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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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CPG Sec. 635.100 Large Volume Parenterals (LVP's) for Animal Use

 

BACKGROUND:
 

Large volume parenterals or LVPs (sometimes called large volume injections) are aqueous solutions usually supplied in volumes of at least 100 ml with sizes of 250 ml, 500 ml, and 1000 ml most common. Directions usually recommend that large quantities be administered. The usual route of administration is intravenous (IV) but other routes, such as intraperitoneal (IP) or subcutaneous (SQ or SC), are sometimes recommended. Examples of LVPs include:
 

  • Calcium solutions
  • Sodium chloride, Ringer's, sodium bicarbonate and other electrolyte solutions
  • Dextrose (glucose) and other sugar solutions
  • Amino acid, peptide and other protein-fraction solutions
  • Solutions containing a combination of the above, sometimes with vitamins added
  • Dextrans, and other plasma expanders
     

All parenterals for animal use including LVPs must be sterile.*

Preservatives (antimicrobial agents) are not permitted in LVPs in the absence of an approved NADA that specifically establishes the safety of the preservative, in a particular product. If a preservative were to be added to an LVP in a concentration adequate to prevent the multiplication of microorganisms, an animal could receive a toxic dose of the preservative because of the large amount of solution administered. Based on limited animal toxicity and epidemiological data it appears that at least one preservative commonly used in small volume parenterals, benzyl alcohol, can be toxic, even fatal, to animals when used in LVPs.
 

Antimicrobial agents are permitted in multiple dose containers where the preservatives are added to protect the products from inadvertent microbial contamination during multiple entry and subsequent storage. Only a small amount of such a product is injected into any particular animal.
 

LVPs should be supplied in container sizes appropriate for their intended use or uses so that the majority of the contents would ordinarily be used promptly following initial entry. Too large a container size relative to intended use would encourage retention of unused contents which could result in microbial contamination of a product containing no preservatives. Labeling of LVPs should clearly indicate the lack of preservatives and should promote use of contents promptly following initial entry and disposal of unused contents. The concentration of individual ingredients should be clearly expressed. If the product is not a compendial item or the physiologic parameters are not otherwise clearly defined, the label should bear an indication of the pH and osmolarity (tonicity) of the solution.
 

Labeling should in all other respects bear adequate directions for use and not be false or misleading in any particular.
 

POLICY:
 

Large volume parenterals must be:
 

1. Sterile.
2. Free of preservatives.
3. Supplied in sizes appropriate to label claims facilitating use of the contents promptly following initial entry.
4. Labeled to indicate that: a) they contain no preservatives, b) they are intended for use promptly following initial entry, and (c) any portions not used promptly should be discarded.
5. Labeled to clearly indicate concentration of individual ingredients and physiological parameters of the solution.
 

LVPs that contain preservatives are considered new animal drugs and, in the absence of an approved NADA, are deemed unsafe under section 512 of the Federal Food, Drug, and Cosmetic Act and adulterated under section 501(a)(5) of the Act. LVPs may also be considered new animal drugs for reasons other than the presence of preservatives (e.g., due to other constituents of the formulation or the claims made for the product). LVPs which are not sterile (or which are produced under unvalidated procedures) would violate 501(a)(2)(B), 501(b), or 501(c). Failure to bear adequate labeling would result in violations of 502(a), 502(f)(1) or (2), among others.
 

The *Center* will review labeling and batch records to determine compliance with this policy. Initial action will ordinarily be a *Warning letter* or, if warranted by the circumstances, seizure.
 

*Material between asterisks is new or revised*

Issued: 12/1/82
Revised: 3/95