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Pharmacy Year 2 Semester 2 > Formulation of biopharmaceuticals > Flashcards

Formulation of biopharmaceuticals Flashcards

1
Q

examples of biopharmaceuticals

A
  • Monoclonal antibodies
  • ADC (antibody-drug conjugate)
  • Interleukins
  • peptides
  • virus-like particles
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2
Q

Name the 3 broad groups of protein therapeutic biopharmaceuticals

A
  • protein therapeutics with enzymatic or regulatory activity
  • protein therapeutics with special targeting
  • protein vaccines
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3
Q

examples of how protein therapeutics with enzymatic or regulatory activity are used

A
  • replacing a protein that is deficient or abnormal
  • augmenting an existing pathway
  • providing a novel function or activity
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4
Q

examples of how protein therapeutics with special targeting are used

A
  • interfering with a molecular pathway or an organism’s physiology
  • delivering other compounds or proteins
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5
Q

examples how protein vaccines are used

A
  • protecting against a deleterious foreign agent
  • treating an immune disease
  • treating cancer
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6
Q

How are mABs classified?

A

4 parts of name

1) unique prefix
2) prefix letters related to type of target (part of body/tissue)
3) prefix reflects source of the variable chain (e.g. mouse, rabbit)
4) suffix -mab

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7
Q

How are biologics formulated?
How are they administered?
Issues?

A
  • either as a liquid formulation or lipophilised (to be reconstituted before use)
  • administration is either subcutaneous or IV
  • issues often linked to frequency of administration
  • adverse effects
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8
Q

Formulation of proteins and mABs

Solid form advantages/disadvantages

A
  • dose and injection volume adjustable
  • can be developed as multi-use formulations
  • can be more expensive to couple a solid form to a delivery device (e.g. dual chambers)
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9
Q

Formulation of proteins and mABs

Liquid form advantages/disadvantages

A
  • more convenient to end user
  • better patient compliance
  • better accuracy
  • chemical degradation hydrolysis therefore less stable, limit shelf life, manipulation etc.
  • physical stability more difficult to control: aggregation (e.g. exposure to final fill finish operations)
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10
Q

Approaches to formulation development of proteins and mABs

A
  • development of stability-indicating assays
  • in silico assessment of protein degradation routes
  • complexity of stability determinations during formulation development (real time vs accelerated stability)
  • liquid formulation development
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11
Q

List excipients for proteins and mABs

A
  • buffers
  • salt and tonicity modifiers
  • surface active agents
  • anti-oxidants
  • protein stabilisers
  • lypophilation development
  • caveats to use of sugars as lypoprotectants
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12
Q

Buffers

examples and info

A

-acetate
-citrate
-succinate
-histidine
-phosphate
Formultions pH range 5-6.5 (IgE pI approx 8)
Buffer concentration kept low to adapt to physiological pH upon administration

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13
Q

Salt and tonicity modifiers

A

Colloidal stability
IV injection requires isotonic preparation
IM or SC injections may be able to handle hypertonic or hypotonic conditions
common excipient is NaCl

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14
Q

Surface active agents

A
  • mABs flexible molecules with hydrophobic and hydrophilic regions
  • unfolding leads to aggregation
  • surfactants cover interfaces (air/liquid and solid/liquid) thus limit unfolding
  • Polysorbates 80 and 20 most common
  • PS degration may contribute to aggregation
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15
Q

Antioxidants

A
  • oxidation reaction catalysed by metals
  • use of EDTA to chelate metals contributes to control oxidation
  • reducing agents such as glutathione can reverse oxidation
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16
Q

Protein stabilisers

A
  • stabilisers are preferentially excluded from the protein’s surface leading to preferential hydration of protein
  • sugars e.g. sucrose
  • amino acids such as Arginine
17
Q

Lypophilisation development

A
  • Use of PEG

- Same mechanism as stabilisers: exclusion by steric hinderance and maintained upon freezing

18
Q

Caveats to use sugars as lypoprotectants

A
  • Disaccharides susceptible to hydrolysis at low pH

- hydrolysis of sucrose to glucose and fructose at pH 5

19
Q

List stability issues with mABs and proteins

A
  • chemical degradation
  • physical degradation
  • chemical oxidation
  • physical stability
20
Q

Chemical degradation

A
  • most common routes are oxidation, de-amidation, Asp isomerisation and cross-linking
  • alteration of residue may lead to conformational changes and/or binding (ex. deamidation of Xolair)
  • Deamidation is a common route and is dependent on amino acids that flank the amide residue
  • Asp isomerisation may lead to degradation in one of the CDR (Herceptin 90% loss of activity)
21
Q

Chemical oxidation

A
  • oxidation is most common route
  • Amino acid susceptibles are: Met, Tyr, His, Trp and Cys
  • Met oxidation in mABs frequent
  • His oxidation via oxidation and metal-catalysed reactions
  • Trp oxidation occurs via metal-catalysed reactions (e.g. Trp in CDR of palivisumab when exposed to UV light)
  • Cys intermolecular disulphide linking occurs in several mABs

-Non-enzymatic protein degradation: fragmentation reported in mABs following storage at 37°C for 3 weeks in acidic or basic conditions

22
Q

Physical degradation

A
  • conformational changes, aggregation and surface adsorption
  • conformational changes=denaturisation=unfolding
  • all information to maintain protein conformation is contained in the amino acid sequence (primary structure)
23
Q

sources of conformational changes

A
  • temperature changes
  • ice formation due to freeze thaw
  • shear forces
  • changes in ions in solution
  • changes in protein-protein interactions
24
Q

Physical stability - aggregation

A

-may originate from conformational changes induced by covalent changes (chemical) but very often related by the hydrophobic/hydrophilic issues

25
Q

“Soluble aggregates”

A
  • no particle visible in solution and aggregates cannot be removed easily by filtration
  • Quantification of sub-visible aggregates (100nm-10um) may be difficult and may be immunogenic (not established unequivocally)
26
Q

reversible aggregates

A
  • self association

- may be the consequence of formulation or delivery

27
Q

Why are aggregates unfavourable?

What is the WHO limit on them?

A

They alter pharmacokinetics and reduce the activity

WHO limits their presence to less than 5%

28
Q

Protein aggregation

A
  • protein aggregation is a consequence of protein-protein interactions
  • aggregation may happen at each steps of the bioprocess, formulation, storage
  • IgG2 is more prone to aggregation than other IgGs
  • aggregation prediction uses accelerated stability testing
  • air water interface: mABs are amphipathic molecules and hence tend to move at the interface
  • Adsorption to surfaces (all solid surfaces of the container closure system) - use surface active agent to limit adsorption
29
Q

Opportunities for aggregation

A
  • cell culture
  • shipping
  • freeze drying/spray drying
  • filtration and filling
  • recovery and purification
  • tangenital flow filtration
  • bulk storage and freeze/thaw
30
Q

Challenges for IV formulations

A
  • leachables and extractables
  • head space
  • preparation bags for infusion
31
Q

What are leachables?

A
  • compounds released from a container closure system when in contact with solvent (depends on pH, temperature, salt concentration)
  • includes metals, organics, volatile compounds
32
Q

What are extractables?

A
  • subset of compounds eluting from normal storage use conditions e.g. Infusion bag, tubing
  • IV bags produced with different polymers (PO may be better than PVC)
  • bags volume may also be considered
33
Q

Clinical use: head space

A

-the pharmacists has the responsibility to ensure product stability in the final administered form and the setting of “beyond-use date” based on United States Pharmacopoeia 797

34
Q

What is the beyond-use date?

A

-the “beyond-use” date is defined as the time the compounded sterile must be used to avoid lack of potency, contamination and safety risks

35
Q

Preparation in bags for IV infusion

A

Dilution of the protective surfactant can lead to noticeable degradation of the product and the generation of an air-water interface on agitation was responsible for aggregate formation

36
Q

Challenges for SC formulations

A
  • small volume (1.5mlL) but high concentrations (50, 100 are more mg/ml)
  • increased protein-protein interactions and risks of aggregation
  • impact on flow, viscosity, internal diameter of needle is small (0.2mm)
  • Glide force max (30N) relation to viscosity
  • Bioavailability of SC delivered mABs may vary widely
  • Development of analytical tools to characterise these solutions
37
Q

use of biopharmaceuticals

A
  • last line antimicrobials

- treat long term diseases

Pharmacy Year 2 Semester 2 (33 decks)

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