• Minimally manipulated (processing does not alter the original characteristics of the cells)
• Intended for hematopoietic reconstitution in patients with hematological malignancies 
• Intended to be used in recipients unrelated to the donor of the stem cells

Manufacturers of cord hematopoietic stem/progenitor cells (HPC-C) for autologous use, or use in a first- or second-degree blood relative, are exempt from this guidance document. However, the FDA encourages that manufacturers of these products follow these recommendations, even though their products may not require premarket review. 

The document provides FDA’s current thinking on what needs to be included within the Biologics License Application (BLA) submission. A facility may chose not to use this guidance document when applying for a BLA. However, the facility must submit a BLA for their HPC-C containing data derived from nonclinical laboratory and clinical studies which demonstrate that the manufactured product meets prescribed requirements of safety, purity, and potency (21 CFR 601.2). This guidance provides specific recommendations if you wish to rely on data in docket number 1997N-0497 (formerly docket number 97N-0497). If you choose not to rely on these data, you need to consult with the FDA about alternative approaches to satisfying applicable regulatory requirements.

The two main sections of the BLA submission that are addressed in the guidance are Chemistry, Manufacturing and Controls Section and Establishment Description Section. Within these two sections, the document addressed the key elements and what documentation must be included for each of those key elements.

A significant portion of the guidance document is devoted to providing assistance to the manufacturer on how to meet the applicable regulations. This is accomplished by a comprehensive review of what regulations a manufacturer must adhere to and the documents that should be submitted as part of their BLA. All manufacturers and their products are subject to the applicable regulatory requirements and when applying for a biologics license, this includes a prelicense inspection. The regulations that are applicable to HPC-Cs include, but are not limited to, the following sections of the CFR: 

• 21 CFR Parts 210 and 211 – Current Good Manufacturing Practice Regulations (CGMP)
• 21 CFR Part 600 – Biological Products: General
• 21 CFR Part 610 – General Biological Products Standards
• 21 CFR Parts 201, and 610 Subpart G – Labeling 
• 21 CFR Part 202 – Advertising

For the most part, in the manufacture of HPC-C, the CGMP regulations will be applied because they are more broadly drafted and subsume the CGTP regulation.

The CGMP regulations applicable to the manufacture of HPC-Cs are contained in 11 subparts in 21 CFR Part 211: 

• Subpart A – General Provisions 
• Subpart B – Organization and Personnel 
• Subpart C – Buildings and Facilities 
• Subpart D – Equipment 
• Subpart E – Control of Components and Drug Product Containers and Closures 
• Subpart F – Production and Process Controls 
• Subpart G – Packaging and Labeling Controls 
• Subpart H – Holding and Distribution 
• Subpart I – Laboratory Controls 
• Subpart J – Records and Reports 
• Subpart K – Returned and Salvaged Drug Products

The CGTP regulations applicable to the collection of the cord blood as well as the manufacture of HPC-C are contained in two subparts in 21 CFR Part 1271:

• Subpart C – Donor Eligibility 
• Subpart D – Current Good Tissue Practice

It important to note that Subpart A – General Provisions, and Subpart B – Procedures for Registration and Listing are applicable to HPC-C. However, 21 CFR Part 1271 Subpart E – Additional Requirements for Establishments Described in § 1271.10 (reporting requirements and labeling), and Subpart F – Inspection and Enforcement of Establishments Described in § 1271.10, are not applicable to HPC-C products described in this guidance.

As an indicator of the quality of products, FDA is recommending that an analysis of postmarketing activities information received from transplant centers on clinical outcomes of individuals who received HPC-C from your facility. The data should be evaluated to determine whether any adverse experiences or other unexpected outcomes identified may be due to problems with product manufacture, and whether corrective actions are needed.