QbA
Judge quality of a medicine by its appearance
QbT
Test quality into a product (quality by testing of finished product)
- product tested at the end of batch manufacturing process
- if product passes test(s), it was deemed to be of good quality
Limitations of conventional product testing
- you test only on a ‘representative’ sample size (most testings are destructive in nature)
- you can test only if you know the analyte (ingredients: APIs, excipients) and you have a test method
- you can test only if test method is specific, accurate and reliable ie. if it is validated
Historical development of pharmaceutical product quality
QbA -> QbT -> QbD
QbD
Design and build quality into a product
Limitations/Disadvantages of Sterility Testing
- high (statistical) probability of passing sterility test, even when contamination level is relatively high
- sterility test is not cheap, several hundred SGD
- 2 weeks of incubation period needed for sterility test
- sterilised product cannot be released in real time: expensive cost of storage space during quarantine of bulky products eg. large volume parenterals (LVP)
Limitations of sterility testing led to develpment of
Parametric release of terminally-sterilised LVPs (annex 17)
parametric release
annex 17: release of a batch of injectable product which has been terminally sterilised (by dry/moist heat sterilisation), without the need to conduct batch sterility testing
- release of a batch of injection based on CPPs (critical process parameters eg. autoclaving - moist heat) which has been rigorously validated (sterilisation assurance level <= 10^-6)
examples of CPPs
temperature, pressure, sterilisation time/cycle, bioburden of pre-sterilised parenteral product
What is the QRM and what is its objective?
annex 20: systemic framework to manage quality risk in a stepwise approach comprising risk identification, analysis, reduction and communication
- objective: assess risks to product qulity/patient, and then manage these risks to an acceptable level
quality should be the concern and business of:
(1) manufacturer
- product and manufacturer’s licence holder
- distributer and advertiser
- r&d scientists
- production/QC experts
(2) regulator ie. HSA
- product quality reviewers
- GMP inspectors
- analytical scientists
^ hard skills set, knowledge and equipment to assure good quality medicines
hard skills and knowledge required: (7)
- pharmacology/pharmacotherapy (drug actions, drug treatments)
- medicinal chemistry (including drug synthesis and analysis)
- pharmaceutics (incl dosage from design, mfg processes)
- pharmaceutical microbiology (especially sterilisation and disinfection)
- pharmaceutical laws (ie MA, HPA)
- GMP and quality standards (including validation and stability studies)
- statistics eg. ANOVA, SPC ie. statistical process control
what is a contaminated medicinal product?
defined as a product that contains undesirable foreign matters
- of chemical or microbiological nature (for non-specific in nature)
- may be present in a starting material, intermediate, bulk product
- introduced during manufacturing: procurement, sampling, processing, packaging, re-packaging, storage or transportation (cross-contamination)
How is homogenity demonstrated?
Through process validation
What is process validation?
US FDA, UK MHRA, EMA, Australia TGA PIC/S, WHO
- means of ensuring and providing documentary evidence
- that manufacturing processes are capable of consistently produce a finished product of required quality
- carried out on at lesat 3 consecutive full-scale batches
