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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

Oxytocin: Storage, Labeling and Monograph Issues

Larry Callahan, Ph.D.

USP, Rockville, Maryland

U s pharmacopeia usp dqi
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
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
USP–NF Today

Effect of usp monograph
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 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
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
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
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
Oxytocin Chemistry and Stability Expiration Dates

  • Chemical Structure

  • MW 1007.2

Degradation pathways
Degradation Pathways Expiration Dates

  • 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.


Degradation pathways 2
Degradation Pathways-2 Expiration Dates

  • 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
pH and Hydrolysis of Peptides Expiration Dates

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
Possible Changes in Storage Conditions for Product Monograph Expiration Dates

  • 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
Storage Temperature Definitions Expiration Dates

  • 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
Storage Temperature Definitions-2 Expiration Dates

  • 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
Storage Temperature Definitions-3 Expiration Dates

  • 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
Consequences of Higher Storage Temperature Expiration Dates

  • 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
How to Increase Shelf-Life Expiration Dates

  • 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
Other Possible Changes in Oxytocin Monographs Expiration Dates

  • 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
Information Needed for Further Monograph Development Expiration Dates

  • 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 Expiration Dates

Larry Callahan, Ph.D.

Scientist, Standards Development

United States Pharmacopeia

12601 Twinbrook Parkway

Rockville, MD 20852

[email protected]