CBER Presentation

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REGULATORY PATHWAYS: WHAT REGULATIONS APPLY

3rd Annual FDA and the Changing Paradigm for HCT/P Regulation
January 24-26, 2007
Ruth Solomon, M.D.

Outline

Regulatory Pathways
Statutes
Regulations
CGTPs and CGMPs

Acronyms

HCT/P = human cell, tissue, or cellular or tissue-based product
CGTP = current good tissue practice
CGMP = current good manufacturing practice
PHS Act = Public Health Service Act
FDC Act = Food, Drug and Cosmetic Act
"361" HCT/P = regulated solely under section 361 of PHS Act and 21 CFR Part 1271
"351" HCT/P = regulated under sections 361 and 351 of the PHS Act and under the FDC Act

Regulatory Pathways

"361" and "351" HCT/s

"361" HCT/Ps

Meet all the criteria in 1271.10
No pre-market review--no application to FDA is required
Compliance determined at FDA inspections
Examples-musculoskeletal tissue; skin; cornea; reproductive cells; cellular therapies that are:

Minimally manipulated
Intended for homologous use only
Not combined with another article (with some exceptions)
for autologous use or use by a first- or second-degree blood relative

21 CFR 1271.10

HCT/P regulated solely under section 361 of PHS Act and regulations in part 1271 if it meets all of the following criteria:

(1) HCT/P is minimally manipulated
(2) HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer's objective intent
(3) Manufacture of HCT/P does not involve the combination of the cell or tissue with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P
(4) Either:

(I) HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or
(ii) HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and is for:

(a) autologous use
(b) allogeneic use in a first-degree or second-degree blood relative, or
(c ) reproductive use

Minimal Manipulation

(1) For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue's utility for reconstruction, repair, or replacement; and
(2) For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of the cells or tissues
Guidance for Industry and FDA Staff: Minimal Manipulation for Structural Tissue Jurisdiction Update

www.fda.gov/cber/gdlns/minimaljur.htm

Homologous Use

The repair, reconstruction, replacement, or supplementation of a recipient's cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor.

"351" HCT/P

Do not meet one or more criteria in 1271.10
Require pre-market review and approval

IND/BLA-biological products are licensed
Pre-license inspection

Subject to routine FDA inspections thereafter
Examples--cellular therapies for unrelated allogeneic use, regardless of whether the cells are:

Minimally manipulated or more than minimally manipulate
Intended for homologous use or nonhomologous use
Because they have a systemic effect and are dependent upon the metabolic activity of living cells, but are not for autologous use or allogeneic use in a first-degree or second-degree blood relative

Statutes (Laws, Acts)

"361" and "351" HCT/Ps

Statutes that apply to "361" HCT/Ps

Public Health Service Act

Section 361. "The Surgeon General, with the approval of the Secretary, is authorized to make and enforce such regulations as in his judgment are necessary to prevent the introduction, transmission, or spread of communicable diseases from foreign countries into the States or possessions, or from one State or possession into any other State or possession.

Statutes that apply to "351" HCT/Ps

(1) PHS Act

Section 361 and

Section 351. Regulation of Biological Products.

(a) No person shall sell, barter, or exchange ..in the District of Columbia, or send, carry, or bring for sale, barter, or exchange from any State or possession into any other State or possession or into any foreign country, or from any foreign country into any State or possession, any virus..or analogous product applicable to the prevention, treatment, or cure of diseases or injuries of man, unless such product has been propagated or manufactured and prepared at an establishment holding an unsuspended and unrevoked license, issued by the Secretary

(2) Federal Food, Drug, and Cosmetic Act

Biological products meet the definition of "drug" in section 201((g)(1)

Statutory GMPs in FDC Act

Section 501(a)(2)(B) of the FD&C Act requires drugs, which include IND products, to comply with current good manufacturing practice:

A drug...shall be deemed adulterated...if...the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess

Statutory GMPs in FDC Act for INDs

Section 505(i) of the FD&C Act (21 U.S.C. 355(i)) directs FDA to promulgate regulations governing IND products to protect human subjects enrolled in investigations.

Regulations

"361" and "351" HCT/Ps

Regulations that apply to "361" HCT/Ps

21 CFR part 1270 (recovered before 5/25/05) and 1271 (recovered on or after 5/25/05)

Part 1271

Subpart A-General Provisions; definitions
Subpart B-Registration and Listing
Subpart C-Donor Eligibility
Subpart D-Current Good Tissue Practice (not reproductive HCT/Ps at this time)
Subpart E-Additional Requirements: Reporting, Labeling (not reproductive HCT/Ps at this time)
Subpart F-Inspection and Enforcement

Regulations that apply to "351" Biological Products that are also HCT/Ps while under IND

21 CFR part 1271

Subpart A
Not required to register while under IND
Subpart C
Subpart D

21 CFR Part 312-Investigational New Drug Application
21 CFR Parts 210/211-Good Manufacturing Practice*
21 CFR Parts 50 (protection of human subjects) and 56 (institutional review boards)

* Proposed rule for phase 1 INDs would exempt from 210/211 but require compliance with "statutory GMPs" and guidance

Regulations that apply to "351" Licensed Biological Products that are also HCT/Ps

21 CFR part 1271

Subpart A
Subpart B
Subpart C
Subpart D

21 CFR Part 201-Labeling
21 CFR Part 202-Advertising
21 CFR Part 210/211-Good Manufacturing Practice
21 CFR Part 600-Biological Products; General (includes Reporting of Adverse Experiences and Biological Deviations)
21 CFR Part 601-Licensing
21 CFR 610-General Biologics Standards

CGTPs and CGMPs

"361"-CGTPs
"351"-CGTPs and CGMPs

CGTP Requirements

Apply to all HCT/Ps
21 CFR Part 1271, Subparts C and D (except that reproductive HCT/Ps are not required to follow Subpart D at this time)
Govern the methods used in, and the facilities and controls used for, the manufacture of HCT/Ps, including recovery, donor screening, donor testing, processing, storage, labeling, packaging and distribution

CGMP Requirements

Apply to:

Drug products
Drugs that are also biological products
HCT/Ps that are also regulated as biological drug products

21 CFR Parts:

210, 211
600 through 680
1271

Govern the methods to be used in, and the facilities and controls to be used for the manufacture, processing, packing, or holding of a drug

CGTPs and CGMPs

Supplement and do not supersede each other
In the event of a conflict, the regulation specifically applicable to the product in question shall supersede the more general
Due to the broader scope of the CGMPs (i.e., not just focused on prevention of communicable disease transmission), some, but not all, CGTPs would be completely covered ("subsumed") under the broader CGMP requirements
Compliance with these CGMP requirements would result in compliance with applicable CGTP requirements.

Some CGTPs are not completely covered by CGMPs

Therefore, for "351" HCT/Ps, these are the CGTPs that you must pay attention to and comply with:

All donor eligibility requirements (Subpart C)
Prevention of the introduction, transmission, or spread of communicable diseases (1271.145)
Certain parts of manufacturing arrangements [1271.150(c )(1)]-Manufacturing arrangements-

(ii) Establishment under contract, agreement or other arrangement must comply
(iii) Establishment that made the contract, agreement or other arrangement must ensure compliance

Exemptions and alternatives to any requirement in Subpart C or D (1271.155)

Certain quality program functions

Procedures for sharing with other establishments information pertaining to possible contamination or potential for transmission of communicable disease [1271.160(b)(2)]
Audits [1271.160(c )]

Prohibition on pooling [1271.220(b)]

Pre-distribution shipment [1271.265(b)]

HCT/P availability for distribution only after donor eligibility is established [1271.265(c )(2)]
Specific packaging and labeling requirements [1271.265(d)]
Record-keeping for 10 years (but facility cleaning records for 3 years) [1271.270(d)]
Certain records for contracts and agreements [1271.270(e)]
Tracking [1271.290(a)-(g)]

Example

HCT/P regulated as a biological drug product
An example of CGMP requirements that completely cover a CGTP requirement (i.e., the CGTP requirement is "subsumed" by the CGMP requirement)---
CGTP requirement: Equipment (1271.200) would be completely covered (subsumed) by:
CGMP requirements:

211.63 Equipment design, size and location
211.65 Equipment construction
211.67 Equipment cleaning and maintenance
211.68 Automatic, mechanical, and electronic equipment

If these CGMPs were followed, you would be in compliance with 1271.200

Contact Information

Ruth Solomon, M.D.
HFM-770
1401 Rockville Pike
Rockville, MD 20852

Ruth.solomon@fda.hhs.gov
301-827-5363