Oxytocin storage labeling and monograph issues
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Oxytocin: Storage, Labeling and Monograph Issues. Larry Callahan, Ph.D. USP, Rockville, Maryland. U. S. Pharmacopeia/USP DQI. USP was founded in 1820 by the medical community to standardize formulations Leading non-government pharmacopeia worldwide

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Oxytocin: Storage, Labeling and Monograph Issues

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Oxytocin: Storage, Labeling and Monograph Issues

Larry Callahan, Ph.D.

USP, Rockville, Maryland


U. S. Pharmacopeia/USP DQI

  • USP was founded in 1820 by the medical community to standardize formulations

  • Leading non-government pharmacopeia worldwide

  • USP Drug Quality and Information Program — current cooperative agreement with U.S. Agency for International Development (USAID) that provides technical assistance in more than 20 countries. Its set objectives:

    • To improve availability and appropriate use of good quality pharmaceutical products

    • To increase availability and use of unbiased health information


USP Monograph Revision Process

  • Monographs are voluntary

  • Monograph (revisions) submitted or suggested by sponsor

  • Sponsor can be anyone, but is usually a manufacturer

  • Monograph drafted by liaison

  • Publication in PF

  • Comments received from public (comment period usually about 5 months)

  • Monograph revised based on comment or forwarded to Expert Committee/Board of Trustees for approval

  • Monograph published in USP-NF

  • Monograph becomes Official


USP–NF Today


Effect of USP Monograph

  • USP standards are enforceable by the U.S. FDA and other governments

  • USP standards are enforceable throughout the lifetime of the product or dosage form

    “From production to consumption”

  • Not necessary to perform every USP test on every batch or vial but must pass all USP tests if tested

  • Monographs are tied to products, not manufacturers; every manufacturer must meet same monograph requirements

  • USP, BP, and JP have monographs on dosage forms; EP has no product monographs


Oxytocin Injection Monograph History

  • Oxytocin activity discovered by Dale 1909.

  • Oxytocin is first reported synthesized by Vincent du Vigneaud in 1953. (Won Noble Prize in 1955)

  • Monograph first appeared in USP XV (1955) Animal derived. 10 USP Units per mL. Packaging and Storage (P&S)–Type I glass (no temperature req.)

  • USP XVI (1960) Allows for synthetic product. P&S-Avoid excessive temperature; pH 2.5-3.6

  • USP XVII (1965) P&S-Refrigerator, Do not freeze; Expiration date 3 years from assay date. pH 2.5-4.5

  • USP XIX (1975) P&S–Do not freeze. No expiration date requirement.

  • USPXX (1980) 85-120% of label.


Oxytocin Injection Monograph History-2

  • USP 23 1st Supp. (1995) 90-110% of label. HPLC assay introduced. pH 3.0-5.0 (Oxytocin monograph becomes official. Greater than 400 USP units per mL. P&S–refrigerator).

  • USP 28 (2005) P&S–Store between 2° and 8°C. Do not freeze removed from monograph.

  • Reason for most recent monograph change — Instability reported at 21°C and 30°C from one manufacturer. At 30°C, 10-12% degradation over 12 months. At 21°C, 3-5% degradation over 24 months. At 5°C, product stable for 60 months. No information on pH or formulation.


Current Monographs in Pharmacopeias

  • USP 29 Potency 90-110% of label; P&S–2-8°C; pH 3.0-5.0

  • EP 5.4 (No Product Monographs) Storage Bulk Solution 2-8°C; pH 3.0-5.0

  • JP (2001) 85-120% of label. Bioassay (Chicken). P&S–In a cold place (<= 15C; avoid freezing.)

  • BP 90-110% of label. pH 3.5 to 4.5; no current temperature criteria (Had temperature control in 1995 of 2-15°C)


Current U.S. Manufacturer Storage Conditions, Typical Expiration Dates

  • American Pharmaceutical Partners Controlled Room Temperature (From MSDS). Expiration labeling 9 months (verbally reported).

  • Parkedale (King) 2-8°C Allows short excursions 30 days at 15-25°C. Expiration date 2-3 years from preparation (Martindale). Acetate buffered?

  • Novartis (New Zealand) 2-8°C Allows 30°C for 3 months.


Oxytocin Chemistry and Stability

  • Chemical Structure

  • MW 1007.2


Degradation Pathways

  • Time scale for degradation at ambient temperatures – weeks, not hours

  • Disulfides (reactions)

    • Reduction

    • Oxidation

    • Disulfide exchange (scrambling)

      Temperature and pH would have some effect but mostly effected by added substances or initial material (free thiols, oxidizers or reductants).

  • Amides (Asparagine (ASN), Glutamine (GLN), C-terminal (C-NH2), Peptide backbone)

    • Deamidation (GLN and ASN)

      • Half-life of ASN in proteins/peptides at 37.0, pH 7.4 (0.5 days-500 days)

      • Half-life of GLN proteins/peptides at 37.0. pH 7.4 (600 days-2000 days)

        From Robinson, N. E. and Robinson, A. B. (2004)

        Molecular Clocks: Deamidation of Asparaginyl and Glutaminyl Residues in Peptides and Proteins.

        http://book.deamidation.org/MolecularClocks.pdf


Degradation Pathways-2

  • Deamidation Pathways

    • Imide (ring) formation, can be very fast dependent on nearest neighbor, conformation predominantly, some temperature and pH effects.

    • Hydrolysis much slower, dependence on sequence, temperature and pH effects predominate. Peptide backbone also effected.

    • Hydrolysis can be both acid and base catalyzed.

    • Oxytocin can degrade by both imide formation and hydrolysis


pH and Hydrolysis of Peptides

Hydrolysis of small peptide from polymeric support at 25°C.

From Kahne and Still, J.Am.Chem.Soc. 110:7529-7534 (1988)


Possible Changes in Storage Conditions for Product Monograph

  • Potential Storage Temperatures

    • No required temperature conditions

    • Controlled room temperature (monitor temperature allow excursions)

    • Controlled cold temperature (monitor temperature allow excursions)

    • Allow dual storage conditions but expiration date must be based on a single storage condition


Storage Temperature Definitions

  • Cold — Any temperature not exceeding 8° (46°F). A refrigerator is a cold place in which the temperature is maintained thermostatically between 2° and 8° (36° and 46°F).

  • Cool — Any temperature between 8° and 15°C (46° and 59°F). An article for which storage in a cool place is directed may, alternatively, be stored and distributed in a refrigerator, unless otherwise specified by the individual monograph.

  • Room Temperature — The temperature prevailing in a working area.


Storage Temperature Definitions-2

  • Controlled Room Temperature — A temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30° (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses. Provided the mean kinetic temperature remains in the allowed range, transient spikes up to 40°C are permitted as long as they do not exceed 24 hours. Spikes above 40°C may be permitted if the manufacturer so instructs. Articles may be labeled for storage at “controlled room temperature” or at “up to 25°,” or at other wording based on the same mean kinetic temperature. The mean kinetic temperature is a calculated value that may be used as an isothermal storage temperature that simulates the non-isothermal effects of storage temperature variations.


Storage Temperature Definitions-3

  • Controlled Cold Temperature — This is defined as the temperature maintained thermostatically between 2° and 8°C (36° and 46° F) that allows for excursions in temperatures between 0° and 15°C (32° and 59°F) that may be experienced during storage, shipping, and distribution such that the allowable calculated MKT is not more than 8°C (46° F). Transient spikes up to 25°C (77°F) are permitted provided that such spikes do not exceed 24 hours, unless supported by data or the manufacturer instructs otherwise.


Consequences of Higher Storage Temperature

  • Reduced Shelf-Life Due to an Increase in Hydrolysis Rate

    • More degradants

  • Greater Chance of “Catastrophic” Failure?

    • Product no longer in solution or completely degraded, precipitation, aggregation, adsorption.

    • Catastrophic failure (precipitation) observed in dilute solution in lactated ringer solutions after 35 days at 30°C. Product seemed fine at 28 days. Cause not specified. Ringer contains calcium. Not seen in other solutions. See Trissel et al. Int. J. Pharm. Comp. 10:156-158 (2006).

    • Microbial growth more likely


How to Increase Shelf-Life

  • Find optimum pH; tighter control on pH. (USP Nasal Solution 3.7-4.3; no storage temp specified)

  • Lyophillization (freeze-dried) long shelf-life ~20 years (Current International RS)

    • More expensive, very little material ~ 20 mg

    • Reconstitution could be problematic

  • Change specification in the monograph. Allow 90-125% of label amount. This would allow “overloading” and a longer shelf-life.

    • The biological half-life of Oxytocin is five minutes. This should allow slightly higher dosing without adverse consequences.


Other Possible Changes in Oxytocin Monographs

  • Oxytocin

    • Eliminate animal test (rat uterus contraction).

    • Replace with LC-MS to allow identification and quantification of impurities and related compounds.

  • Oxytocin Injection

    • Add a related compounds test to monitor the extent of degradation.


Information Needed for Further Monograph Development

  • Rate of Failure (Bad Vials; Catastrophic failure)

  • Identity of the Degradants

    • Bioactivity of the degradants

    • Oxytocin Agonist or Antagonist

    • Substrate or inhibitor of Oxytocinase (a plasma protease produced during pregnancy that appears to target and inactivate oxytocin. In the absence of oxytocinase, the elimination half-life is 3-5 minutes significantly shorter in its presence.


Thank you for your attention

Larry Callahan, Ph.D.

Scientist, Standards Development

United States Pharmacopeia

12601 Twinbrook Parkway

Rockville, MD 20852

[email protected]


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