A new draft guidance document released by the US Food and Drug Administration (FDA) regarding making approved human blood and blood components lays out the agency's recommendations on which changes to a product or its manufacturing processes will require notifications to be made to the agency, and how to do so in a least-burdensome manner.

Three Main Types of Changes

The guidance, released 31 May 2013, is specifically intended for manufacturers of licensed whole blood and blood component products (such as source plasma) intended for either transfusion or further manufacture. Such products are regulated under 21 CFR 601 (applications) and 21 CFR 1271 (quality), but the guidance is only concerned with the former of these, which includes considerations about comparability protocols and labeling changes at 21. CFR 601.12 (e) and (f).

FDA notes that manufacturers frequently request to make changes to their approved products, including the process by which they are made, the quality controls used in production and processing, the equipment used in manufacture, the facilities where they are manufactured, and the labeling affixed to the products. Requests for those changes may be made in one of three ways, depending on the scope of the change:

• a supplement which must be approved before distribution of the product made (a prior approval supplement) using the change (for major changes)
• a supplement submitted at least 30 days before distribution (Changes Being Effected, either CBE-30 or CBE-0 for immediate changes) of the product made using the change (for moderate change)
• as a change described in an Annual Report (AR) (minor change)

The guidance goes on to explain the exact requirements of submitting each of these changes. For example, a Prior Approval Supplement (PAS) under 21 CFR 601.12(b) will require a detailed description of the change, the products involved, the manufacturing site or areas affected, a description of the methods used and studies performance to evaluate the change, the data from performed studies, and a reference list of validation protocols and standard operation procedures.

Prior Approval Supplements

But what is a major change that would require a PAS?

• the implementation of a new manufacturing process
• addition or revision of standard operating procedures if the change is less restrictive than it was before
• implementation of a new donor history questionnaire if it is less restrictive than FDA-accepted donor history standards
• transition from a regular to an abbreviated donor history questionnaire
• implementation of a non-web-based computer-assisted interactive interview software program not previously approved by FDA
• manufacturing additional products using the same equipment
• additional of an immunization program
• requesting an exemption to federal regulations
• collection of Source Plasma from diseased or high-risk donors
• requesting approval for a comparability protocol
• requesting an exemption for which there is no published guidance
• implementing a 24-hour SOP to clarify a donor's response to a question
• changing manufacturing facilities, the manufacturing process, the manufacturing equipment, or the contractor
• changing the legal name of an applicant

Changes Being Effected

Changes Being Effected (CBE) documents require notification for the following, according to FDA:

• collection of plasma for transfusion as part of an approved apheresis program provided the applicant is otherwise approved to manufacture the plasma product
• implementation of a hyperimmunization program for licensed vaccines where the program is consistent with an approved immunization schedule
• change in the manufacturer of a licensed vaccine previously used in an approved vaccine hyperimmunization program
• implementation of 510(k) cleared non-web-based and/or web-based Blood Establishment Computer Software (BECS) for self-administering a donor history questionnaire (DHQ)
• request for an exception or an alternative procedure under 21 CFR 640.120 for which published guidance is available and implementation conforms to the guidance
• use of a 510(k) cleared automated device for separating whole blood into red blood cells and plasma
• implementation of a computer system that is interfaced with an automated blood cell separator device as described in the 510(k) clearance for the software
• changes or upgrades in automated apheresis equipment, for example, software changes, that may have a moderate potential to have an adverse effect on the safety or effectiveness of the product(s)
• software and hardware upgrades to the leukocyte reduction process for apheresis collection that may have a moderate potential to have an adverse effect on the safety or effectiveness of the product(s)
• initial installation of 510(k) cleared BECS that interfaces with an apheresis device
• use of an FDA-registered off-site contract storage facility to store an unlicensed product collected under a pending supplement or for the storage of excess licensed product that meets all product release criteria 

Other Changes

FDA said it advises companies to specify that the changes are being reported as "CBE," and that it will determine if the change has been reported properly. "You do not have to wait for our written approval before distributing a product made using a change in this category," FDA added. However, companies should have tracking tools in place to make sure the products are held for the appropriate amount of time.

All other changes should be made in an annual report, such as changes that are more restrictive than the status quo.

Companies should expect to be able to prove the impact of all changes using a comparability protocol (CP) under 21 CFR 601.12(e), and FDA's guidance devotes an extensive amount of information to the exact circumstances under which one is required and the variable nature of the CP relative to each submission type (PAS, CBE and AR).

Comments on the guidance are due by 29 August 2013.

FDA: Draft Guidance for Industry: Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture

Federal Register