IMPs Flashcards
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 Effectiveness 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 GxPs
What are the highlights of CT directive?
Notification + approval for CT
Common sys of applications and authorisations
EudraCT
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 Protocol IB IMPD 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 Expiry 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
USA: no MRA
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 Randomisation Blinding Labelling and packing Release Shipping and distribution Storage off site Storage and temperature control during transit and at the investigator site Returns Complaints/adverse reactions Recalls or retrieval RE-labelling 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 Covers: 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 2001.20.EC 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
Principle
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
Personnel:
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
Documentation
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
