Challenges for the QP in Managing of CMO’s

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Managing CMOs can sometimes look like this…………….. FR IT

UK

LM 1

India

ES PT

LM 2

Aus

BE DE USA Japan NL

LM 3

Q LM 4 P LM 5

PL SK

Europe Far East

LM 6

HU GR

US

LM 7

Internal Manufacturing

AT IE

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Background • Pre-discussions on your questions and review of the specific challenges noted that similar issues were occurring in many organisations

• Worth noting that there is not one answer to the each challenge and dealing with CMOs is one challenge while dealing with MAHs/HA in other markets also throws up their own specific challenges • Risk assessments, Robust CMO approval systems and ongoing maintenance of your CMO and your QS is key • Give an oversight of how 3 different types/models of Licenced sites have met similar quandaries presented and overcame these challenges.

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Your Questions… QP Forum have had a high level of questions regarding the oversight and management of CMOs and most fall into the following categories - CMOs – how do you decide what level of oversight is required

- Quality oversight – how much, what, how is it handled - Auditing requirements – when, who, how - Technical Agreements – What to include, how is everything covered, legal reviews - PQR – what is the MAHs responsibility, what is the QPs - QP releases – what does it involve for different products - QP responsibilities and Annex 16 updates (HPRA will look at in later session)

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Outsourced CMO activities at Shire Business Model Background: •

Shire Pharmaceuticals Ireland Ltd. (SPIL) currently holds an MIA for the QP certification of Sterile Biological Products.

•

There is no physical manufacturing at Shire Pharmaceuticals Ireland Ltd. and all the bulk filling, packaging, testing, holding and distribution activities performed on behalf of SPIL are carried out at other Shire sites or third parties both within the EEA and outside the EEA.

•

QP at SPIL certifies product in the EU for the release for sale and supply to EU and ROW markets

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CMO Oversight Pathway

On- Going CMO Evaluation - Quality Business Reviews

Annual ReCertification/ - Quality management reviews Periodic Re-evaluation - Routine QP Audits Initial Qualification of CMO- KPIs - KPI review - Due Diligence - Quality Risk Management - Quality Technical Agreement - Qualification Audit

- Classification of CMO in terms of risk level - Defines QP Oversight & audit frequency requirements

- QP approvals of Change control and Major/Critical Deviations

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Challenges for the QP Challenge

Mitigation

Balancing the available QP resources with the appropriate level of QP Oversight

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Classify CMOs – Using a Risk Based approach to determine the level of oversight required in terms of batch review & frequency of auditing

Different Quality Systems at CMOs (different definitions for classifications of deviations, change controls etc.)

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Familiarisation of the QP with the CMO QMS through on-site visits and auditing. Triage and levelling by Shire QA / QP of all deviations and events to ensure consistently assessed.

Monitoring and Evaluation of Process Controls

• •

•

•

Agree with CMO the Quality KPIs to be tracked- defined in TQAs Regular Quality business review meetings to review standard KPIs APQR appoval

MAH Compliance

• •

Shire QA review of all change controls Shire QA and Regulatory review of all batch record revisions

Several QPs in the Supply Chain (SC)

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Ensure the responsibilities of all QPs in the SC are clearly defined and documented through QP agreements

Communication & Language Difficulties

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Ensure translations of batch documentation are available to the QP Build collaborative relationships

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Jazz Background

• US firm Jazz Pharmaceuticals founded in 2003 • Merged with Irish company Azur Pharma in 2012 and an EU based company EU SAPharma in 2013 • Virtual pharma until acquisition of Italian manufacturing company Gentium in 2014 • Building a manufacturing site in Roscommon due for approval in 2016 • Global organisation (~700 headcount) and headquartered in Dublin (~80) • Wide range of products mainly in 3 areas; Sleep (oral dose liquid/tablet), Pain (sterile parenteral) and Oncology (biologic, sterile parenteral) • Jazz is a BLA holder, NDA holder and MAH, while in some territories we have marketing partners • Products manufactured and marketed globally, Dublin QA release into the US • Recently approved WDA and MIA for sterile, non-sterile and biologic 8

Level of oversight of a CMO's Quality Systems

To a large extent the level of CMO oversight is standardised through the MAHs own Quality Systems and procedures, including;

• 1. Supplier Qualification Program (incl. periodic requalification and site audits)

• 2. Deviation/OOS/OOT Management • 3. Change Control • 4. Stability Program • 5. Complaints Management • 6. Batch Record Review and Product Disposition

• 6. Supplier Review Board, Quality Management Review, APQR process • 7. Regular site visits as required (particularly for non-routine activities) 9

Level of oversight of a CMO's Quality Systems

Supplier Qualification • QA participation in due diligence • Site audit • Generation of the Quality Agreement • Addition to the Approved Contractors List (which in turn feeds into the audit schedule and the supplier requalification schedule using a risk based approach regarding frequency) Through the supplier qualification program and the audit program, the MAH evaluates the robustness and acceptability of the CMO's Quality Systems and GMP Compliance. These programs guide the level of oversight required, while taking into account the criticality of the product and the complexity of the manufacturing process or service; e.g. Sterile parenteral versus non-sterile oral tablet, small versus large molecules, manufacturer or primary packager versus a distributor. Therefore need to use a risk based approach.

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Challenges Challenge

Mitigation

Reliance on a third party for Complaints investigation/Stability programme and APQR

Well defined Quality Agreements

Complex supply chain and many CMOs/Quality Agreements for a single product

As above

Operating across many timezones

As above plus global QA support

Significant travel requirements

As above

Regular meetings and positive relationship with CMO QA

Develop QA SME’s per product

Small volume orphan drugs and high market As above plus frequent on site visits (incl. demand, impacts leverage with CMO’s PIP as required)/business review meetings 11

Quality Agreement (Vol.4 Ch.7) A Quality Agreement includes but is not limited to; • Clear Roles/Responsibilities for each Quality System • Contact Details • Reference to the relevant commercial agreement • Reference to the relevant governing regulations and guidelines • Details specific responsibilities and commitments for each Quality System, for example; • CMO will notify the MAH of a confirmed stability OOS within 24 hours • MAH will review/approve changes that could Impact product quality and/or regulatory filings prior to approval for implementation • List the documentation to be provided in support of batch release • Allow the MAH periodic site audits as required

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Level of oversight of a CMO's Quality Systems

Despite oversight by SOP, clearly each CMO must be managed on an individual basis, considering output from: • due diligence, • supplier qualification, • product and process complexity, • CMO supply capacity, • market demand, • the stage of the product lifecycle (development, clinical or commercial), • the CMO's regulatory history and experience as a CMO. E.g., an established CMO with many customers (hosting many audits annually) versus a non-traditional CMO with few customers. E.g. a CMO with a successful regulatory history and a variety of BOH approvals versus working with a CMO to prepare for the first PAI. 13

Strike a balance The type of CMO can be of two extremes, dependent or independent. The dependent CMO requires customer written approval or instruction before carrying most activities. While the independent CMO may not appreciate the MAHs persistent oversight. E.g. we have a Manufacturer of a sterile parenteral biological, for which they maintain the national MA. We are one of a few customers and they do not consider themselves a CMO, rather a manufacturing partner. The challenge is to carefully strike the appropriate balance of oversight, avoiding redundancy in Quality Systems, while ensuring MA compliance in all relevant markets. Overall, the MAH must work at building and maintaining a trusting two way relationship that encourages timely notification of issues. 14

Outsourced CMO activities at Mylan Business Model Background: (Virtual, Internal and CMO) – Mylan (Based in Ireland) currently holds an MIA(ML) and MIA(IMP) for the QP certification of OSD, transdermal, Respiratory and sterile products – Manufacturing, packaging and testing occurs at either Mylan sites in EU or RoW or from 3rd Parties in either EU or RoW. – 3rd Party product Testing and release activities are covered in Mylan Dublin site or at a contracted facility with full Quality oversight and QP certification of all licenced products occurring at Mylan – QP at Mylan certifies product in the EU on behalf of all Mylan MAHs for the release for sale. – All activities for QP and Regulatory activates within Mylan are centralised into a number of Centres of Excellence with all systems falling under a Global Quality System 15

Normal Quality requirements to be addressed for new CMOs QC Lab for 3rd country testing AMT reviews

API Declarations

Validation review/approval

Stability review Sampling requirements

MIA updates Quality Auditing the CMO

Change Controls

Reg File reviews Master Batch Approval Technical Agreements

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Challenges for the QP Challenge Global Org completing Auditing of sites (what contact for the QP)

Mitigation • •

Working closely with the Global Auditing function on what the site is supplying to ensure relevant areas are covered Feedback mechanism with Global Auditing to ensure that they are aware of complaints, investigations etc

Centralised release and oversight of CMO on behalf of several MAHs

• • • •

Standardised TA’s with MAHs to cover all aspects MAHs specifics included in the TA Centralised systems for MAHs to understand Q issues One system used for all products regardless of the QP responsibilities ie launch, CC, Investigations and release go through central system.

QPs understanding entire supply chain

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Reg system in place to ensure that the approved Supply chain as registered is documented and used for QP review QP involvement in approval of the supply chain at set up of the CMO

• IMPs v MA releases

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Same approach for release of IMPs with all QPs releasing IMPs involved with CMOs from start of process with additional emphasis for QP to be involved in auditing of IMP facilities

Pharmacovigilane responsibilities of the MAH

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Managed under PV Tech Agreements by the Centralized PV group.

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