121 is the D-value of the relevant spores at 121° C.

9. F0 value

The F0 value of a saturated steam sterilization process is the lethality expressed in terms of the equivalent time in minutes at a temperature of 121 °C delivered by the process to the load in its container with reference to micro-organisms possessing a theoretical Z-value of 10.

10. Holding time

The time between two process steps.

11. Lethal (process)

A process that kills the microorganisms exponentially.

12. Overkill sterilization

A process with a lethality of F0BIO > 12 minutes. For example a process that provides at least a 12 log reduction of biological indicator microorganisms having a minimum D value of 1 minute.

13. Ph. Eur. sterilization reference conditions

The reference conditions for sterilisation specified in Ph. Eur. 5.1.1, i.e. terminal steam sterilization at ≥121 °C for 15 min, terminal dry heat sterilisation at ≥160 °C for ≥2 h or terminal ionising radiation of 25 kGy.

14. Post-aseptic processing terminal heat treatment

A terminal moist heat process employed after aseptic processing which has been demonstrated to provide a SAL ≤10-6, but where the requirements of steam sterilisation (for example, F0≥8 min) are not fulfilled.

15. SAL (Sterility Assurance Level)

The SAL for a given sterilisation process is expressed as the probability of micro-organisms surviving in a product item after exposure to the process. An SAL of 10-6, for example, denotes a probability of not more than 1 non-sterile item in 1 × 106 sterilised items of the final product.

16. TAMC (Total aerobic microbial count)

The total aerobic microbial count (TAMC) is considered to be equal to the number of CFU found using casein soya bean digest agar.

17. z-value

The z-value is the change in temperature required to alter the D-value by a factor of 10.

Reference for Q 1 to 17:: 6 March 2019 EMA/CHMP/CVMP/QWP/850374/2015, Committee for Medicinal Products for Human use (CHMP), Committee for Medicinal Products for Veterinary use (CVMP), Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container

18. Difference Between F0 and Fh Values

At this point of time, it’ll be better to differentiate the two i.e. F0 and Fh values.

F0 ValueFh Value
Used to evaluate the effectiveness of Steam SterilizationUsed to evaluate the effectiveness of Dry Heat Sterilization
The assumed z-value is 10°C for sterilization range of 100 to 130°CThe assumed z-value is 20°C for sterilization range of 160 to 200°C
Theoretical Requirement121.1°C @ 30 min. of sterile hold timeTheoretical Requirement170°C @ 32 min. of sterile hold time
Targetted to mitigate micro-organisms especially living endosporesTargetted to remove the bacterial endotoxins
Much more complicated because of steam quality requirementsLethality of the microbes is less than that of F0 at the same temperature

19. What are the sterile manufacturing area grades? What are the operations to be carried out in each area?

For the manufacture of sterile medicinal products 4 grades can be distinguished:

Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36–0.54 m/s (guidance value) at the working position in open clean room applications. The maintenance of laminarity should be demonstrated and validated. A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes.

Grade B: For aseptic preparation and filling, this is the background environment for the grade A zone.

Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.

20. Explain correlation between Area Grades, Area Class and ISO Classification “At Rest” and “In Operation”.

GradeISO Class number (At rest)Class (At rest)ISO Class number (At rest)Class (At rest)
A4.81004.8100
B5100710,000
C710,0008100,000
D8100,000Not definedNot defined

Note:

For Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles ≥ 5.0 μm.

For Grade B (at rest) the airborne particle classification is ISO 5 for both considered particle sizes.

For Grade C (at rest and in operation) the airborne particle classification is ISO 7 and ISO 8 respectively.

For Grade D (at rest) the airborne particle classification is ISO 8. (In operation no classification is defined).

Reference – Rules and Guidance for Pharmaceutical Manufacturers and Distributors (MHRA)

21. Provide example of operations to be carried out in the various grades for sterile manufacturing facility.

Examples of operations to be carried out in the various grades are as follows:

GradeExamples of operations for terminally sterilised products.
AFilling of products, when unusually at risk.
CPreparation of solutions, when unusually at risk. Filling of products.
DPreparation of solutions and components for subsequent filling.
GradeExamples of operations for aseptic preparations.
AAseptic preparation and filling.
CPreparation of solutions to be filtered.
DHandling of components after washing.

Reference – Rules and Guidance for Pharmaceutical Manufacturers and Distributors (MHRA)

22. Explain clothing requirements for each grade of manufacturing are for sterile manufacturing facility.

Grade A/B: Headgear should totally enclose hair and, where relevant, beard and moustache; it should be tucked into the neck of the suit; a face mask should be worn to prevent the shedding of droplets. Appropriate sterilised, non-powdered rubber or plastic gloves and sterilised or disinfected footwear should be worn. Trouser-legs should be tucked inside the footwear and garment sleeves into the gloves. The protective clothing should shed virtually no fibres or particulate matter and retain particles shed by the body.

Outdoor clothing should not be brought into changing rooms leading to grade B and C rooms. For every worker in a grade A/B area, clean sterile (sterilised or adequately sanitised) protective garments should be provided at each work session. Gloves should be regularly disinfected during operations. Masks and gloves should be changed at least for every working session.

Grade C. Hair and where relevant beard and moustache should be covered. A single or two-piece trouser suit, gathered at the wrists and with high neck and appropriate shoes or overshoes should be worn. They should shed virtually no fibres or particulate matter.

Grade D. Hair and, where relevant, beard should be covered. A general protective suit and appropriate shoes or overshoes should be worn. Appropriate measures should be taken to avoid any contamination coming from outside the clean area.

Reference – Rules and Guidance for Pharmaceutical Manufacturers and Distributors (MHRA)

23. Explain design consideration in sterile manufacturing area for contamination prevention and clean area separation

  • Airflow direction shall be from areas of higher cleanliness to adjacent less clean areas.
  • Higher air cleanliness shall have a substantial positive pressure differential relative to adjacent rooms of lower air cleanliness.
  • Positive pressure differential of at least 10-15 Pascals (Pa) should be maintained between adjacent rooms of differing classification (with doors closed).
  • When doors are open, outward airflow should be sufficient to minimize ingress of contamination, and it is critical that the time a door can remain ajar be strictly controlled.
  • When unclassified room adjacent to the aseptic processing room, a substantial overpressure (e.g., at least 12.5 Pa) from the aseptic processing room should be maintained at all times to prevent contamination.
  • Continuous monitoring of pressure differentials between cleanrooms with frequently recorded.

24. What is the air changes requirement for Class 100,000 (ISO 8)?

For Class 100,000 (ISO 8) supporting rooms, airflow sufficient to achieve at least 20 air changes per hour is typically acceptable.

Significantly higher air change rates are normally needed for Class 10,000 and Class 100 areas.

25. What is difference between filter leak testing and efficiency testing?

An efficiency test is a general test used to determine the rating of the filter. An intact HEPA filter should be capable of retaining at least 99.97 percent of particulates greater than 0.3 μm in diameter.

The purpose of leak test is to detect leaks from the filter media, filter frame, or seal.

26. What is the limit of HEPA filter leak test?

While performing leak test, a single probe reading equivalent to 0.01 percent of the upstream challenge would be considered as indicative of a significant leak.

27. Why measurement of velocity is important in the aseptic area? What should be measurement location and distance from filter face?

HEPA filter leak testing alone is insufficient to monitor filter performance. It is important to conduct periodic monitoring of filter attributes such as uniformity of velocity across the filter (and relative to adjacent filters). Variations in velocity can cause turbulence that increases the possibility of contamination. Velocities of unidirectional air should be measured 6 inches from the filter face and at a defined distance proximal to the work surface for HEPA filters in the critical area. Velocity monitoring at suitable intervals can provide useful data on the critical area in which aseptic processing is performed. The measurements should correlate to the velocity range established at the time of in situ air pattern analysis studies.

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

28. Drains are preferably not allowed in which area classification zones?

Drains are considered inappropriate for classified areas of the aseptic processing facility other than Class 100,000 (ISO 8) areas.

29. Types of training required to be conducted before an individual is permitted to enter the aseptic manufacturing area?

Fundamental training topics should include aseptic technique, cleanroom behavior, microbiology, hygiene, gowning, patient safety hazards posed by a non-sterile drug product, and the specific written procedures covering aseptic manufacturing area operations.

30. What measures required to be followed by personnel in aseptic area to maintain sterility of sterile items and surafaces?

  • Measures required to be followed by personnel in aseptic area are:
    • Contact sterile materials only with sterile instruments.
    • After initial gowning, sterile gloves should be regularly sanitized or changed, as appropriate, to minimize the risk of contamination.
    • Personnel should not directly contact sterile products, containers, closures, or critical surfaces with any part of their gown or gloves.
    • Move slowly and deliberately.
    • Keep the entire body out of the path of unidirectional airflow.
    • Approach a necessary manipulation in a manner that does not compromise sterility of the product.
    • Maintain Proper Gown Control – Prior to and throughout aseptic operations, an operator should not engage in any activity that poses an unreasonable contamination risk to the gown.

31. What is the impact of rapid movements in Aspetic area?

Rapid movements can create unacceptable turbulence in a critical area. Such movements disrupt the unidirectional airflow, presenting a challenge beyond intended cleanroom design and control parameters. The principle of slow, careful movement should be followed throughout the cleanroom.

32. What is the potential impact if body parts interrupt the path of unidirectional airflow?

Disruption of the path of unidirectional flow air in the critical area can pose a risk to product sterility because, the purpose of unidirectional airflow design is to protect sterile equipment surfaces, container-closures, and product.

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

33. Explain the type of gowning required for aseptic area?

  • The gown should provide a barrier between the body and exposed sterilized materials and prevent contamination from particles generated by, and microorganisms shed from, the body.
  • Gowns should be sterile and non-shedding, and cover the skin and hair (face-masks, hoods, beard/ moustache covers, protective goggles, and elastic gloves are examples of common elements of gowns).
  • An adequate barrier should be created by the overlapping of gown components (e.g., gloves overlapping sleeves).
  • If an element of a gown is found to be torn or defective, it should be changed immediately. Gloves should be sanitized frequently.

34. What is the recommended gowning requalification frequency for aseptic area?

Annual requalification is normally sufficient for those automated operations where personnel involvement is minimized and monitoring data indicate environmental control.

For any aseptic processing operation, if adverse conditions occur, additional or more frequent requalification could be indicated.

35. Sanitizing gloves just prior to sampling is acceptable or not acceptable?

Sanitizing gloves just prior to sampling is inappropriate because it can prevent recovery of microorganisms that were present during an aseptic manipulation.

36. What is the recommended solvent for rinse sampling for pre-sterilization preparation of glass containers? What is the acceptance criterion of final rinse water?

High purity water. Final rinse water should meet the specifications of WFI, USP.

37. What is a log reduction criterion for endotoxin after depyrogenation process?

Validation study data should demonstrate that the process reduces the endotoxin content by at least 99.9 percent (3 logs).

38. Is sterilizing-grade filters and moist heat sterilization effective in removing endotoxin?

Sterilizing-grade filters and moist heat sterilization have not been shown to be effective in removing endotoxin.

39. What is an effective way to inactivate endotoxins?

Endotoxin on equipment surfaces can be inactivated by high-temperature dry heat, or removed from equipment surfaces by cleaning procedures.

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

40. What should be frequency of periodic media fill?

Semi-annual qualification should be conducted for each processing line to evaluate the state of control of the aseptic process.

41. What permutation and combination factors should be covered during the media fill?

Activities and interventions representative of each shift, and shift changeover, should be incorporated into the design of the semi-annual qualification program. E.g. Production shift should address its unique time-related and operational features.

42. What is the requirement of participation of personnel during media fill? What operations need to be done by participants?

All personnel who are authorized to enter the aseptic processing room during manufacturing, including technicians and maintenance personnel, should participate in a media fill at least once a year. Participation should be consistent with the nature of each operator’s duties during routine production.

43. What should be duration of media fill runs?

The duration of aseptic processing operations is a major consideration in media fill design. Although the most accurate simulation model would be the full batch size and duration because it most closely simulates the actual production operations, other appropriate models can be justified. The duration of the media fill run should be determined by the time it takes to incorporate manipulations and interventions, as well as appropriate consideration of the duration of the actual aseptic processing operation. Interventions that commonly occur should be routinely simulated, while those occurring rarely can be simulated periodically.

44. What should be size of media fill runs?

The simulation run sizes should be adequate to mimic commercial production conditions and accurately assess the potential for commercial batch contamination.

The number of units filled during the process simulation should be based on contamination risk for a given process and sufficient to accurately simulate activities that are representative of the manufacturing process. A generally acceptable starting point for run size is in the range of 5,000 to 10,000 units. For operations with production sizes under 5,000, the number of media filled units should at least equal the maximum batch size made on the processing line

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

45. Why high machine speed and low speed should be challenged during media fill runs?

Hgh line speed is often most appropriate in the evaluation of manufacturing processes characterized by frequent interventions or a significant degree of manual manipulation. Use of slow line speed is generally appropriate for evaluating manufacturing processes with prolonged exposure of the sterile drug product and containers/closures in the aseptic area.

46. What types of growth medium should be used during media fill runs?

A microbiological growth medium, such as soybean casein digest medium, should be used.

Use of anaerobic growth media (e.g., fluid thioglycollate medium) should be considered in special circumstances.

47. Which should be characteristic of microbiological growth medium to be used during media fill?

The media selected should be demonstrated to promote growth of gram-positive and gram-negative bacteria, and yeast and mold (e.g., USP indicator organisms).

Environmental monitoring and sterility test isolates can be substituted (as appropriate) or added to the growth promotion challenge.

48. What should be the concentration of organism while testing of Growth promotion units?

Growth promotion units should be inoculated with a <100 CFU challenge.

49. What action should be done if growth promotion test fails?

If the growth promotion testing fails, the origin of any contamination found during the simulation should nonetheless be investigated and the media fill promptly repeated.

50. What should be the incubation duration and temperature for media filled units?

• Incubation temperature should be suitable for recovery of bioburden and environmental isolates and should at no time be outside the range of 20-35 °C. Incubation temperature should be maintained within +2.5 °C of the target temperature.

• Incubation time should not be less than 14 days. If two temperatures are used for the incubation of the media filled units, the units should be incubated for at least 7 days at each temperature (starting with the lower temperature).

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

51. Who should perform inspection of media filled units?

Each media-filled unit should be examined for contamination by personnel with appropriate education, training, and experience in inspecting media fill units for microbiological contamination.

If QC personnel do not perform the inspection, there should be QC unit oversight throughout any such examination.

All suspect units identified during the examination should be brought to the immediate attention of the QC microbiologist.

52. How to perform inspection of media filled units of amber or other opaque containers?

To allow for visual detection of microbial growth, amber or other opaque containers should be substitute with clear containers.

53. After inspection of media filled units which containers shall be incubated and which containers shall not?

All integral units should proceed to incubation. Units found to have defects not related to integrity (e.g., cosmetic defect) should be incubated; units that lack integrity should be rejected.

54. Whether the media filled units generated during the intervention should be incubated or not?

If written procedures and batch documentation are adequate to describe an associated clearance, the intervention units removed during media fills do not need to be incubated. Where procedures lack specificity, there would be insufficient justification for exclusion of units removed during an intervention from incubation. For example, if a production procedure requires removal of 10 units after an intervention at the stoppering station infeed, batch records (i.e., for production and media fills) should clearly document conformance with this procedure. In no case should more units be removed during a media fill intervention than would be cleared during a production run.

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

55. How to interpret test results of media fill?

Recommended criteria for assessing state of aseptic line control are as follows:

i. When filling fewer than 5000 units, no contaminated units should be detected.

One (1) contaminated unit is considered cause for revalidation, following an investigation.

ii. When filling from 5,000 to 10,000 units

One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill.

Two (2) contaminated units are considered cause for revalidation, following investigation.

iii. When filling more than 10,000 units

One (1) contaminated unit should result in an investigation.

Two (2) contaminated units are considered cause for revalidation, following investigation.

56. What should be considered when performing investigation of media fill failure?

The microorganisms should be identified to species level.

The investigation should survey the possible causes of contamination. In addition, any failure investigation should assess the impact on commercial drugs produced on the line since the last media fill.

57. To carryout Filtration Efficacy study, which microorganism should be considered for challenge? Why?

The microorganism, Brevundimonas diminuta (ATCC 19146) when properly grown, harvested and used, is a common challenge microorganism for 0.2 μm rated filters because of its small size (0.3 μm mean diameter).

58. What concentration of organism should be considered for Filtration Efficacy study?

A challenge concentration of at least 107 organisms per cm2 of effective filtration area should generally be used, resulting in no passage of the challenge microorganism. The challenge concentration used for validation is intended to provide a margin of safety well beyond what would be expected in production.

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

59. What are the factors that can affect filter performance?

Factors that can affect filter performance generally include

(1) Viscosity and surface tension of the material to be filtered,

(2) pH,

(3) Compatibility of the material or formulation components with the filter itself,

(4) Pressures,

(5) Flow rates,

(6) Maximum use time,

(7) Temperature,

(8) Osmolality,

(9) and the effects of hydraulic shock

60. What should be frequency of filter replacement for sterilization filters for product manufacturing?

Sterilizing filters should be routinely discarded after processing of a single lot.

However, in those instances when repeated use can be justified, the sterile filter validation should incorporate the maximum number of lots to be processed.

61. What should be frequency of filter integrity testing?

Integrity testing of the filter(s) can be performed prior to processing, and should be routinely performed post-use. It is important that integrity testing be conducted after filtration to detect any filter leaks or perforations that might have occurred during the filtration.

62. What are the generally used methods for filter integrity testing?

Forward flow and bubble point tests, when appropriately employed, are two integrity tests that can be used.

63. What should be frequency of equipment and accessories sterilization?

Sterility of aseptic processing equipment should normally be maintained by sterilization between each batch.

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

64. Why air should be removed from the autoclave chamber while sterilization?

The insulating properties of air interfere with the ability of steam to transfer its energy to the load, achieving lower lethality than associated with saturated steam.

65. Where must to have location for the biological indicator during sterilization validation?

Potentially difficult to reach locations within the sterilizer load or equipment train (for SIP applications) should be evaluated. For example, filter installations in piping can cause a substantial pressure differential across the filter, resulting in a significant temperature drop on the downstream side. We recommend placing biological indicators at appropriate downstream locations of the filter.

66. Why empty chamber mapping studies required during the sterilizer validation?

Empty chamber studies evaluate numerous locations throughout a sterilizing unit (e.g., steam autoclave, dry heat oven) or equipment train (e.g., large tanks, immobile piping) to confirm uniformity of conditions (e.g., temperature, pressure).

67. How heat penetration study shall be done while sterilizer validation?

Heat penetration studies should be performed using the established sterilizer loads. Validation of the sterilization process with a loaded chamber demonstrates the effects of loading on thermal input to the items being sterilized and may identify difficult to heat or penetrate items where there could be insufficient lethality to attain sterility. The placement of biological indicators at numerous positions in the load, including the most difficult to sterilize places, is a direct means of confirming the efficacy of any sterilization procedure. In general, the biological indicator should be placed adjacent to the temperature sensor so as to assess the correlation between microbial lethality and predicted lethality based on thermal input.

68. What types of calibration should be checked which could have impact on sterilization?

i. Temperature and pressure monitoring devices for heat sterilization should be calibrated at suitable intervals. The sensing devices used for validation studies should be calibrated before and after validation runs.

ii. Devices used to monitor dwell time in the sterilizer should be periodically calibrated.

iii. Instruments used to determine the purity of steam (as applicable) should be calibrated. iv. For dry heat depyrogenation tunnels, devices (e.g. sensors and transmitters) used to measure belt speed should be routinely calibrated.

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

69. During aseptic area environmental monitoring program, what should be covered?

The environmental monitoring program should cover all production shifts and include air, floors, walls, and equipment surfaces, including the critical surfaces that come in contact with the product, container, and closures.

70. Which location should be covered during environmental monitoring for aseptic area?

It is important that locations posing the most microbiological risk to the product be a key part of the program.

It is especially important to monitor the microbiological quality of the critical area to determine whether or not aseptic conditions are maintained during filling and closing activities. Air and surface samples should be taken at the locations where significant activity or product exposure occurs during production. Critical surfaces that come in contact with the sterile product should remain sterile throughout an operation. When identifying critical sites to be sampled, consideration should be given to the points of contamination risk in a process, including factors such as difficulty of setup, length of processing time, and impact of interventions. Critical surface sampling should be performed at the conclusion of the aseptic processing operation to avoid direct contact with sterile surfaces during processing.

71. How to ensure that environmental monitoring locations are reproducibly monitored?

All environmental monitoring locations should be described in SOPs with sufficient detail to allow for reproducible sampling of a given location surveyed. Written SOPs should also address elements such as (1) frequency of sampling, (2) when the samples are taken (i.e., during or at the conclusion of operations), (3) duration of sampling, (4) sample size (e.g., surface area, air volume), (5) specific sampling equipment and techniques, (6) alert and action levels, and (7) appropriate response to deviations from alert or action levels.

72. Why environmental monitoring results should not be averaged?

Averaging of results can mask unacceptable localized conditions.

73. What should be covered while performing trend analysis of the environmental monitoring data for aseptic area?

Trend reports should include data generated by location, shift, room, operator, or other parameters. Significant changes in microbial flora should be considered in the review of the ongoing environmental monitoring data.

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

74. Which are the acceptable methods for monitoring the microbiological quality of the environment in aseptic area?

Acceptable methods for monitoring the microbiological quality of the environment include:

a. Surface Monitoring

b. Active Air Monitoring

c. Passive Air Monitoring (Settling Plates)

75. Which surfaces monitored during Surface Monitoring?

Environmental monitoring involves sampling various surfaces for microbiological quality. For example, product contact surfaces, floors, walls, and equipment should be tested on a regular basis.

76. What types of techniques shall be used for surface monitoring?

Touch plates, swabs, and contact plates can be used for such tests.

77. What types of device shall be used for Active Air Monitoring?

Assessing microbial quality of air should involve the use of active devices including but not limited to impaction, centrifugal, and membrane (or gelatin) samplers.

78. What should be considered during method validation of Passive Air Monitoring (Settling Plates)?

As part of methods validation, the laboratory should evaluate what media exposure conditions optimize recovery of low levels of environmental isolates. Exposure conditions should preclude desiccation (e.g., caused by lengthy sampling periods and/or high airflows), which inhibits recovery of microorganisms.

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

79. How microbiological identification is useful in sterile product manufacturing facility environmental monitoring program?

Characterization of recovered microorganisms provides vital information for the environmental monitoring program. Environmental isolates often correlate with the contaminants found in a media fill or product sterility testing failure, and the overall environmental picture provides valuable information for an investigation. Monitoring critical and immediately surrounding clean areas as well as personnel should include routine identification of microorganisms to the species (or, where appropriate, genus) level.

80. How uncontrolled area or lesser controlled areas microbiological identification is useful in sterile product manufacturing facility environmental monitoring program?

In some cases, environmental trending data have revealed migration of microorganisms into the aseptic processing room from either uncontrolled or lesser controlled areas. Establishing an adequate program for differentiating microorganisms in the lesser-controlled environments, such as Class 100,000 (ISO 8), can often be instrumental in detecting such trends.

At minimum, the program should require species (or, where appropriate, genus) identification of microorganisms in these ancillary environments at frequent intervals to establish a valid, current database of contaminants present in the facility during processing (and to demonstrate that cleaning and sanitization procedures continue to be effective).

81. Which method of microbial identification is more accurate?

Genotypic methods have been shown to be more accurate and precise than traditional biochemical and phenotypic techniques. These methods are especially valuable for investigations into failures (e.g., sterility test; media fill contamination). However, appropriate biochemical and phenotypic methods can be used for the routine identification of isolates.

82. What is the goal of microbiological monitoring?

The goal of microbiological monitoring is to reproducibly detect microorganisms for purposes of monitoring the state of environmental control.

83. What should be the capability microbiological culture media used for aseptic area environmental monitoring program?

The microbiological culture media used in environmental monitoring should be validated as capable of detecting fungi (i.e., yeasts and molds) as well as bacteria and incubated at appropriate conditions of time and temperature.

84. What should be incubation condition for environmental monitoring media plates and what should be the duration?

Total aerobic bacterial count can be obtained by incubating at 30 to 35°C for 48 to 72 hours. Total combined yeast and mold count can generally be obtained by incubating at 20 to 25°C for 5 to 7 days.

85. How to ensure that the incoming lots of environmental monitoring media is able to reliably recover microorganisms?

Incoming lots of environmental monitoring media should be tested for their ability to reliably recover microorganisms. Growth promotion testing should be performed on all lots of prepared media. Where appropriate, inactivating agents should be used to prevent inhibition of growth by cleanroom disinfectants or product residuals (e.g., antibiotics).  

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

86. Why controlling of Prefiltration Bioburden is important?

Manufacturing process controls should be designed to minimize the bioburden in the unfiltered product. In addition to increasing the challenge to the sterilizing filter, bioburden can contribute impurities (e.g., endotoxin) to, and lead to degradation of, the drug product. A prefiltration bioburden limit should be established.

87. In which scenario alternate Microbiological Test Methods should be used?

Other suitable microbiological test methods (e.g., rapid test methods) can be considered for environmental monitoring, in-process control testing, and finished product release testing after it is demonstrated that the methods are equivalent or better than traditional methods (e.g.,USP).

88. How Particle Monitoring is useful in clean room?

Routine particle monitoring is useful in rapidly detecting significant deviations in air cleanliness from qualified processing norms (e.g., clean area classification).

89. What should be the environmental condition of sterility testing area?

The testing laboratory environment should employ facilities and controls comparable to those used for aseptic filling operations. Poor or deficient sterility test facilities or controls can result in test failure. If production facilities and controls are significantly better than those for sterility testing, the danger exists of mistakenly attributing a positive sterility test result to a faulty laboratory even when the product tested could have, in fact, been nonsterile.

90. Which USP chapter and which part of 21 CFR describe about sterility testing?

Sterility testing methods are required to be accurate and reproducible, in accordance with 211.194 and 211.165.

USP <71> “Sterility Tests” is the principal source used for sterility testing methods, including information on test procedures and media.

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

91. What is the probability of detection of contamination during sterility testing?

Sterility tests are limited in their ability to detect contamination because of the small sample size typically used. For example, as described by USP, statistical evaluations indicate that the sterility test sampling plan “only enables the detection of contamination in a lot in which 10% of the units are contaminated about nine times out of ten in making the test” (Ref. 13). To further illustrate, if a 10,000-unit lot with a 0.1 percent contamination level was sterility tested using 20 units, there is a 98 percent chance that the batch would pass the test.

92. How to collect the samples for sterility testing?

It is important that the samples represent the entire batch and processing conditions. Samples should be taken:

• At the beginning, middle, and end of the aseptic processing operation

• In conjunction with processing interventions or excursions

93. When sterility test failure results can be invalidated?

An initial positive test would be invalid only in an instance in which microbial growth can be unequivocally ascribed to laboratory error.

Only if conclusive and documented evidence clearly shows that the contamination occurred as part of testing should a new test be performed.

94. In case of inconclusive investigation, what should be the batch disposition decision?

When available evidence is inconclusive, batches should be rejected as not conforming to sterility requirements.

95. What parameters should be considered while performing sterility failure investigation?

The investigation’s persuasive evidence of the origin of the contamination should be based on at least the following:

1. Identification (speciation) of the organism in the sterility test

2. Record of laboratory tests and deviations

3. Monitoring of production area environment

4. Monitoring Personnel

5. Product Presterilization Bioburden

6. Production record review 7. Manufacturing history

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

96. How isolate identification is useful during investigation of sterility testing failure?

Sterility test isolates should be identified to the species level. Microbiological monitoring data should be reviewed to determine if the organism is also found in laboratory and production environments, personnel, or product bioburden. Advanced identification methods (e.g., nucleic-acid based) are valuable for investigational purposes. When comparing results from environmental monitoring and sterility positives, both identifications should be performed using the same methodology.

97. What is the recommended material of construction for aseptic processing design?

Suitable materials should be chosen based on durability, as well as ease of cleaning and decontamination. For example, rigid wall construction incorporating stainless steel and glass materials is widely used.

98. What is expected classification of isolator and surrounding area?

The interior of the isolator should meet Class 100 (ISO 5) standards. The classification of the environment surrounding the isolator should be based on the design of its interfaces (e.g., transfer ports), as well as the number of transfers into and out of the isolator. A Class 100,000 (ISO 8) background is commonly used based on consideration of isolator design and manufacturing situations. An aseptic processing isolator should not be located in an unclassified room.

Reference: FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice – September 2004

99. What should be the laminar air flow systems air speed for Grade A area? Why?

Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position in open clean room applications.

100. Why length of tubing and the radii is important for particle monitoring system?

The length of tubing and the radii of any bends in the tubing must be considered in the context of particle losses in the tubing.

101. What should be pressure differential between adjacent rooms of different grades?

Adjacent rooms of different grades should have a pressure differential of 10 – 15 pascals.

102. What is the recommended temperature for Water for injections storage and distribution? Why?

Water for injections should be produced, stored and distributed in a manner which prevents microbial growth, for example by constant circulation at a temperature above 70°C.

103. For what types of areas, fumigation is useful?

Fumigation of clean areas may be useful for reducing microbiological contamination in inaccessible places.

Reference: EudraLex – The Rules Governing Medicinal Products in the European Union Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1 – Manufacture of Sterile Medicinal Products – 01 March 2009

104. What should be the method of choice for sterilization as per EU Annex-1?

Where possible, heat sterilisation is the method of choice.

105. What should be the verification schedule for sterilization process?

The validity of the sterilization process should be verified at scheduled intervals, at least annually, and whenever significant modifications have been made to the equipment.

106. How to differentiate products which have not been sterilised from those which have?

Each basket, tray or other carrier of products or components should be clearly labelled with the material name, its batch number and an indication of whether or not it has been sterilised. Indicators such as autoclave tape may be used, where appropriate, to indicate whether or not a batch (or sub-batch) has passed through a sterilisation process, but they do not give a reliable indication that the lot is, in fact, sterile.

107. How to ensure temperature during sterilization process?

Each heat sterilisation cycle should be recorded on a time/temperature chart with a sufficiently large scale or by other appropriate equipment with suitable accuracy and precision. The position of the temperature probes used for controlling and/or recording should have been determined during the validation, and where applicable also checked against a second independent temperature probe located at the same position.

108. Can chemical or biological indicator be replacement of physical measurements during sterilization cycle?

Chemical or biological indicators should not take the place of physical measurements.

Reference: EudraLex – The Rules Governing Medicinal Products in the European Union Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1 – Manufacture of Sterile Medicinal Products – 01 March 2009

109. How to monitor moist heat sterilization cycle?

Both temperature and pressure should be used to monitor the process. Control instrumentation should normally be independent of monitoring instrumentation and recording charts. Where automated control and monitoring systems are used for these applications they should be validated to ensure that critical process requirements are met. System and cycle faults should be registered by the system and observed by the operator. The reading of the independent temperature indicator should be routinely checked against the chart recorder during the sterilisation period. For sterilisers fitted with a drain at the bottom of the chamber, it may also be necessary to record the temperature at this position, throughout the sterilization period. There should be frequent leak tests on the chamber when a vacuum phase is part of the cycle.

110. Explain the quality of wrapping material used during sterilization process?

The items to be sterilised, other than products in sealed containers, should be wrapped in a material which allows removal of air and penetration of steam but which prevents recontamination after sterilisation.

111. What challenge should be carried out during validation when for dry heat sterilization when it is intended to remove pyrogen?

Challenge tests using endotoxins should be used as part of the validation.

112. In what scenario, sterilisation by radiation can be adopted?

Radiation sterilisation is used mainly for the sterilisation of heat sensitive materials and products. Many medicinal products and some packaging materials are radiation-sensitive, so this method is permissible only when the absence of deleterious effects on the product has been confirmed experimentally.

113. Which irradiation is not an acceptable method of sterilisation.?

Ultraviolet irradiation is not normally an acceptable method of sterilisation.

Reference: EudraLex – The Rules Governing Medicinal Products in the European Union Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1 – Manufacture of Sterile Medicinal Products – 01 March 2009

114. How to measure radiation while doing irradiation serilization?

During the sterilisation procedure the radiation dose should be measured. For this purpose, dosimetry indicators which are independent of dose rate should be used, giving a quantitative measurement of the dose received by the product itself. Dosimeters should be inserted in the load in sufficient number and close enough together to ensure that there is always a dosimeter in the irradiator. Where plastic dosimeters are used they should be used within the time-limit of their calibration. Dosimeter absorbances should be read within a short period after exposure to radiation.

115. How to prevent mix-up between irradiated and nonirradiated materials?

Radiation sensitive colour disks should also be used on each package to differentiate between packages which have been subjected to irradiation and those which have not.

116. When Sterilisation with ethylene oxide should be used?

This method should only be used when no other method is practicable. During process validation it should be shown that there is no damaging effect on the product and that the conditions and time allowed for degassing are such as to reduce any residual gas and reaction products to defined acceptable limits for the type of product or material.

117. What precaution should be taken while sterilization of material using ethylene oxide?

i. Direct contact between gas and microbial cells is essential; precautions should be taken to avoid the presence of organisms likely to be enclosed in material such as crystals or dried protein. The nature and quantity of packaging materials can significantly affect the process.

ii. Before exposure to the gas, materials should be brought into equilibrium with the humidity and temperature required by the process. The time required for this should be balanced against the opposing need to minimize the time before sterilisation.

iii. Each sterilisation cycle should be monitored with suitable biological indicators, using the appropriate number of test pieces distributed throughout the load.

iv. For each sterilisation cycle, records should be made of the time taken to complete the cycle, of the pressure, temperature and humidity within the chamber during the process and of the gas concentration and of the total amount of gas used. The pressure and temperature should be recorded throughout the cycle on a chart.

v. After sterilisation, the load should be stored in a controlled manner under ventilated conditions to allow residual gas and reaction products to reduce to the defined level.

Reference: EudraLex – The Rules Governing Medicinal Products in the European Union Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1 – Manufacture of Sterile Medicinal Products – 01 March 2009

118. What is preferred method of sterilization as per EU Annex 1?

Filtration alone is not considered sufficient when sterilisation in the final container is possible. With regard to methods currently available, steam sterilisation is to be preferred. If the product cannot be sterilised in the final container, solutions or liquids can be filtered through a sterile filter of nominal pore size of 0.22 micron (or less), or with at least equivalent micro-organism retaining properties, into a previously sterilised container. Such filters can remove most bacteria and moulds, but not all viruses or mycoplasmas. Consideration should be given to complementing the filtration process with some degree of heat treatment.

119. Number of sterilization filters recommended by EU Annex 1 when sterilization is done through filtration method? What should be the location of the filer?

Due to the potential additional risks of the filtration method as compared with other sterilization processes, a second filtration via a further sterilised micro-organism retaining filter, immediately prior to filling, may be advisable. The final sterile filtration should be carried out as close as possible to the filling point.

120. When to perform filter integrity testing and why it is important?

The integrity of the sterilised filter should be verified before use and should be confirmed immediately after use by an appropriate method such as a bubble point, diffusive flow or pressure hold test. The time taken to filter a known volume of bulk solution and the pressure difference to be used across the filter should be determined during validation and any significant differences from this during routine manufacturing should be noted and investigated. Results of these checks should be included in the batch record. The integrity of critical gas and air vent filters should be confirmed after use. The integrity of other filters should be confirmed at appropriate intervals.

121. What is the preferred duration of sterilization filter as per EU Annex 1?

The same filter should not be used for more than one working day unless such use has been validated.

Reference: EudraLex – The Rules Governing Medicinal Products in the European Union Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1 – Manufacture of Sterile Medicinal Products – 01 March 2009

122. Partially stoppered freeze drying vials should be maintained under which grade area?

Partially stoppered freeze drying vials should be maintained under Grade A conditions at all times until the stopper is fully inserted.

123. At which stage of operation, aseptically filled vial cap is considered integral?

The container closure system for aseptically filled vials is not fully integral until the aluminium cap has been crimped into place on the stoppered vial. Crimping of the cap should therefore be performed as soon as possible after stopper insertion.

124. What is the major risk of vial crimping operation in aseptic area? How to mitigate that risk?

The equipment used to crimp vial caps can generate large quantities of non-viable particulates, the equipment should be located at a separate station equipped with adequate air extraction.

125. Vial capping should be done which grade area?

Vial capping can be undertaken as an aseptic process using sterilised caps or as a clean process outside the aseptic core. Where this latter approach is adopted, vials should be protected by Grade A conditions up to the point of leaving the aseptic processing area, and thereafter stoppered vials should be protected with a Grade A air supply until the cap has been crimped.

126. How many filled containers should be visually inspected? Why?

Filled containers of parenteral products should be inspected individually for extraneous contamination or other defects.

127. Explain the process of visual inspection injectable products?

When inspection is done visually, it should be done under suitable and controlled conditions of illumination and background. Operators doing the inspection should pass regular eye-sight checks, with spectacles if worn, and be allowed frequent breaks from inspection. Where other methods of inspection are used, the process should be validated and the performance of the equipment checked at intervals. Results should be recorded.

Reference: EudraLex – The Rules Governing Medicinal Products in the European Union Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1 – Manufacture of Sterile Medicinal Products – 01 March 2009

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Top 10 important Interview Questions and Answers on Pharmaceutical Validation

Interview Questions and Answers on Pharmaceutical Validation

This page covers most of the interview questions and answers asked during a technical interview round of quality assurance and validation professionals.

You will find interview questions and answers on Terminologies associated with process validation, Stages of Process Validation, approach to process validation, Stages of process validation, typical steps for QbD, control strategy of process validation, FDA guidance, EMA guidance, WHO guidance on hold time studies of the products, different guidelines/ regulations describing requirement of cleaning validation, and different guidelines/ regulations describing requirement of equipment qualification.

The interview questions cover questions from basic to advance level of technical aspects. These interview questions and answers will help to crack an interview, enhance your knowledge, and also be helpful for the interviewer who is involved in the recruitment process.

The topics covered here are the sterilization process, aseptic processing, media fill, area classification, and associated topics. In addition, the interview questions and answers cover various equipment used for the manufacturing process of sterile formulations.

You will find it much more enjoyable while going through these interview questions and answers. So enjoy learning, and best of luck with your interview! Happy Learning.

1. Terminologies associated with process validation.

i. Attribute

An attribute is a physical, chemical, or microbiological property or characteristic of an input or output material.

Reference: ICH Quality Guideline Q5E

ii. Critical Quality Attribute (CQA)

A CQA is a physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.

Reference: ICH Quality Guideline Q8 (R2)

iii. Quality Attribute

A Quality Attribute is a molecular or product characteristic that is selected for its ability to indicate the quality of the product. Collectively, the quality attributes define identity, purity, potency and stability of the product, and safety with respect to adventitious agents. Specifications measure a selected subset of the quality attributes.

Reference: ICH Quality Guideline Q6B

iv. Control Strategy

A control strategy is a planned set of controls, derived from current product and process understanding that assures process performance and product quality (ICH Q10).

Every drug substance manufacturing process, whether developed through a traditional or an enhanced approach (or some combination thereof), has an associated control strategy.

A control strategy can include, but is not limited to, the following:

Controls on material attributes (including raw materials, starting materials, intermediates, reagents, primary packaging materials for the drug substance, etc.);

Controls implicit in the design of the manufacturing process (e.g., sequence of purification steps (Biotechnological/Biological Products), or order of addition of reagents (Chemical Products));

In-process controls (including in-process tests and process parameters); Controls on drug substance (e.g., release testing).

Reference: ICH guideline Q11

v. Continued Process Verification (CPV)

The CPV is the Stage 3 of Process Validation. The goal of this stage is continual assurance that the process remains in a state of control (the validated state) during commercial manufacture.

This is science and risk-based approach for collection and evaluation of information and data about the performance of the process, which will allow detecting undesired process variability. Evaluating the performance of the process identifies problems and determines whether action must be taken to correct, anticipate, and prevent problems so that the process remains in control (§ 211.180(e)).

vi. Critical process parameter (CPP):

A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.

Reference: ICH guideline Q8

vii. Critical Material Attribute (CMA)

Critical material attribute (CMA) are defined as A material whose variability (physical, chemical, biological or microbiological property or characteristic of an input material) has an impact a critical quality attribute and therefore it should be monitored or controlled to ensure desired drug product quality.

Reference: http://www.rsc.org/

viii. Design Space

The design space is the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.

Working within the design space is not considered a change. Movement out of the design space is considered to be a change, and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval.

Reference: ICH guideline Q8 (R2)

ix. Formal Experimental Design (synonym: design of experiments)

A Formal Experimental Design is a structured, organized method for determining the relationship between factors affecting a process and the output of that process.

Reference: ICH guideline Q8 (R2)

x. Lifecycle

Lifecycle includes all phases in the life of a product, from the initial development through marketing until the product’s discontinuation.

Reference: ICH guideline Q8 (R2)

xi. Normal Operating Range (NOR)

The NOR is a defined range, within (or equal to) the Proven Acceptable Range, specified in the manufacturing instructions as the target and range at which a process parameter is controlled, while producing unit operation material or final product meeting release criteria and CQAs.

Reference: Process Robustness – A PQRI White Paper, Pharma. Engin. 2006.

xii. Key Process Parameter (KPP; synonym: key operational parameter)

This is an input process parameter that should be carefully controlled within a narrow range and is essential for process performance. A key process parameter does not affect product quality attributes. If the acceptable range is exceeded, it may affect the process (e.g., yield, duration) but not product quality.

Reference: Technical Report No. 42: Process Validation of Protein Manufacturing; Parenteral Drug Association: 2005.

xiii. Non-Key Process Parameter (Non-KPP; synonym: non-key operational parameter)

This is an input parameter that has been demonstrated to be easily controlled or has a wide acceptable limit. Non-key operational parameters may have an impact on quality or process performance if acceptable limits are exceeded.

Reference: Technical Report No. 42: Process Validation of Protein Manufacturing; Parenteral Drug Association: 2005.

xiv. Process Parameter (synonym: operational parameter)

This is an input variable or condition of the manufacturing process that can be directly controlled in the process. Typically, these parameters are physical or chemical (e.g., temperature, process time, column flow rate, column wash volume, reagent concentration, or buffer pH).

Reference: Technical Report No. 42: Process Validation of Protein Manufacturing; Parenteral Drug Association: 2005.

xv.Platform Manufacturing

This means the development of a production strategy for a new drug starting from manufacturing processes similar to those used to manufacture other drugs of the same type (the production for which there already exists considerable experience).

Reference: ICH guideline Q11

xvi.Process Analytical Technology (PAT)

A PAT is a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.

Reference: ICH guideline Q8 (R2)

xvii.Process Performance Qualification (PPQ)

This is the second element of Process Qualification. It includes a combination of the actual facility, utilities, equipment, and trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches. A successful PPQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected. Batches prepared are also called ‘Conformance batches’ or ‘PPQ batches’.

Reference: Guidance for Industry: Process Validation: General Principles and Practices; U.S. Food and Drug Administration: 2011.

xviii.Process Qualification

This qualification confirms that the manufacturing process, as designed, is capable of reproducible commercial manufacturing..

Reference: Guidance for Industry: Process Validation: General Principles and Practices; U.S. Food and Drug Administration: 2011.

It consists of following 2 important elements:

(i) Qualification of Facility, Equipment, and Utilities

(ii) Process Performance Qualification

xix. Process Robustness

Ability of a process to tolerate variability of materials and changes of the process and equipment without negative impact on quality is known as process robustness.

Reference: ICH guideline Q8 (R2)

xx. Process Validation

As per US FDA

Such validation is the collection and evaluation of data from the process design stage to commercial production, which establishes with scientific evidence that a process is capable of consistently delivering quality products.

Reference: Guidance for Industry: Process Validation: General Principles and Practices; U.S. Food and Drug Administration: 2011.

As per EMA

Such validation comprises documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.

Reference: Draft Guideline on Process Validation, MA/CHMP/CVMP/QWP/70278/2012-Rev1; European Medicines Agency: 2012.

xxi. Prospective approach to PPQ

This indicates an approach wherein the Process Performance Qualification batches, manufactured using a qualification protocol, are released for distribution only after complete execution of the Process Performance Qualification Study

Reference: ISPE Guidance

xxii. PPQ re-verification

This indicates the repeating of a part of or a complete PPQ study in the event of changes in the process, equipment, etc. or as a recommendation of the CPV process to verify whether a process continues in a validated state of control and/or to verify that the changes do not adversely impact process characteristics and product quality or the validated state of control of the process

Reference: ISPE Guidance

xxiii. Product Lifecycle

All phases of product stats from the initial development through marketing until the product discontinuation.

xxiv. Process Validation Master Plan (synonym: validation master plan)

This is a document that defines the process validation scope and rationale and that contains the list of process validation studies to be performed.

Reference: Technical Report No. 42: Process Validation of Protein Manufacturing; Parenteral Drug Association: 2005.

xxv. Quality

This indicates the suitability of either a drug substance or drug product for its intended use. This term includes such attributes as the identity, strength and purity.

Reference: ICH guideline Q6A

xxvi. Quality by Design (QbD)

This means a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.

Reference: ICH guideline Q8 (R2)

xxvii. Quality Target Product Profile (QTPP)

QTPP is a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.

Reference: ICH guideline Q8 (R2)

xxviii. Verification

Verification is a systematic approach to verify that manufacturing systems, acting alone or in combination, are fit for intended use, have been properly installed, and are operating correctly. This is an umbrella term that encompasses types of approaches to ensure that the systems are fit for the designed purpose. Other terms used are qualification, commissioning and qualification, system validation, etc.

Reference: ASTM E2500-07. Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment; American Society for Testing and Materials: 2007.

xxix. Worst Case

A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, that pose the greatest chance of process or product failure (when compared to ideal conditions). Such conditions do not necessarily induce product or process failure.

Reference:  EudraLex: The Rules Governing Medicinal Products in the European Union: Volume 4 Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex. 15.

Qualification and Validation; European Commission: 2014.

2. What are the Stages of Process Validation?

Stage 1 – Process Design

Stage 2 – Process Qualification

Stage 3 – Continued Process Verification

3. What is an integrated team approach to process validation?

Integrated team approach to process validation that includes expertise from a variety of disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance).

4. Explain “Process Design”, Stage 1 of process validation.

Objective: To design a process that can consistently deliver a commercial product meeting quality attributes.

a. Building and Capturing Process Knowledge and Understanding from

• Previous experience with similar processes

• Product and process understanding (from clinical and pre-clinical activities)

• Analytical characterization

• Published literature

• Engineering studies/ batches

• Clinical manufacturing

• Process development and characterization studies

• Product development activities

• Design of Experiment (DOE) studies to develop process knowledge and relationships between the variable inputs (e.g., component characteristics 13 or process parameters) and the resulting outputs (e.g., in-process material, intermediates, or the final product)

• Computer-based or virtual simulations of certain unit operations or dynamics can provide process understanding and help avoid problems at commercial scale

• Documentation of process understanding, activities and studies

b. Establishing a Strategy for Process Control

An appropriate control strategy is based on knowledge and experience gained in Stage 1 that will help to control the manufacturing process.

Strategy for Process Control includes the following elements:

• Raw material controls

• In-process and release specifications

• In-process controls

• Performance parameters

• Process parameter set points and ranges

• Process monitoring (data review, sampling, testing)

• Processing and hold times

• Process Analytical Technology (PAT)

5. In which scenarios process control through operational limits and in-process monitoring is essential?

In case of following two possible scenarios, process to be controlled using operational limits and in-process monitoring:

a. When the product attribute is not readily measurable due to limitations of sampling or detectability (e.g., viral clearance or microbial contamination) or

b. When intermediates and products cannot be highly characterized and well-defined quality attributes cannot be identified.

6. Explain “Process Qualification”, Stage 2 of process validation.

Objective: In this stage, the process design is evaluated to determine if it is capable of reproducible commercial manufacture.

This stage has two elements:

i. Design of the facility and qualification of the equipment and utilities

ii. Process performance qualification (PPQ).

a. PPQ Protocol

b. PPQ Protocol Execution and Report

CGMP-compliant procedures must be followed. Successful completion of Stage 2 is necessary before commercial distribution. Products manufactured during this stage, if acceptable, can be released for distribution.

7. Explain “Continued Process Verification”, Stage 3 of process validation.

Objective: The goal of the third validation stage is continual assurance that the process remains in a state of control (the validated state) during commercial manufacture. A system or systems for detecting unplanned departures from the process as designed is essential to accomplish this goal.

8. Explain typical steps for QbD steps.

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9. What is Quality Target Product Profile (QTPP)? Explain with examples.

The QTPP is defined by capturing all relevant quality requirements of the drug product to be developed.

It consists of following:

i. Dosage form and strength, route of administration, delivery systems, container and closure system etc.

ii. Drug substance quality attributes required for intended drug product, i.e. physical, chemical, and biological properties

iii. Drug product quality attributes required for dosage form, i.e. physical, chemical and microbiological attributes of drug products.

iv. Bioavailability attributes, i.e. dissolution requirement or other relevant characteristics. v. Excipient quality attributes, input material compatibility, stability, pharmacology, etc.

10. What is a control strategy? What shall be included while defining control strategy?

• Raw material controls

• In-process and release specifications

• In-process controls

• Performance parameters

• Process parameter set points and ranges

• Process monitoring (data review, sampling, testing)

• Processing and hold times

• Process Analytical Technology (PAT)

11. Which FDA guidance or Code of Federal Regulation suggests having hold time studies of the products?

Establishing production time limits is an example of a control to prevent growth of objectionable microorganisms. Per 21 CFR 211.111, time limits for the completion of each phase of production, when appropriate, must be established and followed. For example, if a firm finds it necessary to hold a bulk topical or liquid product for several months until it is filled, the firm might establish a holding time limit to help prevent objectionable microbial buildup. Validation and control over microbial content of purified water systems used in certain topical products are also examples of such procedures (see FDA guidance, referenced below).

References: 

21 CFR 211.113: Control of microbiological contamination

21 CFR 211.165: Testing and release for distribution

21 CFR 211.111: Time limitations on production

FDA Guidance for Industry, 2011, Process Validation: General Principles and Practices

12. Which EMA guidance suggests having hold time studies of the products?

4 July 2017, EMA/CHMP/QWP/245074/2015, Committee for Human Medicinal Products (CHMP), Guideline on manufacture of the finished dosage form

As per guideline

“Depending on the nature of the process and the product (e.g. sterile products), manufacturing durations of critical steps and hold times should be stated and justified”.

“Where relevant, the maximum holding times of the bulk product or, alternatively, the maximum batch manufacturing time from start of product manufacture to completion of packaging into the final primary container for marketing should be stated, appropriately justified and supported by data in relevant parts of the dossier (e.g. challenging the maximum hold time in process validation studies or providing dedicated stability studies for the bulk storage)”.

13. Which WHO guidance suggests having hold time studies of the products?

WHO Technical Report Series No. 992, 2015, Annex 4, General guidance on hold-time studies.

As per guidance

“Normally, intermediate and bulk products should not be stored beyond the established hold time. The choice of maximum holding period should be supported by relevant data. Studies may extend beyond the chosen maximum but it is not necessary to extend testing to determine the extreme limits at which failure occurs”.

14. What are the different guidelines/ regulations describing requirement of cleaning validation?

A. U.S. Food and Drug Administration (U.S. FDA)

PART 211 — CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS – Subpart D – Equipment

Source: Sec. 211.67 Equipment cleaning and maintenance.

Questions and Answers on Current Good Manufacturing Practices – Equipment

Source: https://www.fda.gov/drugs/guidances-drugs/questions-and-answers-current-good-manufacturing-practices-equipment

GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES

Source: https://www.fda.gov/validation-cleaning-processes-793

B. European Medicines Agency (EMA)

20 November 2014, EMA/CHMP/ CVMP/ SWP/169430/2012, Committee for Medicinal Products for Human Use (CHMP), Committee for Medicinal Products for Veterinary Use (CVMP), Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities

Source: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-setting-health-based-exposure-limits-use-risk-identification-manufacture-different_en.pdf

19 April 2018 EMA/CHMP/CVMP/SWP/246844/2018 Committee for Medicinal Products for Veterinary Use (CVMP) Committee for Medicinal Products for Human Use (CHMP) Questions and answers on implementation of risk-based prevention of cross-contamination in production and ‘Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’ (EMA/CHMP/CVMP/SWP/169430/2012)

Source: https://www.ema.europa.eu/en/documents/other/questions-answers-implementation-risk-based-prevention-cross-contamination-production-guideline_en.pdf

C. World Health Organization (WHO)

QAS20 849 Points to consider on the different approaches –including HBEL – to establish carryover limits in cleaning validation for identification of contamination risks when manufacturing in shared facilities

Source: https://www.who.int/medicines/areas/quality_safety/quality_assurance/QAS20_849_points_to_consider_on_cleaning_validation.pdf?ua=1

WHO good manufacturing practices for active pharmaceutical ingredients 

Source: https://www.who.int/medicines/areas/quality_safety/quality_assurance/GMPActivePharmaceuticalIngredientsTRS957Annex2.pdf

Quality assurance of pharmaceuticals: A compendium of guidelines and related materials 

Source: https://www.who.int/medicines/areas/quality_safety/quality_assurance/QualityAssurancePharmVol2.pdf

Points to consider when including6 Health-Based Exposure Limits (HBELs) in cleaning validation 

Source: https://www.who.int/medicines/areas/quality_safety/quality_assurance/QAS20_849_Rev.1_points_to_consider_hbels_in_cleaning_validation.pdf?ua=1

D. Pharmaceutical Inspection Co-operation Scheme (PIC/S)

Cross-contamination in shared facilities (PI-043-1)

Source:  https://picscheme.org/docview/2270

Guideline on Setting HBEL for use in risk identification in the manufacture of different medicinal products in shared facilities (PI 046-1)

Source: https://picscheme.org/docview/2467

Guide to GMP for medicinal products Part 1 (PE 009-14 (Part I))

Source: https://picscheme.org/docview/4205

Inspection of Health Based Exposure Limit (HBEL) Assessment and use in Quality Risk Management (PI 052-1)

Source: https://picscheme.org/docview/1947

E. Therapeutic Goods Administration (TGA)

The TGA is adopting version PE009-13 of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products (PIC/S Guide to GMP)

Source: https://www.tga.gov.au/sites/default/files/transition-new-gmp-requirements-medicinal-products.pdf

TGA interpretation and expectations for demonstrating compliance  ‍

Source: https://www.tga.gov.au/resource/pe009-pics-guide-gmp-medicinal-products

A presentation on Cleaning Validation by TGA

Source: https://www.tga.gov.au/sites/default/files/presentation-cleaning-validation.pdf

F. Health Canada

Cleaning validation guide (GUI-0028)

Source: https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/good-manufacturing-practices/validation/cleaning-validation-guidelines-guide-0028.html

G. Active Pharmaceutical Ingredients Committee (APIC)

Guidance on aspects of Cleaning Validation in Active Pharmaceutical Ingredient Plants APIC Cleaning Validation 2016

Source: https://apic.cefic.org/pub/APICCleaningValidationGuide-updateSeptember2016-final.pdf

Guidance on aspects of Cleaning Validation in Active Pharmaceutical Ingredient Plants APIC Cleaning Validation 2021

Source: https://apic.cefic.org/publications/APIC_Cleaning-validation-guide_2021.pdf

H. Parenteral Drug Association (PDA)

PDA Technical Report 29: Points to Consider for Cleaning Validation

PDA Technical Report 49: Points to Consider for Biotechnology Cleaning Validation

I. International Society For Pharmaceutical Engineering (ISPE)

Baseline Guide Vol 7: Risk-Based Manufacture of Pharma Products 2nd Edition ISPE Risk-MaPP

Cleaning Validation Lifecycle – Applications, Methods, and Controls ISPE Cleaning Validation Guideline

J. American Society For Testing and Materials (ASTM)

ASTM E3106 – 18e1 (Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation)

Standard Guide for Derivation of Health-Based Exposure Limits (HBELs) ASTM E3219

15. What are the different guidelines/ regulations describing requirement of equipment qualification?

a. EU GMP Annex 15 “Qualification and Validation”, Eudralex 2015

b. PIC/S GMP for Medicinal Products Annex 15 “Qualification and Validation” PE009-14 (Annexes) 2018

c. PE 009-15 (Annexes) ANNEX 15 – Qualification and validation

d. PI 006-3 – Validation Master Plan installation and operational qualification non-sterile process validation cleaning validation

e. Subpart C – Building and Facilities Section 211.42 – Design and Construction Features

f. USP 37: “Analytical Instrument Qualification”, (section 1058), The United States Pharmacopeial Convention, 2016

g. ISPE Baseline Guide Volume 5: “Commissioning & Qualification”, Second Edition, 2019

h. ASTM E2500: “Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment”, ASTM 2020

i. ISPE Good Practice Guide: Applied Risk Management for Commissioning and Qualification, ISPE 2011

j. PDA Technical Report 54-5: “Quality Risk Management for the Design, Qualification, and Operation of Manufacturing Systems”, PDA 2017

k. EU GMP Annex 11 “Computerised Systems”, Eudralex 2011

l. US FDA Guidance for Industry: “Process Validation: General Principles and Practices, 2011

m. ISPE GAMP® 5 Guide: “A Risk-Based Approach to Compliant GxP Computerized Systems”, ISPE 2008

n. ISPE Guide: “Science and Risk-Based Approach for the Delivery of Facilities, Systems, and Equipment”, ISPE 2011

o. FDA US CFR 21 part 11 Electronic Records; Electronic Signatures 2003

p. Health Canada: Guide to validation – drugs and supporting activities (GUI-0029)

q. WHO Technical Report Series, No. 937,  Annex 4: Supplementary guidelines on good manufacturing practices: validation

For more interview questions and answers Click Here

Top 70+ Interview Questions for Pharmaceutical Microbiology

Interview Questions and Answers on Pharmaceutical Microbiology

This page covers most of the interview questions and answers asked during a technical interview round of Pharmaceutical Microbiology.

You will find interview questions and answers on microbiology basics, pharmacopoeial chapter and sections applicable for microbiology, Culture Media, Growth Promotion test, microbiological quality control for sterile and non-sterile dosage forms, good practice in a microbiological laboratory, aseptic technique to be followed in the microbiological laboratory, pure culture, Pyrogens and endotoxins, different staining techniques used in the pharmaceutical microbiology laboratory, microbial identification, Gram-staining technique, fungal staining, approved culture collections, sterility testing and environmental monitoring.

The interview questions cover questions from basic to advance level of technical aspects. These interview questions and answers will help to crack an interview, enhance your knowledge, and also be helpful for the interviewer who is involved in the recruitment process.

You will find it much more enjoyable while going through these interview questions and answers. So enjoy learning, and best of luck with your interview! Happy Learning.

1. Explain the parts of compound light microscopes used in the pharmaceutical microbiology laboratory?

Compound light microscopes - pharmaceutical microbiology

Illuminator: Light source at the base of the microscope enable better view of object;

Condensor: This is a two lens system that collects and concentrates light from the illuminator and directs it to the iris diaphragm;

Iris diaphragm: regulates the amount of light entering the lens system;

Stage: This is a platform for the slide with hole in the center to let light from the illuminator pass through. It consists of clips to hold the slide lace;

Eye pieces: To view object;

Objectives: To magnify the object as per rating on it

2. What are the pharmacopoeial chapter and sections applicable for microbiology?

Pharmacopoeial chapter(s)Use
Microbiological examination of nonsterile products: total viable aerobic count (Ph. Eur. 2.6.12, USP <61>)   USP <2021> Microbial enumeration tests-nutritional and dietary supplements   USP <2023> Microbiological attributes of nonsterile nutritional and dietary supplementsOrganism count in raw materials, water, finished products
Microbiological examination of nonsterile products: tests for specified organisms (Ph. Eur. 2.6.13, USP <62>)   USP <2022> Microbiological procedures for absence of specified microorganismsnutritional and dietary supplementsType of organisms present in raw materials, water, finished products
Ph. Eur. 5.1.4 Microbiological quality of pharmaceutical preparations/USP <1111> Microbiological attributes of nonsterile pharmaceutical productsDetermining limits and control factors
Sterility (Ph. Eur. 2.6.1, USP <71>) Pyrogens/endotoxin Rabbit Pyrogen Test (Ph. Eur. 2.6.8, USP<151>) Limulus amoebocyte lysate (LAL) bacterial endotoxin test (Ph. Eur. 2.6.14, USP<85>)Sterility test for finished products endotoxin test for raw materials, pharmaceuticals waters, finished products
Antimicrobial preservative efficacy testing (Ph. Eur. 5.1.3, USP <51>)Antimicrobial preservative efficacy
Microbiological assay of antibiotics (E.P 2.7.2., USP<81>)Assays of antibiotic
USP <1112> Application of water activity determination to nonsterile pharmaceutical productsWater activity can be used to predict microbial proliferation in the product
USP <1211> Sterilization and sterility assurance of compendial articles. There are a series of subchapters that describe specific sterilization methodsSterilization and microbial reduction
USP <55> Biological indicatorsBiological indicators for assessing microbial reduction
USP <1113> Microbial characterization, identification, and strain typingMicrobial identification
USP <1117> Microbiological best laboratory practiceManagement of microbiological good laboratory practice
USP <1116> Microbiological control and monitoring of aseptic processing environmentsEnvironmental monitoring for aseptic environments
Ph. Eur. 5.1.6 Alternative methods for control of microbiological quality/ USP <1223> Validation of alternative microbiological methodsAlternative methods/ Rapid microbiological methods
USP <1115> Bioburden control of nonsterile drug productsBioburden control
USP <1227> Validation of microbial recovery from pharmacopeial articlesMicrobial method validation

3. Which factors of culture media affects the cultivation of microorganisms?

Culture media factors affecting the cultivation of microorganisms are optimum nutrients, oxygen or other gases, moisture, pH, and temperature.

4. What are the important nutrients of culture media that affects the cultivation of microorganisms?

The key nutrients of culture media that affects the cultivation of microorganisms are sources of carbon, nitrogen, water, inorganic phosphates and sulfur, vitamins, and trace metals.

5. Whose name recognize as “The Father of Culture Media”?

Robert Koch (1843–1910) discovered that broths based on fresh beef serum or meat extracts (so-called bouillons, the term “broth” for liquid culture medium being analogous to broth or soup) produced optimal growth.

6. Who was the first scientist cultivated the microorganisms on a growth medium?

The French chemist and microbiologist, Louis Pasteur (1922–1985).

7. Petri dish is named based on which scientists’ contribution?

Julius Richard Petri (1852–1921)

8. What are the different types of culture medium used in pharmaceuticals and what is the purpose of those?

Types of mediumUse
Nutrient agar or broth and tryptone soya agar or broth. Tryptone soya agar (equivalent to soyabean casein digest medium)→ Environmental monitoring→ Isolation and cultivation of nonfastidious and fastidious microorganismsNote: Fastidious bacteria are bacteria that need special nutritional supplements and conditions to grow on agar plates. Nonfastidious bacteria are bacteria that do not need special nutritional supplements and conditions to grow on agar plates
Tryptone soya brothSterility testing and as a general growth broth in microbial enumeration tests, as well as used for media simulation trials
vegetable peptone brothMedia filling trials
fluid thioglycollate mediumused for the growth of bacteria (aerobic and anaerobic) as a part of the sterility test
fungiSabouraud dextrose agar or malt extra agar
R2AMicrobiological examination of water (This is a low nutrient agar used for the cultivation of heterotrophic microorganisms).
Columbia blood agarDetection of hemolytic reactions by Staphylococci

9. What is the process of Growth Promotion test of microbiology culture media? What should be the acceptance criteria?

1. Medium to be inoculated with a microorganisms <100 Colony Forming Units (CFU).

2. Use not less than five unique strains as recommended by the pharmacopoeias and two organisms from environment isolates on rotation basis (It should be within the five passages from the original reference culture seed lot).

3. Compare the growth on the medium with medium previously approved culture lot.

4. Acceptance is no more than a factor of 2 differences in productivity ratio calculations.

10. What is the calculation of productivity ratio and what is the acceptance criterion for agar media plate or solid media for growth promotion test?

Productivity ratio =

Mean of two test plates (cfu)/ Mean of two comparative control plates (cfu)

An acceptable productivity ratio should be (0.5 – 2.0). That is equivalent to a 50 – 200 % recovery.

11. What are the quantitative techniques of Growth Promotion Tests for Solid media?

Quantitative techniques of Growth Promotion Tests are of two types.

● Ecometric

● Miles – Misra (Drop Count)

12. Explain ecometric method of Growth Promotion Tests?

This technique is semi-quantitative variant of the streaking.

This technique is operator-dependent and has lower precision. However, it can be used to great effect with practice.

Following are the steps:

● A fresh suspension of the challenge organism is taken into a calibrated loop (One loopful of inoculm).

● Five streaks are streaked out into four quadrants onto the agar plate along with a final streak in the center of the plate.

● These plates are then incubated overnight for growth.

● The patterns of growth are interpreted to provide an Absolute Growth Index (AGI)

13. Explain Miles – Misra technique (the drop count technique) of Growth Promotion Tests?

This technique involves spreading droplets of known quantities (10 μL) of microbial suspensions.

The test plate is compared against control plate after incubation to verify number of colonies recovered.

Note:

The accuracy of the method is dependent on following factors:

● Dilution used

● Number of colony forming units (cfu) in the inoculum

● Volume of the inoculums

● Spreading technique

14. What are the quantitative techniques of Growth Promotion Tests for Broth Media?

Quantitative techniques of Growth Promotion Tests for Broth Media are of four types.

● Copious Growth

● End-point Methods

● Most Probable Number (MPN)

● Kinetic Parameters

15. Explain Copious Growth method of Growth Promotion Tests for Broth Media?

This is the method of choice as per compendial. The challenge of broth media is done by comparing the growth over the period of time with a control batch (which provides a qualitative assessment of copious growth). In this method, the challenge organism is inoculated at a very low level (< 100 CFU per unit) and incubated at the prescribed temperature for the prescribed period of time (3 days or 5 days).

The advantage of this method is that it does not require a great deal of labor. Semi-quantitative assessment can be done by constructing a growth index from slight to copious growth (normally a scale of +, ++, or +++).

16. Explain End-point Methods method of Growth Promotion Tests for Broth Media?

In this method, very low levels of inoculum are added to multiple tubes of the two media under testing. Growth frequency is compared between the two media to understand the equivalency.

17. Explain Most Probable Number (MPN) method of Growth Promotion Tests for Broth Media?

This is a Microbial Limits Test. In this method, the unknown sample is prepared in a ten-fold dilution series and added to nutrient broth in replicate tubes. The tubes will then either turn turbid (growth) or remain clear, and allow for an estimate of the most probable number of microorganisms.

18. Explain Kinetic Parameters method of Growth Promotion Tests for Broth Media?

The growth promoting testing of two lots of broth can be compared by measuring the growth curves of same inocula grown side-by-side. The growth rate of an organism can be determined by spectrophotometrically or by viable count.

19. How Growth Promotion Tests for selective media is performed?

Selective media requires a different approach than general purpose media.  The objective of the test for selective media is to see that the media supports the growth of specific microorganisms. Inhibition, colony morphology and pigment are verified during the testing. In order to determine growth of selective media, specific microorganisms are used as positive or negative indicators.

20. What are the steps involved in the manufacturing of culture media?

a. Collection of prerequisite

● Decide batch size

● Vessel for holding or dispensing the media

● Weighing balance

● Petri dishes/ Containers

● Dehydrated media

b. Rehydration of media

● Media powder is rehydrated by mixing the medium in the volume of water (Amount should be based on manufacturer’s instruction)

● Homogenize the solution by mixing

● Care must be taken to avoid scorching the media.

● The media should clarify near boiling (95–100 °C), and the media should only be allowed to boil less than 1 min.

c. Sterilization

d. Addition of supplements (depending on the types of media requirement)

e. Filling in container

f. Status labeling

21. What are the acceptance criteria for microbiological quality of non-sterile dosage forms and raw materials?

ApplicationTAMCTYMCSpecified microorganisms
Non-aqueous preparations for oral use1000100Escherichia coli absent in 1 g or 1 mL
Aqueous preparations for oral use10010Escherichia coli absent in 1 g or 1 mL
Rectal use1000100Need based
Oromucosal use Gingival use Cutaneous use Nasal use Auricular use10010Staphylococcus aureus absent in 1 g or 1 mL Pseudomonas aeruginosa absent in 1 g or 1 mL
Vaginal use10010Staphylococcus aureus absent in 1 g or 1 mL Pseudomonas aeruginosa absent in 1 g or 1 mL Candida albicans absent in 1 g or 1 mL
Inhalation use  10010Staphylococcus aureus absent in 1 g or 1 mL Pseudomonas aeruginosa absent in 1 g or 1 mL Bile-tolerant gram-negative bacteria absent in 1 g or 1 mL
Transdermal patches10010Staphylococcus aureus absent in 1 g or 1 mL Pseudomonas aeruginosa absent in 1 g or 1 mL
Raw material for pharmaceutical use1000100Need based

22. What are the risks because of microorganism in the pharmaceutical formulation if not within the acceptable limit?

● Decomposition of the product

● Degradation of product

● Infection to the patient

23. Give few examples of good practice in a microbiological laboratory.

● Required equipment and media should sterilized prior to use.

● Sterilized equipment and media should be maintained and stored in such a way that it should not be contaminated.

● Frequently disinfect hands and working surfaces while carryout aseptic operations.

● Fly, rodent and pest control.

● Use personnel protective equipment such as laboratory coat, safety glasses, and gloves.

● Drinkable and eatables should not be allowed in the laboratory.

● Sterilize contaminated used media and waste prior to disposal.

● Pipetting should not be done mouth.

24. Why aseptic technique should be followed in the microbiological laboratory?

To prevent contamination and cross-contamination in microbiology laboratory. Probability of contamination in the laboratory is – samples, media, environment, facility etc.

25. How asepsis can be achieved in the laboratory?

● Frequent washing and disinfecting hands.

● Use of unidirectional airflow station for critical operations.

● Handling of positive control at the end of analysis.

● Not touching the samples and accessories directly by hand.

26. What is pure culture?

A pure culture is a population of cells or multicellular organisms growing in the absence of other species or types in which cells are genetic clones of one another.

27. What is most common method to isolate individual cells and produce a pure culture?

The most common method to isolate individual cells and produce a pure culture is to prepare a streak plate method.

28. Explain Streak Plate Method.

a. Sterilize the inoculating loop by heating it until red hot in a flame until it is red hot. Allow it to cool.

b. Pick up a loop full of liquid inoculum or bacterial growth from the surface of an agar plate and, starting about 2.5 cm in from the edge of the plate, streak lightly back and forth with the loop flat, making close, parallel streaks back to the edge of the plate to a quarter of the plate.

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c. Sterilize the loop and cool again, going back to the edge of area first quarter that you just streaked, extend the streaks into the second quarter of the plate.

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d. Repeat the same process for remaining two quarter of the plate.

e. Flame and cool the loop again.

29. What should be done during microbiology testing if sample exhibit antimicrobial activity?

When the sample possesses antimicrobial activity, it that requires neutralization. Following are commonly used principle for neutralization:

● Chemical neutralization

● Enzymatic neutralization

● Dilution

30. What is Pyrogens and endotoxins?

Pyrogens and endotoxins are a heterogeneous group of chemical entities that cause fever when injected.

31. What is the source of pyrogens and endotoxins?

Pyrogens can be nonbacterial as well as bacterial in origin.

In the pharmaceutical industry, mostly observed source is from Gram-negative bacteria. That is the lipopolysaccharide (LPS) from the bacterial cell wall.

Pyrogens are the metabolic byproduct of the Gram-negative bacteria.

32. Explain types of microbial identification methods.

Identification methods can be divided into two types:

● Phenotypic

● Genotypic

33. What are the differences between Phenotype and Genotype?

● “Genotype” is an organism’s full hereditary information.

● “Phenotype” is an organism’s actual observed properties, such as morphology, development or behavior.

34. What are the different staining techniques used in the pharmaceutical microbiology laboratory?

● Gram-stain

● Bacterial spore stain

● Fungal staining

● Ziehl–Neelsen stain

35. What is the objective of microbial identification?

The objective of microbial identification is to differentiate one microbial isolate from another with respect to family (genus) and a species or a particular strain.

36. What are the taxonomic terms for microbial identification?

● Family: group of similar genera

● Genus: group of similar species

● Species: group of similar strains

● Type: strains within a species

● Strain: an isolate of a particular species

37. What is the first step of microbial identification?

The first step of most identification program is colony and cellular morphology of the microorganism.

Colony morphology is a method that used to describe the characteristics of an individual colony of bacteria on agar media in a Petri dish.

Colony morphology is normally classified based on the form, elevation and margin. This can be further classified as follows.

38. What is Gram-stain?

The Gram stain is an important technique for identification of bacteria. It divides bacteria into two groups, Gram-positives and Gram-negatives.

39. How the Gram-staining technique is useful?

Gram-staining technique that allows to visualize the morphological types of bacteria using a compound light microscope under magnification of 100x.

40. Explain the principle of the Gram-staining technique?

Step 1: Crystal violet (primary stain) aqueous solutions consist of +ve and –ve ions. These ions penetrate through the cell wall and cell membrane of all types of bacteria. The +ve ion stains the bacterial cells and stains the cells purple.

Step 2: Iodide (the mordant) interacts with crystal violate and forms complexes.

Step 3: Decolorizer (made of acetone and alcohol 95%) interacts with the lipids of the cell membrane. A Gram-negative cell loses its outer lipopolysaccharide membrane, and the inner peptidoglycan layer is left exposed.

On the other hand, a Gram-positive cell becomes dehydrated because of property of decolorizer. The complexes trapped within the Gram-positive cell due to the multilayered nature of the peptidoglycan.

Step 4: When decolorization is added, the Gram-positive cell remains purple, and the Gram-negative cell loses its purple color.

Step 5: A Safranin, the counterstain is used to provide color to Gram-negative bacteria a pink/ red color.

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41. What is the procedure of Gram-staining technique?

a. Take a clean, grease free slide.

b. Prepare the smear of suspension on the clean slide with a loopful of sample.

c. Air-dry or heat-fix smear of cells for around 1 minute with crystal violet staining reagent. (Note: Too heavy or too light cell concentration will affect the Gram Stain results.)

d. Rinse the slide with gentle stream of tap water for 2-3 seconds.

e. Flood the gram’s iodine for 1 minute and wash with gentle stream using tap water for 2-3 seconds.

f. Flood slide with 95% alcohol or acetone for about 15-20 seconds until decolorizing agent running from the slide shows clear liquid.

g. Add counterstain, safranin and wait for 1 minute

h. Wash slide in a gentile stream of tap water until it appear colorless.

i. Blot dry with absorbent paper.

j. Observe under oil immersion using a Brightfield microscope.

k. Results:

Gram-negative bacteria will stain pink or red

Gram-positive bacteria will stain blue or purple

42. What is the procedure of Gram-staining technique?

a. Primary Stain: Crystal Violet Staining Reagent.

Solution A for crystal violet staining reagent

Crystal violet (90% dye content) – 1g

2g Ethanol, 95% (v/v) – 10 ml

Solution B for crystal violet staining reagent

Ammonium oxalate, 0.4 g

Distilled water, 40 ml

Mix solution A and solution B to obtain crystal violet staining reagent. Store for 1 day and then filter using filter paper.

b. Mordant: Gram’s Iodine

Iodine, 0.5 g

Potassium iodide, 1.0 g

Distilled water, 150 ml

Triturate iodine and potassium iodide in a mortar and add water slowly with continuous trituration until the iodine is dissolved. Store in amber bottles.

c. Decolorizing Agent

Ethanol, 95% (vol/vol)

Alternate decolorizing agent – 1:1 acetone and ethanol mixture.

d. Counterstain: Safranin

Use 1.25g Safranin O and mix it with 50 ml 95% Ethanol (Solution A). Take this Solution A 5 ml and mix it with 45 ml distilled water

43. Which indicators are used for spore staining?

Malachite green (a triarylmethane dye) and a safranin (an azonium compound) counterstain is useful tool in identifying the presence or absence of spores.

This is referred to as the Schaeffer-Fulton stain.

44. Explain the Schaeffer-Fulton staining method for endospore staining technique?

1. Prepare a bacterial smear on a clean slide, air dry and gently heat fix.

2. Cover the slide with a piece of paper towel, and place on a staining rack over the water bath with boiling water.

3. Flood the paper towel on the slide with Malachite green (primary stain). Steam the slide for about 5 minutes.

4. Remove the slide from the water bath, and remove the paper towel from the slide.

5. Allow the slide to cool, and then rinse with deionized water until the water runs clear.

6. Drain excess water and apply Safranin (counterstain) for 2 minutes.

7. Rinse Safranin off with deionized water, and blot the slide dry with blotting paper.

8. Examine the slide with a light microscope under oil immersion objective

Result:

Endospores appears green

Vegetative cells appear red or pink

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45. What is Lactophenol cotton blue stain or fungal staining?

Lactophenol cotton blue stain is used to examining yeast and filamentous fungi under microscope.

Phenol acts as a disinfectant to kill living organisms

Lactic acid used to preserve the fungal structures

Cotton blue is used to stain fungal cell wall and other fungal structures

On staining, it fungus will be with blue colored spores and structures, such as hyphae.

The identification of fungi using macroscopic and microscopic techniques is difficult and requires a trained eye.

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46. What reagents used to prepare Lactophenol cotton blue staining solution?

Distilled water

Cotton Blue or Aniline Blue

Phenol Crystals

Glycerol

Lactic acid

70% ethanol

47. What is use of Ziehl-Neelsen stain?

The objective of Ziehl-Neelsen stain is to differentiate bacteria into acid fast group and non-acid fast groups.

48. What Acid-Fast stain called as Ziehl-Neelsen stain?

This technique was first developed by Ziehl and later on modified by Neelsen, therefore, this method is also called as Ziehl-Neelsen staining techniques.

ReagentsColor of Acid fastColor of Non-acid fast
Primary dye – Carbol fuchsinRedRed
Decolorizer – Acid alcoholRedColorless
Counter stain – Methylene blueRedBlue

49. What is Total viable aerobic count?

Total viable aerobic count is designed to count the number of microorganisms (as colony forming units, CFUs) in a non-sterile pharmaceutical product or raw materials.

It is father divided into two parts, total aerobic microbial count (TAMC) and total yeast and mould counts (TYMCs).

50. Which are the methods used for analysis of total viable aerobic count?

● Membrane filtration technique – Sample is filtered and the filter is placed on defined media

● Pour plate technique – Sample aliquot is taken and placed in a Petri dish and specified media poured onto the sample

● Spread plate technique – Sample aliquot is placed on the surface of defined media and smeared evenly over the surface

● Most probable number (MPN) technique – This method is used for mainly insoluble materials. The sample dilutions are placed into a series of replicate tubes and the number of tubes showing growth give a statistical evaluation of the number of microorganisms in the sample.

51. Which is Bioburden test Method Validation?

The Bioburden Method Validation is done to demonstrate the adequacy of  sample preparation method and the ability of the media to recover microorganisms in the presence of the test sample. Following should be considered during the method validation.

(a) Growth promotion of media

(b) Sample preparation

(c) Test method (d) Sample neutralization

52. Which are the various organization from where approved culture collections of different train of microorganisms can be obtained?

● American Type Culture Collection (ATCC)

● National Collection of Industrial and Marine Bacteria (NCIMB)

● Collection of Institute Pasteur (CIP)

● Imperial Mycological Institute (IMI)

● National Collection of Pathogenic Fungi (NCPF)

● National Biologicals Resources Centre (NBRC)

53. Explain the sample preparation process for Bioburden test.

● Sample handing area: Sample should be prepared on a laboratory bench, within unidirectional airflow cabinet or an isolator.

● Bacteria cultures handling area:  Biosafety cabinet or Microbiological Safety Cabinet should be used.

● Sample preparation for Water-soluble products:

a. Dissolve or dilute the product with ration of 1 in 10 dilution in phosphate buffer solution pH 7.2, If necessary, adjust to a pH of 6 – 8.

b. If required, further dilutions can be done to get not more than 250 CFU/plate in case of TAMC, 50 CFU/plate in case of TYMC.

c. If needed, to dissolve the sample completely, triturate it in a sterile mortar and pestle in an aseptic environment to get a fine powder.

● Sample preparation for Non-fatty and insoluble material in water:

a. Suspend the product with 1 in 10 dilution in phosphate buffer solution pH 7.2.

b. A surfactant such as 1 g/L of polysorbate 80 can be used to assist the suspension of poorly wettable substances.

c. If require, adjust to a pH of 6–8.

d. If required, further dilutions can be done to get not more than 250 CFU/plate in case of TAMC, 50 CFU/plate in case of TYMC.

● Sample preparation for fatty products:

a Dissolve in isopropyl myristate sterilized by filtration, or mix the product to be examined with the minimum necessary quantity of sterile polysorbate 80.

b. Heat if required for NMT 40 °C or, in exceptional cases, to not more than 45 °C and maintain the temperature in a water bath.

c. Add pre-warmed diluent to make a 1 in 10 dilution of the product.

d. Form of an emulsion.

c. If needed, further serial tenfold dilution can be prepared using the diluent containing a suitable concentration of sterile polysorbate 80 or another non-inhibitory sterile surfactant.

54. Explain the method of measurement of microbial concentration in suspension by optical density?

A spectrophotometer method is used to measures turbidity of inoculum suspension. When light passes through a suspension of microorganisms, light gets scattered and the amount of scatter is an indication of the concentration present in the suspension.

While doing the estimation using this method, a calibration curve needs to be constructed using series of the known concentration. Based on the calibration curve, unknown concentration can be easily identified.

55. What are the common sources of pyrogens?

Non-bacterial source:

● Antigens

● Poly nucleotides

● Steroids

● Adjuvants

● Viruses

● Fungi

Bacterial source:

● Streptococcal toxins

● Staphylococcal enterotoxins

● Mycobacterial cell wall components

● Bacterial cell wall – lipopolysaccharides (endotoxins)

56. What are the method used to test pyrogens and endotoxins?

● Rabbit pyrogen test

● Limulus Amoebocyte Lysate (LAL) testing for bacterial endotoxin

57. Is sterility test qualitative or quantitative test?

The sterility test is a qualitative test. Results are written as presence or absence of turbidity based on growth for bacteria and fungi in media.

58. Which are commonly used sterility testing methods?

● Membrane filtration: This is further classified as open method and closed system method.

● Direct inoculation method

59. What components required performing sterility testing by membrane filtration method?

● Filter with pore size 0.45 μm

● Filter diameter about 50 mm

● Cellulose nitrate filters for aqueous, oily, and weak alcoholic solutions

● Cellulose acetate filters for strong alcoholic solutions

60. What are the growth mediums used to perform sterility testing?

● Fluid Thioglycollate Medium for anaerobic bacteria and it also isolates aerobic bacteria

● Soya-bean Casein Digest Medium for the isolation of fungi and aerobic bacteria

61. What types of growth promotion test (GPT) to be done for growth medium used to perform sterility testing?

● GPT for Fluid thioglycollate medium shall be done using Clostridium sporogenes, P. aeruginosa, S. aureus;

● GPT for Soya-bean casein digest medium shall be done using A. niger, B. subtilis, C. albicans.

The medium shall be inoculated with not more than 100 CFU and incubated for 3 days (bacteria) or 5 days (fungi).

Result: Clearly visible growth must be observed.

62 What should be incubation conditions and times for sterility testing?

Incubation conditions and times for sterility testing are as follows:

● Fluid Thioglycollate Medium at 30 – 35 °C

● Soya-bean Casein Digest Medium at 20 – 25 °C ● Total incubation period of 14 days with visual examination for turbidity.

63. How to interpret sterility test validation outcome?

There are two outcomes with the sterility test:

(1) Clearly visible growth – test sample and the control tubes are equivalent

(2) No clearly visible comparable growth – Test needs to be modified and the validation needs to be repeated

64. What should be the environment for sterility testing?

The sterility test environment should be EU GMP Grade A with a Grade B background or a Grade A isolator operator with background Grade C or D.

65. How to collect sterility testing sample during the batch?

The test samples for sterility testing needs to be representative of the batch and entire filling operation that is, beginning, middle, and end of the aseptic fill process. Additionally, sterility test sample required to be collected when unplanned intervention occurred during the batch.

66. What is the composition of Fluid thioglycollate medium?

The composition of Fluid thioglycollate medium is as follows:

Name of ingredientWeight
L-Cystine0.5 g
Agar0.75 g
Sodium chloride2.5 g
Glucose monohydrate/anhydrous5.5/5.0 g
Yeast extract (water-soluble)5.0 g
Pancreatic digest of casein15.0 g
Sodium thioglycollate or0.5 g
Thioglycollic acid0.3 ml
Resazurin sodium solution (1 g/l of resazurin sodium), freshly prepared1.0 ml
Water R1000 ml

pH after sterilization 6.9 to 7.3.

67. What is the composition of Soya-bean casein digest medium?

The composition of Soya-bean casein digest medium is as follows:

Name of ingredientWeight
Pancreatic digest of casein17.0 g
Papaic digest of soya-bean meal3.0 g
Sodium chloride5.0 g
Dipotassium hydrogen phosphate2.5 g
Glucose monohydrate/anhydrous2.5/2.3 g
Water R1 000 ml

pH after sterilization 7.1 to 7.5.

68. While sterility testing using membrane filtration, what should be suitable volume of diluent and sample quantity of product to be examined prescribed?

Liquids sample

Minimum quantity to be used for each medium Quantity per containerMinimum quantity to be used for each medium unless otherwise justified and authorized
• less than 1 mlThe whole contents of each container
• 1-40 mlHalf the contents of each container but not less than 1 ml
• greater than 40 ml and not greater than 100 ml20 ml
• greater than 100 ml10 per cent of the contents of the container but not less than 20 ml
Antibiotic liquids1 ml

Insoluble preparations, creams and ointments sample

Minimum quantity to be used for each medium Quantity per containerMinimum quantity to be used for each medium unless otherwise justified and authorized
Insoluble preparations, creams and ointments to be suspended or emulsifiedUse the contents of each container to provide not less than 200 mg

Solids sample

Minimum quantity to be used for each medium Quantity per containerMinimum quantity to be used for each medium unless otherwise justified and authorized
• less than 50 mgThe whole contents of each container
• 50 mg or more but less than 300 mgHalf the contents of each container but not less than 50 mg
• 300 mg – 5 g150 mg
• greater than 5 g500 mg

Reference: WHO, Document QAS/11.413 FINAL, March 2012

69. Types of filter preferable for sterility testing using filtration method.

Cellulose nitrate filters: For aqueous, oily and weakly alcoholic solutions

Cellulose acetate filters: Strongly alcoholic solutions

70. What is preferred filter diameter for sterility testing using filtration method?

50 mm in diameter

71. Explain Membrane filtration method for sterility testing?

● The filtration apparatus and membrane are sterilized by appropriate means.

● Use membrane filters with nominal pore size not greater than 0.45 μm and diameter 50 mm.

● Solution to be examined shall be filtered under aseptic conditions.

● Aseptically remove the membrane and transfer to the medium.

Method for aqueous solutions:

● Transfer a small quantity of a suitable, sterile diluent such as a 1 g/l neutral solution of meat or casein peptone pH 6.9 to 7.3 onto the membrane in the apparatus and filter.

● Use diluent containing suitable neutralizing substances and/or inactivating substances in the case of antibiotics.

● Transfer the contents of the container or containers to be tested to the membrane or membranes, if necessary after diluting to the volume used in the method suitability test with the chosen sterile diluent but in any case using not less than the quantities of the product to be examined prescribed in Table-1.

● Filter immediately.

● If the product has antimicrobial properties, wash the membrane not less than three times by filtering through it each time the volume of the chosen sterile diluent used in the method suitability test.

● Do not exceed a washing cycle of five times 100 ml per filter, even if during method suitability it has been demonstrated that such a cycle does not fully eliminate the antimicrobial activity.

● Transfer the whole membrane to the culture medium or cut it aseptically into two equal parts and transfer one half to each of two suitable media.

● Use the same volume of each medium as in the method suitability test.

● Alternatively, transfer the medium onto the membrane in the apparatus. Incubate the media for not less than 14 days.

Soluble solids:

Use for each medium not less than the quantity prescribed in Table 3 of the product dissolved in a suitable solvent such as the solvent provided with the preparation, water for injections R, sodium chloride (9 g/l) TS or peptone (1 g/l) TS1 and proceed with the test as described above for aqueous solutions using a membrane appropriate to the chosen solvent.

Oils and oily solutions:

● Use for each medium not less than the quantity of the product prescribed in Table 2.

● Oils and oily solutions of sufficiently low viscosity may be filtered without dilution through a dry membrane.

● Viscous oils may be diluted as necessary with a suitable sterile diluent such as isopropyl myristate R shown not to have antimicrobial activity in the conditions of the test.

● Allow the oil to penetrate the membrane by its own weight then filter, applying the pressure or suction gradually.

● Wash the membrane at least three times by filtering through it each time about 100 ml of a suitable sterile solution such as peptone (1 g/l) TS1 containing a suitable emulsifying agent at a concentration shown to be appropriate in the method suitability test, for example polysorbate 80 at a concentration of 10 g/l.

● Transfer the membrane or membranes to the culture medium or media or vice versa as described above for aqueous solutions, and incubate at the same temperatures and for the same times.

Ointments and creams:

● Use for each medium not less than the quantities of the product prescribed in Table 2.

● Ointments in a fatty base and emulsions of the water-in-oil type may be diluted to 1 per cent in isopropyl myristate R as described above, by heating, if necessary, to not more than 40 °C.

● In exceptional cases it may be necessary to heat to not more than 44 °C.

● Filter as rapidly as possible and proceed as described above for oils and oily solutions.

Table: 1 – Liquids sample

Minimum quantity to be used for each medium Quantity per containerMinimum quantity to be used for each medium unless otherwise justified and authorized
• less than 1 mlThe whole contents of each container
• 1-40 mlHalf the contents of each container but not less than 1 ml
• greater than 40 ml and not greater than 100 ml20 ml
• greater than 100 ml10 per cent of the contents of the container but not less than 20 ml
Antibiotic liquids1 ml

Table: 2 – Insoluble preparations, creams and ointments sample

Minimum quantity to be used for each medium Quantity per containerMinimum quantity to be used for each medium unless otherwise justified and authorized
Insoluble preparations, creams and ointments to be suspended or emulsifiedUse the contents of each container to provide not less than 200 mg

Table: 3 – Solids sample

Minimum quantity to be used for each medium Quantity per containerMinimum quantity to be used for each medium unless otherwise justified and authorized
• less than 50 mgThe whole contents of each container
• 50 mg or more but less than 300 mgHalf the contents of each container but not less than 50 mg
• 300 mg – 5 g150 mg
• greater than 5 g500 mg

Reference: WHO, Document QAS/11.413 FINAL, March 2012

72. Explain the direct inoculation of the culture medium for sterility testing?

● Transfer the quantity of the preparation to be examined prescribed in the following Table directly into the culture medium so that the volume of the product is not more than 10% of the volume of the medium, unless otherwise prescribed.

Table: 1 – Liquids samples

Minimum quantity to be used for each medium Quantity per containerMinimum quantity to be used for each medium unless otherwise justified and authorized
• less than 1 mlThe whole contents of each container
• 1-40 mlHalf the contents of each container but not less than 1 ml
• greater than 40 ml and not greater than 100 ml20 ml
• greater than 100 ml10 per cent of the contents of the container but not less than 20 ml
Antibiotic liquids1 ml

Table: 2 – Insoluble preparations, creams and ointments samples

Minimum quantity to be used for each medium Quantity per containerMinimum quantity to be used for each medium unless otherwise justified and authorized
Insoluble preparations, creams and ointments to be suspended or emulsifiedUse the contents of each container to provide not less than 200 mg

Table: 3 – Solids samples

Minimum quantity to be used for each medium Quantity per containerMinimum quantity to be used for each medium unless otherwise justified and authorized
• less than 50 mgThe whole contents of each container
• 50 mg or more but less than 300 mgHalf the contents of each container but not less than 50 mg
• 300 mg – 5 g150 mg
• greater than 5 g500 mg

● If the product to be examined has antimicrobial activity, carry out the test after neutralizing this with a suitable neutralizing substance or by dilution in a sufficient quantity of culture medium.

● When it is necessary to use a large volume of the product it may be preferable to use a concentrated culture medium prepared in such a way that it takes account of the subsequent dilution.

● Where appropriate the concentrated medium may be added directly to the product in its container.

Oily liquids:

● Use media to which have been added a suitable emulsifying agent at a concentration shown to be appropriate in the method suitability of the test, for example polysorbate 80 at a concentration of 10 g/l.

Ointments and creams:

● Prepare by diluting to about 1 in 10 by emulsifying with the chosen emulsifying agent in a suitable sterile diluent such as peptone (1 g/l) TS1.

● Transfer the diluted product to a medium not containing an emulsifying agent.

● Incubate the inoculated media for not less than 14 days. Observe the cultures several times during the incubation period.

● Shake cultures containing oily products gently each day. However when fluid thioglycollate medium is used for the detection of anaerobic microorganisms keep shaking or mixing to a minimum in order to maintain anaerobic conditions.Reference: WHO, Document QAS/11.413 FINAL, March 2012

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