Proposed GMP infant formula specifications "ill-advised" -- Infant Formula Council.

INFANT FORMULA GMP SPECIFICATIONS "ILL-ADVISED," IFC MAINTAINS in Dec. 5 comments to FDA on its proposed infant formula current Good Manufacturing Practices. Published in the July 9 Federal Register, the proposed rule would augment the existing infant formula regulations by establishing requirements for quality factors and current GMPs; amending quality control, notification and reporting requirements; and requiring nutrient testing ("The Tan Sheet" July 15, p. 22).

The Infant Formula Council is composed of Nestle's Carnation Nutritional Products, Abbott Labs' Ross Products Division and Wyeth-Ayerst International.

Setting specifications as defined in the proposed cGMPs is "ill-advised," IFC says, because they represent "extreme outer acceptability limits," and "a manufacturer who controlled its process only with extreme outer limits could be expected to produce formulas of disturbingly variable quality."

"Setting extreme outer acceptability limits would result in the widest possible specification bands," IFC asserts. "These bands would have very little meaning for day-to-day operations, because a manufacturer should be encouraged to control its manufacturing process tightly," the group declares.

Another reason to change the proposed specifications provisions, IFC says, is that "infant formula manufacturers control processes and set specifications well inside outer acceptability limits for most situations," and have therefore "not identified every extreme outer limit for every process and product parameter." Implementation of the "extreme outer acceptability limit approach...would require an overwhelming amount of technical and administrative resources and would require years of effort to complete," the industry group says. "Even if these limits were finally obtained, their application would be questionable in complex, multi-factorial situations," IFC adds.

Moreover, "setting tighter specifications than these extreme outer acceptability limits is scientifically justified," IFC maintains. "The approach of having target values ranges within tight specifications, both of which are well within any extreme outer acceptability limits, keeps the product and the process well centered, tightly controlled and consistent."

The group recommends that the final reg "preserve the IFC members' current practice of tight control ranges, coupled with a review and documentation requirement for deviations." If FDA does go ahead and adopt the "extreme outer acceptability limits," IFC urges, the agency should allow manufacturers to retain the current tighter control range approach and decide whether the broader limits are necessary.

IFC describes FDA's GMP proposal as a "good initial effort at establishing a GMP regulation for infant formula that is flexible enough both to accommodate each manufacturer's current manufacturing methods and to allow for incorporation of the inevitable improvements in technology that the future holds." However, the group raises "a number of very significant concerns with the proposal."

IFC comments that FDA's impact analysis says infant formula manufacturers already comply with "many" of the proposed rule's requirements, an assessment that is relevant to the financial impact of the final reg, as well as the length of time it will take manufacturers to comply. "Contrary to FDA's assessment, the IFC's analysis of the proposal has identified a number of significant proposed provisions with which manufacturers are not currently complying," the comments state. The provisions include requirements for cold storage, physical storage, validation and lowering Bacillus cereus limits.

If FDA accepts IFC's suggestions, the group is "reasonably" confident that an effective date of 180 days after publication is achievable. If one or more of IFC's recommendations are ignored, however, the group predicts that the time needed for compliance will "far" exceed 180 days. IFC also expresses concern with the "relatively short" comment period for this "complex regulation."

Another problem area in the GMPs pinpointed by IFC is the proposed requirements for systems validation, which the group asserts exhibits an "ever-reliance on a `drug' GMP model."

"The agency has proposed an all-encompassing definition of `validation' that would require validation of all automated systems associated with formula product," IFC explains. "If finalized, it would force existing infant formula manufacturers to minimize process improvements and quality and product innovations, as well as close the doors to many potential new manufacturers."

"This degree of validation is well beyond the scope that has been applied even in the drug industry," IFC declares, maintaining that it would cost "many millions of dollars" and take "years" to achieve compliance. "Neither the industry nor consumers are ready for such an exhaustive and unwarranted burden, which would entail significant additional costs to infant formula manufacturing."

The validation section is "so vague," and the potential impact "so enormous" that implementation would be "counterproductive" without "significant" dialogue with the agency, IFC asserts. If FDA retains the validation provisions, IFC urges the agency to form a working task force with industry to define the scope and content of systems validation for infant formula.

The GMP proposal also is not in line with the Clinton Administration's "Reinventing Government" initiative, IFC maintains, in that many of its provisions are "inflexible and overly prescriptive."

FDA's proposal, "without scientific justification...mandates the use of only one method to prevent infant formula adulteration; alternative, equally effective, methods are not described, compared or permitted." ReGo "requires the least burdensome means of preventing adulteration, which would include allowing alternative methods," IFC states.

Several provisions in the GMP proposal "exceed the premarket notification structure intended by Congress when it enacted the 1986 Infant Formula Act Amendments," IFC declares. "The notification requirement was intended by Congress as a means of assuring customers a reasonable standard of safety while not unreasonably burdening the industry through a potentially cumbersome system of premarket clearance."

The group also states that the proposed record-keeping/documentation requirements are "very burdensome," and should be limited to "necessary" documents rather than the broader language of the proposal.

Bristol-Myers Squibb's Mead Johnson Nutritional Group, in Dec. 3 comments on the GMPs, argues against the proposed establishment of quality factors for fat, calcium, phosphorus balance and iron status because of difficulties in recruitment for testing and in the test procedures themselves. Parents do not readily volunteer their infants for such testing because it involves hospitalization, restraining of infants and additional blood draws at a time when infants are already being given immunizations, BMS notes.