1. CBER Cooperative Manufacturing Arrangements (Contractors) Jennifer Jones Consumer Safety Officer CBER, OBRR, DBA September 15, 2009

2. CBER 2 Outline Definitions Cooperative Manufacturing Arrangements Contract Manufacturing Submission Categories Short Supply Arrangements Labeling Inspectional Issues

3. CBER 3 Definitions Product Manufacturer - need not perform all manufacturing steps or own facilities where steps are performed; may contract with another to perform manufacturing steps; responsible for compliance Contractor – manufacturer not under direct control of product manufacturer, but who performs part or all of manufacturing steps as service for product manufacturer Cooperative manufacturing arrangements – manufacturing relationship between two or more manufacturers; usually includes written description of responsibilities of each party

4. CBER 4 Cooperative Manufacturing Arrangements Shared manufacturing – both parties licensed to perform different manufacturing steps Divided manufacturing – both parties licensed to perform all manufacturing steps, joint manufacturing Contract manufacturing – need not be licensed but performs some manufacturing steps as service Short supply – unlicensed product shipped interstate for manufacture into licensed final product

5. CBER 5 Product Manufacturer’s Responsibilities Responsible for compliance of all manufacturing steps on their product, even if not performed in own facility (600.3(t)) – Includes compliance with PHS Act and FD&C Act – Should determine if contractor is manufacturing properly Have adequate SOPs for interacting with contractor – Product/sample shipment to/from contractor – Written/oral communication with contractor – Procedures for determining contractor’s compliance Licensed manufacturers must notify CBER if use or change contractor (601.12)

6. CBER 6 Contract Manufacturer’s Responsibilities Manufacture product according to regulations, cGMPs, FDA recommendations and product standards Inform product manufacturer of any changes in manufacturing or inspections that impact product Contractors performing certain manufacturing steps must be registered (610.40(f), 607.20(a)) Contractors are subject to FDA inspections under FD&C Act and PHS Act (for licensed products)

7. CBER 7 Contract Arrangement Should describe product manufacturer and contractor activities and responsibilities – Examples of items possibly in arrangement: Contractor notify product manufacturer of changes Share proficiency tests, inspection reports, agree to audits May contain varying amounts of information, additional specifications may be described in appendix documents (e.g., SOPs) Should be up-to-date, contain current information Not reviewed by CBER

8. CBER 8 Examples of Contract Manufacturing Outside testing labs that perform tests of record for determining donor suitability – Includes test labs that perform confirmatory tests for infectious diseases for counseling donors (610.40(f)) Facilities that irradiate blood components Suppliers of Red Blood Cells for immunization programs Donor collection personnel Warehouses that cull unacceptable products from inventory Offsite storage and distribution facilities* *Registration not required (607.20, 607.65)

9. CBER 9 Submission Categories Guidance for Industry: Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion for Further Manufacture, July, 2001 – Prior Approval Supplement (PAS) (601.12(b)) – Changes Being Effected in 30 days (CBE30) (601.12(c)) – Annual Report (601.12(d))

10. CBER 10 Submission Categories (cont.) Prior Approval Supplement – Use of, or change to, a facility not previously engaged in blood product testing as a contract testing laboratory (infectious disease screening testing and supplemental and/or confirmatory testing) – Use of, or change in, a contractor that was previously not engaged in performing a manufacturing step on blood products to perform the manufacturing step Examples: – Contractors who irradiate blood products – Contractors who supply Red Blood Cells for immunization

11. CBER 11 Submission Categories (cont.) Changes Being Effected in 30 days – Use of, or change to, an FDA registered contract testing laboratory, currently engaged in blood product testing, to perform the routine serologic and infectious disease screening testing, and supplemental and/or confirmatory testing – Use of, or change to, an FDA registered contractor currently engaged in performing manufacturing steps on blood products to perform a specific manufacturing step (e.g., irradiation) – Use of an off-site storage facility to store unlicensed product collected under a pending license application or for the storage of excess licensed product that meets all product release criteria

12. CBER 12 Submission Categories (cont.) Annual Report – Use of, or change in, a contract testing laboratory that performs reference or quality control testing or tests not required by FDA – Temporary use of a previously approved alternate or back- up contractor to perform a manufacturing step – Notification of changes in operations made by approved contractor – Change in infectious disease test methodology that is required or recommended by FDA at a previously approved contract testing laboratory

13. CBER 13 Submission Example Addition of an outside testing laboratory that is registered and currently performing testing CBE30 Reporting Category Include the following information: – Form FDA 356h – Name/address/registration number of testing laboratory – List of tests or services the testing laboratory will perform Review includes: – Compliance check – Will approve if satisfactory compliance history

14. CBER 14 Short Supply Arrangement Described in 21 CFR 601.22 Allows for unlicensed source product to be shipped in interstate commerce and made into licensed final product Short supply product is manufactured at facility other than facility making licensed final product (e.g., plasma derivative fractionator) Licensed final product manufacturer must apply for short supply arrangement; responsible for ensuring short supply product is in compliance Arrangement must be in effect before collection of short supply products can begin

15. CBER 15 Short Supply Arrangement (cont.) Short supply product manufacturers are subject to FDA inspections Short supply product shipped only to licensed final product manufacturer (may be shipped through a broker) Applies only to unlicensed source products Examples of products shipped under short supply: – Recovered Plasma – Red Blood Cells for further manufacture into noninjectable products (reagents) – Platelets for further manufacture into noninjectable products (test kit controls)

16. CBER 16 Labeling Requirements Name, city/state, license/registration number Shared manufacturing – Both manufacturers on final product label Divided manufacturing (610.63) – Both manufacturers on final product label Contract manufacturing – Contractor not on blood component label, only manufacturer with full responsibility for blood component Short supply – Only short supply product manufacturer on blood component label

17. CBER 17 FDA Inspectional Issues What manufacturing steps are being performed and where? If by contractor: – Who is contractor? – What steps are they performing? – Where are they located (address)? If necessary, is contractor registered? Is short supply arrangement required? – Date it was in effect? Is blood component labeled properly? Has CBER been notified of changes, if required?

18. CBER 18 Where to obtain information Guidance for Industry: Cooperative Manufacturing Arrangements for Licensed Biologics (11/08) FDA’s Policy Statement Concerning Cooperative Manufacturing Arrangements for Licensed Biologics, November 25, 1992 – Federal Register Notice Vol. 57, p.55544 Guidance for Industry: Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture (07/01)