Extemporaneous Preparation with Unknown Stability

Introduction

Recently, you are assigned the task of updating extemporaneous preparation formulae at your hospital.

  • Much to your surprise, quite a number of extemporaneous preparations are dated back to The Pharmaceutical Codex 1973.
  • Although you managed to identify the extemporaneous preparation formulae, but no stability data is provided.

Today, stability information can be obtained from manufacturer’s labelling information (such as in the package insert), the USP compounding monographs, or peer-reviewed articles and references, such as articles in American Journal of Health-System Pharmacy, the International Journal of Pharmaceutical Compounding.

However, what should you recommend if stability data is unavailable?



USP General Chapter <795> and <797>

USP Compounding Compendium

USP General Chapter <795> and <797> both describe compounded preparations that are required to be sterile or can be prepared as nonsterile.

  • In general, preparations designed to be delivered to any body space that does not normally freely “communicate” or have contact with the environment outside of the body, such as the bladder cavity or peritoneal cavity, are typically required to be sterile. Additionally, ophthalmic products and compounded aqueous inhalation solutions and suspensions are required to be sterile.
  • Otic preparations are not required to be sterile unless being administered to a patient with a perforated eardrum.
  • Irrigations for the mouth, rectal cavity, and sinus cavity are not required to be sterile, nor are nasal sprays.

The revision of <795> and <797> published on November 2022 will become official on 1 November 2023.

  • Replacing the previous revision of <795> in 2014 and <797> in 2008.
  • More information can be found here.

USP Compounding Standards and Beyond-Use Dates
Comparison of BUD Limits
Comparison of BUD Limits



British Pharmacopoeia

British Pharmacopoeia

For official preparations for solutions and suspensions, the British Pharmacopoeia employs two definitions.

  • “Freshly Prepared” refers to a preparation that has been compounded less than 24 hours prior to issue for use.
  • “Recently Prepared” should be applied to compounded items that are likely to deteriorate if stored for a period greater than four weeks when maintained at 15-25°C.



Pharmaceutical Compounding and Dispensing, 2010

Pharmaceutical Compounding and Dispensing

According to Pharmaceutical Compounding and Dispensing 2010, in the absence of any guide, it is suggested that

  • Creams are given a four-week discard date. This is significantly shorter than the suggested discard date for extemporaneously prepared ointments (which is three months) because of the susceptibility of creams to microbial contamination. Diluted creams would normally be given a two-week discard date.
  • Ointments and pastes are given a three-month discard date. This is significantly longer than the suggested discard date for extemporaneously prepared creams (which is four weeks) owing to the fact that ointments are less susceptible to microbial contamination. Diluted ointments would normally be given a two-week discard date.
  • Gels, which have a higher water content, will attract a shorter discard date. In the absence of any official guidance, it is suggested that gels are given a four-week expiry date.



The International Pharmacopoeia, 2022

Acceptance Criteria for Microbiological Quality of Non-sterile Dosage Forms

According to The International Pharmacopoeia, 2022, the acceptance criteria for non-sterile pharmaceutical products are based upon the total aerobic microbial count (TAMC) and the total combined yeasts/moulds count (TYMC) as table above. When an acceptance criterion for microbiological quality is prescribed, it is interpreted as follows:

  • 101 CFU: maximum acceptable count = 20,
  • 102 CFU: maximum acceptable count = 200, and so forth
  • 103 CFU: maximum acceptable count = 2000, and so forth

In addition to the microorganisms listed in the table, the significance of other microorganisms recovered should be evaluated in terms of:

  • the use of the product: hazard varies according to the route of administration (eye, nose, respiratory tract);
  • the nature of the product: its ability to support growth, the presence of adequate antimicrobial preservation;
  • the method of application;
  • the intended recipient - risk may differ for neonates, infants, the debilitated;
  • use of immunosuppressive agents, corticosteroids;
  • presence of disease, wounds, organ damage.



Australian Pharmaceutical Formulary and Handbook (APF)

According to Australian Pharmaceutical Formulary and Handbook (APF) 25th edition, the following guidance applies to expiry dates for non-sterile compounded medicines:

  • The expiry date is 28 days or less from the date the medicine is compounded, unless otherwise specified in the APF or in a reliable stability study. An expiry date of less than 28 days may be more appropriate in some clinical circumstances.
  • The expiry date of compounded capsules or powders is 6 months or less from the date the medicine is compounded, provided the ingredients are stable in air and not hygroscopic or deliquescent.
  • If the expiry date from a reliable stability study that uses the same formulation, packaging and storage conditions as the compounded medicine differs from the expiry date guidance in the APF (longer or shorter), the expiry date from the stability study should be used.
  • The expiry date of a compounded medicine must never be longer than 6 months.
  • The expiry date of a compounded medicine must not be later than the expiry date of any ingredient.

Nonetheless, the expiry dates guidance in APF 26th edition is aligned with the United States Pharmacopoeia.



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