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Flashcards in Law&Admin Deck (33):

Can you give me the Legal Duties of the QP?

The legal duties of the QP are outlined in the 3 directives:
Art 13 of the Clinical Trial Directive 2001/20/EC
Art 51 of the Human medicines Directive 2001/83/EC
Art 55 of the Vet Medicines Directive 2001/82/EC
2001/83/EC states:
1. Member States shall take all appropriate measures to ensure that the qualified person referred to in Article 48, without prejudice to his relationship with the holder of the manufacturing authorization, is responsible, in the context of the procedures referred to in Article 52, for securing:
(a) in the case of medicinal products manufactured within the Member States concerned, that each batch of medicinal products has been manufactured and checked in compliance with the laws in force in that Member State and in accordance with the requirements of the marketing authorization;
(b) in the case of medicinal products coming from third countries, that each production batch has undergone in the importing Member State a full qualitative analysis, a quantitative analysis of at least all the active constituents and all the other tests or checks necessary to ensure the quality of medicinal products in accordance with the requirements of the marketing authorization.
The batches of medicinal products which have undergone such controls in a Member State shall be exempt from the controls if they are marketed in another Member State, accompanied by the control reports signed by the qualified person.
2. In the case of medicinal products imported from a third country, where appropriate arrangements have been made by the Community with the exporting country to ensure that the manufacturer of the medicinal product applies standards of good manufacturing practice at least equivalent to those laid down by the Community, and to ensure that the controls referred to under point (b) of the first subparagraph of paragraph 1 have been carried out in the exporting country, the qualified person may be relieved of responsibility for carrying out those controls.
3. In all cases and particularly where the medicinal products are released for sale, the qualified person must certify in a register or equivalent document provided for that purpose, that each production batch satisfies the provisions of this Article; the said register or equivalent document must be kept up to date as operations are carried out and must remain at the disposal of the agents of the competent authority for the period specified in the provisions of the Member State concerned and in any event for at least five years.


What are the routine duties of the QP and where can they be found?

Routine duties are outlines in Annex 16 of the GMP directive: 2003/94/EC:
8. Routine duties of a Qualified Person
Before certifying a batch prior to release the Q.P. doing so should ensure, with reference to the guidance above, that at least the following requirements have been met:
a) the batch and its manufacture comply with the provisions of the marketing authorisation (including the authorisation required for importation where relevant);
b) manufacture has been carried out in accordance with Good Manufacturing Practice or, in the case of a batch imported from a third country, in accordance with good manufacturing practice standards at least equivalent to EC GMP;
c) the principal manufacturing and testing processes have been validated; account has been taken of the actual production conditions and manufacturing records;
d) any deviations or planned changes in production or quality control have been authorised by the persons responsible in accordance with a defined system. Any changes requiring variation to the marketing or manufacturing authorisation have been notified to and authorised by the relevant authority;
e) all the necessary checks and tests have been performed, including any additional sampling, inspection, tests or checks initiated because of deviations or planned changes;
f) all necessary production and quality control documentation has been completed and endorsed by the staff authorised to do so;
g) all audits have been carried out as required by the quality assurance system;
h) the QP should in addition take into account any other factors of which he is aware which are relevant to the quality of the batch A Q.P. may have additional duties in accordance with national legislation or administrative procedures.
Legislated in UK under SI 2012 No. 1916


Describe sections in SI 2012 No. 1916

Part 1 – General
Part 2 – Administration
Part 3 – Manufacturing and wholesale dealing
Part 4 – Requirement for authorisation
Part 5 – UK marketing authorisations
Part 6 – Certification of homeopathic medicinal products
Part 7 – Traditional herbal registrations
Part 8 – 126a authorisations

Part 9 – Borderline products
Part 10 – Exception to requirement for marketing authorisation
Part 11 – Pharmacovigilance
Part 12 – Dealings with medicinal products
Part 13 – Packaging and leaflets
Part 14 – Advertising
Part 15 – British Pharmacopoeia

Part 16 – Enforcement
Part 17 – Miscellaneous and general


Can you provide me with the latest legislative updates in EU?

The most recent updates have been both in EU and UK:
For EU this has included the Falsified Medicines directive 2011/62/EU published in July 2011. This must be accomplished within 18months (Jan2013) and safety features within 5-6years.
The 4 main pillars of the directive are:
1. Safety: must be able to verify authenticity, be able to ID individual packs, tamper evident
2. Good Distribution Practice: Wholesale dealers are obligated to notify authorities if they suspect medicines to be falsified. There is an expectation for Brokers to be registered with the authorities.
3. Active Substances: If from outside EU then non EU reg authority must certify product made to EU GMP.
4. Internet Sales: Protection of public health by approving pharmacies in all member states with also EU logo on authorised shows.

In the last 2 years: 2003/94/EC GMP directive updates have included:
Chapter 1 which was updated in line with ICH Q10 concepts. Pharmaceutical Quality system. Deadline to take effect from Jan 2013.
Chapter 4 was updated due to the increased us of electronic documents in the GMP environment. This has already come to effect in June 2011.
Chapter 7 has been renamed to Outsourced activities with an increased scope beyond contract manufacture and analysis operations. Due to take effect from 31Jan2013.
Part 2 and Part 3 have been introduced.
Part 2 is the Basic requirements for GMP for Active Substances.
Part 3 contains general sections: SMF requirements , Q9 Q risk management, Q10 Quality System, MRA Batch certificate, written confirmation template for exported API


Who are EDQM?

EDQM is the European Directorate for the Quality of medicines and is a key EU organisation involved in Harmonisation, co-ordination of standardisation, regulation and QC of medicines, Blood transfusion, organ transplantation, pharmaceuticals, pharmaceutical care


What is the organisation of a CTD

in Vol 2 of Eudralex
Module 1: Regional Admin information
Module 2: TOC, Intro, Overall Quality summary, non-clinical overview and summary, clinical overview and summary
Module3: Quality
Module 4: Non Clinical study reports
Module 5: Clinical study reports


What is the content of Module 3:

Quality Overall summary
2.3 S Drug Substance
Control of DS
reference standard
Container closure system
2.3 P Description and composition
Pharmaceutical development
Control of excipients
Control of drug products
Ref stds or materials
Container closure\
A1: Facilities and Equipment
A2: Adventitious agents
A3: Excipients
2.3 R Regional info


Name the divisions of the MHRA: Human Meds

Operations and finance
Human resources
Inspection enforcement and standard
Vigilance and risk management of medicines


Divisions of VMD



Can you name & briefly describe the various routes that you can gain a marketing authorisation for a product.

There are 4 ways: National procedure
For MRP you must first hold a national licence and then that site becomes RMS and country upon which your MRP application is based.
Then there is the DCP and the CP.
DCP- Human medicines Agency involved in coordination. The product is for all NEW applications for which no other licence previously existed and for which a CP licence is not mandatory.
CP mandatory for Biotech, Orphan drugs, New actives for Aids, cancer, diabetes& neurodegenerative conditions. Vet products that are performance enhancers, and new chemical entities for treatment of autoimmune diseases, immune dysfunctions and viral diseases.


Can you tell me about Marketing authorisation variations?

Article 2 of regulation 1234/2008 classifies variations as:
Type 1A: Do and tell: minor: 12months
Type 1B: Tell, acknowledge do: minor : 30days
Type 2: Tell, acknowledge, implement: Major: 60-90 days
Extensions are are a change in Active suctive strength, form, route of administration, Note: New MAA if change in tradename
Urgent safety restrictions: 24hr and follow type 2.


Describe Type 1A variations?

These are
a)change in the ID and contact details of
- the holder
- the manufacturer or supplier of any starting material, reagent, active, intermeidate, used in Manufacturing process or finished product.
b) Deletion of a manufacturing site, incl active, intermediate or FP, pacakaging site, manufacturer responsible for batch release, site where batch ocntrol takes place.
c) minor changes to approved physico-chemical test, updated procedure is demonstrated to be equivalent to previous. Apppropriate validation studies have been conducted and results show equivalence.
d) Variations to active or excipient to comply with the monograph of ph. Eur or national Pharmacopoeia of the member state. Where the change is made exclusively to comply with the pharmacopoeia and te spec for product specific properties are unchanged.
e) Variation to packaging material not in contact with FP, which DO NOT affect the delivery, use, safety or stability of the medicianl product.
f) Tightening of specifications limits where the change is NOT a consequence of any commitment from previous spec liits and does not result from an unexpected event during manufacture.


Can you describe Type 2 variatiaon examples?

A) New Therepeutic indication or modification of an exiisting one.
b) Significant modification to SmPC due to new quality, pre-clinical, clinical or PV findings
c) changes outside the range of approved specifications, limits or acceptance criteria
d) substantial changes to manufacturing process, formulation, specifications or impurity profile of the active substance or FP which mayhave a significant impact on qulaity, safety or efficacy of medicinal product.


Do imports have to be tested?

No if from EU ((per Art51 f 2001/83/EC) or CT material (per Art 11 of 2003/94/EC)
If MRA then also not required for certain products`
All testing for imports coming from 3rd countries is mandatory.


MRA- What are they and which ones are effective?

MRA= Mutual recognition agreement. Allows bodies based in 3rd countries to perform assessments against the EU requirements and vice versa.
Countries that EU have effective agreements with Canada, Switzerland, Australia, New Zealand, Japan.
MRAs reduce technical barriers to trade. Ensure greater international harmonisation.
Australia- from Jan1999 Human meds (2001 vets) no exceptions.
Canada: from Feb2003: not pre-approval inspections, vet immunological products and stable products derived from human blood or human plasma.
NZ: Jan 1999 humans (Jun2002 vets) No exceptions.
Switzerland: Jun2002
Japan: May 2004. Exceptions: Homeopathic: covered if med in Japan and subject to GMP.
Vitamins, minerals and herbals only if medicinal by both.
Not coverred in Japan MRA: Medicinal gases, In-vitro diagnositcs, Blood, plasma, unstable medicinals from human blood or plasma, Biologics, APIs, CT, Steriles, Stable medicinal



What are the GMP directives?

2003.94.EC - Human
91.412.EC - Vet


What are the main updates on 2001.83.EC when it was amended by 2004.27.EC?

Include CT MFG and CT
Update MA application - introduce decentralised procedure
Replace Proprietary medicinal product with medicinal product and homeopathic medicinal product
EMEA - GMP cert + EudraGMP website
Permits testing of imported products in EU - not just importation country
GMP req for API


What are the different types of EU legislation?

Regulations: Immediate impact
Directives: Transposed into national laws - binding by its effect
Decisions of the council: binding on individual/organisation
Recommendations/opinions: not binding


What is the EU legal process?

The Commission consults intersted parties and makes a proposal to the Council
Parliament gives an opinion on and proposes amendments to the proposal
The Commission takes a veiw of the Parliament's opinion
The Council adopts a common position on the proposal
Parliament approves, amends, rejects
The Council adopts, amends or abandons the proposal


What are the volume of Eudralex?

Vol 1: Pharmaceutical legislation (Human)
Vol 2: Notes to applicant (Human) - 2A: Procedure for MA / 2B: Presentation and content of the dossier / 2C: regulatory guideline
Vol 3: Scientific guideline (Human)
Vol 4: GMP (Human and Vet)
Vol 5: Pharmaceutical legislation (Vet)
Vol 6: Notes to applicant (Vet)
Vol 7: Scientific guideline (Vet)
Vol 8: Maximum residual solvent (Vet)
Vol 9: Pharmacovigilance
Vol 10: GCP


What are the key directives and regulations?

2003.94.EC - GMP directive
91.412.EC - GMP directive (Vet)
93.42.EC - Medical Devices directive
Reg 2309/93 - establish EMEA
Reg 276/2004 Establish EMA
2001.20.EC - CT directive
2005.28.EC - GCP directive
2001.83.EC - Codification directive (Human)
2001.82.EC - Codification directive (Vet)
2002.98.EC - Blood directive
2004.23.EC - tissue and cell directive
2004.24.EC - Traditional Herbal medicines
2004.27.EC - Human medicines amendments - GMP for API
2004.28.EC - Vet medicines amendments
Reg 1901/2006 - Paediatric use of medcinal products
Reg 1394/2007 - Adv therapies


Summary of 2001.83.EC

Art 1: Definition
Art 2-5: Scope
Art 6-12: Marketing Authorisations
Art: 13-16: Homeopathic
Art 16a to i: Traditional Herbal Medicine
Art: 17-26: MA procedures
Art 27-39: Mutual recognition or authorisations
Art 40-53: Manufacturing and importation (40-47: need for a MIA; 48-53 - need for a QP
Art 54 - 69: Labelling and package leaflet
Art 70-75: Classificaiton of medicinal products
Art 76-85: Wholesale distribution
Art 86-100: advertising
Art 101-108: Pharmacovigilance
Art 109-110: Human blood and plasma
Art 111-119: supervision and sanctions
Art 120-121: standing committee
Art122-127: general provisions
Art 128-130: final provisions - repeal
Annex I: CTD format
Annex II: Lists repealed directives + correlation table
Total 130 articles


Summary of key articles of 2001.83.EC

Art 40:
Need for MIA for manufacture and import
MIA needed for sole export
MIA format follow Inspectors Complilation of Procedures
Art 41:
Lists the basis ofor MIA and require at least one QP
Art 42:
Requires MS to grant MIA by inspection
Art 43&44:
Requires MIA to be ussed within 90 days and variation to be granted within 30 days
Art 46:
MIA duties
Have appropriate staff
Sell/market according to local regulations
Seek variations if changes occur
Allow inpsections/access by authorities
Allow QP to perform duties
Comply with GMP


When was the EMA created?

European Agency for the Evaluation of Medicinal Product - EEC No 2309/93 in 1993
EMA - Reg 726/2004 - centralise procedure - EMA


What is the definition of a medicinal product according 2001.83.EC?

Any substance or combination of substances:
Treat or prevent disease
Restore, correct or modify physiological functions
by exeritng a pharmacologicla, immunilogical or metabolic action
or making a medical diagnosis


What does EMA do?

Coordinates existing scientific resources in MS
Evaluate and supervise medicinal products for both human and bet use in EU
Primarily Centralised procedure but also in Mutaul Recognition
Evaluate : via centralised procedures
Arbitration: via decnetralised procedures and MR procedure
Coordinate MS resources: evaluation of MA + PV activities + Inspections + scientific advice to companies
Harmonisation: Facilitate harmonisation of standards and guidelines


What are the (7) scientific committes of EMA?



What aspects do the inspection directorate of EMA cover?

Third party inspection on healf of EMA: MS inspectors + inside and outside EU for centralised MA application
Inspector working parties: Develop GMP guidelines and harmonise GMP inspections


What are the differences in US and EU GMP legislations?

EU: QP release required
EU: GMP for API only started in 2004; US required for many years
EU: Formal requireent of GMP for IMP - inspection and licence - US do not inspect
EU: MIA licence for MFG - no US equivalent


What are the differences in GMP expectations between US and EU?

US: RO allowed for WFI production EU: specifies R2A as media for water testing
EU: expect capping under Grade A laminar flow; US: unclassified
EU: SP + CP + BT US: BT only
Differences in autoclave validation strategy: steam quality + BI etc
US: RM sampling - square root of N+1 approach - not risked based
US: OTC products are not inspected as often
EU: additional req on PQR (starting and packaging material + QTA + qualificaiton status


Structure of product info

Annex I - Summary of product characteristics
Annex IIA - Manufacturing-authorisation holder responsible for batch release
Annex IIB - Conditions of the marketing authorisation
Annex IIIA - Labelling
Annex IIIB - Package leaflet


SPC structure?

4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Fertility, pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling


Structure of QP declaration?

PartA: manufacturing sites
PartB: gmp declaration
PartC: basis for declaration (audit)
PartD: API supply chain
PartE: sign off