GMP topics of increasing importance

Question 1

What is Industry 4.0

Answer 1

Use of cyber-physical systems to monitor, analyze & automate businesses
Disruptive production: Internet of Things, AI, data & technology

Question 2

Pharma 4.0 includes

Answer 2

1) Biotechnology & biopharmaceuticals
2) Genetic engineering & cell/tissue based, advanced therapy products (ATPs)
3) Nanotechnology & nanomedicines
4) Process analytical technology & QbD
5) Integrated computerized systems & continuous manufacturing / process validation
6) Single use technology & cross-contamination control / flexible manufacturing
7) Supply chain integrity of health products, APIs, excipients
8) Pharmaceutical data integrity & control of falsified medicines

Question 3

Pharmaceutical inspection trends in Industry 4.0

Answer 3

1) Regulating/Inspecting health products derived from new technology
2) Continuous manufacturing
3) Managing excipient & API quality & supply chain integrity
4) Single use technology
5) Data integrity assurance and fighting falsified medicine
6) Migrating from QbT to QbD via process analytical technology

Question 4

Size of nanomedicine

Answer 4

< 10^-9 m (nm range)

Question 5

How nanomedicine works

Answer 5

Nanoparticles can interact with biomolecules to treat pathological diseases even before the expression disease symptoms

Question 6

Advantages of nanomedicine

Answer 6

1) Able to reach difficult-to-target (tumour) sites
2) Improved solubility, bioavailability
3) Reduced side effects
4) Able to achieve same therapeutic effect with smaller doses
5) Overall, offers promising breakthroughs in diagnosis and treatment of diseases (cancers)

Question 7

Nanomedicine safety concerns

Answer 7

1) Nanoparticles released into the environment during manufacture can pose potential health and cross-contamination hazards
2) Nanoparticles have been shown to accumulate in organs and hemolyze erythrocytes

Question 8

A _____ is needed to facilitate development & public acceptance of nanomedicines

Answer 8

Clear and globally acceptable regulatory framework

Question 9

Limitations of QbT

Answer 9

1) Can only test a statistically representative sample size
2) Can only test if analyte is known and there is a suitable test method & reference standards available
3) Can only test if test method is specific, accurate, reliable
4) Defects only detected at the end of manufacturing –> defective products cannot be reworked/rectified
5) QC tests not conducted/released in real time, leading to expensive cost of storage during quarantine of bulky products

Question 10

Limitations of QbT led to development of ________

Answer 10

Parametric release of LVPs and QbD of other dosage forms by PAT

Question 11

Examples of process analytical technology (PAT)

Answer 11

1) NIR
2) Raman spectroscopy
3) X-ray diffraction

Question 12

Advantages of QbD

Answer 12

1) Non-destructive
2) Deeper process understanding, better control and higher QA of entire batch
3) Real time release of products
4) Reduced post-approval submissions to regulator
5) Cost savings for industry

Question 13

Challenges of implementing QbD/PAT

Answer 13

1) Limited understanding of QbD and PAT by both manufacturers & regulators
2) High financial investment due to high initial capital outlay, technology maintenance & testing and training costs BUT may lead to long term savings due to decreased QC testing, increased yield and immediate release. Overall, more success stories should be published/reported to encourage manufacturers
3) Manufacturers are used to not reviewing a validated process (based on QbT) and there is also fear of revealing inadequacies in existing QbT process, leading to voluntary recalls
4) Regulators are not ready for QbD/PAT submissions

Question 14

Traditional batch manufacturing process

Answer 14

1) Consists of multiple discrete steps
2) Intermediate products collected after each unit operation (sent for QC testing)
3) Final product collected at the end of manufacturing
4) QC testing conducted at off-site laboratories and final product quarantined at warehouse while waiting for QC results

Question 15

Limitations of traditional batch manufacturing

Answer 15

Total batch processing time: week(s) –> increased costs

Question 16

Continuous manufacturing process

Answer 16

1) Materials are fed through an assembly line of fully integrated components and moved non-stop within the same facility
2) At-line/On-line QC testing using non-destructive PAT/other technology

Question 17

Advantages of continuous manufacturing

Answer 17

1) Real time release of finished products, thus saving warehouse space and storage costs
2) Integrated process (fewer steps) with minimal manual handling, thus reducing contamination
3) Similar equipment & facilities, thus more flexible operation, decreased inventory, lower capital cost
4) Total batch processing time: day(s) –> cost savings, increased efficiency
5) On-line monitoring & QC testing, thus there is higher level of QA, more consistent quality, real time relase
6) Overall: Cost savings

Question 18

Regulation of continuous manufacturing

Answer 18

No regulatory hurdles / No additional regulations needed

Question 19

Challenges in implementing continuous manufacturing

Answer 19

1) Experience is still lacking in manufacturers and regulators
2) Lack of knowledge on deeper science and technology required for QbD / PAT
3) Manufacturers need to understand integration amongst unit operations and manage continuous manufacturing data from all on-line/at-line/in-line measuring systems
4) Inspectors/Manufacturers need to understand, support and facilitate continuous manufacturing, which is both science and risk based

Question 20

How to conduct inspection for GMP compliance at API manufacturing sites

Answer 20

1) Should be inspected using PIC/S GMP Guide for APIs

2) API inspection should be conducted regularly using risk-based approach

Question 21

GMP compliance and process controls in API manufacturing/supply chain can affect:

Answer 21

1) Quality of APIs (e.g. particle size)

2) Purity of APIs

Question 22

An ____ in API/product supply chain can lead to ____ of API/product, hence increasing risk of falsified medicine

Answer 22

Increased no. of players

Many potential points of interference

Question 23

Importance of GDP/GMP compliance and vigilance in API quality and supply chain

Answer 23

1) Assures quality of API/finished products
2) Deter manipulation by unscrupulous supply chain players
3) Detect falsified, counterfeit and adulterated products

Question 24

Types of excipients (with examples)

Answer 24

1) Diluent e.g. starch
2) Disintegrant e.g. cellulose
3) Lubricant e.g. Mg stearate
4) Solvent/Co-solvent e.g. glycerin, propylene glycol, polyethylene glycol
5) Antioxidant e.g. silicon dioxide
6) Flavoring agent
7) Antimicrobial preservative e.g. paraben
8) Water

Question 25

Pharmaceutical excipient industry is highly ____ and the supply chain of pharmaceutical excipients is increasingly ____, making it easier for falsified excipients to enter the supply chain

Answer 25

Globalized

Complex

Question 26

Growth of SUT is driven by

Answer 26

Biotechnology manufacturing industry

Question 27

SUTs are used in biopharmaceutical manufacturing during

Answer 27

1) Cell banking & culturing
2) Chromatography
3) Filtration
4) Filling
5) Finishing

Question 28

Examples of SUTs used in biopharmaceutical manufacturing

Answer 28

1) Single-use cell banking bags
2) Bioreactors
3) Pre-packed chromatographic columns & buffers
4) Single-use syringes & injection ports
5) 3D printing valves

Question 29

Advantage of SUTs

Answer 29

1) Increased containment and cross-contamination controls, thus higher level of QA
2) Flexible manufacturing which takes up less space, thus saving time and cost

Question 30

Test considerations in inspection of SUTs

Answer 30

1) Material compatibility (chemical resistance)
2) Bioburden / Bacterial endotoxin
3) Particulate control
4) Extractables
5) Biocompatibility
6) Animal origins
7) Absorption

Question 31

ASEAN sectoral MRA on GMP inspections is based on ____ and covers ____

Answer 31

PIC/S GMP standards

Medicinal products in finished dosage form

Question 32

ASEAN ____ was formed to implement MRA

Answer 32

Joint Sectoral Committee (JSC)

Question 33

LIS stands for

Answer 33

Listed Inspection Service

Question 34

Register of LIS includes inspectors/regulatory agencies that have ___

Answer 34

Met PIC/S inspection framework

Question 35

Criteria to become member of LIS

Answer 35

1) PIC/S member OR

2) Approved by ASEAN panel of experts (PoE)

Question 36

Benefits of ASEAN MRA on GMP inspection

Answer 36

1) Avoid duplication of GMP audits within ASEAN
2) Save time, resources and costs for regulator and industry
3) Facilitate trade of medicinal products across ASEAN
4) Quicker access to medicinal products by ASEAN patients
5) Increased attractiveness to pharmaceutical investors from bigger countries
6) Harmonization of ASEAN inspection system with that of PIC/S

Question 37

Future ASEAN developments & collaborations

Answer 37

1) Increase no. of LIS
2) Continually train ASEAN inspectors
3) Expand scope of MRA to include APIs and biologicals
4) Connect ASEAN to rest of the world