GMP topics of increasing importance Flashcards
What is Industry 4.0
Use of cyber-physical systems to monitor, analyze & automate businesses
Disruptive production: Internet of Things, AI, data & technology
Pharma 4.0 includes
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
Pharmaceutical inspection trends in Industry 4.0
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
Size of nanomedicine
< 10^-9 m (nm range)
How nanomedicine works
Nanoparticles can interact with biomolecules to treat pathological diseases even before the expression disease symptoms
Advantages of nanomedicine
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)
Nanomedicine safety concerns
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
A _____ is needed to facilitate development & public acceptance of nanomedicines
Clear and globally acceptable regulatory framework
Limitations of QbT
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
Limitations of QbT led to development of ________
Parametric release of LVPs and QbD of other dosage forms by PAT
Examples of process analytical technology (PAT)
1) NIR
2) Raman spectroscopy
3) X-ray diffraction
Advantages of QbD
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
Challenges of implementing QbD/PAT
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
Traditional batch manufacturing process
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
Limitations of traditional batch manufacturing
Total batch processing time: week(s) –> increased costs
Continuous manufacturing process
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
Advantages of continuous manufacturing
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
Regulation of continuous manufacturing
No regulatory hurdles / No additional regulations needed
Challenges in implementing continuous manufacturing
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
How to conduct inspection for GMP compliance at API manufacturing sites
1) Should be inspected using PIC/S GMP Guide for APIs
2) API inspection should be conducted regularly using risk-based approach
GMP compliance and process controls in API manufacturing/supply chain can affect:
1) Quality of APIs (e.g. particle size)
2) Purity of APIs
An ____ in API/product supply chain can lead to ____ of API/product, hence increasing risk of falsified medicine
Increased no. of players
Many potential points of interference
Importance of GDP/GMP compliance and vigilance in API quality and supply chain
1) Assures quality of API/finished products
2) Deter manipulation by unscrupulous supply chain players
3) Detect falsified, counterfeit and adulterated products
Types of excipients (with examples)
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
