Can containers, closures, and packaging materials be sampled for receipt examination in the warehouse?

TELUGU GMP
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Can containers, closures, and packaging materials be sampled for receipt examination in the warehouse? Yes.  Generally, we believe that sampling in a typical drug manufacturing facility warehouse would not represent a risk to the container or closure or affect the integrity of the sample results. But whether the act of collecting a sample in the warehouse violates the CGMP requirement that containers "be opened, sampled, and sealed in a manner designed to prevent contamination of their contents..." will depend on the purported quality characteristics of the material under sample and the warehouse environment.

Can containers, closures, and packaging materials be sampled for receipt examination in the warehouse?

Yes.  Generally, we believe that sampling in a typical drug manufacturing facility warehouse would not represent a risk to the container or closure or affect the integrity of the sample results. But whether the act of collecting a sample in the warehouse violates the CGMP requirement that containers "be opened, sampled, and sealed in a manner designed to prevent contamination of their contents..." will depend on the purported quality characteristics of the material under sample and the warehouse environment. For containers or closures purporting to be sterile or depyrogenated, sampling should be under conditions equivalent to the purported quality of the material: a warehouse environment would not suffice (see 21 CFR 211.94 and 211.113(b)).  This is to preserve the fitness for use of the remaining containers or closures as well as to ensure sample integrity, if they are to be examined for microbial contamination.  At a minimum, any sampling should be performed in a manner to limit exposure to the environment during and after the time samples are removed (i.e., wiping outside surfaces, limiting time that the original package is open, and properly resealing the original package). Well-written and followed procedures are the critical elements.

Note that the CGMPs at 21 CFR 211.84 permit a manufacturer to release for use a shipment of containers or closures based on the supplier's certificate of analysis and a visual identification of the containers or closures.  Once a supplier's reliability has been established by validation of their test results, a manufacturer could perform the visual examination entirely in the warehouse.

References: 21 CFR 211 cGMP guidelines

  • 21 CFR 211.84: Testing and approval or rejection of components, drug product containers, and closures
  • 21 CFR 211.94: Drug product containers and closures
  • 21 CFR 211.113(b): Control of microbiological contamination
  • 21 CFR 211.122: Materials examination and usage criteria


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. 

(b) Representative samples of each shipment of each lot shall be collected for testing or examination. The number of containers to be sampled, and the amount of material to be taken from each container, shall be based upon appropriate criteria such as statistical criteria for component variability, confidence levels, and degree of precision desired, the past quality history of the supplier, and the quantity needed for analysis and reserve where required by 211.170. 

(c) Samples shall be collected in accordance with the following procedures: 

(1) The containers of components selected shall be cleaned when necessary in a manner to prevent introduction of contaminants into the component. 

(2) The containers shall be opened, sampled, and resealed in a manner designed to prevent contamination of their contents and contamination of other components, drug product containers, or closures. 

(3) Sterile equipment and aseptic sampling techniques shall be used when necessary. 

(4) If it is necessary to sample a component from the top, middle, and bottom of its container, such sample subdivisions shall not be composited for testing. 

(5) Sample containers shall be identified so that the following information can be determined: name of the material sampled, the lot number, the container from which the sample was taken, the date on which the sample was taken, and the name of the person who collected the sample. 

(6) Containers from which samples have been taken shall be marked to show that samples have been removed from them. 

(d) Samples shall be examined and tested as follows: 

(1) At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used. 

(2) Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals. 

(3) Containers and closures shall be tested for conformity with all appropriate written specifications. In lieu of such testing by the manufacturer, a certificate of testing may be accepted from the supplier, provided that at least a visual identification is conducted on such containers/closures by the manufacturer and provided that the manufacturer establishes the reliability of the supplier's test results through appropriate validation of the supplier's test results at appropriate intervals. 

(4) When appropriate, components shall be microscopically examined. 

(5) Each lot of a component, drug product container, or closure that is liable to contamination with filth, insect infestation, or other extraneous adulterant shall be examined against established specifications for such contamination. 

(6) Each lot of a component, drug product container, or closure with potential for microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use. 

(e) Any lot of components, drug product containers, or closures that meets the appropriate written specifications of identity, strength, quality, and purity and related tests under paragraph (d) of this section may be approved and released for use. Any lot of such material that does not meet such specifications shall be rejected.

211.94 Drug product containers and closures.

(a) Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements. 

(b) Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product. 

(c) Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use. Such depyrogenation processes shall be validated. 

(d) Standards or specifications, methods of testing, and, where indicated, methods of cleaning, sterilizing, and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures. 

(e) Medical gas containers and closures must meet the following requirements  - 

(1) Gas-specific use outlet connections.  Portable cryogenic medical gas containers that are not manufactured with permanent gas use outlet connections (e.g., those that have been silver-brazed) must have gas-specific use outlet connections that are attached to the valve body so that they cannot be readily removed or replaced (without making the valve inoperable and preventing the containers' use) except by the manufacturer. For the purposes of this paragraph, the term “manufacturer” includes any individual or firm that fills high-pressure medical gas cylinders or cryogenic medical gas containers. For the purposes of this section, a “portable cryogenic medical gas container” is one that is capable of being transported and is intended to be attached to a medical gas supply system within a hospital, health care entity, nursing home, other facility, or home health care setting, or is a base unit used to fill small cryogenic gas containers for use by individual patients. The term does not include cryogenic containers that are not designed to be connected to a medical gas supply system, e.g., tank trucks, trailers, rail cars, or small cryogenic gas containers for use by individual patients (including portable liquid oxygen units as defined at § 868.5655 of this chapter). 

(2) Label and coloring requirements.  The labeling specified at § 201.328(a) of this chapter must be affixed to the container in a manner that does not interfere with other labeling and such that it is not susceptible to becoming worn or inadvertently detached during normal use. Each such label as well as materials used for coloring medical gas containers must be reasonably resistant to fading, durable when exposed to atmospheric conditions, and not readily soluble in water.

211.113 Control of microbiological contamination.

(a) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed. 

(b) Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of all aseptic and sterilization processes.

211.122 Materials examination and usage criteria.

(a) There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials; such written procedures shall be followed. Labeling and packaging materials shall be representatively sampled, and examined or tested upon receipt and before use in packaging or labeling of a drug product. 

(b) Any labeling or packaging materials meeting appropriate written specifications may be approved and released for use. Any labeling or packaging materials that do not meet such specifications shall be rejected to prevent their use in operations for which they are unsuitable. 

(c) Records shall be maintained for each shipment received of each different labeling and packaging material indicating receipt, examination or testing, and whether accepted or rejected. 

(d) Labels and other labeling materials for each different drug product, strength, dosage form, or quantity of contents shall be stored separately with suitable identification. Access to the storage area shall be limited to authorized personnel. 

(e) Obsolete and outdated labels, labeling, and other packaging materials shall be destroyed. 

(f) Use of gang-printed labeling for different drug products, or different strengths or net contents of the same drug product, is prohibited unless the labeling from gang-printed sheets is adequately differentiated by size, shape, or color. 

(g) If cut labeling is used for immediate container labels, individual unit cartons, or multiunit cartons containing immediate containers that are not packaged in individual unit cartons, packaging and labeling operations shall include one of the following special control procedures: 

(1) Dedication of labeling and packaging lines to each different strength of each different drug product; 

(2) Use of appropriate electronic or electromechanical equipment to conduct a 100-percent examination for correct labeling during or after completion of finishing operations; or 

(3) Use of visual inspection to conduct a 100-percent examination for correct labeling during or after completion of finishing operations for hand-applied labeling. Such examination shall be performed by one person and independently verified by a second person. 

(4) Use of any automated technique, including differentiation by labeling size and shape, that physically prevents incorrect labeling from being processed by labeling and packaging equipment. 

(h) Printing devices on, or associated with, manufacturing lines used to imprint labeling upon the drug product unit label or case shall be monitored to assure that all imprinting conforms to the print specified in the batch production record.

*Source: FDA website

Can containers, closures, and packaging materials be sampled for receipt examination in the warehouse?

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