1
Q
whats Primary packaging?
A
Directly in contact with product
2
Q
Primary packaging requirements?
A
- compatible with content and protection form hazards
- Consider incompatibility: nothing leaving product/ entering and affecting packaging/product
- Provide info on content: bar code, expiry date, batch num etc
- Ideally be child-resistant but easy to open and re-seal by patient
- Be tamper-resistant/ offer proof of tampering
- Be fit for purpose i.e. blister packs for tablets but not for semi-solids
3
Q
how many types of packaging? (stages)
A
primary
secondary
tertiary
3
4
Q
Secondary packaging Containment. role?
A
- Added layer of protection from light etc.
- Get more info on product- dose, use, image- important for patient to ensure correct content. May be bottle/box
- Dispensing label also provided.
e.g. pill boxes
5
Q
requirements for packaging in general?
A
should
• NOT leak
• NOT allow diffusion/permeation of product vice versa
• BE strong enough during all steps of handling, storage, transport, use
• NOT be altered by the formulation it contains.= may not be fit fr purpose during shelf life
6
Q
what do you want to maintain w pharm product?
A
quality, safety, stability of pharmaceutical product throughout shelf lfie
7
Q
4 types of hazards?
A
mechanical: shock/impact
chemical: adsorption/ loss of volatiles/ leaching
biological: contamination
climatic: tesmp, moisture, pressure
8
Q
Identification, Presentation and information
A
- Additional roles of packaging
- essential source of information on medicinal products.
- Info leaflet still part of packaging
9
Q
what information is added on packaging?
A
- Product name
- Type of product
- Quantity / strength / BN
- Mode of administration
- Date of manufacture
- Shelf-life / expiry / date
- Storage instructions
- Contraindications / precautions
- MA / ML numbers
- Legal classification
- Manufacturer’s name / address
- Bar code
- Warnings (i.e. KOOROC)
- Formulation details (i.e. Ingredients)
i.e. on pill box
10
Q
Risks due to similar looking packaging
A
could be same drug, different doses/ different salts of same drug/ different drug but similar packaging.
Very confusing for patient and carer to distinguish
11
Q
types of Containers for primary packaging
Can be multiple at same time, need to be most appropriate for product and use
A
single / multi dose airtight sealed tamper evident well closed child resistant
12
Q
characteristics of tablet bottles
A
o Made of glass or plastic
o Amber-coloured
o Child-resistant cap
13
Q
types of medicine bottles?
A
o Amber-coloured bottle
o Fluted amber bottle
Child resistant cap
o Dropper bottle
14
Q
Single dose containers e.g:
A
- Glass ampoules
- Infusion bags
- Single-dose syringes
- Nebuliser ampoules
- Don’t need preservatives
15
Q
Multi dose containers
A
- Multi-dose vials for injectables
- Multi-dose glass/plastic bottle.
- Pressurised metered dose inhalers
- Dry powder inhalers
- Cream jar/bottle/tube (semi-solids)
16
Q
role of Light Resistant Containers?
A
- Protect the contents from the effects of UV radiation at a wavelength between 290 nm and 450 nm.
- For example amber bottles
17
Q
what are Sealed containers and give examples
A
i.e. closure and container form same unit
sealed during packaging and cant be resealed once used
Prevents product from contaminants such as air or moisture. e.g.
• Ampoules
• Aluminium bags
• Plastic eye-drops
18
Q
Laminates from foil and films
Used for …
A
suppositories, sachets, Blister packs: • Tray with lid used as packaging for tablets and capsules • Provides hermetic seal • Good barrier properties • Metal (excellent barrier) • Plastic (coated PVC) • Tamper-evident- packaging damaged with tablet removal
19
Q
Unit dose packaging- strips use?
A
- In the Strip packaging, the tables or capsules are sealed between two same materials, such as aluminium foil, heat sealed.
- This packaging protects the tablets/capsules from environment
20
Q
Tubes and jars types?
A
Collapsible tubes for semi-solids
Ointment jars
21
Q
2 forms of Collapsible tubes for semi-solids
A
Lacquered aluminium
Sealed at both end
Pierce to use
LDPE/HDPE/PP
Can be heat sealed
Made of plastic with layer of foil that must be removed
22
Q
Ointment jars
A
Wide-mouthed
Semi-solid preparations
Risk of contamination by patient
23
Q
Repackaging- what req must be met
benefits?
A
• Patient can access all the information about the product
• Less time-consuming: so more time for counselling
• Lower risk of errors or cross-contamination
From bulk bottle:
number of capsules/tablets counted and transferred to bottle.
24
Q
Compliance aid problems
A
higher risk of error
• Less info to patient
• May be cross-contaminations/ incompatibilities with meds. Stability affected compared to original packaging.
• If meds stopped- right product removed from this. Legal issues to- removal into compliance aids
Other options to aid compliance and help patient remember dose.
Date/ scratch label on blister pack: good for 1 med a day
25
packaging material what to consider?
```
dosage form
shelf life
dispensed/ OTC?
cost
MoAdmin
product
patient
```
26
types of Glass
```
Traditional material, made of:
• Silica
• Limestone (calcium carbonate)
• Soda ash (sodium carbonate)
• Cullet. Broken glass
```
27
why may additives be added to glass?
o Hardness
o Heat-shock resistance
o Opacity/clarity
o Colour
Amber-coloured glass: protection against sun rays
• Iron, carbon or manganese oxides & sulphur containing compounds
28
Advantages of glass
* Inert (relatively)
* Impervious to air
* Impervious to moisture
* Protects from loss of volatiles. GTN
* Easy inspection of the content
* Can be tinted to block harmful light rays
* Easy to clean
* Easy to sterilise by heat
29
disadvantages of glass
• Brittleness
Release of glass fragments- filter before injected into body
Contamination through cracks
• Release of alkaline compounds- degradation lectures
• Cost- used scarcely for extra protection
• Weight
• Leaching of glass components
e.g. weatherisation (bloom
30
```
whats Weatherisation (bloom) destabilisation of glass?
and what can be done?
```
Appearance of white, opaque stains on glass
o Storage at high temperatures/humidity
o Storage under conditions where temperature/humidity fluctuate
= Migration of carbonate crystals on the glass surface
May be more problematic for Type II glass (soda-lime)
What can be done?
o Leaching can be reduced by soaking in hot water or dilute acid solution
31
hm types of glass and which is highest quality?
Type I: highest quality
Type II
Type III
32
Type I glass examples
```
Borosilicate glass
Most inert type of glass
Lowest risk of leaching
Low coefficient of thermal expansion
Resistance to sudden temperature changes.- heat sterilisation, less likely to crack
££££
```
E.g.
• Ampoules
• Injection vials
Suitable for packaging slightly acidic solutions
33
Type II glass examples
Soda-lime glass
• Treated soda-lime glass (sulphur dioxides)
• Lower risk of leaching vs. Type III
• Type III
Use: Aqueous solutions (slightly acidic/neutral)
34
Type III glass examples and use
Soda-lime glass (also type II)
• Similar to food packaging (NP glass)
Use:
• Non-aqueous parenteral products
• Powders for injection (not freeze-dried)
NP glass
Large volume non-parenteral products (> 100 mL)
35
Plastic use?
Many uses primary and secondary e.g. infusion bags in a plastic bag:
• packaging of tablets, capsules: rigid bottles
• for eye drops, nasal sprays: squeezable
• as jars or flexible tubes
• in blister or strips packs
• as infusion bags and for the packaging of SVPs
• as closures for bottles
36
2 types of plastics?
thermoplastics
- can be remoulded + heated multiple times, keep same properties
- e.g. PE, PS, PPE, PET, PVC, nylon, acrylic
thermosettling plastics
- Can only be heated and moulded once
- As cross-linked polymer chains
- e.g. epoxides, polyester resin, urea formaldehyde
37
4 Typical plastic containers:?
* Polymer
* Polymerisation residues
* Additives added to modify the properties of the plastic- consider conpatibility
* Processing aids
38
additives to plastic?
```
plasticisers
lubricants
stablisers
UV absorbers
antioxidants
toughening agents
flame retardants
colouring agents
filling/ reinforcing agents
```
39
plastics and additives: Advantages
* Low cost
* Low particle release
* Light in weight
* Heat sealable
* Easily moulded (above)
* Multipurpose
* Can be clear/opaque
* Resistant to shocks (mostly)
40
plastics and additives: disadvantages
Not as inert as Type I glass
Stability issues
• Stress-cracking. Wetting agents, oils, organic solvents (LDPE)
• Distortion e.g. dimpling during autoclaving
• Sensitivity to heat- Problematic for sterilisation. All will soften under heat
• Electrostatic charge
• Leaching of additives *
Adsorption
• Loss of preservative- affect stability
Poor barrier properties
• to sun rays (unless black)
• to gas/vapour
(squahed milk carton)
41
7 different plastics?
```
PE
PP
PVC
PVDC
PCTFE
PS
PET
```
42
describe plastic 1: Poly(ethylene) [PE]
Good compatibility with drugs overall but can sorb preservatives
Low-density polyethylene (LDPE)
- Clear & flexible e.g. squeeze bottles, blister packs
High-density polyethylene (HDPE)
- Strong, rigid & translucent
- Compared to LDPE: Lower permeability to gases and moisture; better resistance to oils; heat-resistant
- Can be pigmented e.g. solid dosage form bottles
43
which plastic has poor odour barrier and permeable to oxygen?
Polyethylene PE
44
describe plastic 2: Poly(propylene) [PP]
* Clear, strong & rigid
* Heat-resistant, excellent barrier to moisture!
Compared to PE:
• Less additives and lower risk of adsorption
• better barrier to odours and better resistance to grease/oil
• Good resistance to cracking when bent
e.g. hinged closures, solid dosage form containers, blister packs (films)
45
describe plastic 3: Poly(vinyl chloride) [PVC]
• Variable rigidity, clear & glossy
• Plasticisers added to improve flexibility (i.v. bags)
• Heat-sensitive
• Poor impact resistance
• Can be improved by additives to the detriment of permeability
• Resistant to oils, fats, flavouring
• e.g. component of intravenous bags
not used as much as hard to get rid of PVC waste
46
describe plastic 4: Poly(vinylidene chloride) [PVDC]
* Provides best barrier to moisture, gases, flavours & odours
* Mixed with other plastics to improve barrier properties
* Heat-resistant, clear, flexible
* ££££ Expensive
* Excellent barrier properties- remains integrity of drugs. Good if longer shelf life
* e.g. blister packs
47
what plasticmakes blister packs?
```
Poly(vinylidene chloride) [PVDC]
or Poly(chlorotrifluoroethylene) [PCTFE]
```
48
describe plastic 5: Poly(chlorotrifluoroethylene) [PCTFE]
* Clear plastic
* Heat-resistant
* ££££
* Excellent barrier properties. e.g. blister packs
49
describe plastic 6: Poly(styrene) [PS]
* Crystal PS: clear, strong, rigid but brittle
* PS foam: cushion, insulation, in urinalysis packaging
* Poor impact resistance
* Can be improved by additives to the detriment of permeability
* Poor barrier to moisture, gases; poor chemical resistance
* Insufficient heat resistance to resist autoclaving
* Good for general purpose use
* e.g. Bottles for tablets/capsules
50
describe plastic 7: Poly(ethylene terephthalate) [PET; polyester]
* Clear and strong
* Good resistance to high temperatures
* Sterilisation process possible
* Good barrier to moisture, gases, oils, chemicals
* Popular for cough syrup bottles and other liquid dosage forms
* Replacement for PVC bottles
* Sterilisation pouches (PET films)
51
Closures and counterfeiting measures
Rubbers and elastomers
| Metals
52
what are elastomers?
elastic polymers
Rubbers are formulations of elastomers + additives
Some formulations may contain more additives than plastics!
Increased risks of incompatibility? consider
• Mostly used in closures (e.g. parenteral vial stoppers)
o Soft and easy to mould
Adopt the shape of the container to provide a tight sea
53
What additives may be in plastic?
Colouring agents
Antioxidants
Lubricants
Anti-slip
54
Advantages of plastic?
lightweight, easy to mold, cheap, can't be corroded, durable and strong
55
Disadvantages of plastic for packaging
Stress-cracking
Distortion
Sensitivity to heat
56
Disadvantage of poly(ethene) PE
can sorb preservatives
57
Why is poly(propylene) PP better than poly(ethene)
Lower risk of adsorption
Less additives
Good barrier to moisture
58
Disadvantages of PVC
poor impact resistance
59
Characteristics of PVDC
Best barrier to moisture, gases, flavours and odours.
Heat resistant, clear, flexible.
Excellent barrier properties
EXPENSIVE
60
What is the primary use of elastomers in packaging?
Closures
61
2 types of elastomers?
natural- form rubber trees
| synthetic- form petrochemicals
62
elastomers: examples of the 2 types?
natural: latex
sytnhetic: neoprene, nitrile, butyl, chlorobutyl, bromobutyl, silicone (most inert, poor barrier)
63
how are natural elastoemrs betetr than synthetic?
better resealing
| better resitante to coring/fragmentation
64
how are SYNTHETIC elastoemrs betetr than natural?
better:
barrier to moisture, gases
resistance to aging
resistant to multiple autoclaving
lower risk of preservative adsorption
65
Metals use?
Containers
o Collapsible tubes
o pMDI canisters
o Pouches, blister and strip packs
Closures. Pierce/remove to access containers. Tamper proof
o Rolled-on closures
o Rolled-on pilfer proof closures
o Foil caps
66
what metals used?
Mostly aluminium, tin, stainless steel
67
metaks Advantages
* Impermeable to Light, moisture, gases
* Rigid and shock resistant. pMDIs
* Light weight vs. glass
* Heat resistant
* Opaque- protect from UV rays
* Imprinted labels- info in blister packs on foil backing
68
metals Disadvantages
* Cost (less than glass)
* Chemical reactivity. Coated metal (epoxy resins)
* Opacity- cant see inside packaging to check
69
Paper and cardboard when used?
* Rarely used for primary packaging- extemporaneous preparation of sachets
* Secondary packaging: more common e.g. cover labels, cartons, dispensing bags, PILs etc
70
paper and card: ads?
* Low cost, can be tailored for application
* Easy to recycle, non-toxic
* Easy to cut and fold
* Rigid and strong. Cardboard
71
paper and card: disads?
* Poor barrier properties
* Moisture-sensitive
* Required additives to be sealed i.e. glue, not just pressed closed like metal
* Poor transparency
72
Closures
| Function:
```
• Provide effective hermetic seal:
o Protect product from external contaminants
o Retains contents inside container
• Effective microbiological seal
• Provide seal suitable for product
```
73
Closures
| Considerations
* Compatibility: with product and environment: air/space
* Barrier properties
* Ease of use: open and reseal
* Resistance to processing: maintains integrity when processed at high speed too
* Appearance: fits with container for visual appealing product, decrease risk of leaks
74
Additional functionalities of closures
o May help with drug administration- liquids: cap has info for dose
o May provide child-resistance and evidence of tampering
75
Glass vial closures (3)
Dust cap
Aluminimum ring
Rubber plug
76
Rubber plug- what is it and describe?
Glass vial closures
in direct contact with produc. Reisitant to punctures
77
Aluminium ring - what is it and describe?
Glass vial closures
| seals rubber plus onto vial. Can be lifted: been tampered. Gets punctured with needle
78
Dust cap - what is it and describe?
Glass vial closures
| not direct contact but extra protection
79
7 Type of closures
```
Screw caps
Lug caps:
Crown caps
Roll on
Roll-on pilfer proof closures
Child-resistant caps
Tamper-evident closures- Jaycap® closure
```
80
Type of closures: Screw caps
• Seal produced by the liner inside the cap which presses against the container’s opening
• Typically made of plastic and metal
o Thermoplastic/ thermosetting
o Tin plated or aluminium metal
81
Type of closures: lug caps
• Similar to threaded screw cap
o only requires a quarter of turn
• Normal and vacuum pressure closing
• Jams jars. Less common with meds
82
Type of closures:roll on
• Hermetic seal
o Easily removed
o Easily re-sealed
82
Type of closures:roll on
• Hermetic seal
o Easily removed
o Easily re-sealed
83
Type of closures: crown caps
• Crimped closure
| o Used for beverages (often in glass bottles)
84
Type of closures: Roll-on pilfer proof closures
• Similar to roll-on
o Tamper-evident: add on level compared to just roll-on:
o Band broken when first opened
85
What are the three types of anti-counterfeiting strategies
o Overt measures
o Covert measures
o Forensic markers
-Serialisation & Track and trace (e.g. bar code, microchip (radiofrequency)
86
Overt strategies
| what and target?
* Out in the open
| * Target: end user to determine if correct product.
87
overt strategies ads and disads?
Advantages
• Product verified by user
• Can be decorative
• Can be a deterrent
```
Disadvantages
• Used must be educated
• May be easy to mimic
• Can increase production cost
• False assurance
• Must not be re-usable or recyclable
• Should damage the pack once opened
```
88
Covert strategies ads and disads?
```
Advantages
• Can be simple and low cost
• Easy to add and modify
• No approval required
• Can be in-house or supplied
```
```
Disadvantages
• Can be easy to copy
• Risk of being compromised
• Secure supply chain
• Higher cost for more secure measures
```
89
examples of overt strategies?
* Holograms
* Colour shifting inks/films
* Security graphics
* Sequential product numbering
* On product marking
90
examples of Covert strategies?
* Invisible ink
* Embedded images
* Digital watermarks
* Odour
* Laser coding
* Watermarks in PIL
* Substrates
91
what are covert strategies and whos target?
* Hidden (‘need to know basis’)
| * Target: brand owner
92
forensic markers- whos target?
brand owner
93
forensic markers ads and disads?
Advantages
• Highly secure
• Allows authentication
• Not detectable under normal conditions
```
Disadvantages
• Cost
• Proprietary technologies
• Increased risk of compromise with wider use
• Requires access to specific equipment
• Availability may be limited
```
94
forensic markers examples?
```
Taggants
o Chemical
o Biological
o DNA
o Microscopic
Isotope ratio
```
95
What is Class 1 to Class 4 in product recall.
Class 1 - Death
Class 2 - Affect Patient Safety
Class 3 - No harm would be caused
Class 4 - Cannot be used effectively
96
What makes a quality product (at each time process carried out)
for tabs?
* Content of drug
* Disintegration
* Dissolution
* Stability and shelf life- term 2
97
Poor quality products
| Complaints by:
* Wholesalers
* Distributors
* Pharmacies
* Consumers: appearance- colour, solution precipitated, packaging/product not coming out i.e. nasal spray nozzle
98
Impact of not meeting quality standards 4
* Lack of therapeutic efficacy
* Toxic and adverse reactions
* Waste of limited financial resources- cost increased
* Loss of credibility of the health care delivery system- assumed inadequate checks in place to maintain quality
99
What is a certificate of analysis?
Proof of quality of product
Details of tests carried out to show starting raw materials are good quality and sourced well.
100
Quality of pharmaceutical products
• Pharmaceutical quality is affected by
...
```
o Starting materials
o Manufacturing processes
o Packaging
o Transportation
o Storage conditions
```
101
• Quality of pharmaceutical products is measured by
o Physical analysis
| o Chemical analysis
102
Starting ingredients for quality of pahrm product?
CofAs = certificates of analysis
• Demonstrates quality of product
• Evidence that starting material is good
103
What are polymorphic forms of a drug?
Different. crystalline forms whihc differ in their physical properties.
104
Substance for Pharmaceutical use under same heading in BP (4)
Description/Characters
o a qualitative statement about the state (e.g. solid, liquid) and colour of the new drug substance.
Identification
o identification tests should be specific for the drug substance
Assay
o A specific, stability-indicating procedure should be included to determine the content of the new drug substance.
Impurities
o a method to detect and quantify impurities is required
105
What are Class 1 to Class 3 solvents?
Class 1 - To be avoided
Class 2 - To be limited
Class 3 - Low toxic potential
106
examples of Class 1 to Class 3 solvents?
1: Known human carcinogens, strongly suspected human carcinogens, and environmental hazards.
2: Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity.
Solvents suspected of other significant but reversible toxicities.
3: Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have (permitted daily exposure) PDEs of 50 mg or more per day.
107
particle size assessment acceptance criterial?
include acceptable particle size distribution
o in terms of the percent of total particles in given size ranges.
• Acceptance criteria should be set based on the observed range of variation, and should take into account
o the dissolution profiles of the batches as well as the intended use of the product
coarse
mod fine
fine
very fine
108
Microbiological quality 4
```
• Bioburden
• Sterility
• Bacterial endotoxins
• Pyrogens
Last two different in term of meeting the specifications
```
109
What are specials?
unlicensed medicinal products manufactured for human use to meet a specific prescription requirement ordered for individual patients without the need for the manufacturer to hold a marketing authorisation for the medicinal product
110
why/when specials supplied?
Special can be supplied: To meet individual patient needs when no equivalent licensed product exists. E.g. allergies, difficulty to swallow
111
2 types of specials?
• Batch manufactured products
• Bespoke products: made for specific patient, tests possible on these are limited
Required a Manufacturer’s Specials licence
• To ensure that products meet regulatory standards
112
Specials and quality issues
| 2 certificates:
Certificate of analysis:
o batch manufactured special.
o Proof of physical, chemical, or microbiological assay of sample of final product. Tests done
o Special medicine manufactured as bespoke will not have end product analytical testing
Certificate of conformity
o bespoke products meets purchaser’s specifications
o Limited info provided.
o Get this certificate for either type of special.
o Available for all specials produced by a license holder
113
Pharmacists responsibility and specials what to check?
• product is of a suitable standard.
• product comes with a certificate of analysis or a certificate of conformity. Good if have info on raw materials
• product is appropriate and suitable for the patient
• certificate and/or label mentions
o Strength
o Formulation details
o Excipients list
• is evidence to support the labelled shelf life of the product
114
What is a specification?
A list of tests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges or other criteria for the tests
115
How specifications are set:
* help confirm quality of a drug substance/product
* not meant to provide a detailed description of all characteristics
* should focus on ensuring drug substance/product is safe and effective
* need to collect relevant data: some degree of variability naturally linked with analytical methods/ manufacturing processes
116
physicochemical tests for...
- tabs
- caps
- injections
- buccal films
- transdermal patches
- oitments/creams
- aerosols
- bitter dosage forms
- dissolution, mech strength
- drug release
- precipitation
- strength
- adhesivity
- rheology
- P size, aerodynamic diameter
- taste sensation
117
• Development of pharmaceutical products should include
• Definition of the quality target product profile (QTPP)
• Identification of critical quality attributes (CQAs)
o For the drug product- final pharmaceutical prep
o For the drug substance/excipients- raw starting materials
• Selection of suitable manufacturing processes
• Control strategy- give assurance that process is fit for purpose and gives quality product
118
What is a QTTP?
Quality Target Product Profile
A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into consideration safety and efficacy of the drug product
119
What is a CQA?
A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range or distribution to ensure the desired product quality.
120
What is a critical process parameter?
A process parameter whose variability has an impact on critical quality attribute (CQA) and therfore should be monitored or controlled to ensure the process priduces the desired quality.
121
What is the requirement for bioequivalence for generic medicines?
The drug should not be better or worse than the reference product, but allows products to be used interchangeably.
122
whta type of approach is: quality by testsing (QbT) and quality by design? (QbD)
- empirical
| - systematci
123
QTTP what to consider?
* Intended use, route, dosage form
* Dose strength
* Closures and other packaging
* Drug release/delivery, parameters affecting pharmacokinetics
* Product quality criteria: sterility, purity, stability
124
CQAs can be defined for
* Drug substances
* Drug products
* Excipients
* Intermediates (in-process testing)
125
what 4 things are a quality attribute of drug (CQA)? - and targets of each?
!!!
Identification
- positive for labelled drug
Assay
- 100% of labelled claim
Content uniformity
- conforms to BP criteria?
dissolution
- >80% released at 30 mins
everything else = QTPP
126
Critical process parameter
For tablets, CPPs could include any step in manufacturing:
* Mixing
* Granulation
* Drying
* Compression
* Coating
127
CPP
Solid dosage forms
```
• Identification
• Assay
• Uniformity of content
• Dissolution, can be affected by:
Hardness
Friability
Disintegration
```
128
What controls dissolution
pyramid image...
Can define limits for hardness etc if known to impact
Have limits for each section, predict which batch will perform well etc
129
dissolution specification
example for a simple immediate release tablet:
Analytical measurement to see how much drug released must be
...
* Linear (calibration curve)
* Must be accurate (> 98%)
* Must be repeatable (< 5% RSD)
* Must be reproducible
130
Bioequivalence (specifications)
| Aim
To determine if two pharmaceutical products demonstrate in vivo biological equivalence- both have same therapeutic effect.
131
Generic medicines must prove bioequivalence to an existing medicine... (2)
Patient compliance: The expected result
Effective therapy
o Neither toxic nor ineffective as same
o Medicines may be interchanged= good for patient and NHS. Efficient
132
To establish bioequivalence, we will often rely on ...
PK parameters
133
why Plasma concentration vs time curves used for bioequivalence establishing?
as blood circulation commonly site of action
134
Need to know X and X, carefully consider how often and when to take samples
absorption and elimination
135
what do we need adequate estimates of for bioequiv?
Cmax
o ideally few points before and after
o shouldn’t be first conc in conc vs time profile!
tmax
o Need enough info for this
o Don’t want it to be at first/end itime point again- want some before and after
* Sufficient duration of sampling to provide a good estimate of exposure (80% of the AUC extrapolated to infinity). Need full picture, from enough time points
* At least 3-4 samples to have a good estimate of the terminal half-life
* Single/multiple doses? If multiple doses give additional sampling points will be required
136
Acceptable range: in graph for bioequiv?
AUC ratio: Total exposure to drug
- within the 90% confidence interval: 0.80 – 1.25 of the reference value
Cmax ratio: Max conc acheived
- within the 90% confidence interval: 0.80 – 1.25 of the reference value
However this can be
- tighter for drugs with a narrow therapeutic index;
- wider in some cases where we expect high variability in PK to 0.75-1.33
for both: look at test and compare with BP
137
bioequiv criteria for accpetance of durg?
within the 90% confidence interval: 0.80 – 1.25 of the reference value
