TECHNICAL ADVISOR'S REPORT TO THE FOOD, DRUG, AND COSMETIC PACKAGING MATERIALS COMMITTEE

November 30, 2001

Lester Borodinsky, Ph.D.

Ladies and Gentlemen:

It is a great pleasure for me to be with you once again in the role of the Committee's Technical Advisor. This report will describe one of the current technical issues we are dealing with in establishing satisfactory regulatory positions for plastic materials in contact with food, drugs, cosmetics, and medical devices. Specifically, this report will provide observations on technical elements of good manufacturing practices (GMP) for materials or articles used in contact with food, drugs, cosmetics, and medical devices, or used as components of medical devices

Good Manufacturing Practices

Under the Federal Food, Drug, and Cosmetic Act (the Act), food will be deemed adulterated if (1) it has been manufactured under conditions that render it unfit for food or (2) it has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth or rendered injurious to health. 21 U.S.C. § 342(a)(3), (a)(4). The statutory definition of "food" includes "articles used for food or drink" and "components of any such article." 21 U.S.C. § 321(f) (emphasis added).

Similarly, Section 301(a) of the Act prohibits the introduction into interstate commerce of any drug that is "adulterated." 21 U.S.C. § 331(a). The Act defines a drug as adulterated under the following circumstances inter alia, "(A) if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health; or (B) if it is a drug and 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 Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess." Federal Food, Drug, and Cosmetic Act § 501(a)(2); 21 U.S.C. § 351(a)(2).

Furthermore, Section 501 of the Act states that a medical device shall be deemed to be adulterated if "the methods used in, or the facilities or controls used for its manufacture, packing, storage, or installation are not in conformity with applicable [good manufacturing practice] requirements under Section 520(f)(1)." Federal Food, Drug, and Cosmetic Act § 501(a); 21 U.S.C. § 351(h).

The Act does not explicitly refer to "good manufacturing practices" for cosmetics.

Clearly, the Act requires that food, drugs, and medical devices be manufactured in accordance with good manufacturing practices. To ensure that food is not adulterated, FDA has issued good manufacturing practices regulations for food (21 C.F.R., Part 110), direct food additives (21 C.F.R. § 172.5), food-contact materials (referred to as "indirect food additives") (21 C.F.R. § 174.5), drugs (21 C.F.R. Parts 210 and 211), and medical devices (21 C.F.R. § 820.1). The question that arises is - how do these requirements for food, drugs, and medical devices bear on packaging materials used for the above? Before attempting to answer this question, it is useful to first briefly examine the regulatory GMP requirements that FDA has established for food, drugs, and medical devices.

Food GMPs

FDA has promulgated reasonably detailed GMP's for food processing plants under Part 110 ("Current good manufacturing practices in manufacturing, packing, or holding human food"). These regulations address general requirements for buildings and grounds (plants and grounds, sanitary operations, and sanitary facilities and controls), equipment (including utensils), and production and process controls (including warehousing and distribution).

Direct Food Additives

Rather than detailed requirements, FDA has promulgated Section 172.5 to provide general but limited guidance on good manufacturing practices for direct food additives. Namely, this regulation indicates that food additives must be used under conditions of good manufacturing practices, and must be of an appropriate food grade, and prepared and handled as a food ingredient.

Although the definition of "food" in Section 201 (f)(3) of the Act includes components of food, and therefore would seem to make components of food subject to the detailed requirements in Part 110, the Part 110 GMP's are intended to be applicable in every detail only to the production and packaging of actual foods. It is impractical for these food related GMP's to be applied to a manufacturer of food additives. Thus, while one should look to the regulations in Part 110 for guidance in developing good manufacturing practice standards, these requirements are not applicable in detail to the production of food additives. Section 172.5(a)(2) indicates that good manufacturing practices include the principle that "[A]ny substance intended for use in or on food is of appropriate food grade and is prepared and handled as a food ingredient." This provision makes explicit that the manufacturing process for a direct food ingredient must take that intended use into account and include reasonable precautions to assure the suitable purity of the chemical for direct addition to food. Overall, a manufacturer of such chemicals for food processing applications needs to exercise a reasonable degree of care to minimize the possibility of contamination of its products and maintain records that document the compliance of the materials with applicable FDA requirements.

Indirect Food Additives</p>

Even more limited guidance is provided by FDA in Section 174.5, which indicates that indirect additives must be of a "purity suitable for [their] intended use." As with direct food additives, the regulations in Part 110 may be used for guidance in determining appropriate good manufacturing practices for food-contact materials. However, it is important once again to recognize that the regulations in part 110 are intended to apply in every detail only to actual food products; they are not intended to cover specifically the production of food-contact materials. Practically speaking, good manufacturing practices for food-contact materials only require the use of common sense measures to assure that products are made under conditions that minimize the possibility of contamination which may result in the adulteration of food.

Drug GMPs

As indicated above in the definition of adulterated drugs in the Act, every drug intended for introduction into interstate commerce must be manufactured, processed, packed, and held in accordance with current good manufacturing practice or it will be considered adulterated. Section 501 of the Act does not distinguish between finished drugs and their components; thus, a failure to comply with GMPs for either the finished product or a component of the finished drug may constitute a failure to comply with the Act.

As with food additives, the term "GMP" when applied to the manufacture of drugs is a broad one. It generally refers to standards of manufacture equivalent to those employed by others similarly situated in the manufacture of similar substances, as well as the documentation that the product is made in accordance with those standards. Since drug product manufacture is a multi-step process occurring over a continuum with simple chemical manufacture at one end and finished drug product manufacture at the other, FDA recognizes that the need for definition of, and compliance with, GMPs is relative to the proximity of the manufacturing step to the finished drug product. Accordingly, in 21 C.F.R. Parts 210 and 211, FDA has defined and explicitly described those practices with which compliance is required during the final manufacturing step for finished pharmaceuticals.

Although FDA has not defined by regulation those good manufacturing practices applicable to the manufacture, processing, packing, and holding of components of drugs, the Agency has indicated in the preamble to the final rule promulgating the GMP regulations for finished pharmaceuticals that the regulations will be utilized "as guidelines during the inspection of manufacturers of bulk drug components under the jurisdiction of this Act." 43 Fed. Reg. 45013, 45045-46 (Sept. 29, 1978). In addition, FDA has issued a draft guidance document in 1998 that reflects the Agency's expectations regarding current good manufacturing practices for manufacturing, processing, packing or holding (i.e., storage) of active pharmaceutical ingredients; although this document focuses on active pharmaceutical ingredients, much of the guidance may be useful for the manufacture of excipients (i.e., inert ingredients which take and hold together the other ingredients).

Medical Device GMPs

As described above, Section 501 of the Act states that a device shall be deemed to be adulterated if the methods used in, or the facilities or controls used for its manufacture, packing, storage, or installation are not in conformity with applicable good manufacturing practice requirements.

Pursuant to Section 520(f)(1) of the Act, FDA promulgated Part 820 of the medical device regulations, which sets forth good manufacturing requirements for medical devices that are applicable to manufacturers, packers, storers, installers and servicers of all finished devices intended for human use. 21 C.F.R. § 820.1. Manufacturers of device components are specifically exempted, although they are encouraged to use good manufacturing practice (GMP) standards appropriate to the production of medical device components. 21 C.F.R. § 820.1.

Accordingly, a manufacturer of a medical device component or packaging material is under no obligation to manufacture the product in keeping with the full scope of the medical device GMP regulations; however, in keeping with FDA's recommendation, the manufacturer may wish to use these regulations as a source of guidance in developing procedures that are appropriate for the production of components of or packaging for medical devices.

Good Manufacturing Practice - Technical Elements

Necessarily, FDA has not provided a "recipe" for a good manufacturing program that would be applicable to all food, drug, or medical device plants, as the products vary enough that it would not be feasible to issue such a general document. Needless to say, such guidance also is not available for the packaging materials for food, drugs, or medical devices. Thus, one size does not fit all. However, where there is the need for establishing a good manufacturing practice program, the following elements should be considered (although all of them may not be relevant for a given product).

Organization and personnel

Personnel responsible for various quality control activities should be identified. Employees need to be aware that the products being manufactured will be used in a food, drug, or medical device application. Suitable training of employees should be established and documented, along with standards for the process. Personal attire should be appropriate to avoid contamination of product and employees should follow sound sanitation and personal hygiene practices.

Buildings and facilities

Grounds need to be kept clear of vegetation or standing water, commensurate with the nature of the product(s). Buildings and facilities should be designed to facilitate sanitary operations. Structures should not encourage nesting of rodents, birds, or other pests; where pest control is needed, a regular program should be established. Particular attention should be paid to prevent birds from nesting in facility areas, such as loading docks. Windows and doors should seal tightly. Regular and documented housekeeping is needed. Adequate controls of plumbing are needed, and temperature controlled (where needed). Hazardous material should be stored in a designated area.

Equipment

If the equipment used for manufacturing the product is not dedicated for FDA grade products, measures must be taken to ensure that non-FDA grade materials do not contaminate the FDA grade materials; such preventative measures should be documented. The extent of the clean-out will depend on the nature of the potential contaminants: more toxic contaminants require a greater degree of care to assure their removal, or, in the alternative, should be produced on a separate line entirely. Equipment should be properly maintained (e.g., cleaned, calibrated, and repaired) and such maintenance documented.

Raw materials

Adequate control over raw materials is needed. For example, shipping and storage vessels should be suitable for control of receiving, inspection and, testing (where needed) of raw materials. A plan for dealing with rejected raw materials is needed. If non-FDA products as well as FDA products are manufactured at the facility, adequate control to segregate the raw materials is needed. Proper rotation of stock may be needed. Adequate documentation relating to raw materials should be maintained.

Manufacturing procedures

Written procedures for producing each product are needed, including identification of specific raw materials used, operating parameters, cleaning procedures (where needed), and corrective measures for operating deviations. The process description may be reflected in a diagram or flow chart of the equipment and processes used. Changes in production procedures should be handled in a manner that ensures compliance with established product specifications; such changes should be properly documented.

Testing of finished products

Testing of products or intermediates should be performed in accordance with a written plan. The testing plan should include procedures for handling material that fails to meet appropriate specifications.

Packaging/loading procedures

Packaging (and repackaging) of products should be accomplished to protest purity and stability of product. Tank trucks or railcars should be properly inspected before loading. If dedicated tank trucks or railcars, or new (unused) shipping containers, are not used, they should be properly cleaned out before loading; documentation of same should be maintained.

FDA status of products

FDA status of products should be identified and documented. Changes in formulation should be properly documented. A plan to address customer FDA-related inquiries should be established. A designated "morgue" area for damaged or returned goods should be established.

Record keeping

Specific employees should be designated for various record keeping activities. Records on cleaning, maintenance, repairs, specific lots and specifications of raw materials, specific lots and specifications of products, process operating parameters, and FDA status should be maintained. A plan for product removal and correction procedures should be established; such corrective actions should be documented.

Internal auditing procedures

Written internal audit procedures should be established, including procedures to ensure that deficiencies identified are properly addressed in a timely fashion.

Hazard Analysis and Critical Control Point (HACCP) Plan

"Hazards" inherent to the items being manufactured should be identified and procedures should be in place to control such hazards. Critical hazard limits should be identified, and deviation and verification procedures established. Appropriate documentation of the process should be established.

Conclusion

The foregoing is a discussion of the need for good manufacturing practices and an overview of the elements that should be included in a good manufacturing practice program. The above overview is necessarily general because specific details needed to establish good manufacturing practices for a given product will vary not only from material to material but also because of the specific FDA application(s) in which the material will be used. Nonetheless, the foregoing demonstrates that forethought and planning are needed to establish a GMP program.

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