Management of GMP Outsourced Activities
The Role of Technical Agreements / Quality Contracts
Presented by: Karen S Ginsbury
PCI Pharmaceutical Consulting Israel Ltd
For: IFF, Copenhagen, Denmark
October 2011
1
Course Objective
• Clarify and ensure that matching
expectations exist
• Define who is responsible for what:
NO shared responsibilities
• Understand that outsourcing doesn’t mean
“no oversight”
2
To be covered
• The regulations and guidelines (EU and US) pertaining
to contract manufacture and the requirements for
technical agreements / quality contracts
• Define and Synchronize expectations for "The Work"
• Who is responsible for initiating the contract: sponsor
or contractor
• Defining contact persons
• Quality Contract template
• List of key responsibilities
• Key elements of the contract
• Contract Review
3
4
Purpose of Contract
• Regulatory requirement
• Business necessity
• Reduce:
– Costs
– Frustration
– Confusion
• Increase / improve:
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Clarity
Communication
Value for $ (Euro(
Efficiency and benefits
associated with pharmaceutical outsourcing
5
Not the Purpose of the Contract
•
•
•
•
To replace due diligence
To replace audits
To replace oversight
To negate the need for sponsor / contract
giver oversight of outsourced activities
• To negate the need for management review
at the contract giver relating to outsourced
activities
• To mitigate all risks associated with contract
manufacturing in lieu of other mitigation
measures
6
Regulation
• EU Chapter 7: Contract Manufacture- under
revision – new title “Outsourcing”
• US cGMPs - both the contractor and your
company would have responsibility in the event
of failure
• Q10 talks about contractors as does ISO 9000
requiring “ Contract Review”
7
Contract 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 company
• 21 CFR 211.84
Testing and approval or rejection of components,
drug product containers, and closures
• 21 CFR Part 200.10
Contract manufacturers are an extension of the
manufacturer's own facility
8
21 CFR 200.10(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
9
How 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
10
FDA 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 provided
specification-setting responsibilities
communication mechanisms
training, qualifications, and monitoring expected
Harmony with both parties‟ quality standards
i.e., they should not be in conflict
11
FDA on Quality Agreements
• Identification of the contract site address, building, and
equipment/line, and services/materials to be provided
• Description of the drug, its intended use: all
specifications
• Provide for periodic audits to CGMP and contract
specifics
• Commitment to share regulatory inspection findings
• Procedures for change control
• new equipment, facility modifications, change in key
personnel, change in SOPs and test methods
• Full disclosure of all errors, deviations, changes, OOS
results, investigations, as well as adverse events that
did or might impact drug
12
EU – Chapter 7 current
• Current version: contract manufacture and
analysis – 2 pages
• Describes need for a quality / technical
agreement so nothing new there
13
Concept 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.
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Qualification and validation work for new premises
Maintenance and calibration of equipment and premises
Storage and distribution
Artwork generation and print ready material
Assessment and sourcing of starting and packaging materials
QP and other professional services such as GMP audits of
suppliers
– Washing and depyrogenation and or sterilisation of packaging
materials used in manufacture.
– Hosting of IT functions
– Document archiving and storage
14
EU Chapter 7 – Nov 2010
for comments
• Title: Outsourced Activities
• 3.5 pages
• The pharmaceutical quality system of the
Contract Giver, including management
responsibilities, extends to the control and
review of any outsourced activities
• The Contract Giver is ultimately responsible
to ensure processes are in place to assure
the control of outsourced activities
• These processes should incorporate quality
risk management
15
EU 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
improvement
• The Contract Giver should be responsible for
reviewing and assessing the records and the
results related to the outsourced activities
• He 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
16
ICH Q10 on Outsourcing
2.7 Management of Outsourced Activities and
Purchased Materials
• The pharmaceutical quality system, including
management responsibilities… extends to the
control and review of any outsourced activities and
quality of purchased materials
• The pharmaceutical company is ultimately
responsible to ensure processes are in place to
assure the control of outsourced activities and
quality of purchased materials
• These processes should incorporate quality risk
management and include:
17
ICH Q10 on Outsourcing
• Assessing 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 parties
• For outsourced activities, this should be
included in a written agreement between the
contract giver and contract acceptor
18
ICH Q10 on Outsourcing
• Monitoring 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 )
19
ISO 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 -DISCUSS
– You have resolved all differences between the original
tender or proposal and the final contract or sales order
– Your organization is capable of supplying the
products ordered by the customer
• Amendments
– Develop procedures which specify how customer contracts
are amended, and which ensure that changes in contracts
are communicated throughout the organization
• Records
– Develop a record keeping system that you can use to
document the review of customer orders and contracts.
20
The Process of Outsourcing
1.
2.
3.
4.
5.
Identify potential candidates
Narrow list to 1 / 2 / 3?
Mail questionnaire?
Select 2?
Perform audit / introductory visit
(assess transparency / cooperation)
6. Initiation of contract
21
21
Who 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
22
Which activities does your
company outsource?
23
Who is responsible?
• Is there a single, key contact person
responsible for the success and oversight
of the outsourced activity?
24
Defining / 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 reviewed
• Do you report to senior management at
Management Review meetings on
problems with outsourcing?
25
Process Mapping
• Have you mapped out the processes –
what about when they become really
complex
26
Process
Map: virtual
company
Lead Contractor
Sponsor?
1
Manufacture
DS and DP
Synthesis
Formulation, Filtration,
Aseptic filling, labelling
DP
Company B
DS
Company A
QC testing by: All
parties
LC
Coordinate
shipping
DS QC
testing
2
4
DP QC
testing
A
LC
Company A
LC
Except Assay
Perform Assay
NMR
Assay
3
CoA and DS
Batch Release
by Company A
Company A
5
Shipping
Company B
Rest
CoA and QP Batch
Release of DP
Company B
6
What is Risk?
• The likelihood that a particular hazard will
occur
• The severity of HARM if that hazard
occurs
• The likelihood of detection of that hazard if
it occurs
28
The goal
Safe and Effective
Product
29
Control Strategy: Definition
• A planned set of controls, derived from current
product and process understanding, that
assures process performance and product
quality
• The 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)
30
Outsourcing Control Strategy
31
Factors Affecting
Outsourcing Risk
32
What needs to be in there?
• Giver:
– Overall responsibility for product
– Responsibility for Ctx, IMPD / MA / IND /
NDA information and COMMUNICATION of
critical issues to the Acceptor
– Auditing and evaluation of contractor
– Product release / review of results unless QP
agreement included
– Notification of any hazards related to their
materials
33
What needs to be in there?
• Acceptor
– Will work in accordance with relevant GxP
regulations . need to itemize which are relevant
e.g:
• EU
• US
• Other?
– Accepts that they are open to inspection by
regulatory authorities
– Agrees to be transparent regarding regulatory
findings?
34
What needs to be in there?
• Change control
• Deviation and OOS reporting
– Significant? Time frames ?
• List of responsibilities
(does it duplicate the actual content of the
contract and if so – which takes
precedence?)
• Archiving and retained samples
35
Contacts
• 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 critical
• What happens if a listed contact leaves –
who is responsible at Giver and Acceptor for
ensuring contracts get updated / notification –
is there a formal method
36
Specifications / MMIs /
Analytical test methods etc.
• In or out?
• What about if they get updated?
37
Factors Affecting Risk
• Dosage Form Type
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Parenteral and ophthalmic products (sterile products)
Inhalation solutions (sterile products)
Aerosol and dry powder inhalants
Nasal sprays
Vaginal suppositories, ointments and creams
Topicals
Rectal suppositories, ointments and creams
Oral liquids (aqueous)
Oral liquids (non-aqueous)
Oral tablets Liquid- and powder-filled capsules
38
Factors Affecting Risk
•
•
•
•
•
•
Drug Substance Synthesis
Formulation
Physical Characterization
Manufacturing Process
Packaging System: Container / Closure
Prior Experience
39
What needs to be controlled...
Specifications (YOURS)
(THEIRS)
Please provide a brief description of your quality
system
Do 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 / QC
Name and details of contact person (job function)
(special questions for particular product)
40
Some Little Details
• Address of contract site
• Agents / brokers: transparency regarding
manufacturer
• Do you manufacture / pack / distribute /
test etc. from any other site?
• Do you use sub-contractors
• What else do you manufacture
• capacity
41
Requirements
1.
2.
3.
4.
5.
6.
7.
Need a formal purchase order for each consignment /
activity with a copy in the warehouse
Need the contractor to appear on a controlled list of
approved outsourcers
Damaged units where material was exposed or
potentially damaged will not be accepted
OOS / out of trend / questionable results?
Formal contract review
Annual? Contract review / update
Update key contact(s)
42
Define the scope of the Project
• Need to be exceedingly precise
• E.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 contract
– If the former, the contractor will have to perform
technology transfer…to your company
PUT IT IN THE CONTRACT
43
Define the scope of the Project
• Need to be exceedingly precise
• Need to discuss the scope with relevant
functions within your company and put out
a document agreed and signed by relevant
parties
• E.g. outsourcing production only
who is responsible for technology transfer
/ process transfer to the contractor?
Your R&D? Your production?
44
Defining Your Company’s Requirements
• What are you outsourcing:
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All aspects of manufacture and control?
Part of the manufacturing process?
Process development and manufacture?
Only manufacture
Analytical methods development?
Bioanalytical methods development?
Toxicity testing
Proof of Concept
Management of Clinical trial from start to finish?
45
Define the scope of the Project
• Need to be exceedingly precise
• E.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?
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–
–
–
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?!
46
Defining the Project
• Takes time
• May require input from consultants
• Particularly for a small start-up company
without the necessary input in-house
• If poorly defined will result in failure of the
project
47
Define the scope of work
• Manufacturing operation
• Calibration / Qualification of HPLC
• Packaging and labelling of clinical trials
materials including randomization and
blinding
• Integrity testing of HEPA filters
• Sterility testing
48
Define applicable GMP regulations
and guidances
49
FDA : Recent Industry Guidance
• Process validation
• ICH Q10 pharmaceutical quality system
• Identifiers for solid oral dosage form drugs
• Risks for melamine contamination
• Testing of glycerin for diethylene glycol
• Contract manufacture (under development 2011)
FDA view: Help industry be responsible through the
development of standards and best practices
Industry: are your contractors familiar with
these guidances – not enough if you are!
50
EU: Currently Being Updated
EudraLex Vol. 4 GMP for Medicinal Products (EU-GMP)
•Part I: Basic Requirements for Medicinal Products
Implementation ICH Q9, Q10 principles
Chapter 1 Quality Management
e.g. Management review, QRM
Chapter 2 Personnel
Implementation ICH Q9, Q10 principles
Chapter 3 Premise and Equipment Dedicated Facilities (incl. Ch5)
CSV
Chapter 4 Documentation
Chapter 5 Production
QbD, Right first time, Contract manufacturing
Chapter 6 Quality Control Transfer of analytical methods
Chapter 7 Contract Manufacture & Analysis Implementation
ICH Q9,Q10 principles
Quality Defect contact
Chapter 8 Complaints and Product Recall
points & QRM
Chapter 9 Self Inspection
GDP – expanded from 4 pages to 32!
FDA on: Corporate Responsibility
for Outsourcing
• Assure preventive controls
• With suppliers and their suppliers
• With contractors and subcontractors
• Investigate and act on nonconformities
52
You just might want to take a
look…
53
FDA Concerns
• Transparency 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?
54
Transparency
• Some 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 PAI
• How 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?
55
FDA 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.
56
Consider…
• 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?
57
Questions 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?
58
How 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?
59
Use 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 issued
• Would you have identified the issue?s
YOU need to assure YOUR audits of contract firms are
robust enough to identify serious system deficiencies
in spite of limitations imposed by confidentiality
agreements
60
Two for One Warning Letters
Kathleen Culver, FDA June 2010
My FDA Crystal Ball
• FDA acknowledges the reality of contract operations in the
drug manufacturing community
• FDA 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 nonGMP 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?
61
Drawing up a Technical Contract
• Define project timelines
• If 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 floundering
• MUST have inter-dependent activities
aligned
62
Drawing up a Contract
• Allow for catastrophes:
– The CRO spills all your material
– The methods validation fails
– Fire at the contract manufacturer
• Define project milestones and when they
MUST be achieved
• NAME names: who is responsible for what
at your company and at the contractor
63
Quality Issues
7.10 A contract should be drawn up between the Contract
Giver and the Contract Acceptor
specifying 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 Practice
All arrangements for manufacture and analysis must be
in accordance with the marketing authorisation and
agreed by both parties
64
Quality Issues - Complaints
•
•
Who is responsible for investigating complaints?
Will the contractor allow your QA person /
consultant access to:
– Facility
– Personnel
– Records
•
in order to conduct a detailed investigation?
…or will you have to make do with their
abbreviated report saying it is not their
responsibility
65
Quality Issues
•
•
•
The contract should permit the Contract
Giver to visit the facilities of the Contract
Acceptor
In 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]
66
Quality 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
67
When 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?
68
Contract 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
times
– Need to have access to batch records and analytical
results (if they are doing analysis)
– Need a clause in the contract concerning:
• Deviations
• Changes
• from approved manufacturing process and methods,
including reporting deviations relating to operator, machine,
materials malfunction
• Complaints may result in audit
• Annual audit essential
69
Contract Analysis
• What about OOS??
• Your contract lab may claim to be
“GLP compliant”
• You need them to be GMP compliant with
respect to laboratory regulations
• ISO 17025 does not address out of
specification results
70
CRO / Toxicology / Other
• Audit by mail prior to signing contract
• Particularly for animal studies, choices are quite
limited
• Are some very large concerns involved that
become quite lax in their procedures if not
carefully audited
• Initiation visit / audit
• Ongoing audit during study
• If close by, request company rep present during
study performance
71
Project Oversight
• Generally have at least two functions
involved:
– Operations or (for small company may be
CEO) overseeing timelines and meeting
milestones
– QA (may be a consultant for a virtual
company) overseeing quality issues
• QA cannot perform their part unless the
contract requires punctual reporting,
especially deviations
72
Project 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
requests
– You know that he is going to help realize your product
to market timeline and are happy to invest that money
– Mutually beneficial arrangement
73
Quality Issues
•
•
Contract must address QP release
Who is responsible for:
– purchasing materials
– Testing and releasing materials
– undertaking production and quality controls
including IPC
– who has responsibility for sampling and
analysis
74
Quality Issues
•
•
Manufacturing, analytical and distribution
records, and reference samples should be kept
by, or be available to, the Contract Giver
Any 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
75
Define contract giver responsibilities
76
Define contract acceptor
responsibilities
77
What about Specifications
•
•
•
•
•
Are they appended
What about manufacturing instructions
Test methods
Packaging instructions
Clinical trial protocols etc.
78
Who is responsible for updating
79
Deviations and Changes
• What is “significant?”
• What is “immediate” notification
• OOS – and laboratory error – do you want
to be notified?
80
What to do about Regulatory Inspections
•
•
•
•
•
•
Can you be present?
On call?
Notified immediately? Of adverse outcome
Involved in response writing?
Notified of responses?
Involved in ANY response directly involving your
product
• Other?
• DISCUSS with their QA / regulatory BEFORE initiating
a Technical Service or Master Service Agreement
• AND contract giver must notify acceptor if they are to
be inspected because support (rapid) may be needed
81
In Conclusion
• The quality of the output is:
– Dependent on the contract acceptor
– Highly dependent on the contract giver
– Requires a lot of work before initiation
– Requires a lot of work during the project
– Must have face to face meeting before kick-off
– Cannot be left to chance
• If the contracted work is to be of value
82
In conclusion
•
•
•
•
Outsourcing is growing and is global
It is a business necessity and will continue to grow
There are business needs that must be met
There are compliance and quality needs that if not
met will bring down your company
• It is a partnership both with the contractor and
within your company
• It needs to be managed – but it is not a Quality
Assurance “Responsibility” on a day to day basis
83
THANK YOU FOR YOUR
ATTENTION
84