Best Practices In Ensuring
Quality Standards
When Outsourcing To
Contract Manufacturers,
Licensees And Consultants
Alex D. Kanarek, PhD
BioProcess Technology Consultants, Inc.
Strategic Institute Quality & Regulatory Strategies Summit
Toronto, Ontario
March 5/6, 2009
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Agenda
Outsourcing Overview:
• Contract Manufacturers
• Licensing Out
• Use of Consultants
Regulatory Environment
CMOs, Contracts & Quality Agreements
Ensuring Quality by Partnering
PIP, Inspections & Audits
Key “Take-Home” Points
Discussion
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CMO Outsourcing Overview
Transfer of Sponsor’s Technology
Product Development
Process Development
Manufacture: Clinical & Commercial
Process Validation (FDA: “Process Performance Qualification”)
Analytical Method Development & Validation
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Best Practices in Technology Transfer
Have a well-defined TT process (written)
• Define roles and responsibilities clearly
Use software-based planning & scheduling devices such as “SuperPro” or MS Project to ensure no bottlenecks or conflicts
Some examples of pitfalls:
• Process uses custom raw materials (short supply?)
• Long lead equipment will delay project
• Instrument calibration tolerances do not match process needs
• Column packing requirements not clearly defined
• Mixing or filtration studies needed with different equipment
• Hold times may vary – stability concerns?
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CMO Development Activities
Product Development, e.g.:
• Expression System Development/Improvement
• Cell Line Selection
• Formulation Development
Process Development, including:
• New Process Creation
• Existing Process Improvement
• Scale-up Studies
• Process Validation
CMO should have the expertise, but may not
FDA Rules on Validation are changing
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Clinical and Commercial Manufacture
CMOs vary significantly in Capacity and Experience
Differing GMP Requirements for Phase I thro’ III
Commercial Manufacture uses Validated Processes and Methods
CMO must have Functional Quality Unit (QA/QC)
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Analytical Method Development & Validation
Essential Part of Product Development
Often outsourced – possibly to another contractor
Contractor Provides Specialized Expertise & Equipment, for
• Characterization
• Potency Assays
• Impurities Profile
Problems
• Bringing method in-house
• Demonstrating robustness
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Licensing Out
Early-stage Products
• Not usually done – originator loses control
• More often the research is sold to “Big Pharma”
• Or, there is a joint venture for further drug development
Products in Clinical Trial
• Licensee shares or undertakes the cost of clinical manufacture and testing and the trials
• If Licensee manufactures in-house, Quality Agreement needed
• If Licensee uses a CMO, the rules still apply
Approved Products
• Licensee must comply with all provisions of the Marketing Approval
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Consultants
Work in-house or with other contractors
Provide specialized expertise and advice
Consulting agreement contains quality clauses
Typical Consultants’ Services:
• Product/Process Development
• Process/Method Validation
• In-house Audits for Regulatory Compliance
• Assistance with Training Programs
• Assistance with Documentation/Submissions
• Supplier Audits
• Selecting, Monitoring, Auditing CROs, CMOs; may be PIP
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The Basic GMP Regulations (1)
Canada Federal Drug Regulations Division 2, Part C
• Need for Establishment License
• GMP Guidance 2002, revised 2007 - draft for comments
Defines Quality Management System, QA/QC
• QA ensures that “Outsourced activities are subject to appropriate controls and meet GMP requirements”
• Specifies qualifications/experience of responsible staff
USA Regulations, 21CFR 210 + 211 for all drugs, 600 series for biologics, 820 for devices
• All facilities must be registered
• No specific mention of outsourcing in 21CFR211
• Guidance on “split” manufacture of biologics Nov. 2008
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However, A Recent FDA Warning Letter Stated:
“Specifically, your firm has not established and approved quality system procedures that delineate the specific responsibilities and manufacturing operations for each of your contract manufacturing facilities…”
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The Basic GMP Regulations (2)
EU Regulations EUDRA Volume 4 + Annexes
• Chapter 7 “Contract Manufacture & Analysis “
Defines responsibilities of both parties clearly.
Some following slides are based on this chapter.
ICH Q7: Guidance on GMP for APIs
• Section 16: Specific provisions for contract manufacturers
Must comply with GMP – sponsor to evaluate
Must allow sponsor audits
Written contract
Sponsor approves changes
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General GMP Provisions
USE QUALITY SYSTEM MANAGEMENT (& Risk Evaluation) for:
Proper Design & Operation of Facilities & Equipment
Control of Raw Materials and Components
Adequate Qualification & Training of Staff
Written Procedures for all Critical Activities
Quality Control of In-Process & Final Product
• To preset specifications
Full Records of Manufacture & Testing
Validation of Processes and Test Methods
Process Change Control & Documentation
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The Ideal CMO:
Has the competence to manufacture/test the product
Complies with the quality standards of the sponsoring company
Has the necessary legal manufacturing authorizations
Has an infrastructure and culture capable of providing accurate, comprehensive and timely information
Provides a good fit with the Sponsor’s corporate culture
Has the capacity to meet product demand for clinicals or sales
Can supply the product at an acceptable cost/dose
Has commitment to your business and can deliver orders on time and in full
Is a secure business capable of long-term tenure of supply, which invests sufficiently in maintaining up-to-date technologies.
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Managing the Relationship
The Sponsor should:
• Provide dedicated project management/contact person(s)
• Maybe a Person in the Plant (PIP)
• Maintain clear communication channels
• Provide for conflict resolution
• Manage overly optimistic deliverable requirements
The CMO should:
• Be attuned to a cultural fit with the sponsor
• Be a good partner
• Be responsive to sponsor’s needs & concerns
• Manage overly optimistic forecasts
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CMO Contracts & Quality Agreements
There must be a Written Contract
Defining the Responsibilities of:
• The Sponsor
Technology Transfer
QA/Regulatory Support
• The Contractor
To use established processes or develop new ones
To comply with GMP
Providing an Assurance of Quality
• In Contract or Separate Agreement
All arrangements must be in accordance with the marketing authorization (if it exists)
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Define the Responsibilities (1)
“The Contract Giver is responsible for assessing the competence of the Contract Acceptor to carry out successfully the work required and…
For ensuring by means of the contract that the principles and guidelines of GMP ... are followed.” - EUDRA Vol. 4, Chapter 7.
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In Other Words...
The Sponsor
• Retains overall responsibility for compliance
• Must have a Quality Assurance/Quality Control unit
• Must assess, monitor and audit the CMO’s operations
• Must perform annual product quality review with CMO
Will prepare and submit the CTA, NDS, etc. (IND, NDA)
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Define the Responsibilities (2)
“The Contract Acceptor must have adequate premises and equipment, knowledge and experience, and competent personnel to carry out satisfactorily the work ordered by the Contract Giver.
Contract manufacture may be undertaken only by a manufacturer who is the holder of a manufacturing authorization.” EUDRA.
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In Other Words…
The CMO
• Must be in compliance with GMP, according to the phase of manufacture
• Must have a QA/QC Unit
• Must work to Master Formulae (MBR) and maintain full Batch Production Records
• Must monitor and audit internally
• Must be licensed or registered with Regulatory Agency
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Define the Responsibilities (3)
Consultants and Contract Auditors
• Are required to have appropriate training and qualifications
• Must comply with GMP
• Contract Giver must record
Consultant’s qualifications
The services provided
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The Quality Agreement
“Quality systems call for contracts (quality agreements) that clearly describe the materials or service, quality specification responsibilities, and communication mechanisms” – FDA
Should Summarize:
• The Sponsor’s expectations
• The CMO’s commitment
Should Contain:
• A Reference to the relevant Regulations
• The Agreed Specifications of In-process and Final Product
• Provision for QA Oversight (by Sponsor and Contractor)
• System for product approval/release
Should Define the handling of Deviations/Errors/OOS Results
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Quality Agreements – Opinion from FDA
“Should clearly outline all responsibilities of both
parties for notification of manufacturing-related
issues to one another…”
“Should contain a full description of all reporting
relationships for issues related to contract
manufacturing operations based upon the nature
of the relationship”
Dr. Mark Elengold, CBER Deputy Director, Operations
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Questions to Answer – Opinion from FDA
How is information shared specific to investigations of deviations?
How is the contract manufacturer going to evaluate changes in equipment and facility use that may impact on the
product, and how will they notify the license holder? Who has ultimate responsibility for the product and does this
entity have full access to all potential product impacts or contractor operations?
Elengold
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Compliance Assurance - Initial Audit
Investigate:
• The competence of the Contractor’s staff,
• His history of successful projects,
• His SOPs for all manufacturing & control operations,
• The results of previous Audits and Regulatory Inspections, DMFs filed
Inspect the plant, QMS, operations, validation reports, production records etc.
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Compliance Assurance – During Operations
Clearly define all critical GMP compliance requirements in the contract
Have a Person in the Plant (PIP) if necessary
Arrange for periodic QA visits to inspect (audit) actual manufacturing of the contracted product
Obtain process validation reports as they are generated
Ensure QC testing is done with qualified methods
Ensure that production/testing records are complete and accurate.
Ensure notification of all process/testing deviations and that all OOS results are investigated
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Ongoing Surveillance – FDA’s Recommendations
Ask to be notified of all changes which could affect the processing of your (approved) product
• New equipment
• Change in key personnel
• Change in test methods
• Change in SOPs
Ask to be notified when the contract facility is visited by the FDA
• Ask for a copy of all FDA-483s which are issued to the firm
Ask to be notified if a test result was obtained as a result of a re-test (and why…)
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The Person in Plant – Friend…?
The primary conduit of information between the two companies
Will help coordinate production schedules, document reviews/approvals, and general project-related tasks
Will personally observe batch manufacturing activities
May conduct site audits, if qualified
Must be able to communicate progress, issues, concerns and questions to sponsor colleagues
And communicate responses to CMO staff
CMO will expect the PIP to have authority to participate in on-the-spot trouble-shooting and be able to make decisions regarding product quality when anomalies occur, But…
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The Person in Plant – …or Foe?
It is rare for the PIP to have the authority to approve products for continued processing when a process deviation or OOS is encountered – Sponsor’s QA Unit must be involved
Must be a consummate politician…
• Will always be the outsider looking in
• Everyone at the CMO is aware that they are being observed
• May be a drain on CMO resources
May have to function as a partner, mentor, auditor and project sponsor simultaneously
Must always be careful not to interfere with operations
• Can create liability problems
Can enhance or destroy a sponsor’s relationship with a CMO
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Sponsor’s Inspections & Audits
Use the Six Systems Approach:
“Compliance Program Guidance Manual
for FDA Staff: Drug Manufacturing Inspections Program”,
Implemented February 2002
Apply Risk Analysis to determine critical processes/procedures to inspect
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The Six Systems
1) Quality System - Always inspect this! a) SOPs & other Document Management
b) QA Audit Reports, Internal & External
c) Regulatory Inspection Reports (Canada Inspection Exit Notice, FDA Form 483), Warning Letters
2) Facility & Equipment – walk through a) Environmental Control & Monitoring
b) Staff & Materials Movement Control
c) Equipment Placement, Maintenance & Calibration
d) Cleaning Validation
3) Materials a) Raw Material & Container Specifications
Vendor Audits
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The Six Systems, continued
4) Production
a) SOPs for standard operations – being followed?
b) Critical procedures qualified/validated?
c) Batch records – critical measurements countersigned?
5) Packaging & Labeling – as needed
6) Laboratory Control
a) Using agreed test procedures & specifications?
b) Qualified/validated methods
c) OOS Investigations
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Data Audits
Should confirm the accuracy and integrity of reported data and results.
Involve comparison of batch records and reports with “raw data”, e.g.:
• Operators’ in-process records,
• Analysts’ laboratory notebooks.
Should also cover deviation reports and failure analyses.
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What Can Go Wrong?
A 2007 survey revealed the following TOP 6 Categories of COMPLAINTS:
Type of Complaint Percentage of Respondents
Competence 21.4%
Quality 13.1%
Communication 13.1%
Delivery 11.9%
Customer Service 10.7%
Costs 7.1%
Source: Contract Pharma
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Some Recommended Best Practices
Appoint a “Technical Product Owner”
• To follow product over the entire life cycle
• Continuity is critical
External Quality Manager must be technically competent
• Often a Sponsor’s resource constraint
Key Performance Indices should be well defined
Establish clear time-frames for responses either way
Encourage the CMO to Think, not just Do
• Continuous Improvement is the Aim
Remember - Your CMO is Your Partner
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Finally…
Questions?
Comments?
Thank You
519-856-4710
BioProcess Technology Consultants, Inc.
289 Great Road, Suite 303 Acton, MA 01720 USA
1-978-266-9101 (phone) 1-978-266-9152 (fax)
[email protected] www,bioprocessconsultants.com
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