Presentation on theme: "Presented by: Karen S Ginsbury"— Presentation transcript:
1Management of GMP Outsourced Activities The Role of Technical Agreements / Quality Contracts Presented by: Karen S GinsburyPCI Pharmaceutical Consulting Israel LtdFor: IFF, Copenhagen, DenmarkOctober 2011
2Course Objective Clarify and ensure that matching expectations exist Define who is responsible for what: NO shared responsibilitiesUnderstand that outsourcing doesn’t mean “no oversight”
3To be coveredThe regulations and guidelines (EU and US) pertaining to contract manufacture and the requirements for technical agreements / quality contractsDefine and Synchronize expectations for "The Work"Who is responsible for initiating the contract: sponsor or contractorDefining contact personsQuality Contract templateList of key responsibilitiesKey elements of the contractContract Review
5Purpose of Contract Regulatory requirement Business necessity Reduce: CostsFrustrationConfusionIncrease / improve:ClarityCommunicationValue for $ (Euro(Efficiency and benefitsassociated with pharmaceutical outsourcing
6Not the Purpose of the Contract To replace due diligenceTo replace auditsTo replace oversightTo negate the need for sponsor / contract giver oversight of outsourced activitiesTo negate the need for management review at the contract giver relating to outsourced activitiesTo mitigate all risks associated with contract manufacturing in lieu of other mitigation measures
7RegulationEU Chapter 7: Contract Manufacture- under revision – new title “Outsourcing”US cGMPs - both the contractor and your company would have responsibility in the event of failureQ10 talks about contractors as does ISO 9000 requiring “ Contract Review”
8Contract Manufacturing: Legal Framework – Regulations21 CFR 211.22(a) The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company21 CFR Testing and approval or rejection of components, drug product containers, and closures21 CFR Part Contract manufacturers are an extension of the manufacturer's own facility
921 CFR (b)The Food and Drug Administration is aware that many manufacturers of pharmaceutical products utilize extramural independent contract facilities, such as testing laboratories, contract packers or labelers, and custom grinders, and regards extramural facilities as an extension of the manufacturer’s own facility
10How FDA Perceives Responsibilities Contract manufacturers are responsible for manufacturing product in conformance to CGMP.The firm that hires a contract manufacturer may also assume certain specified responsibilities under 211 or elsewhere.Sponsors and private-label distributors are also accountable under the statute
11FDA Guidance for Industry: Quality Systems Approach to Pharmaceutical CGMP Regulations(2006) / Q10? “Outsourcing involves hiring a second party under a contract to perform the operational processes that are part of a manufacturer‟s inherent responsibilities.... Quality systems call for contracts (quality agreements) that clearly describe...”materials or service to be providedspecification-setting responsibilitiescommunication mechanismstraining, qualifications, and monitoring expectedHarmony with both parties‟ quality standards i.e., they should not be in conflict
12FDA on Quality Agreements Identification of the contract site address, building, and equipment/line, and services/materials to be providedDescription of the drug, its intended use: all specificationsProvide for periodic audits to CGMP and contract specificsCommitment to share regulatory inspection findingsProcedures for change controlnew equipment, facility modifications, change in key personnel, change in SOPs and test methodsFull disclosure of all errors, deviations, changes, OOS results, investigations, as well as adverse events that did or might impact drug
13EU – Chapter 7 currentCurrent version: contract manufacture and analysis – 2 pagesDescribes need for a quality / technical agreement so nothing new there
14Concept paper on revision 2009: Which types of activities are included “GMP inspectors commonly see outsourced activities which if performed normally would be subject to inspection e.g.Qualification and validation work for new premisesMaintenance and calibration of equipment and premisesStorage and distributionArtwork generation and print ready materialAssessment and sourcing of starting and packaging materialsQP and other professional services such as GMP audits of suppliersWashing and depyrogenation and or sterilisation of packaging materials used in manufacture.Hosting of IT functionsDocument archiving and storage
15EU Chapter 7 – Nov 2010 for comments Title: Outsourced Activities3.5 pagesThe pharmaceutical quality system of the Contract Giver, including management responsibilities, extends to the control and review of any outsourced activitiesThe Contract Giver is ultimately responsible to ensure processes are in place to assure the control of outsourced activitiesThese processes should incorporate quality risk management
16EU Chapter 7 – Nov 2010 for comments The Contract Giver should monitor and review the performance of the contract acceptor and the identification and implementation of any needed improvementThe Contract Giver should be responsible for reviewing and assessing the records and the results related to the outsourced activitiesHe should also ensure that all processed products and materials delivered to him by the Contract Acceptor comply with their specifications or that the products have been released by a Qualified Person
17ICH Q10 on Outsourcing2.7 Management of Outsourced Activities and Purchased MaterialsThe pharmaceutical quality system, including management responsibilities… extends to the control and review of any outsourced activities and quality of purchased materialsThe pharmaceutical company is ultimately responsible to ensure processes are in place to assure the control of outsourced activities and quality of purchased materialsThese processes should incorporate quality risk management and include:
18ICH Q10 on OutsourcingAssessing prior to outsourcing or selecting suppliers, the suitability and competence of the other party to carry out the activity(e.g audits, material evaluations, qualification)Defining responsibilities and communication processes for quality-related activities of involved partiesFor outsourced activities, this should be included in a written agreement between the contract giver and contract acceptor
19ICH Q10 on OutsourcingMonitoring and review of the performance of the contract acceptor or the quality of the material from the provider, and the identification and implementation of any needed improvements(Monitoring incoming ingredients and materials to ensure they are from approved sources using the agreed supply chain )
20ISO 9001:2008 on Contract Review Contract review procedures should make sure that:Your customer's order is clearly and completely defined. When verbal orders are received, make sure that you and your customer agree on what is required -DISCUSSYou have resolved all differences between the original tender or proposal and the final contract or sales orderYour organization is capable of supplying the products ordered by the customerAmendmentsDevelop procedures which specify how customer contracts are amended, and which ensure that changes in contracts are communicated throughout the organizationRecordsDevelop a record keeping system that you can use to document the review of customer orders and contracts.
21The Process of Outsourcing Identify potential candidatesNarrow list to 1 / 2 / 3?Mail questionnaire?Select 2?Perform audit / introductory visit (assess transparency / cooperation)Initiation of contract21
22Who does what?Who is responsible for identifying potential candidates?Who is responsible for initial contact?Audits?Are these procedures covered by a company policy / SOP?Are there records of outcomes maintained?22
24Who is responsible?Is there a single, key contact person responsible for the success and oversight of the outsourced activity?
25Defining / Synchronizing Expectations Have you defined the scope of what you are going to outsource?Does everyone in the company agree?In writing, signed off “basis for design”Is it periodically reviewedDo you report to senior management at Management Review meetings on problems with outsourcing?
26Process MappingHave you mapped out the processes – what about when they become really complex
27Process Map: virtual company Lead ContractorSponsor?Manufacture DS and DP1SynthesisFormulation, Filtration, Aseptic filling, labellingDSCompany ADPCompany BQC testing by: All partiesLCCoordinateshippingDS QC testingDP QC testing254ShippingAExcept AssayLCPerform AssayCompany ANMRLCAssayCompany BRestCoA and DS Batch Release by Company ACoA and QP Batch Release of DP3Company ACompany B6
28What is Risk? The likelihood that a particular hazard will occur The severity of HARM if that hazard occursThe likelihood of detection of that hazard if it occurs
29Safe and Effective Product The goalSafe and Effective Product
30Control Strategy: Definition A planned set of controls, derived from current product and process understanding, that assures process performance and product qualityThe controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control (ICH Q10)
31Outsourcing Control Strategy MachinesManSafe and Effective ProductMaterialsMethodsOther
33What needs to be in there? Giver:Overall responsibility for productResponsibility for Ctx, IMPD / MA / IND / NDA information and COMMUNICATION of critical issues to the AcceptorAuditing and evaluation of contractorProduct release / review of results unless QP agreement includedNotification of any hazards related to their materials
34What needs to be in there? AcceptorWill work in accordance with relevant GxP regulations . need to itemize which are relevant e.g:EUUSOther?Accepts that they are open to inspection by regulatory authoritiesAgrees to be transparent regarding regulatory findings?
35What needs to be in there? Change controlDeviation and OOS reportingSignificant? Time frames ?List of responsibilities (does it duplicate the actual content of the contract and if so – which takes precedence?)Archiving and retained samples
36Contacts Who is the key / primary contact for each side Limit it (preferably to one person) because of misunderstandings that arise if there are several persons listed communication is criticalWhat happens if a listed contact leaves – who is responsible at Giver and Acceptor for ensuring contracts get updated / notification – is there a formal method
37Specifications / MMIs / Analytical test methods etc. In or out?What about if they get updated?
38Factors Affecting Risk Dosage Form TypeParenteral and ophthalmic products (sterile products)Inhalation solutions (sterile products)Aerosol and dry powder inhalantsNasal spraysVaginal suppositories, ointments and creamsTopicalsRectal suppositories, ointments and creamsOral liquids (aqueous)Oral liquids (non-aqueous)Oral tablets Liquid- and powder-filled capsules
40What needs to be controlled... Specifications (YOURS) (THEIRS)Please provide a brief description of your quality systemDo you have any certifications / FDA / EU / ISO etc. Do you have a registered DMF? #When was the company founded? Owners?How many employees: operations, QA / QCName and details of contact person (job function)(special questions for particular product)
41Some Little Details Address of contract site Agents / brokers: transparency regarding manufacturerDo you manufacture / pack / distribute / test etc. from any other site?Do you use sub-contractorsWhat else do you manufacturecapacity
42RequirementsNeed a formal purchase order for each consignment / activity with a copy in the warehouseNeed the contractor to appear on a controlled list of approved outsourcersDamaged units where material was exposed or potentially damaged will not be acceptedOOS / out of trend / questionable results?Formal contract reviewAnnual? Contract review / updateUpdate key contact(s)
43Define the scope of the Project Need to be exceedingly preciseE.g. outsourcing process development and production:who will own the developed process? Your company or the contractor?If the latter you may be paying royalties forever, so be aware of this upfront and define in the contractIf the former, the contractor will have to perform technology transfer…to your company PUT IT IN THE CONTRACT
44Define the scope of the Project Need to be exceedingly preciseNeed to discuss the scope with relevant functions within your company and put out a document agreed and signed by relevant partiesE.g. outsourcing production only who is responsible for technology transfer / process transfer to the contractor? Your R&D? Your production?
45Defining Your Company’s Requirements What are you outsourcing:All aspects of manufacture and control?Part of the manufacturing process?Process development and manufacture?Only manufactureAnalytical methods development?Bioanalytical methods development?Toxicity testingProof of ConceptManagement of Clinical trial from start to finish?
46Define the scope of the Project Need to be exceedingly preciseE.g. outsourcing an entire clinical trial from start to finish does the contract include:Auditing sites?Before, during at end of trial or all of these?Selection of statistical methods?Analysis of data?Auditing of data?Who decides on the clinical protocol?Patient exclusion criteria, inclusion criteria etc?How much input from your company? Who went to the FDA pre-IND meeting?!
47Defining the Project Takes time May require input from consultants Particularly for a small start-up company without the necessary input in-houseIf poorly defined will result in failure of the project
48Define the scope of work Manufacturing operationCalibration / Qualification of HPLCPackaging and labelling of clinical trials materials including randomization and blindingIntegrity testing of HEPA filtersSterility testing
50FDA : Recent Industry Guidance Process validationICH Q10 pharmaceutical quality systemIdentifiers for solid oral dosage form drugsRisks for melamine contaminationTesting of glycerin for diethylene glycolContract manufacture (under development 2011)FDA view: Help industry be responsible through the development of standards and best practicesIndustry: are your contractors familiar with these guidances – not enough if you are!
51EU: Currently Being Updated EudraLex Vol. 4 GMP for Medicinal Products (EU-GMP)Part I: Basic Requirements for Medicinal ProductsChapter 1 Quality ManagementChapter 2 PersonnelChapter 3 Premise and EquipmentChapter 4 DocumentationChapter 5 ProductionChapter 6 Quality ControlChapter 7 Contract Manufacture & AnalysisChapter 8 Complaints and Product RecallChapter 9 Self InspectionImplementation ICH Q9, Q10 principles e.g. Management review, QRMImplementation ICH Q9, Q10 principlesDedicated Facilities (incl. Ch5)CSVQbD, Right first time, Contract manufacturingTransfer of analytical methodsImplementation ICH Q9,Q10 principlesQuality Defect contact points & QRMGDP – expanded from 4 pages to 32!
52FDA on: Corporate Responsibility for Outsourcing Assure preventive controlsWith suppliers and their suppliersWith contractors and subcontractorsInvestigate and act on nonconformities
54FDA ConcernsTransparency between sponsor and contract site regarding drug application commitments is crucial.Potential high costs of selecting contract sites based solely on unit dose cost for NDA and ANDA products under FDA’s GMP systems inspection approach.How thorough are sponsor audits of contract sites when they can not audit the entire universe of data due to limitations imposed by confidentiality agreements?
55TransparencySome sponsors do not provide a copy of the drug application commitments to the contract site that will perform that operation.Red Flag for the FDA PAIHow can the contract site assure they are meeting the drug application commitments if they do not have a copy of them?What if the NDA/ANDA sponsor fails to disclose critical drug application information to the contract site?
56FDA will do it if you don’t When the contract site does not have a copy of the drug application commitments applicable to their contracted responsibilities, FDA must conduct the GMP audit and also audit the integrity of the drug application information transfer process between the sponsor and the contract site.
57Consider…Sponsors: Is it a good business practice to withhold relevant drug application information from your Contract partner? How can you be assured the Contract site understands the drug application commitments if you don’t provide a copy of them?Contract Sites:Is it a good business practice to make or test a drug application product without having a copy of the relevant sections of the drug application? How can you be sure you are meeting the drug application commitments?
58Questions for Evaluating a Potential Contractor Good FDA GMP track record for consecutive inspections?Robust GMP systems?Quality assurance oversight of operations & product?Well controlled raw materials system?Production system under control?Facility & equipment well maintained?Lab is capable of generating scientific, sound test data?Packaging & labeling system is well defined and controlled?
59How Robust can an Audit Be? How can you thoroughly audit a GMP system when you can not review all the deviations, investigations or data generated in that system?If the Contract site makes a drug product for Client A and Client B comes to do a GMP audit, then Client B can not see Client A’s records.What if evidence of a serious GMP system failure is contained in client A’s records, but Client B can’t review that record?
60Use of unapproved material Personnel in the receiving warehouse & Materials Management indicated they do things quite differently than what is described in the SOPs. SOP ABC was not followed.Warehouse –Don’t actually look at the official Material Specification Sheets in the binder when an order arrives. If the order received matches what’s in the computer, then it’s OK because that’s what Materials Management ordered.Materials Management: That raw material was in short supply so we had to switch to another supplier. QA was not notified of this change.FDA-483 issuedWould you have identified the issue?sYOU need to assure YOUR audits of contract firms are robust enough to identify serious system deficiencies in spite of limitations imposed by confidentiality agreements
61Two for One Warning Letters Kathleen Culver, FDA June 2010 My FDA Crystal BallFDA acknowledges the reality of contract operations in the drug manufacturing communityFDA has to deal with and manage the complexity contract operations brings to the FDA evaluation process before and after drug application approval.What happens when a commercial drug product produced by a contract firm under the sponsor’s oversight is found to be non-GMP compliant and adulterated/misbranded?Aren’t both parties, the sponsor and the contract site, RESPONSIBLE for assuring the drug product is made under GMP control and meets all legal specifications?If the contract manufacturing site gets a Warning Letter because the drug product is adulterated or misbranded, shouldn’t the sponsor also be held accountable by FDA?
62Drawing up a Technical Contract Define project timelinesIf you need an analytical method developed and validated prior to a clinical trial there is no point in having product manufactured, CRO ready to go with patients lined up and the method development flounderingMUST have inter-dependent activities aligned
63Drawing up a Contract Allow for catastrophes: The CRO spills all your materialThe methods validation failsFire at the contract manufacturerDefine project milestones and when they MUST be achievedNAME names: who is responsible for what at your company and at the contractor
64Quality Issues7.10 A contract should be drawn up between the Contract Giver and the Contract Acceptorspecifying respective responsibilities for manufacture and control of product [could apply equally to CRO, proof of concept, tox, etc.]Technical aspects of the contract should be drawn up by competent persons suitably knowledgeable in pharmaceutical technology, analysis and Good Manufacturing PracticeAll arrangements for manufacture and analysis must be in accordance with the marketing authorisation and agreed by both parties
65Quality Issues - Complaints Who is responsible for investigating complaints?Will the contractor allow your QA person / consultant access to:FacilityPersonnelRecordsin order to conduct a detailed investigation?…or will you have to make do with their abbreviated report saying it is not their responsibility
66Quality IssuesThe contract should permit the Contract Giver to visit the facilities of the ContractAcceptorIn the case of contract analysis, the Contract Acceptor should understand that he is subject to Inspection by the competent Authorities […and of course for contract manufacture… also CRO’s]
67Quality Issues Who makes product release decisions? What about when a deviation is involved?How do you know that you have transparency to allow you to make an informed decision?Disposition decision may be affected by who bears the cost of a failed batch…does the contract address that?What about laboratories: could use a third party to decide where results differ at giver / acceptor provided have provision in contract
68When to Audit Prior to signing contract? Prior to initiation of work? During Work – don’t audit – do be on site (and of course annual or periodic audits)By mail prior to signing contract?
69Contract Manufacture: Auditing Need to audit prior to signing contract, but need a company representative close at hand during all manufacture – needs to be closely controlled at all timesNeed to have access to batch records and analytical results (if they are doing analysis)Need a clause in the contract concerning:DeviationsChangesfrom approved manufacturing process and methods, including reporting deviations relating to operator, machine, materials malfunctionComplaints may result in auditAnnual audit essential
70Contract Analysis What about OOS?? Your contract lab may claim to be “GLP compliant”You need them to be GMP compliant with respect to laboratory regulationsISO does not address out of specification results
71CRO / Toxicology / Other Audit by mail prior to signing contractParticularly for animal studies, choices are quite limitedAre some very large concerns involved that become quite lax in their procedures if not carefully auditedInitiation visit / auditOngoing audit during studyIf close by, request company rep present during study performance
72Project Oversight Generally have at least two functions involved: Operations or (for small company may be CEO) overseeing timelines and meeting milestonesQA (may be a consultant for a virtual company) overseeing quality issuesQA cannot perform their part unless the contract requires punctual reporting, especially deviations
73Project Partnering Outsourcing involves large amounts of funds Need to partner the contractor:he knows that you are going to put a lot of money into her company (setting up a cell bank can be 1 million dollars) so she wants to accommodate your Q requestsYou know that he is going to help realize your product to market timeline and are happy to invest that moneyMutually beneficial arrangement
74Quality Issues Contract must address QP release Who is responsible for:purchasing materialsTesting and releasing materialsundertaking production and quality controls including IPCwho has responsibility for sampling and analysis
75Quality IssuesManufacturing, analytical and distribution records, and reference samples should be kept by, or be available to, the Contract GiverAny records relevant to assessing the quality of a product in the event of complaints or a suspected defect must be accessible and specified in the defect/recall procedures of the Contract Giver[these are regulatory requirements… what will you do if you didn’t address them in the contract and you have an IP issue with the contractor
80Deviations and Changes What is “significant?”What is “immediate” notificationOOS – and laboratory error – do you want to be notified?
81What to do about Regulatory Inspections Can you be present?On call?Notified immediately? Of adverse outcomeInvolved in response writing?Notified of responses?Involved in ANY response directly involving your productOther?DISCUSS with their QA / regulatory BEFORE initiating a Technical Service or Master Service AgreementAND contract giver must notify acceptor if they are to be inspected because support (rapid) may be needed
82In Conclusion The quality of the output is: Dependent on the contract acceptorHighly dependent on the contract giverRequires a lot of work before initiationRequires a lot of work during the projectMust have face to face meeting before kick-offCannot be left to chanceIf the contracted work is to be of value
83In conclusion Outsourcing is growing and is global It is a business necessity and will continue to growThere are business needs that must be metThere are compliance and quality needs that if not met will bring down your companyIt is a partnership both with the contractor and within your companyIt needs to be managed – but it is not a Quality Assurance “Responsibility” on a day to day basis