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D Si f i d S h itt PAREXELDr Siegfried Schmitt, PAREXEL

EU GMP REQUIREMENTS AT THE CLINICAL DEVELOPMENT STAGE & QP RELEASE

AGENDA

GMPs for Investigational Medicinal Products (IMP) and their Qualified Person (QP) releasetheir Qualified Person (QP) release

N d l t d i t i th EUNew developments and requirements in the EU

INVESTIGATIONAL MEDICINAL PRODUCTS (IMP)( )

Definition of Investigational Medicinal Products (IMPs)

“a pharmaceutical form of an active substance or placebo beingftested or used as a reference in a clinical trial, including products

already with a marketing authorization but used or assembled(formulated or packaged) in a way different from the authorisedform, or when used for an unauthorised indication, or when used togain further information about the authorised form.”

An IMP must be registered in the EudraCT database

http://tinyurl.com/3rya6w7

NON INVESTIGATIONAL MEDICINAL PRODUCTS (NIMP)

Definition of Non Investigational Medicinal Products (NIMPs)

Products which are not the object of investigation (i.e. other than)the tested product, placebo or active comparator) may be supplied

to subjects participating in a trial and used in accordance with theprotocol. For instance, some clinical trial protocols require the useof medicinal products such as support or rescue/escape medicationfor preventive, diagnostic or therapeutic reasons and/or to ensurethat adequate medical care is provided for the subject. They mayq p j y yalso be used in accordance with the protocol to induce aphysiological response.

http://tinyurl.com/3rya6w7

THE QUALIFIED PERSON (QP)( )

The person defined in Article 48 of Directive 2001/83/EC and Article 52 of Directive 2001/82/EC

The QP is the only person that can release product to be placed on the market in the EUplaced on the market in the EU

The QP is personally liable for the release decision

The regulations apply also to IMPs

THE EUROPEAN UNION

EU - LEGAL INSTRUMENTS

Primary EU Law:Treaty of the Function of the European Union (TFEU)Treaty of the Function of the European Union (TFEU)

Secondary EU Law: Medicinal (Drug)Secondary EU Law:a) Legislative Acts:Regulation, Directive, Decisionb) Non Legislati e Acts

Medicinal (Drug) Products:

E d L V l 1b) Non-Legislative Acts:Recommendation, Opinionc) New Legal Acts (created by

EudraLex Vol 1 (human) & EudraLex Vol 5

the Treaty of Lisbon):Delegated Act, Implementing Act

(veterinary)

http://europa.eu/legislation_summaries/institutional_affairs/treaties/lisbon_treaty/ai0032_en.htm_ y _

EU REGULATIONS

A regulation is a legal instrument that is immediatelyenforceable

Example: Council Regulation (EEC) No 2309/93 on Communityprocedures for the authorization and supervision of medicinalprocedures for the authorization and supervision of medicinalproducts for human and veterinary use and establishing aEuropean Agency for the Evaluation of Medicinal Products

EU DIRECTIVES

• Require Member States to achieve a certain result

• Do not dictate the means of achieving the result

• The contents of the Directive must be transposed intonational law by Member States - and carried out by MemberState “National Competent Authorities”State National Competent Authorities

E l C i i Di ti 2003/94/EC th i i lExample: Commission Directive 2003/94/EC on the principlesand guidelines of good manufacturing practice in respect ofmedicinal products for human use and investigationalmedicinal products for human use

EU GUIDELINES

Do not have the force of law, but represent the agreed views ofregulators on a certain topic. It is possible not to follow them ifscientifically justifiedscientifically justified

Are complemented by Questions and Answers to clarifyspecific points in guidelines

• EMA scientific guidelines - http://tinyurl.com/d2qvbjx

• The GMP guide - http://tinyurl.com/crj4qb3g p y j q

• The guideline publication process - http://tinyurl.com/c6dpjrx

EU LEGISLATION ON THE WEB

EU Legislation

http://eur-lex.europa.eu/en/index.htm

Legislation for Medicinal Products in the European Union

http://ec.europa.eu/health/index_en.htm

GXP FOR IMPS - APPLICABLE REGULATIONS

The regulations cover the lifecycle from development todiscontinuation

EU GXP FOR IMPS - APPLICABLE REGULATIONS

EudraLex Volume 4 Annex 13 Manufacture of InvestigationalMedicinal Products

EudraLex Volume 4 Parts I, II and III

EudraLex Volume 4 Annex 16 Certification by a Qualifiedperson and Batch Release July 2001person and Batch Release July 2001

Draft revision of Annex 16 2013

htt // /h lth/d t / d l / l 4/i d hthttp://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

EU GXP FOR IMPS - PHASE APPROPRIATE

PDA Technical Report 56 - www.pda.org

GXP FOR IMPS VERSUS GXP FOR COMMERCIAL PRODUCT

Particularly for Clinical Phases I and IIy

• Changes need to be documented, but do not need to gothrough a formal change approval process

• Deviations will be the exception

• Analytical methods need to be documented and suitabilityy yestablished, but do not need to be validated

• Documentation has to be controlled, but laboratory journalsb d i t d f b t h dmay be used instead of batch records

• Operational and analytical personnel may be the same

• Critical parameters and quality attributes not fullyestablished (e.g. yield not a critical parameter)

GXP FOR IMPS VERSUS GXP FOR COMMERCIAL PRODUCT

What must be in place for IMPs and Commercial product:

• A formal quality system

• Job descriptions and training

• Calibration program

• Appropriate environmental conditions (e.g. Laminar AirFumehood (LAF) or HVAC)

• Process controls

• Rationales, e.g. for changes, analytical method selection,process and process controls

GXP FOR IMPS - SOME SPECIFIC ISSUES

Sterilisation steps in IMP manufacture

• Must be fully validated

• Associated analytical methods must be fully validated

Biotech Products

• Production scale for Clinical Phase III material must beequivalent to commercial scale (preferably the sameequipment)

GXP FOR IMPS - SOME SPECIFIC ISSUES

Clinical Trial Logistics

Pharmaceutical Engineering Nov/Dec 2014 www.ispe.org

GXP FOR IMPS - SOME SPECIFIC ISSUESClinical Trial Logistics

PAREXEL International

GXP FOR IMPS - SOME SPECIFIC ISSUESOptimising IMP Utilisation

PAREXEL International

THE ROLE OF THE QP IN IMP RELEASE

The QP is responsible for certifying that each batch of IMP hasbeen produced and tested / checked in accordance with:

G• EU GMP

• The Product Specification File

• The IMPD (Investigational Medicinal Product Dossier) or theCTA (Clinical Trial Authorisation)

Th P d t S ifi ti Fil ( di A 13 t th EU• The Product Specification File (according Annex 13 to the EU-GMP Guide)

THE ROLE OF THE QP IN IMP RELEASE

The IMP QP is accountable from manufacture all the way to thepatient by:

G• assessing GMP issues

• participating in inspections and audits at sites involved in themanufacturing and distribution of IMPsmanufacturing and distribution of IMPs

• being a reliable contact for the health authorities

k i li bl l i l ti d i l di• knowing applicable legislation and processes includingexceptions which may impact the quality and safety of the IMP

• being involved in complaint handling and recall processesbeing involved in complaint handling and recall processes

www.gmp-compliance.org 2014

QP RELEASE - ABOUT THE QP

There is very little harmonisation in Europe regarding theprerequisites for becoming a QP

E.g. in the UK a biologist, a chemist or a pharmacist will beeligible to become a QP if they have chartered status with theeligible to become a QP if they have chartered status with therespective Royal Society

E.g. in Italy the QP must be employed by the MAIHg y Q p y y

E.g. in Germany the QP must have police clearancecertification

QP RELEASE - THERE IS A PRICE TO PAY

Wentworth Pharmaceutical QP Survey 2015

THE BASIS OF THE QP DECLARATION

For human and veterinary medicinal products, the QPdeclaration should be based upon an audit of the activesubstance manufacturers. It is established good practice thatsubstance manufacturers. It is established good practice thatthe audit should be conducted at the manufacturing site i.e. anon-site audit

Audits should be by or on behalf of the ManufacturingImportation Authorisation Holder (MIAH), by suitably trainedand experienced person(s), who may be a third partyp p ( ), y p ycontractor

The audit cannot be replaced by GMP certificates from arelevant competent authority

QP RELEASE - TEMPLATES FOR API AND IMP

EMA Guidance for the template for the qualified person’sdeclaration concerning GMP compliance of active substancemanufacture “The QP declaration template” 2014 -manufacture The QP declaration template 2014http://tinyurl.com/pmnkfgg

The template - http://tinyurl.com/o63p7og

Template for the qualified person’s declaration concerningp q p gGMP compliance of investigational medicinal productsmanufactured in non-EU countries - http://tinyurl.com/pnh4m68

QP RELEASE - TEMPLATES FOR BATCH RELEASE

Internationally harmonised requirements for batch certification- http://tinyurl.com/posc88w

This certificate may also be used for active pharmaceuticalingredients and investigational medicinal products used in clinicalt i l th i titrial authorisations.

IMP RELEASE - TWO-STEP PROCESS

Step 1 Certification by the QP

Step 2 Release following fulfilment of the requirements of(C f ) fArticle 9 (Commencement of a clinical trial) of Directive

2001/20/EC - i.e. the clinical trial must be authorised

QP RELEASE - SOME SPECIFIC ISSUES

Q: How do you perform batch record review of batchesproduced in China, when they are not bilingual or translated?

fHow about the following options:

• Not required

• Only in audits

• Translation of one example

• Full translation of every batch

• Only summary

QP RELEASE - SOME SPECIFIC ISSUES

Q: How do you perform batch record review of batchesproduced in China, when they are not bilingual or translated?

fA: A translation of one batch record as an example and asummary of each batch would be required together with aCoA. It is important that the QP can understand the processand whether there were any excursions, CAPAs, changes, etc.,and what they were and how they were concluded

Please note: The QP has to release each individual batch

QP RELEASE - SOME SPECIFIC ISSUES

Q: Can a member state can invalidate a procedure because aGMP Certificate was not provided for an API for which the QPdeclaration was provided?declaration was provided?

A: No. A satisfactory QP Declaration is always necessary andis normally sufficient to confirm that the manufacture of activepharmaceutical ingredients (APIs) comply with GoodManufacturing Practice (GMP), as required by Article 8Paragraph 3 (ha) of Directive 2001/83/ECg p ( )

CMDh/268/2012 - http://tinyurl com/p7uecnqCMDh/268/2012 http://tinyurl.com/p7uecnq

GXP FOR IMPS - INDUSTRY EXPERIENCE

There will be a shortage of QPs as many QPs are due to retirein the coming years

f QFor logistical reasons it is often practical to use the QPservices of a Contract Research Organisation (CRO)

QPs often rely on third party audit reports provided they areQPs often rely on third party audit reports, provided they areprepared by suitably qualified auditors

It may be advisable to have a second QP named as a back-upy Q poption

SUMMARY AND OUTLOOK

The level of GMP applied to IMP manufacture has toincrease depending on the clinical phase. Rationales for(necessary) changes need to be documented(necessary) changes need to be documented

IMPs require a QP release in Europe

The specific requirements for QPs differ in each EUThe specific requirements for QPs differ in each EUmember state

IMP manufacture, IMP supply and clinical trial management, pp y gare intricately linked - working with a suitably qualified andexperienced third party may be advisable

YOUR PRESENTER

Siegfried Schmitt, PhD FRSC CChem CSci

Principal Consultant

PAREXEL International

+44 7824 592401

siegfried.schmitt@parexel.com