FDA Current Perspective on Contract, Divided and Shared Manufacturing

1
FDA Current Perspective on Contract, Divided and
Shared Manufacturing

• Rebecca A. Devine, Ph.D.
• Associate Director for Policy, CBER
• PDA Symposium April 13, 1999

2
Background

• Reasons for Increase in Cooperative Arrangements
• FDAMA Section 123
• Licensed Manufacturer

3
Reasons for Increase in Cooperative Arrangements

• Highly complex and specialized technology
• Facilitates product development
• Firms not equipped to perform all steps
• Firms interested in sharing parts of manufacture

4
FDAMA Section 123

• A biologics license shall be in effect
• Prior to such product being introduced into
  interstate commerce
• FDA shall approve a biologics license
  application
• Product is demonstrated to be safe, pure and
  potent
• Facility meets standards designed to assure
  continued safety, purity and potency

5
Concerns for Multiple Manufacturer Involvement

• Introduction of contaminants
• Adequate controls over the manufacturing process
• Lot to lot consistency

6
FDA Policy Statement Concerning Cooperative
Manufacturing Arrangements for Licensed Biologics

• November 25, 1992
• 57 FR 55544

7
Cooperative Manufacturing Arrangements November
1992 Policy Statement

• Short supply
• Divided manufacturing
• Shared manufacturing
• Contract manufacturing

8
Short Supply

• 21 CFR 601.22
• Manufacturer may obtain source materials from
  unlicensed facilities
• Limited to initial and partial manufacture
• Facility is registered
• Product is in short supply
• peculiar growth requirements
• scarcity of the source

9
Short Supply (cont)

• Manufacturer assures the facility is in
  compliance with applicable regulations
• Facility may be inspected
• Limited applicability
• Examples
• Certain pollens and insects for allergenics
• Plasma with rare antibodies
• Venoms for antitoxins

10
Divided Manufacturing

• 2 or more manufacturers
• licensed
• registered
• Participate jointly in the manufacture
• Submitted as supplements to each application
• Describes role of each participant

11
Divided Manufacturing (cont)

• Labeling
• Intermediates
• Final product

12
Divided Manufacturing

• Factors considered
• Equivalence of intermediate products
• Stability of intermediate products during
  shipment
• Labeling
• Handling of post marketing recalls, ADRs,
  complaints

13
Shared Manufacturing

• Two or more manufacturers are licensed for
  specific steps in the process
• Neither is licensed for all steps
• May perform or contract for the performance of
  the steps it is assuming
• Assumes responsibility for or performs
  significant product manufacturing

14
Considered Adequate for Separate Licensing

• Inoculation of vessels or animals
• Cell culture production and characterization
• Fermentation and harvesting
• Isolation
• Purification
• Physical and Chemical Modifications

15
Steps Not Warranting Separate Licensure Alone

• Chemical and biological testing
• Formulation
• Sterile filling
• Lyophilization
• Labeling
• Caveats
• Instrumental in product development and
• Is performing or responsible for several final
  steps

16
Applying for Shared Manufacture

• Registration
• Separate BLAs
• Facilities and operations applicable
• Storage and shipping
• Labeling
• Submitted concurrently with all others
• Approved simultaneously

17
Intermediates

• Criteria for lot to lot acceptability
• Sterility/Bioburden
• Product characterization
• Potency
• Purity

18
Final Product

• Data demonstrating
• Identity
• Purity
• Strength
• Quality
• Potency
• Safety and efficacy
• Post approval obligations

19
Contract Manufacturing

• License applicant contracts with another entity
• Other entity performs some or all of the
  manufacturing as a service to the applicant
• Broader applicability now
• Revision of Cooperative Manufacturing Policy
  Statement underway

20
Licensed Manufacturer21 CFR 600.3 (t)

• Any legal person or entity
• Holding an unsuspended or unrevoked Biologics
  License
• Ultimately responsible for compliance
• Will have US license number
• Holds the Biologics License

21
Effect of the Definition of Manufacturer

• Innovators can apply for the license
• The applicant may or may not own the facilities
  in which product is manufactured
• Applicant assumes responsibility for meeting
  standards
• Each contract facility need not be separately
  licensed if doing significant manufacturing

22
Applicant Assumes Responsibility

• What does this mean?

• Affects the term as used in 21 CFR 600-680
• Responsibility is for meeting the standards in
  600-680
• Contract firms continue to be subject to cGMPS

23
Pitfalls Sure to Doom the Arrangement

• Lack of
• A written agreement
• Clear delineation of responsibilities
• Communication (sharing of information)
• Non GMP compliance at contract location
  (applicants should verify status)

24
Written Agreement

• Manufacturer and Locations to be used
• Responsibilities of each party (QA and
  Supervision and control)
• Description of the product shipped and shipping
  conditions
• Description of periodic assessments

25
Written Agreement (cont)

• Operations performed
• SOPS
• Commitment to inform applicant of proposed
  changes
• Commitment to inform applicant of errors and
  deviations in manufacture or testing, ADRs

26
Complicating Factors

• Applicant files information on the contractor
• Master file is not a preferred option for FDA
• Contractor may be unwilling to share certain
  information with applicant
• Identity of other products in the plant
• Plant proprietary information

27
Recommended

• Access by applicant to
• Floor plans
• Equipment validation
• Other production info necessary to assure safety,
  purity and potency
• Important proposed changes to process and
  facilities

28
Inspectional Issues

• Inspection of the contractor is an inspection of
  the contract facilities and operations
• Also an inspection of the process
• 483 goes to the contractor
• GMP issues affect applicant
• Team Biologics inspections
• Compliance action may affect all parties

29
Things Applicants Need to Do

• Regular assessments of contractors
• Clearly outline duties and responsibilities of
  each partner
• Ensure access to the information you need
• Have written procedures
• Prepare and submit proper documentation to FDA

30
What Contractors Need To Do

• Adhere to written agreements
• Keep applicant informed of key issues
• Share information on GMP inspections
• Facilitate audits
• Follow written procedures

31
What FDA Considers

• How has the applicant shown it assumes
  responsibility?
• Are all facilities in GMP compliance?
• There is no negative impact on the safety,
  purity, or potency of the product.
• Shipping of intermediates.
• Is application information complete and accurate?

32
Summary

• New definition of manufacturer has broadened
  options
• Cooperative Manufacturing Guidance Revision
  underway
• Contact the Applications division for specific
  questions

33
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