Assuring quality of biological medicinal products Flashcards
Characteristics of biologics
- Large and complex molecules produced in/extracted from living cells/systems
- Heat-sensitive and susceptible to microbial contamination
- May be: Proteins, sugars, nucleic acids/ living cells/tissues
Name some examples of biotechnology-derived medicinal products
- Biological products produced in living cells –> microbial, mammalian, insect, rodent, plant cells
- Food products made from fermentation technology
- Medicinal products made from modern biotechnology such as insulin, hormones, enzymes, mabs, vaccines
Genetic basis for manufacture of biotech derived medicinal products
Transcription of DNA and translation into protein
Name the critical GMP and QA issues in manufacture of biotechnology-derived medicinal products.
- Assure genetic stability of cell substrates with plasmid/vector and gene of interest
- Ensure absence of impurities in nutrient materials and starting materials
- Assure quality and yield through consistent manufacturing process
- Ensure absence of endogenous viruses
- Ensure elimination of residual DNA from hybridomas of mammalian cells
What are biosimilars?
biological product highly similar to and has no clinically significant differences from an existing FDA-approved reference product (innovator product)
Criteria to determine degree of similarity between an innovator biologic and its biosimilar(s)?
- Molecular structure and potency
- Toxicity study
- Pharmacodynamics
- Pharmacokinetics
- Immunogenicity
Major steps in manufacture of biotech medicinal products
- Cell banking
- Cell cultivation
- Harvesting
- Purification
- Viral clearance
- Batching and storage of bulk biological API
Types of tests conducted for genetic stability
- DNA fingerprinting and sequencing
- Southern blot
What are the details to look out for when inspecting the management of cell banks
- Appropriate storage conditions
- SOP and records on replacement of liquid nitrogen
- Stock control/reconcillation of ampoules/vials
- Cross contamination measures taken during sampling, QC testing and cell expansion
- Restricted access to authorized personnel
- Maintenance and backup arrangements
Categories of control of cell cultivation:
Materials, methods, manpower, premises
Why do nutrients for cell culture have to undergo AC testing?
Nutrient media composition is crucial to consistent quality and yield
Minor deficiencies in nutrients have major effect on cell growth and protein production
Why is serum-free media more commonly used over bovine serum now?
- Safety
2. Cost
The 3 steps involved the process of inspecting cell cultivation?
- control of starting materials
- control of cell culture conditions
- Maintenance and cleaning of fermentors and bioreactors
Inspection of purification processes, specifically in chromatography
Control of chromatographic columns buffers, and other materials:
- Supplier approval
- Specifications of columns/buffers
- Maintenance and storage of columns/buffers
- Effective cleaning of columns
- Single use, disposable columns
What are the impacts/consequences of viral contamination in biopharmaceutical industry?
- Product quality
- Facility shutdowns
- Disruption of medicine supply
- Business impact
Virus inactivation methods
- Chemical: Low pH incubation, surfactant/detergent
- Physical: Heat, UV
Virus removal methods
- Precipitation using ammonium sulfate
- Column chromatography (ion exchange, affinity, size exclusion, reverse phase, hydrophobic interaction)
- Membrane filtration
- Nanofiltration
Why is there a need for validation of viral clearance methods?
- No single test able to demonstrate presence of all known viruses
- All test systems require minimum level of viral contamination to record postive results
- Tests limited by statistical considerations in sampling
What is considered a batch?
Specific quantity of drug or other material intended to have uniform character and quality within specified limits and produced according to single manufacturing order during same cycle of manufacture
Considerations for formulation, filling and packaging into finished products
- Choice of excipients
- Water purification system
- Design and construction of facilities
- Environmental/microbiological monitoring
- Validation of aseptic filling
- Validation of autoclaving of packaging components
- Validation of final container-closure integrity
Name some key performance tests parameters of a bioanalytical test method validation
- Sensitivity
- Specificity
- Precision
- Repeatability
- Intermediate precision
- Reproducibility
- Accuracy
- Quantitation range
- Linearity
- Robustness
Which PIC/S GMP annex is applicable for biological products?
2
What types of viruses are concerned in the manufacture of biologics?
- Endogenous virus
2. Adventitious viruses (introduced during production)
Why are critical GMP and QA of consistency important in the manufacture of biologics?
Slight changes and faults to manufacturing processes can have a major impact of the quality of the biologics produced as cell substrates are living factories
Do the same sets of Quality requirements and GMP used in the manufacture of innovator product apply to biosimilars?
Yeah!
The processes involved in the inspection of a cell bank
- Documentation of cell origin and history
- Management of Cell banks (WCB and MCB)
- Contract testing labs if cell bank tests are outsourced
During the inspection of contract testing labs in the inspection of cell banks, what must the inspector look out for?
- Comprehensive written contract
2. Roles and responsibilities of Contract Acceptor and Giver
Distinguish between upstream and downstream processes
- Upstream: Cell banking, expansion ,cultivation, and harvesting
- Downstream: Purification, storage and formulation
Describe the 3 types of fermentation for bacteria.
- Batch fermentation: Closed system with only O2 addition Less contamination, but low yield
- Continuous fermentation: Open system with continual addition of fresh media and removal of waste products. High yield, but more contamination
- Fed-Batch fermentation: Periodic addition of media and removal of waste products; semi-closed system
Describe the 2 types of cell culturing for mammalian cell growth
- Anchored system (cells attached to solid support)
2. Suspension system (suspended in liquid medium)
For a microbial cell system, recombinant proteins are contained ________. Proteins are released by __________, which can be _______________.
Intracellularly, disruption, mechanical & non-mechanical
Why is rapid purification necessary in purifying the recombinant protein produced by bacterial cells?
Prevent cleavage by proteases released by lysed bacteria
Methods of purification employed?
- Chromatography (common)
- Ultra-filtration (common)
- Adsorption
- Precipitation
What are the two main aims of Validation Study of Viral Clearance?
- Demonstrate that manufacturing/purification process can eliminate more virus than what may be present in unprocessed bulk material
- Obtain best reasonable assurance that product is free of virus contamination
What is inspected in the storage of biologics?
- Product temperature is maintained between limits stated on product label based on stability study
- Storage space are adequate to prevent overcrowding, and fit for purpose
- Fridge and freezers have recording and alarm systems
