Limitations of conventional product testing (3)
- Need representative sample
- Need to know what to test for and how to test them
- Need to validate testing processes (specific, accurate and reliable)
Limitations of batch sterility test
Means test for sterility between batches w/o GMP compliance etc
- Sterility test are not cheap (few hundreds)
- High probability of passing sterility test even if contamination is rather high
- Req storage space in the meantime and thus increase COP
Led to the development of Parametric Release of terminally sterilised LVPs
Quality Risk Management framework/steps (4)
- Risk identification
- Risk analysis
- Risk reduction
- Risk communication
Skills require by manufacturer and regulators
- Hard skills
eg pharmaco theories - Soft skills
eg assertiveness, confidence, integrity and impartiability, tact and diplomacy
Definition of quality of medicines
Fitness for use for treating patients
Characteristics of quality of medicines
- Identity
- Potency
- Purity (cross-contamination & impurities)
- Stability (shelf-life)
- Homogeneity (consistency within batches and equivalency among batches)
- Critical quality attributes (CQA)
Sources of impurities (internal contamination)
- Process-related
eg excess reagents & by-products - Drug-related
eg degraded API (after API formed)
3. Polymorphism (diff 3D crystalline structures) eg carbamazepine (inactive and active)
- Stereoisomers (diff spatial structures)
eg L and D isomers of dopamine and propranolol - Container-closure system and labels
They are identifiable
Sources of cross-contaminations (external contamination)
- Personnel
- Premises
- Equipments
They are non-specific.
Preventable through manufacturer’s compliance to GMP and inspectors to carry out audit regularly
Types of stability testing for medicinal products (3)
Takes into account both environmental and product-related factors
- Real-time study
- predict stability for 6months - Accelerated study
- predict stability beyond 6months - Continual stability study
- establish shelf life post marketing when stored, distributed and used under recommended temperature
Factors affecting stability of medicinal products (2)
- Environment
- Product-related
eg dosage forms
What is process validation?
Process validation is the means of ensuring and providing documentary evidence that manufacturing processes are consistently producing a finished product of required quality standards
Major steps in process validation (6)
- Establish tablet quality specification
eg hardness, friability - Identify Critical Process
eg milling, blending - Design sampling plan
- Design testing plan
- Set acceptance criteria (LSL and USL)
- Perform statistical analysis (intra and inter batch)
- Intrabatch: Process Capability (Cp)
- Interbatch: Coefficient of Variance (CV)
Purpose of intra-batch analysis
To ensure consistency within batches
Cp >= 1.3 or outlier =< 63ppm
Purpose of inter-batch analysis
To ensure equivalency among batches
Conventional product testing & batch sterility testing
NOT THE SAME.
Conventional product testing is test for API.
Batch sterility testing is test for contamination in a product.
Parametric release
- release of products based on key ‘parameters’ of a validated sterilisation process
eg temp, RH, bioburden of pre-sterilised parental products
Developed from batch sterility test
Allows parametric release of terminally-sterilised large volume parentals (LVPs)
Controls to reduce impurities (internal contaminants)
- QC testing of materials and finished product
- Assessment of impurity profile by HSA product reviewer
- GMP compliance
- Periodic GMP audits
Controls to reduce cross-contamination
- Personel
- wear PPE - Premises
- clean areas, pest control - GMP compliance
- Periodic GMP audits
How to show homogeneity of products produced?
Homogeneity is demonstrated through process validation
Quality Risk Management (QRM) objective
To assess risks to product quality/patients and then manage these risks to an acceptable level
Quality of medicinal products should be the concern and business of __ and __
- Manufacturers and distributors
2. Regulators
What is contaminated products
Products that contains undesirable foreign matters
Can be from :
- impurities (intrinsic contamination)
eg in starting materials
- cross-contamination (extrinsic contamination)
eg during procuring, packing
Why is there a need to control impurities? (2)
Therapeutic effects of medicinal product depends on :
- API pharmacological properties
- toxicity of impurities present
