Quality Assurance of Investigational Medicinal ProductsSue McKenziePPQA (A)

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Agenda for Today

IMP Regulations - CTD and Annex 13

Role of QP for IMP

Challenges of IMP Manufacture for the QP

IMP RegulationsClinical Trials Directive (2001/20/EU), Annex 13

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IMP Regulations

The Clinical Trial Directive became effective in the UK on 1st

May 2004 and has now been implemented across the EU

The Directive brought into force the following requirements– Clinical Trial Authorisations.

• authorise the sponsor to carry out a clinical study.– Manufacturing Authorisations

• licence the facility for manufacture of Investigational Products.

– Good Manufacturing Practice • Including Annex 13

– Requirement for QP Certification of all batches

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Clinical Trial Authorisations.

Authorise the sponsor to carry out a clinical study and are study not product specific – they include:– Clinical Protocol– Labels– Clinical and safety data– Investigational Medicinal Products Dossier (IMPD) which

contains the CMC documentation.

There is a single EEA reference number (EUDRACT)– CTAs are assessed by each member state

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Clinical Trial Protocol

Defines the basic information and details for the study– planned study objectives– Procedures– patient population– clinical trial materials– clinical laboratory testing– safety assessments– data analysis

May be for a single or a multiple-site study

Packaging, labelling and assembly requirements defined

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CTA Amendments

Amendments far more common than with licenced products– New data becomes available as development progresses

e.g. stability/shelf-life

Function of the development process– Route of synthesis for API will almost certainly be

changed to improve yield and manufacturability.– Formulation of drug product may change during

development and when the process is optimised.

Impact on existing studies which use materials currently in stock needs to be carefully assessed before submission

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Manufacturing AuthorisationsManufacturing Authorisations for Investigational Products authorise a site to carry out particular activities such as manufacture, assembly, import and distribution.– No separate WDL

Operations sites supplying IMP must be included in the IMPD and a copy of their Manufacturing Authorisation or GMP certificate may be required.

CROs must be included in the IMPD and have a valid MA or GMP certificate, an agreement defining responsibilities of each party is required.

The Clinical Pharmacology Units within AstraZeneca are included in the IMP Manufacturing Authorisation.

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Good Manufacturing Practice

The Rules Governing Medicinal Products in the European Union apply with some specific guidance in Annex 13– Annex 13 recognises the ‘additional complexity

of IMP in comparison to marketed products by virtue of the lack of fixed routines, variety of clinical trail designs, the need for randomisation and blinding and increased risk of cross-contamination and mix up…………….’

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Product Specification File

Includes or refers to:– Specifications and analytical methods– Manufacturing methods– In-Process testing and methods– Approved Label Copy– CT Protocols and randomisation codes– Relevant technical agreements– Stability data– Storage and shipment conditions– Etc.

The Role of the Qualified Person in IMP ManufacturePAR&D PPQA (A)

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IMP Legal Duties (1)

Ensuring that products have been manufactured and assembled according to– GMP– Product Specification File (PSF)– Appropriate regulatory authorisations e.g. CTA

Ensuring that all testing has been carried out and that results comply with the product specification

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IMP Legal Duties (2)

Ensuring that all IMP being imported from outside the EU has been manufactured to GMP at least equivalent to 2003/94

Ensuring that comparators sourced outside the EU and which have a marketing authorisation have been manufactured to GMP at least equivalent to 2003/94

Certifying in a register or equivalent document that the product has fulfilled these requirements and can be released for clinical evaluation

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Legal Duties & PAR&D PPQA(A)

So, how do we fulfill our Legal Duties?

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Manufactured to GMP….

Ensuring that suitable local GMP quality systems are in place

Approving the GMP procedures and documents

Ensuring that a GMP training program exists

Providing expert advice and guidance to their line function on the interpretation of relevant GMP requirements

Providing input into Compliance Improvement Plans

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Manufactured to GMP….

Providing expert advice and guidance to the line functions on the GMP design and validation requirements for new equipment and facilities

Reviewing and approving validation documentation.

Approving Change Control and investigations of deviations that affect existing processes and specifications.

Auditing of internal Quality Systems.

Management and approval of suppliers and contractors

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Compliance with PSF

QA Representative on the Therapeutic Area Project Team is involved in the approval of PSFPSFs are available in an electronic libraryQP checks library to ensure that PSF for a particular study is approvedChange Control Process for Regulatory Submission updates is in place

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Compliance with Regulatory SubmissionPSF and Change Control process is keyIND/CTA/IMPD references are checked at ‘Bulk Product’ release stageRegulatory approval status is checked for each market in an electronic database

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Testing and Specification ComplianceQA review the Specification Justifications and approve the Specifications C of As reviewed as part of ‘Bulk Product’ release process for compliance with specification

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Imported IMP/Comparators

Auditing by PAR&D/GQO etc.MRAsService Level AgreementsTechnical Agreementsetc.

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Certifying in a Register

Records of ALL secondary pack releases are kept– In electronic inventory management systems where

relevant– ‘wet ink’ registers where electronic systems not used e.g.

• Contractor packed material• IVRS Studies• Exports

Daily register is printed and signed by QP on ‘routine release’

Challenges of IMP Manufacture for the QPAnd how to overcome them….

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Manufacturing Issues

Various sites, including contractors, can be used– Need to transfer between sites efficiently

Multi-purpose facilities– Capacity and scheduling issues– Equipment may be different at smaller scale– Cleaning verification/validation– Development and GMP batches produced

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Personnel and Training Issues

Many ‘non-routine’ jobs – single batchesProcesses not robust – training difficultModifications required during processing– Documentation skills required– Change control, Deviations, Variances

Possible incomplete safety profile

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Documentation Issues

Manufacturing Instructions not necessarily established or only provisionalSpecifications may changeIn-process controls may changeMulti-product facility requires control of room/equipment logs etc

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Comparator Issues (1)

Blinding requires consideration of– Coat and core colours– Shape– Size– Thickness– Smell/taste– Weight– Container design

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Comparator Issues (2)

CANNOT use market presentation for blinded studiesAdditional manufacturing steps may be needed– Supported by stability data, expiry, etc.– May need to develop and validate assay methods

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Packing Issues - General

Packaging is ALWAYS a key risk areaCompounded in IMP– Blinded products look identical– Labels are the same for all treatments– CANNOT easily check afterwards that all operations

have been performed correctly– Packaging designs can be extremely complex

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Packing Issues - Labels

Requires security of label text submission and printing processMaster labels need to have unique codeReconciliation is 100%Sample labels need to be retained– Difficult with randomised studies

Secure, segregated storage of approved labels needed

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Packing Issues - Assembly

Operations are largely manualMany small orders processed– Large variability from one to the next

Equipment is very simpleClearance checks are criticalSegregation of orders is vital

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ancePacking Issues - Documentation

Instructions must be approved before useMust give full traceability of activities, people, product, materialsExpiry date must be clear– expiry dates can be updated if relevant

Expiry date of patient pack linked to product with shortest life– Issues with re-supplies

Documentation retained for trial life + 5 years

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Regulatory Issues

Submissions are made for each study not for a productApprovals are on a country by country basisNeed to be aware of the exact regulatory statusNot all countries require submissionsSome countries require notification onlySimilar variety with significant amendmentsEU GMP does not apply to all countries in a studyEU GMP not applied consistently across EU member states

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Regulatory Issues(2)Ongoing Studies

– Regulatory submissions have not been made in many countries for studies that pre-date the CTD

Comparators– AZ may wish to use comparators not yet available commercially in the EU

– Sourcing can be an issue

Investigator Sponsored Studies - AZ is more similar to a contractor– QP Agreement required

CPU based studies may require a CPU facility with a Manufacturer’s Licence (IP) as there are no licenced pharmacies for IMP c.f. For commercial product some labelling may be done in a licenced pharmacy.

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Summary

The decision to release product depends on confidence that:

– people have followed the principles of GMP

– manufacturing conditions are satisfactory

– utilities and process equipment are suitable

– process controls and environmental data (where relevant) is available and measurements are within specified limits

– production and analytical documentation is completed and properly authorised e.g. batch sheets, labels

– deviations have been identified and evaluated

– evidence has been provided to demonstrate compliance with product specifications e.g. by sampling and testing

– regulatory requirements have been met

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Solutions?

Communication and Training!!– Understand the systems and processes operated– See and be seen– Ear to the ground– Create open and trusting environment– Know the key personnel– Regular meetings– Collate and trend any issues– Risk Assessment– Change Control