1. business and industrial
2. advertising and marketing
3. marketing

Challenges for the QP
in Managing
of CMO’s
1
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.
3
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)
4
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
5
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
•
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.)
•
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)
•
Ensure the responsibilities of all QPs in the SC are clearly
defined and documented through QP agreements
Communication & Language Difficulties
•
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
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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)
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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
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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.
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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.
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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
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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
•
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
•
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
•
Managed under PV Tech Agreements by the Centralized PV group.
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