Description
Additional copies are available from:Office of Combination ProductsFood and Drug AdministrationWO32, Hub/Mail Room #512910903 New Hampshire AvenueSilver Spring, MD 20993(Tel)301-796-8930(Fax)301-847-8619http://www.fda.gov/CombinationProducts/
Scope & Applicability
Product Classes
10Products combining drug, device, or biological constituents; Generally recommended for Enhanced Documentation; Requires 14971-based framework incorporating ICH Q9; A drug-device combination where the device constituent part detects ingestion.
Human cells, tissues, and cellular and tissue-based products regulated as devices; Human cells, tissues, and cellular and tissue-based products regulated as medical devices; Human Cell, Tissue or Cellular or Tissue-Based Product
Example of a product type for EDDO identification.; Example of a device constituent part and primary container closure.
Example of a single-entity combination product; Specific example of a combination product (DES)
Example of a combination product analyzed in scenarios
Regulated under section 351(i) of the PHS Act; Virus, therapeutic serum, toxin, vaccine, or protein applicable to prevention or treatment; Alternative regulation category for products meeting device definition
Human cells, tissues, or cellular or tissue-based products defined in 21 CFR Part 1271
Constituent parts need only comply with requirements otherwise applicable to that type of product; Products packaged separately but intended for use together
Subject to part 4 compliance options; Combination products where constituent parts are physically or chemically combined; Specific type of combination product mentioned regarding purchasing controls.; Tamper-evident packaging requirements apply to the packaging for the combination product as a whole.; A prefilled syringe is a single-entity combination product under 21 CFR 3.2(e)(1); Classification of drug-coated mesh and drug-eluting stents; Components are physically, chemically, or otherwise co
Subject to part 4 compliance options; Combination products where constituent parts are packaged together; Specific type of combination product mentioned regarding purchasing controls.; Requirements can be met through appropriate packaging of the drug constituent part(s) within the larger co-package.; Two or more separate products packaged together
Stakeholders
7Entity responsible for submitting NDINs
Person whose actions may cause a product to be deemed adulterated
Facility supplying raw materials or ingredients; Facility providing raw materials to a manufacturer
External entity responsible for manufacturing activities
Senior management responsible for quality policy
Initiates specifications for a device manufactured by a second party
holder of the marketing authorization
Regulatory Context
Attributes
5intended storage conditions throughout the proposed shelf-life
specifications for the purity, strength, and composition of dietary supplements
Property of a device that may be changed via established protocols
quantity that would be produced in the absence of any loss or error
regulatory qualifier allowing for documented justification of non-implementation
Identified Hazards
Hazards
4Environmental factors affecting biological products
Risk of febrile reaction
Potential safety or performance risks in combination products
risk related to HCT/P products
Related CFR Sections (16)
- 21CFR4.4§ 4.4 How can I comply with these current good manufacturing practice requirements for a co-packaged or single-entity combination product?
(a) Under this subpart, for single entity or co-packaged combination products, compliance with all applicable current good manufacturing practice requirements for the combination product shall be achieved through the design and implementation of a current good manufacturing practice operating systemRead full regulation →
- 21CFR3.2§ 3.2 Definitions.
For the purpose of this part:Read full regulation →
- 21CFR211.170§ 211.170 Reserve samples.
(a) An appropriately identified reserve sample that is representative of each lot in each shipment of each active ingredient shall be retained. The reserve sample consists of at least twice the quantity necessary for all tests required to determine whether the active ingredient meets its establishedRead full regulation →
- 21CFR211.167§ 211.167 Special testing requirements.
(a) For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be appropriate laboratory testing to determine conformance to such requirements. The test procedures shall be in writing and shall be followed.Read full regulation →
- 21CFR211.166§ 211.166 Stability testing.
(a) There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include:Read full regulation →
- 21CFR211.137§ 211.137 Expiration dating.
(a) To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability testing described in § 211.166 .Read full regulation →
- 21CFR211.132§ 211.132 Tamper-evident packaging requirements for over-the-counter (OTC) human drug products.
(a) General. The Food and Drug Administration has the authority under the Federal Food, Drug, and Cosmetic Act (the act) to establish a uniform national requirement for tamper-evident packaging of OTC drug products that will improve the security of OTC drug packaging and help assure the safety and eRead full regulation →
- 21CFR211.103§ 211.103 Calculation of yield.
Actual yields and percentages of theoretical yield shall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product. Such calculations shall either be performed by one person and independently verified by a second person, or, if Read full regulation →
- 21CFR211.180§ 211.180 General requirements.
(a) Any production, control, or distribution record that is required to be maintained in compliance with this part and is specifically associated with a batch of a drug product shall be retained for at least 1 year after the expiration date of the batch or, in the case of certain OTC drug products lRead full regulation →
- 21CFR211.22§ 211.22 Responsibilities of quality control unit.
(a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no eRead full regulation →
- 21CFR211.84§ 211.84 Testing and approval or rejection of components, drug product containers, and closures.
(a) Each lot of components, drug product containers, and closures shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit.Read full regulation →
- 21CFR820.1§ 820.1 Scope.
(a) Applicability. Current good manufacturing practice (CGMP) requirements are set forth in this quality management system regulation (QMSR). The requirements in this part govern the methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, insRead full regulation →
- 21CFR210.2§ 210.2 Applicability of current good manufacturing practice regulations.
(a) The regulations in this part and in parts 211 , 213 , 225 , and 226 of this chapter as they may pertain to a drug; in parts 600 through 680 of this chapter as they may pertain to a biological product for human use; and in part 1271 of this chapter as they are applicable to a human cell, tissue, Read full regulation →
- 21CFR600.11§ 600.11 Physical establishment, equipment, animals, and care.
(a) Work areas. All rooms and work areas where products are manufactured or stored shall be kept orderly, clean, and free of dirt, dust, vermin and objects not required for manufacturing. Precautions shall be taken to avoid clogging and back-siphonage of drainage systems. Precautions shall be taken Read full regulation →
- 21CFR4.3§ 4.3 What current good manufacturing practice requirements apply to my combination product?
If you manufacture a combination product, the requirements listed in this section apply as follows:Read full regulation →
- 21CFR211.165§ 211.165 Testing and release for distribution.
(a) For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Where sterility and/or pyrogen testing are conducted on sRead full regulation →
Related Warning Letters (10)
- 2025-12-23
CGMP/Finished Pharmaceuticals/Adulterated
SV Labs Corporation
- 2025-12-23
CGMP/Finished Pharmaceuticals/Adulterated
Guangdong Renhe Guozhuang Biotechnology Co., Ltd.
- 2025-12-23
CGMP/Finished Pharmaceuticals/Adulterated
Medinatura New Mexico, Inc.
- 2025-12-16
CGMP/Finished Pharmaceuticals/Adulterated
Sklar Personal Care Inc.
- 2025-12-16
CGMP/Deviations/Biologics License Application (BLA)
Microvascular Tissue, Inc.
- 2025-12-16
Deviations/CFR/Regulations for Human Cells, Tissues & Cellular Products (HCT/Ps)
Green Valley Fertility Partners
- 2025-12-11
CGMP/Finished Pharmaceuticals/Adulterated
Catalent Indiana, LLC
- 2025-12-09
Unapproved New Drug/Unlicensed Biological Product/Biologics License Application (BLA)
BioXtek LLC
- 2025-12-09
CGMP/Finished Pharmaceuticals/Adulterated
DeVere Manufacturing Inc.
- 2025-12-09
CGMP/Finished Pharmaceuticals/Adulterated
CDL Services, Inc. DBA Technichem
See Also (8)
- Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications (Status: Final)
- Rheumatoid Arthritis: Developing Drug Products for Treatment (Status: Draft)
- Contract Manufacturing Arrangements for Drugs: Quality Agreements Guidance for Industry: Guidance for Industry (Status: Final)
- Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA: Draft Guidance for Industry (Status: Draft)
- ANDAs: Pre-Submission of Facility Information Related to Prioritized Generic Drug Applications (Pre-Submission Facility Correspondence) Guidance for Industry (Status: Draft)
- Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products--Quality Considerations (Status: Draft)
- Heparin-Containing Medical Devices and Combination Products: Recommendations for Labeling and Safety Testing: Guidance for Industry and Food and Drug Administration Staff (Status: Final)
- Compliance Policy for Combination Product Postmarketing Safety Reporting: Immediately in Effect Guidance for Industry and Food and Drug Administration Staff (Status: Final)