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week 23 (Y2) > the medicine > Flashcards

the medicine Flashcards

1
Q

what are clinical presentations of rheumatoid arthritis
RA

A

amthmitis -
symmetrical
swelling
nodules

hand involvement early and in disease -
MCP and PiP joints

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2
Q

describe the joints in the hand
RA

A

closer to wrist: DIP
middle: MCP
closest to fingertips: PIP

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3
Q

what happens in swan neck as disease progresses
RA

A

PIP if hyper extended

DIP is flexed

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4
Q

what happens in boutonniere as disease progresses
RA

A

PIP is flexed

DIP is hyper extended

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5
Q

what is synovitis
RA

A

inflammation of the synovial membrane

causing pain and swelling

leading to bone and cartilage breakdown and erosion

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6
Q

what is z deformity of the thumb, ulnam deviation
as disease progresses RA

A

a side effect of progressing RA

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7
Q

what do macrophages do in RA cellular level

A

secrete cytokines

TNF alpha
Interlukin-1
Interlukin-6

all leading to inflammation

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8
Q

what do the cytokines secreted by the macrophage stimulate
RA

A

FIBROBLAST II - LIKE SYNIOVITES (FLS)

activates them

proliferate

stimulates RANKL expression along with the cytokines to stimulate osteoclast activty (bone arthritis)

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9
Q

what happens when FLS are stimulated
RA

A

secretes proteases

cause cartlage to break down
cartilage degredatin
cartilage also secretes proteases

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10
Q

how do we get symmetrical arthritis in RA

A

FLS can migrate from joint to joint

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11
Q

what do T cells in the synovium do
RA

A

secrete interlukin-17 which can promote macrophage activity and stimulate FLS

also help in expression of RANKL

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12
Q

what do plasma cells do
RA

A

stimulate inflammation through cytokines and antibodies

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13
Q

what do neutrphils do in the synovium fluid
RA

A

produces proteases and recative O2 species
lead to bone and cartilage degredation

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14
Q

what do immune complexes in the synovium fluid do
RA

A

abs that bind to one another

promote inflammation

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15
Q

what is angiogenesis
RA

A

increases vacular permeability

increases adhesion molecules
allowing immune cells to migrate into the joints

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16
Q

tell me about pre rheumatoid arthritis

A

genetics
smoking
porphyromungs gingivitis leading to gingivitis

cause modification of autuantigens

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17
Q

what is modification of autuantigens in RA

A

mod of own antigens to make it seem foreign to own body, leading to immune response

inflammation can aslo lead to this

APC initiate immune response, goes to lumph node, activates T cells here, CD4, activates B cells (costimulation), proliferate, plasma cells, produce autuantibodies, against own antigen. migrates to joint tissue.

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18
Q

what are the two main abs in RA

A

rheaumatoid factor IGM and anti citrulinated protein ab

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19
Q

wat is the IGM abs in RA

A

persesnt in 75% of ppl with IGM

forms immune complexes

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20
Q

what does anti citrullinated ab do in RA

A

targets citrullenated proteins such as fibrin and fillagbin
more specific for RA

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21
Q

what happens with the cytokines in the blood
RA

A

increase of inflammatory cytokines in the blood

skin - nodules
liver - more CRP inflammotory marker, more hepctoin = anaemia

CV - plaque formation, MI/stroke

neurological - fatigue and depression

muscles - insulin resistance, muscle weakness

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22
Q

What blood tests will the GP order given the suspected diagnosis of RA?

A

FBC, RF, ANA, CRP, ESR, Kidney and Liver function, anti-CCP*

*Negative results and normal inflammatory markers do not exclude the diagnosis in the presence or a good history and examination findings.

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23
Q

Should Mrs Montoya follow a specific diet to help with her
suspected new diagnosis?

A

No specific diet has been evidenced to help; encourage Mediterranean diet

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24
Q

NSAIDs can cause peptic ulceration. Will the EC coating prevent this adverse effect. Explain your reasoning.

A

No. Systemic inhibition of COX-1, a key enzyme involved in prostaglandin biosynthesis; inhibition of prostaglandin mediated alkaline mucus secretion which protects GI epithelium.

In summary, while enteric coatings on NSAIDs can help reduce the risk of peptic ulceration by protecting the stomach lining from direct irritation, they may not completely eliminate the risk. It’s essential for healthcare providers to consider individual patient factors and closely monitor patients who are at higher risk for GI complications when prescribing NSAIDs, regardless of whether they are enteric-coated or not.

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25
Q

What other safety concerns are there with the long term use of NSAIDs such as naproxen?

A

Salt and water retention  increase BP and precipitate/worsen heart failure
Reno-toxic
Increased risk of thrombotic events (MI and stroke)
GI Toxicity

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26
Q

Why is early diagnosis important in RA?

A

Damage to joints is irreversible; can lead to gross deformity and functional impairment

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27
Q

How does MTX act to treat rheumatoid arthritis?

A

Inhibits dihydrofolate reductase. Most likely mechanism is that MTX leads to an accumulation of an inhibitor of the enzyme adenosine deaminase  accumulation of adenosine which has anti-inflammatory effects via its receptors.
Also action against various cytokines including IL1, 2 and 6 are more likely to be of significance

Usual first line choice of DMARD for RA – most effective and quickest acting

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28
Q

What are the main side effects associated with MTX therapy?

A

Nausea, stomatitis
Blood disorders
Liver and lung toxicity
Kidney damage

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29
Q

What points should you cover when counselling Mrs Montoya regarding MTX therapy?

A

Not an analgesic – takes time to work
Once a week dose (choose a day)
Side effects, including blood disorders and lung function warning
Need for follow up and blood tests
Limit alcohol
Avoid OTC NSAIDs and aspirin; inform all HCPs taking MTX

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30
Q

Mrs Montoya is also prescribed folic acid 5 mg tablets. Why? When should it be taken?

A

MTX inhibits dihydrofolate reductase leading to lower serum folate. Supplementation counteracts this, reducing incidence of mouth ulcers, stomatitis and nausea
Different regimens depending on hospital Trust – usually once a week the day after MTX

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31
Q

How should Mrs Montoya’s response to the MTX be
monitored?

A

Symptoms
Side effects
DAS28 score
Health Assessment Questionnaire

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32
Q

What dose of infliximab should Mrs Montoya be started on?

A

Initial dose: 3mg/kg, so 3 x 82 = 246 mg

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33
Q

What precautions have to be taken when infliximab is
administered?

A

Close monitoring for hypersensitivity reactions
Resus equipment available, anaphylaxis kits

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34
Q

How does infliximab work to treat RA?

A

Infliximab inhibits the activity of the inflammatory cytokine, tumour necrosis factor  (TNF)

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35
Q

what type of arthritis is OA

A

Osteoarthritis (OA) is the most common type of arthritis and is often referred to as degenerative joint disease. It primarily affects the cartilage, the protective tissue that covers the ends of bones within a joint. OA is characterized by the breakdown of cartilage, leading to pain, stiffness, and decreased range of motion in the affected joint(s).

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36
Q

difference between OA and RA?

A

OA: Degenerative joint disease, cartilage breakdown, aging, wear-and-tear.
RA: Autoimmune disease, chronic synovial inflammation, systemic symptoms, rapid onset.
OA: Gradual onset, affects weight-bearing joints, hands.
RA: Can develop at any age, affects multiple joints symmetrically.
OA: Not primarily inflammatory, minimal elevation in inflammatory markers.
RA: Significant inflammation, elevated inflammatory markers.
OA: Manage symptoms, improve joint function, lifestyle modifications.
RA: Suppress inflammation, alleviate symptoms, prevent joint damage, use of DMARDs and biologics.

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37
Q

Why did the GP not order any blood tests?
OA

A

No specific blood tests for OA
 Usually based on Hx and clinical examination

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38
Q

What advice and treatment would you expect the GP to give Mrs Walker?
OA

A

Try to lose weight
Physical activity
Supportive footwear
Signpost to Arthritis Action website
Topical NSAID and/or regular paracetamol
If not effective, oral NSAID (with PPI cover)

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39
Q

Functions of the Nose

A

Hairs and mucous in each nostril act as filters/barriers for air-borne particles and microorganisms

Warms and moistens incoming air

Nasal mucosa connected to the conjunctiva of the eye, middle ear.

Also, only location in the body that provides direct connection between brain and outside

Bypasses Blood Brain Barrier (BBB) !!

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40
Q

describe anatomy of the nose

A

olfactory tract
olfactory bulb
olfactory nerves (fingerlike structures)

cribriform plate (nexr to / aside olfactory)

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41
Q

Three delivery modes within Nose

A

local
systemic
delivery to the CNS

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42
Q

tell me about local delivery in the nose

A

conventional use

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43
Q

tell me about systemic delivery in the nose

A

Absorption happens from nasal mucosa
after ingestion and absorption from the gastrointestinal tract

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44
Q

tell me about delivery to the CNS (nose)

A

Olfactory neurons located in olfactory bulb
Supporting cells and capillary bed
Directly to cerebrospinal fluid

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45
Q

tell me about nasal sprays

A

These are the main delivery devices used.

Mainly non-pressurised systems, operated by mechanical pump.

They produce a spray plume made of drops of pre-determined size

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46
Q

examples of local products (nose)

A

For the treatment of various conditions such as decongestion, sinusitis and rhinitis.

E.g. Beconase® Aqueous Nasal Spray
Contains beclometasone dipropionate 50 micrograms

Inflammation in the lining of nose (rhinitis) due to seasonal allergies, such as Hayfever.

Droplets/drug particles are deposited topically on the mucosal tissues.
Drug action through local absorption/effect at target tissue (not systemic).

XHANCE® nasal spray
Contains fluticasone propionate (93 mcg)
Aqueous suspension of microfine fluticasone propionate having a particle size distribution (0-5 um)

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47
Q

what are some complications with local delivery (nose)

A

However, local product sometimes can result in:
1- some systemic absorption depending on drug/formulation properties.
2- dripping down the throat into the
GIT and undergoes oral absorption.

Exhalation helps elevate and seal the soft palate.

This may limit medication from dripping down the throat
and helps guide the exhaled breath to pass behind the nasal septum and out the opposite nostril.

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48
Q

Examples of Delivery to CNS
nose

A

Onzetra Xsail®
Sumatriptan nasal powder (11 mg per nosepiece)
For acute treatment of migraine

Onzetra Xsail®
Powder targets highly vascularised upper posterior area of nose (Fig B)

Note that TRUE nose-to-brain delivery via the olfactory nerve is yet to be commercialised!

However, there are preclinical and clinical trials happening currently to explore this route.

For Alzheimer’s and Parkinson’s disease as well as other CNS diseases.

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49
Q

Examples of Systemic products
nose

A

Zomig® Nasal Spray
Contains 5 mg zolmitriptan
Spray contains only one dose.
Fast absorption through the nasal mucosa
May result in faster headache relief compared with oral formulations.

Miacalcin®
Calcitonin nasal spray for
postmenopausal osteoporosis
Synthetic peptide

-Absorbed rapidly by nasal mucosa (max plasma conc. achieved in 13 min)
Replaces injectable calcitonin
Reduces risk of new vertebral fractures

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50
Q

advantage of the nasal route
nose

A

1- Rapid absorption and onset of action as a result of the highly vascularised nature

2- Avoidance of first-pass metabolism

3- Non-invasive route for systemic delivery (convenience)

4- Potential route for delivery of peptides or other large molecules

5- Delivery to the brain through olfactory nerve.

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51
Q

Challenges of nasal route
nose

A

1- Short retention time as a result of mucociliary clearance (happens every 20 min)

2- Challenging to deliver sustained formulations

3- May require solubility enhancers for poorly soluble drugs

4- May require permeation enhancers if drug absorption is poor or large molecules (>1000 Da in Mwt.)

5- Molecule susceptibility to degradation by enzymes (e.g. proteolysis)

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52
Q

Types of nasal formulations
nose

A

Nasal formulations are often liquids and mostly liquid solutions.

solutions - all patricles are dissolved

suspention - all particles are suspended

emulsion - o/w or w/o

53
Q

Excipients
(depends on formulation type)
in nasal medications

A

Mucoadhesive excipients to improve retention (e.g. HPMC)
Solvents/co-solvents to improve drug solubility (e.g. PEG)
pH buffers (e.g. citric acid buffer)
Penetration enhancers (e.g. liposomes and surfactants)
Suspending agents or viscosity modifiers (e.g. CMC-Na)
Antioxidants (e.g. Butylated
Hydroxytoluene) and preservatives (e.g. Benzalkonium
Chloride)
Osmolality and tonicity agents (e.g. Mannitol)

54
Q

Considerations during development of nasal formulations
nose

A

Important to recognise that the prime purpose of nasal airway is to protect the lungs from hazardous materials.

So need to consider factors such as:
- Droplet size (solution and suspension)
- Particle size (suspension)
- Stability and compatibility between device and
formulatio

55
Q

Droplet Size & Particle Size in nasal drug formulations
nose

A

To avoid lung inhalation of drugs intended for nasal delivery.

Droplets < 10 μm may travel through the nasal cavity and be deposited in the lung.

Droplets > 300 μm might drip back out of the nose

Particle size of suspended particles (0-5 um)  affects dissolution and absorption

Volume per dose: The delivered volume for nasal sprays typically lies within the 25–100 μL range.

56
Q

stability and compatability of nasal drug formulations
nose

A

Issues are similar to those of oral solutions or suspension.

E.g. Suspensions: Precipitation issues leading to Caking (closely packed sediment at base of container)

Leachables from plastic containers.

Drug-Plastic/device container interaction

For emulsions, coalescence of droplets is the main issue.

Spray device mechanical failure.

57
Q

manufacturing process basics in nasal drug formulations
nose

A

Issues are similar to those of oral solutions or suspension.

E.g. Suspensions: Precipitation issues leading to Caking (closely packed sediment at base of container)

Leachables from plastic containers.

Drug-Plastic/device container interaction

For emulsions, coalescence of droplets is the main issue.

Spray device mechanical failure.

58
Q

summary of nasal delivery nose

A

Nasal delivery presents great opportunity to deliver medicines where oral bioavailability is poor.

A potential alternative to deliver large molecules without inconvenience of injectables.

Careful selection of device, formulation type/excipients and consideration of impact on lung/oral exposure.

59
Q

Why does the pharmaceutical industry matter?

A

economic value of the pharmaceutical industry contnues to rise

60
Q

Why do Clinical Trials?

A

To establish safety …
… and efficacy of new drugs.
To compare existing treatments to find out which is best.
To study different ways of using standard treatments so that they will more effective, easier to use and/or decrease side effects.
To learn how best to use a treatment in a different population, such as children, in whom the treatment was not previously tested.

61
Q

give an overview of the frug development process

A

drug discovery - targets and rcepetors, small molecules, macromolecules

drug development - ADME, toxicology, delivery systems

Clinical trials in humans

product locence application

marketed drug

62
Q

Preclinical Development in the pharmaceutical industry

A

Drug metabolism and pharmacokinetics
determine Absorption, Distribution, Metabolism and Excretion (ADME) in various test species

Pharmaceutical development
formulations for biological testing
dosage forms for administration

Safety assessment
safety pharmacology
in vitro and in vivo toxicology

63
Q

safety testing

A

Safety assessed throughout the life of the product
During preclinical investigations
During pre-registration clinical trials
During post-marketing surveillance

Not uncommon for drugs to be withdrawn after being in clinical use owing to unforeseen side-effects
e.g. terfenadine, rofecoxib, cerivastatin

64
Q

Preclinical Safety Pharmacology

A

Core tests
CNS – motor activity, behavioural changes, coordination, reflex responses, temperature
CVS – BP, pulse, ECG
Respiratory – rate, tidal volume

Follow-up tests (examples)
memory, cardiac output, blood gases

Supplementary tests (examples)
Monitoring renal function, nervous system, GI system

65
Q

Preclinical Toxicology Testing

A

Exploratory toxicology
rough estimate of compound toxicity when given acutely
indication of major organs/systems affected

Regulatory toxicology
performed to GLP standards
required before drug may be administered to humans

28-day repeated-dose studies in two species, one of which is non-rodent (usually dog)
In vitro and in vivo genotoxicity tests
Safety pharmacology
Reproductive toxicity assessment
Chronic 3-12 month toxicological studies
18-24 month carcinogenicity and reproductive toxicity testing
Drug-drug interaction testing

66
Q

Types of adverse drug effect

A

Exaggerated pharmacological effects
dose related, generally predictable

Side effects
pharmacological effects due to action of drug on receptors other than that intended

Toxic effects
dose related effects unrelated to intended action

Idiosyncratic reactions
rare, sometimes serious, reactions that occur in certain individuals
not dose related

67
Q

Clinical drug development

A

Approximately 80% of the cost of bringing a drug to market is incurred during clinical development

Only 1 in every 5 compounds will get approved for clinical use

Of the drugs that fail during clinical development,
30% fail of lack of efficacy
25% fail for safety reasons

68
Q

Clinical Trial Protocols

A

Objective – what do you want to achieve
Hypothesis – how we decide if we’ve achieved the objective
Method
Inclusion criteria – who will go in
Exclusion criteria – who don’t you want
Visits – what will you do
Assessments – what will you measure
Analysis – how will you test your hypothesis
Administration

69
Q

The clinical trial paradigm

A

Administration of new, potentially therapeutic substances to man
Controlled conditions to enable determination of:
bioavailability, efficacy, safety, tolerability and acceptability
Legal requirement before a new drug can be sold or any claims for its therapeutic benefit
Studies are subject to international, national and local regulation, to meet requirement of the three major pharmaceutical development regions
USA, EU, Japan

70
Q

Phase I Clinical Trials

A

First administration and safety evaluation in man
usually healthy (male) volunteers
cytotoxic drugs tested in cancer patients
Key aim is to collect preliminary information:
safety
tolerability
bioavailability
Pharmacokinetics

71
Q

Phase 1a Studies

A

Single dose trials
First Dose in Man – hugely critical time for drug development process
Usually 4-8 cohorts of 6-8 subjects
subsequent cohorts receive higher doses
dose escalation stopped if tolerability issues
provides Maximum Tolerated Dose data
Each volunteer usually receives one dose only
placebos are administered to some volunteers

72
Q

Phase Ib clinical studies

A

Repeated dose trials
tests safety, tolerability and PK following repeated administration
frequency of dosing designed to maintain necessary PK profile for therapeutic effect

Two or three-step dose escalations

Successive groups of 12-24 volunteers
take drug repeatedly for several days at each dose level

73
Q

Phase II Clinical Trials

A

Early exploratory and dose-finding studies in patients

Phase IIa studies
proof of concept and go/no-go decision making
“First in Class” and “Follower” drugs

Phase IIb studies
confirmatory, dose-finding studies
Clinical surprises at this are bad news

74
Q

Phase III Clinical Trials

A

Large-scale studies in patients
demonstrate efficacy compared to placebo
demonstrate advantages over existing treatments
safety, tolerability, efficacy, acceptability, compliance, cost-effectiveness

Commonly designed to compare new drug’s performance against competitor product

Often multi-region studies

75
Q

Phase IV Clinical Trials

A

Post-marketing studies to monitor safety of drug in very large numbers of patients
not all adverse effects detected before drug is marketed
denying promising new drugs is not in patients’ best interests

Around 1 in 5 new drugs may be ultimately recalled or cause serious side effects
hence requirement for Phase IV studies

76
Q

Further directed learning - clinical trials

A

Single Arm Trial: No control group, all receive investigational treatment.
Placebo-Controlled Trial: Randomly assign to investigational treatment or placebo, assesses beyond placebo effect.
Positive Controlled Trial: Randomly assign to investigational treatment or active comparator, compares to standard care.
Open Trial: Both participants and researchers aware of treatment, evaluates real-world effectiveness.
Single-Blinded Trial: Participants unaware, researchers aware, reduces outcome bias.
Double-Blinded Trial: Neither participants nor researchers aware, minimizes bias.
Cross-Over Trial: Sequentially receive multiple treatments, compares efficacy and safety.
Clinical Trials in Humans: Evaluate new treatments in humans, informs clinical practice.

77
Q

medicines can be dangerous hence the need for regulation

why do meds need monitoing

A

side effects

78
Q

Who controls the use and regulation of medicines ?

A

European & National Law outline the basis of medicine regulation

79
Q

1925 THERAPEUTIC SUBSTANCE ACT
clinical trials

A

The anti-syphilis drug, Salversan 606 contained toxic impurities. Each batch of product was submitted to the Medicines Research. Council for assessment before release for marketing in UK.

80
Q

1956 THALIDOMIDE
clinical trials

A

First launched in West Germany. Marketing and distribution rights sold to other countries, e.g. USA, UK.
May 1961 licensees reported 75-90 cases of polyneuritis, then phocomelia (sealed limbs).
Nov 1961 Withdrawn from W German market.
The Ministry of Health issued a statement that thalidomide was a major factor in causing phocomeila (a teratogen). It was withdrawn from UK market.

Thalidomide, marketed as “Distaval” in the UK, caused severe birth defects when prescribed to pregnant women in the late 1950s and early 1960s. Withdrawn in 1961, the UK implemented stricter regulations for drug approval and monitoring. Thalidomide survivors receive support from the Thalidomide Trust. Today, it’s used under strict controls for conditions like leprosy and multiple myeloma.

81
Q

1962 THE COMMITTEE ON SAFETY OF DRUGS
clinical trials

A

Voluntary agreement by the Ministers of Health to look at the safety of new drugs. The Committee on Safety of Drugs consisted of scientists, physicians and pharmacists (Chairman; Mr Dunlop), they checked the “reasonable safety of a drugs intended purpose”.
Products already on the market were granted a provisional Licence of Right.

82
Q

1968 UK MEDICINES ACT
clinical trials

A

Approved by the UK Government in 1968. Came into force in 1971.
AIM: to assess evidence of the safety, quality, efficacy of all medicinal products (new and old).

83
Q

The UK and the interface with Europe

A

1965 65/65/EC
EEC directive to “safeguard public health”
1973 UK JOINED THE EEC
UK required to comply with all EEC directives.
Most important ones: 75/318/EC and 75/319/EC, a harmonised view of what should be in a Licence Application.
i.e. Physicochemical, biological, microbiological tests Toxicological and pharmacological and clinical tests
1994 UK Medicines Act updated by SI 1994/3144
Legislation to bring UK into line with Europe.
(except for Clinical Trials, sale and supply controls, ML/WDL
and advertising)

84
Q

What is a medicinal product?

A

Any substance or article (not being an instrument, apparatus or appliance) …manufactured, sold, supplied, imported or exported for use… by being administered to
… human beings for a medicinal purpose

85
Q

What is a Medicinal Purpose?

A
  1. Treating or preventing disease
  2. Diagnosing disease or ascertaining the existence, degree or extentent of a physiological condition
  3. Contraception
  4. Inducing Anaesthesia.
  5. Otherwise preventing or interferring with the normal operation of a physiological function.
86
Q

Medicines Act 1968:

A

Except in accordance with a Licence granted for the purposes of this section (“a product licence”) no person shall in the course of business sell, supply or export any medicinal product

SECTION 8(2):
No person shall in the course of business manufacture or assemble any medicinal product except in accordance with a Licence granted for the purposes of this section

NOTE: there are exemptions to this rule……

87
Q

Exemptions from Licensing

A
  1. PHARMACISTS, MIDWIVES, CHIROPODISTS, ETC.
  2. VITAMINS - classed as a food not a medicinal product
  3. IMPORT - for administration to the person importing product (at the specific request of a doctor)
88
Q

Criteria required for granting a product licence

A

MA- Qaulity, safety, efficacy

NOT CONSIDERED for the granting of license:- medical need or price
NB. UK has other controls beyond the simple granting of a licence e.g. Local Formularies, National Institute of Clinical Excellence (NICE)

89
Q

The Common Technical Document (CTD)

A

The Common Technical Document (CTD) is a set of specification for application dossier for the registration of Medicines.

Designed to be used across Europe, Japan and the United States.

Developed by:
European Medicines Agency (EMA, Europe),
Food and Drug Administration (FDA, U.S.)
Ministry of Health, Labour and Welfare (Japan).

The CTD is maintained by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

90
Q

The structure of the Common Technical Document

A

module 1 - administrative and prescribng information

module 2- quality overall summary, nonclinical overview, nonclinical summary, clinical overview, clinical summary

module 3 - quality data

module 4 - non clinical study reports

module 5 - clinical study reports

91
Q

facts on MAAs

A

Assessing a poor-quality Marketing Authorization Application (MAA) takes three times longer than assessing a high-quality one.

92
Q

Every medicine must possess:

A

Label use packaging components labelling
Summary of Product Characteristics (SPC)
Patient Information Leaflet (PIL)
User leaflet for products used by Health Care Professionals (HCP)

93
Q

What system is used to register medicines in Europe?

A

Mutual Recognition
Centralised
National (pre-1/1/98)

94
Q

what is multi recognition
clinical trials

A

Mutual Recognition
First application is made to one EC Member State AuthorityNational Authorisation grantedMutual recognition of this authorisationby other Concerned Member StatesAuthoritiesEach member state issues anAuthorisation

95
Q

what is centralised
clinical trials

A

One single application is made to the EMATwo Member State Authorities act asrapporteurs with other Member StateAuthoritiesOne single European Authorisation isgranted by EMA

96
Q

Marketing Authorisation Maintenance

A

(Product Launch/Promotion)
Renewals
Variations
Pharmacovigilance

97
Q

what is parmacovigilance

A

Pharmacovigilance involves monitoring and assessing the safety of medications after they’re approved. It aims to detect, assess, and prevent adverse effects and other drug-related problems, ensuring safe medication use.

98
Q

Typical reasons for MA variations

A

ADR monitoring
stability data
production modifications
QC procedures updated
new clinical trial data
modification synthetic route of active
pack changes
formulation modificatons
new manufacture assembler

99
Q

Emerging issues:- Marketing Authorisation

A

Line extensions
new formulations (e.g. modified release)
new indications

Legal status (switches)
POM to P (e.g. Simvastatin, chloramphenicol)

Generics

100
Q

Revoking an MA

A
  1. False application details
    1. Contravention of licence terms
    2. Actual product does not comply with product licence /MA
    3. Failure to provide requested information
    4. Unsuitable premises
    5. Not on the market within 3 years of grant
    6. No longer safe/satisfactory risk/benefit balance
    7. No longer manufactured to a suitable standard
101
Q

thermoplastics?

A

Soften on heating to a viscous fluid and harded on cooling
Autoclavable (for injections)
High density polyethylene (HDPE)
Poor visual clarity
Polyvinylchloride (PVC)
Poor flexibility
Plasticisers have to be added to form infusion bags
Polypropylene (PP)
Higher heat resistance than PE

102
Q

what is PS plastic

A

polystyrene
General purpose and impact modified
Tablet bottles for dispensing

103
Q

what is PTFE plastics

A

polytetrafluoroethene
High chemical resistance
Very Expensive
Coatings or liners

104
Q

what is PET

A

polyester
Increasingly popular for oral liquids
Inert
Low temperature resistance

105
Q

Plastics - Advantages

A

Large material choice
Broad range of physical and chemical properties
Large Number of fabrication processes
Range of decorative and printing options
Numerous design options
Simple squeezable bottles for eye medication
Complex valve systems for MDI’s
Clean Process
Light and robust

106
Q

Plastics - Disadvantages

A

Possible extraction of chemical additives from the plastic
PVC plasticisers
Interaction with medicament
diazepam absorbed onto PVC
Absorption of components of the pharmaceutical formulation
Lightweight
All plastics permeable to some extent to moisture, oxygen and CO2
Most plastics build up electrostatic charge
Transmit light unless pigmented

107
Q

Other possible disadvantages (1)
plastics

A

Stress cracking
Caused in LDPE by certain agents
detergents and volatile oils
Surface crazing
Fine-scales cracking especially in PS caused by exposure of amorphous plastics to certain chemicals
Poor printability
Polyolefins in PE and PP require pre-treatment to enable ink to “key” to surface
Additives in plastics can migrate to the surface interfering with printing

Poor impact resistance with PS and PVC
Can be improved by inclusion of impact modifiers eg Rubber
BUT permeability of plastic increased
Gamma irradiation of LDPE
Induces cross-linking and leads to brittleness

Negative aspects of plastics for pharmaceutical packaging can be overcome or minimised by suitable design
Loss of preservatives from by dissolution in LDPE can be reduced by enclosing bottle in PVC blister pack.
PVC impermeable to volatilised preservative
Equilibrium of volatile preservative forms in air space between formulation, bottle and pack air space

108
Q

Stability Profiles of Injections in Plastics (1)

A

Simulate in-use conditions and examine for:
Sensory, chemical, physical changes
Changes in weight or volume
Plastic permeability
pH changes
Effect of light
Effect of extractables on the injection
plasticiser from PVC bags detected in IV fluid

Permeability of gases and solvent vapours through plastic into injection
Cyclohexane - solvent for PVC - extracted from infusion bags
Absorption of active, bactericides and other components
Drug absorption - diazepam on PVC

109
Q

plastic additives

A

Polymer
Residues associated with polymerisation
Additives used to modify properties
Process aids

Knowledge of constituents of plastic essential
May be extracted from plastic into the medicament

110
Q

what are residues in plastics

A

Residues in plastics refer to any substances or materials that remain within the plastic after it has been manufactured or used. These residues can come from various sources

111
Q

what are additives in plastics

A

property modifiers

Additives in plastics are substances added during manufacturing to modify properties. Types include plasticizers, stabilizers, flame retardants, colorants, fillers, and processing aids. They enhance performance, appearance, and manufacturability.

112
Q

what are rpocess aids in plastics

A

Process aids in plastics are additives used during manufacturing to improve processing characteristics. They enhance flow properties, reduce friction, prevent sticking, and improve mold release, optimizing production efficiency and product quality. Examples include lubricants, flow enhancers, and mold release agents.

113
Q

examples of residues

A

monomers
catalysts
accelerators

114
Q

axamples of additives / property modifiers

A

fillers
anti-static agents
anti-oxidants
plasticisers
pigments
dyes
mhitners
opacifiers
UVabsorbers
flame retardants

Additives can change other properties of the plastic eg fillers (chalk and talk) increase moisture permeation

115
Q

examples of process aids

A

solvents
release agents
emulsifiers
lubricants
stabilisers

116
Q

tell me about what PE has in it
plastics

A

PE : low in residues, small quantity of anti-oxidant

117
Q

Plastic Fabrication Process

A

The plastic fabrication process involves several steps to transform raw plastic materials into finished products.

Options far greater than glass
Injection moulding
Blow moulding
Thermoforming
Vacuum forming
Extrusion
Solid phase pressure forming
Basic Moulding Operations
Plastic heated to melt or soften the material
Material shaped in a mould
Cooling to solidify plastic

118
Q

New Plastic IV Bags

A

Multi-layer, co- extruded polyolefine based material with inert polyethylene layer in contact with solution
Polypropylene / Polyamide over wrap

119
Q

Metal and Metal Containers (1)
plastics

A

Metals widely used 10 to 20 years ago for rigid containers
Tablets, capsules, powders and liquids
Example Product
Collapsible tubes (Eye ointment or cream)
Aluminium, tin or tin coated lead
Manufactured by “impact extrusion”
Replaced by plastic

Modern Applications
Mainly aluminium and its alloys
Foils
Facings for “wadded closures”
Pressurised containers
Aerosols including MDI’s
Closures
Particularly ROPP (Rolled on Pilfer Proof)
Important for security and tamper evidence

120
Q

Paper and Board
packaging

A

Remains a significant part of SECONDARY pharmaceutical packaging
Labels, cartons, bags, information, shrink wrap trays
Cartons traditionally used for a high percentage of pharmaceutical products
Increase product display area
Improve stacking
Physical protection
Collapsible tubes
Information
Inside and out
Protection from light

121
Q

Films, Foils Laminates (2)
packaging

A

End uses
Sachets, bottle seals, strip packs, blister packs, liners, over-wraps
Blister packs
Lid
Board, paper, foil*, coated film
Thermoformed Tray
PS, PVC, PET, foil, PE (Or combinations of above)
Push through systems
Lid firmly bonded to the tray
Peelable system
Lid easily pulled back
Foil blisters or foil overwrap
Provides a hemetic pack – excludes virtually exchange of gases between product and surroundings

122
Q

Closures
packaging

A

Essential part of primary and secondary pack
Possible functions
Totally hermetic seal
Fused glass ampoule
No exchange occurs between contents and outside environment
Microbiological Seal
Rubber bung with metal over-seal
Effective seal
Adequate for the product, closure not HERMETIC nor a total guarantee against entry of bacteria

123
Q

Rubber Closures
packaging

A

Ideal Properties and Requirements
Good aging properties and oxidation resistance
Hardness and elasticity should allow needle to pass through without blunting
Puncture should close immediately on withdrawing needle (Does not core)
No change in properties during sterilisation
Impermeable to air and moisture
Penicillin is water sensitive

124
Q

Closure Types
packaging

A

2 main types of closure
Physical Compression
Heat sealing

  1. Plug in : friction or push in (eg rubber closure for injections)
    2 Push-Over or “snap-fit (eg LDPE)
  2. Screw Cap (eg Aluminium PE, PP)
  3. Rolled on (RO)aluminium alloy caps
    Rolled on pilfer proof (ROPP) aluminium alloy caps
    Popular for security of export products
125
Q

Synthetic Rubber
4 Main types use in Pharmaceutical Packaging

A

butyl rubber
nitrile rubber
chloroprene rubber
silicone rubber

More resistant to high temperature and ageing than natural rubber
More expensive
Latex Free

126
Q

Pharmaceutical Problems

A

Components of injection can be extracted by rubber
Bactericide absorption
Chlorocresol and phenyl mercuric nitrate strongly attracted to and absorbed by rubber
Treat closures in solutions containing bactericides
Twice concentration of product solution
Volatilisation of Bactericide from closure after equilibrium attained
Loss limited by
Sealing closure with less permeable material such as paraffin wax (consider fragmentation of wax)
Reduction of upper surface area
Increase closure thickness

Reduction of antioxidant activity
Sodium metabisulphite or sulphur dioxide can be absorbed from injection solutions
Particulate contamination by “Rubber Coring” during withdrawal of dose
Rubber is, to some extent, permeable to moisture and gases
Seal may not be strictly hermetic

127
Q

Rubber Closures for Injections

A

Greater emphasis must be placed on the packaging material
and effects of sterilisation process

  1. Discoloured
  2. Rubber generally will not withstand dry heat (cf silicone rubber)
  3. Unacceptable physical & chemical changes can occur by molecular cross-linking
  4. Only suitable for a few plastics
  5. Ethylene oxide treatment – degassing is essential to remove TOXIC residues of
    ethylene oxide, ethylene glycol (hydrolysed ethylene oxide), epichlorhydrin
    (if Cl- ions present)
128
Q
A

week 23 (Y2) (3 decks)

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