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PR3145 (pharm law) > Lecture 4 Biological Medicinal Products > Flashcards

Lecture 4 Biological Medicinal Products Flashcards

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1
Q

what are biopharmaceuticals

A
  1. large molecules produced in/extracted from living cells or system
  2. complex structures and are more difficult to characterised
  3. heat sensitive and susceptible to microbial contamination
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2
Q

traditional biological medicinal products

A

historically extracted directly from human and animal tissues

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3
Q

biotechnology-derived medicinal products

A

newer biological products now produced in living cells (microbial mammalian, insect, rodent)

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4
Q

what is biotech

A
  • use of living cells/ organisms, or their products to modify humans and animal health, mankind and its environment
  • used in agriculture, vet, food production, pharmaceuticals
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5
Q

examples where biotech is used

A
  1. medicinal products: vaccines, insulins, hormones

2. food: cheese, yogurt, wine

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6
Q

benefits of microbial host over mammalian

A
  1. faster cultivation, relatively straight forward fermentation
  2. proteins secreted within cells: disruption of cell needed during harvesting to obtain product
  3. lower yield due to more difficult purification
  4. simpler proteins which are non-glycoslated
  5. relatively safe biotech products
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7
Q

critical GMP and QA issuers in manufacture of biotech derived medicinal products

A
  1. assuring genetic stability of cell substrates with plasmid/vector and gene of interest
  2. absence of biological and chemical impurities from nutrient media and starting materials
  3. assuring quality (&yield) through consistent manufacturing processes
  4. absence of inherent endogenous virus (herpes, EBV, Retro)
  5. elimination of residual DNA (hybridoma)
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8
Q

what is a biosimilar product

A

biological product that is highly similar to, and has no clinically significant differences from an exisiting FDA approved reference product, often the innovator product

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9
Q

comparative test and studies to determine a high degree of similarity between biosimilar in terms of

A
  1. molecular structure and potency (bioactivity)
  2. toxic study (non-clinical/ animal study)
  3. pharmacodynamics (clinical/human study)
  4. pharmacokinetics (clinical/human study)
  5. immunogenicity (clinical/human study)

minor differences in terms of clinically-inactive components are acceptable (eg. buffers and stabilisers)

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10
Q

major steps in manu of biotech medicinal products

A
  1. cell banking
  2. cell cultivation
  3. harvesting
  4. purification
  5. viral clearance (inactivation/ removal)
  6. batching and storage of bulk biological API
  7. Formulation, Packaging & Release of Finished Product (Injection)
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11
Q

control of Cell banking

A

Master cell bank and working cell bank

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12
Q

master cell bank

A
  • contains well characterised cells derived from specific cell line, at a specific passage level
  • cells re stored frozen under definied conditions (liq nitro -196 deg)
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13
Q

working cell bank

A
  • used to provide ‘working’ cells for manu
  • WCB derived from one or more containers of MCB
  • WCB must be tested before use
  • test are usually less than those conducted at MCB
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14
Q

types of tests conducted at cell banks

A
  1. test for genetic stability (DNA fingerprinting)
  2. endogenous viruses (inherent in mammalian cell lines)
  3. adventitious viruses (intro during sampling or cell expansion)
  4. residual DNA (for mammalian cell lines)
  • needs to be highly specialised activity
  • requires sophisticated equipment
  • sometimes outsourced to specialised contract testing labs
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15
Q

inspection of cell bank system

A
  1. documentation of cell origin and Hx:
    - evidence of well characterised cell line (QC test)
    - records of QC tests conducted on cell banks
  2. management of Cell banks (MCB&WCB):
    - appropriate storage conditions
    - SOP and records on replacement of liq nitro
    - stock control/reconcil or ampoules/ vials of cells
    - cross-contamination measures taken during sampling, QC testing and cell expansion
    - Restricted access to authorised personnel
    - maintenance and backup arrangements, standby power supply, off-site MCB
  3. contract testing lab:
    - avail of comprehensive written contract
    - roles and responsibilities of contract acceptor and giver
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16
Q

cell cultivation

A
  • fermentation of microbial cells (E.Coli, yeast)

- cell culturing of mammalian cells (CHO cells)

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17
Q

upstream processes

A
  1. cell banking
  2. cell expansion and scale up
  3. cultivation
  4. harvesting
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18
Q

downsteam processes

A
  1. primary purification (affinity chromatography)
  2. viral inactivation (low pH, detergent)
  3. secondary purification (column chromatography)
  4. viral removal (nanofiltration)
  5. batching and storage of bulk biological API
  6. formulation, filling and packaging, QC of finished Biological product
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19
Q

types of fermentation

A
  1. batch fermentation
  2. continuous fermatation
  3. fed batch fermentation
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20
Q

batch fermentation

A
  • closed system of bacteria cells and media (only O2 is continuously added)
  • [media] decreases continuously, toxic meta. accumulate
  • curve: lag, log stationary and decline phase
  • advantage: minimal chance of contamination (close system)
  • disadv: low product yield
21
Q

continuous fermentation

A
  • open system of bacteria cell and media (fresh sterile media added continuously)
  • waste products removed continuously
  • adv: very high product yield
  • disadv: higher chance of contamination
22
Q

fed-batch fermentation:

A

media added and waste products removed at period intervals (semi-closed system)

23
Q

types of cell culturing

A
  1. anchored system: mammalian cells attached to solid support
  2. suspension system: mammalian cells suspended in liquid medium
24
Q

things to note about cell culturing

A
  1. no lag, log, stationary and decline phase
  2. nutrient media composition is crucial to consistent quality and yield
  3. minor deficiencies in nutrients have major effect on cell growth and protein production
  4. nutrient media containing bovine serum have long been preferred, but there are concerns with BSE prions
  5. move towards use of serum-free nutrient media for safety and cost reasons
    6 mammalian cells are more fragile than microbial cells due to their larger size and lack of rigid cell wall
  6. optimal stirring speed, circulation and shearing dynamics in bioreactor are crucial parameters
25
Q

objective of control of cell cultivation

A

to achieve high quality and high yield product

26
Q

factors affecting product quality

A
  1. materials: cell lines, nutrients media, buffers, reagents, water
  2. method:
  3. machine: bioreactor, sensors, computer hardware and software
  4. man: aseptic processing tech and restricted access
  5. premises: clean room, microbiological monitoring programme
27
Q

control of starting materials

A
  • supplier of starting material
  • specification of starting materials
  • test results for starting materials
  • water purification system
28
Q

control of cell culture conditions

A
  • formulation of nutrient media (BSE free)
  • temp, O2, pH
  • fermentation/culture time
  • growth rate, culture purity and fatty acid profile
29
Q

maintenance and cleaning of fermentors/bioreactors

A

sop and records of maintenance and cleaning

30
Q

harvesting (isolation/recovery)

A
  1. microbial cell system

2. mammalian cell system

31
Q

microbial cell system

A
  • recombinant proteins are contained intracellularly within microbial cells
  • to release proteins, microbial cells have to undergo disruption (Lysis)
  • during disruption, cell envelope is physically broken, releasing all intracellular components, including protein, into surrounding medium
  • disruption may be mechanical and non-mechanical
32
Q

types of mechanical disruption

A

HUMO

  1. homogenisation
  2. ultrasonification
  3. milling
  4. oscillation
33
Q

types of non-mechanical disruption

A

SALSO

  1. surfactants
  2. alkalis
  3. lysozyme
  4. solvents
  5. osmotic shock
34
Q

challenges of cell disruption

A
  1. heat denaturation of protein product
  2. oxidation of protein product
  3. uncontrolled release of other cell components, together with protein product during disruption
35
Q

points to note for inspectors during harvesting process

A
  1. for mammalian cell culture, proteins/MABs are secreted directly into media
  2. cell separation (by centrifugation and filtration) results in significant purification
  3. for E.coli or other bacteria-derived products, lysis of bacteria required to obtain protein products
  4. rapid purification necessary to prevent cleavage by protease release by lysed bacteria
36
Q

objective of purification

A

removal of all known impurities (chem and bio) to obtain pure protein product

37
Q

method of purification

A
  1. precipitation
  2. adsorption
  3. ultra filtration!
  4. chromatography!
38
Q

chromatography

A
  • in addition ton ultra-filtration, chromatograpohy is one of the most common methods of protein purification
  • chromatography is based on principe where differnt molecules in a mixture (statyionary phase, are separated from on another while moving in a mobile phae
  • in affinity chromatography, protein interacts or bond specifically with stationary phase, and bound protein is subject to further purification
  • chromatography separates/isolates desired protein product from a complex mixture- cells, components and other impurities
39
Q

control of chromatographic columns, buffers, other materials used for purification process

A
  • supplier approval
  • specifications of columns/ buffer
  • maintenance and storage of column/buffers
  • effective cleaning of columns
  • use of single use, disposable columns
40
Q

viral contamination

A
  • risk to all biologics
  • risk due to material of animal / human origin
  • virus only identified many years after product manu
  • cause: contamination of starting or source material
41
Q

what significant impact can viral contamination cause

A
  1. product quality
  2. facility shutdown
  3. disruption of medicine supply
  4. business impact
42
Q

viral clearance methods

A
  1. virus inactivation method:
    - *chemical methods: low pH incubation, surfactant/detergent
    - *physical method: heat/ UV
  2. virus removal method:
    - precipitation: ammonium sulfate
    - *column chromatography: ion exchange, size exclusion, affinity, reverse phase, hydrophobic interaction
    - membrane filtration
    - *nanofiltration
43
Q

why is validation of viral clearance necessary

A
  1. no single test is able to demonstrate the presence of all known virus
  2. all test systems require a minimum level of viral contamination to record a positive result
  3. tests are also limited by statistical considerations in sampling
44
Q

aim of validation study of viral CL

A
  1. demonstrate that man/purification processes can eliminate substantially more virus than what may potentially be present in the unprocessed bulk material
  2. to obtain the best reasonable assurance that the product is free of virus contamination
45
Q

batching and storage inspection of bulk biological api

A
  • biological products can be manufactured in sub-lots and pooled as batch
  • bulk batch of biological API can be packed in different containers or packs in term of volume
  • containers of biological APIs should be made of appropriate material, inert and compatible with API
46
Q

requirement of storage in buildings and facilities

A

maintain the product temperature between the limits as defined on the product label based on stability study

47
Q

factors to consider about formulation, filling and packaging into finished product

A

CWDEVVV

  • choice of excipients
  • water purification system
  • design and construction of facilitity
  • environmental / microbiological monitoring
  • validation of aseptic filling
  • validation of autoclaving of packaging components
  • validation of final container-closure integrity
48
Q

QC test methods

A
  • DNA sequencing
  • DNA hybridisation tech
  • reverse transcriptase
  • PCR
  • SDS page immunoassays
  • peptide mapping, IEF, MS
  • microbial limit test and sterility test
  • pyrogen test
  • modified 21 CFR method
49
Q

bioanalytical test parameters

A
  1. sensitivity
  2. specificity
  3. precision
  4. repeatability
  5. intermediate precision
  6. accuracy
  7. quantitation range
  8. linearity
  9. robustness

PR3145 (pharm law) (6 decks)

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