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Flashcards in IMPs Deck (20):

what is a psf

a product specification file is a ref document used in CT that contains information on the manufacture, labels and packaging of CT material.
It a requirement for all sites manufacturing IMP for CT to release to a PSF per Annex 13.


What are the different types of CT?

CT of a non-authorised IMP
CT of an authorised medicinal product for a new indication
CT for new condition o fuse i.e. dosage scheme, new route
CT according to SMPC


What are the different phases of drug development?

1. Research programme (4-10 yrs)
ID research targets
Include in integrated research programme
Test hypothesis
ID development candidates
i.e. Medical needs + Market research + Commercial viability + biochem/pharm screening + Candidate drugs + patents
2. Exploratory Development (3+ yrs)
Establish general pharmacology
Evaluate safety and tolerability
Define dose regimen
Develop MFG process
i.e. Toxicology + pharmacology + Clinical safety + ADME + Dose selection + formulation dev + Analytical method + package
Phase I + II
3. Regulatory development (3+yrs)
Document clinical safety/efficacy
ID MFG capacity
Prep regulatory submission
Phase III
4. Commercialism (3+yrs) MFG
Register product
Gain market approval
Launch and sell
Phase IV


What are the different phases of CT?

Phase 1
Safety study + establish dosage range + ID side effects+ ADME
First in man
Define dose and safety (dose escalation + ADME)
20-100 healthy volunteers
Phase 2
Further safety data + decide dose and dose range + efficacy
Pharmacological activity + short term safety
100-300 patients
Phase 3
Head to head with gold standard + Quantify adverse effect
300-3000 patients
Phase 4 (post market)
More about side effects and safety
Long term risk and benefits
Many thousands …
Phase 0
Human micro dosing
Sub-pharmacological doses (100mcg)
n = 10


What should be included in a CT protocol?

Selection criteria
clinical hypothesis
Schedule: tests + procedures + Medications + dosage
Length of the study
Trial design and underpinning stats


What are the different types of CT design?

Open study: pt and clinician knows Tx - subjectivity?
Single blind study: Clinician knows - pt don’t'
Double blind: Tx supplied to clinician as pt pack
Cross over: 2 treatments same patient (Cross over)
Parallel: Same treatment through out trial


What is the definition of GCP?

Standard for CT trial
data integrity
subject rights, integrity and confidentiality


What is the scope of CT directive?

Phase 1 - 4
Bioavailability and bioequivalence studies
All trials involving human
Vet and devices not included


What are the highlights of CT directive?

Notification + approval for CT
Common sys of applications and authorisations
MFG + import of IMP: GMP + Annex 13
QP batch release
GMP inspection on IMP MFG
Set standards as 2005.28.EC GCP directive
GCP inspections of clinical data and records


What should be included in a CT application?

CTA form
NIMP dossier
Scientific advice - from EMA or MS if available
EMA PIP decision if available
Content of the labelling of the IMP
Proof of payment
MIA import or MIA(IMP)
QP declaration on GMP for each MFG site


What is a trial master file?

Art 16 2005.28.EC
Consists essential documents
conduct of a CT
quality of the data produced to be evaluated
Essential doc: permits evaluation of the conduct of CT and quality of data generated
Group in stages: Before + during and after CT
TMF should be at investigator and sponsor's office


What are the labelling requirements for an IMP?

name + address + tel of sponsor/CRO or investigator - main contact
Pharmaceutical dosage form, route of admin, quantity of dosage units, name, strength/potency
Batch number / code
Trial ref code
Trial subject id / treatment number
Name of the investigator
Direction for use
For clinical trial use only
Storage condition
Keep out of reach of children
Annex 13 does provide further guidance as to what info is required if space is limited.


What are the contents of Eudralex Vol 10?

Chapter 1: Application and application form
Chapter 2: Monitoring and PV
Chapter 3: Info on the quality of the IMP
Chapter 4: Recommendation on inspections
Chapter 5: Additional info
Chapter 6: Legislation


What are the differences in IMP in EU and USA?

EU: PSF requirement - no US requirement
Expiry date: not a requirement in US
QP: QP batch release in E


MRA arrangements on IMP imports?

Canada: site needs authorisation - not always the case
Oz and NZ: Phase I excluded
Japan: Sterile IMP not included


How can IMP QP assure equivalent EU GMP?

Source comparator within EU
Or MRA countries
Otherwise need to test on importation
Audit site to assess EU GMP compliance


What are the contents of a PSF?

Ref file containing, referring to files containing all info to draft W/S on processing, packaging, QC testing, batch release and shipping
Specification and analytical methods for starting materials + packaging materials + intermediate + bulk + finished product
MFG methods
IPC testing and methods
Approved label copy
Relevant clinical trial protocols and randomisation codes as appropriate
Relevant TA as appropriate
Stability data
Storage and shipment conditions


What are the GCP/GMP interfaces?

Order initiated by sponsor
Labelling and packing
Shipping and distribution
Storage off site
Storage and temperature control during transit and at the investigator site
Complaints/adverse reactions
Recalls or retrieval
Repacking of comparators
Site to site transfer


What is the link between 2001.20.EC and 2005.28.EC?

Art 1.3: principle of GCP to be published
Principle of GCP = 2005.28.EC
The rights, safety and well being of trial subjects shall prevail over the interests of science and society
Ethics committee responsibilities
Sponsor's responsibilities
Investigator's brochure
MIA (IMP) required for manufacture and importation of IMPs
Purpose of the trail master file
Qualifications and training requirement for GCP inspectors
Inspection procedure
Scope: Art 1
Definition: Art 2
Protection of trial subject: Art 3-5
Opinion of the EC: Art 6-8
Commencement of a CT: Art 9
Conduct of a CT: Art 10
Exchange of info: Art 11
Suspension of the trial or infringement: art 12
MFG and import of IMP: Art 13
Labelling: Art 14
Verification of compliance of IMP with GCP and GMP: Art 15 - inspection
General provision: Art 16-24


Annex 13 content

Follow GMP + Protect subject + ensure outcome not affected by MFG + more complex than commercial
Quality Management:
Need highly effective QMS
Product spec and MFG instruction may change - need control and traceability
All personnel involved with IMP should appropriately trained
QP should in particular ensure fulfilment of the req of Annex 13 and be knowledgeable of dev and CT processes
Premises and equipment:
Min risk of cross contamination
Campaign working where possible
Cleaning is of particular important
Equipment and premises design should reflect the risks
Spec + formulae + instructions: as clear as possible - version number
SOP to cover changes which consider impact on quality
Not necessary to product master formulae or master processing instructions
Order should be written, precise, formally authorised and refer to PSF and protocol