How to “Vet” An Extemporaneously Prepared Ophthalmic Therapy Gigi Davidson, BSPharm DICVP NC State University College of Veterinary Medicine Director of Clinical Pharmacy Services
How to “Vet” An Extemporaneously Prepared
Ophthalmic TherapyGigi Davidson, BSPharm DICVP
NC State University College of Veterinary MedicineDirector of Clinical Pharmacy Services
Introduction
Evaluation of ophthalmic compounds must be objective
Veterinary ophthalmologists must have a quality rubric by which to evaluate both:• Ophthalmic compound quality• Compounder credentials
Aims
Equip veterinary ophthalmologists with rubric to evaluate quality and safety of ophthalmic compounds for:• Patient use• Development of research project materials for ophthalmic drug delivery• Critical evaluation of compounded preparations cited in peer‐reviewed journals
Arming veterinary ophthalmologists with compound quality knowledge will encourage compounder accountability
Questions to Ask:Where is the target of therapy? (eyelids, corneal surface, cornea, anterior segment, lens, posterior segment)• Surface targets (more forgiving) vs. intraocular targets (less forgiving)
What is the character of the drug?
• Lipophilic? Hydrophilic?• What is the molecular weight?• What is the inherent toxicity of the drug to the eye? To the caregiver? To the patient?• Is there data to support what concentration is necessary for corneal penetration?• Has a threshold for ocular tissue (e.g. cornea, retina) toxicity been established?
More Questions:Is the drug soluble in a vehicle that is not toxic to the eye?
• If not soluble, will the particle size of the suspension or the ointment be small enough to facilitate ocular penetration and not large enough to scratch the corneal or conjunctiva?
What is the pH of the final product? Is this in an acceptable range to avoid irritation?
What is the tonicity of the final product?
• Hypertonic? • Hypotonic? • How long will the product be in contact with the cornea if not isotonic?
Will the viscosity need to be enhanced in order to prolong contact with the eye? Which agent is compatible?
What is the duration of therapy? Will the product require preservation if long term multiple use? Which preservative is compatible?
Checklist For Success
Verify absence of appropriate commercially available products• Shortage status changes daily• Reporting systems vary greatly across Europe
Checklist For Success
Identify evidence to support efficacy, safety, and quality • Use:• Does the pharmacy have evidence to support use of compound that they are promoting?
• Safety:• Does the pharmacist have evidence of previous safe use in other patients?
• Quality:• Does the pharmacist have evidence of appropriate pH, tonicity, sterility, particle size, stability for each batch prepared?
• Where did the pharmacist obtain the formula?• Compendial standard? (EP. BP, JP, ChP, USP)
• How did the pharmacist determine the discard time?• Is the discard time based in both stability and sterility?
Checklist For SuccessCheck the formula and all calculations
• Many mathematical errors have been printed in:• Textbooks• Peer‐reviewed journals• Formularies
Request a copy of the compounding record for the preparation
• Check all ingredients and calculations• “Hawthorne Effect”
The subtle but significant difference between % and mg/mL• 4% vs. 4 mg/ml• Decimal point “trick”• Percentage to mg/ml: move one decimal point to the right• 4% = 40 mg/mL
• Mg/mL to percentage: move one decimal point to the left• 10 mg/mL = 1%
Checklist For SuccessVerify sterility
• US tragedies from non‐sterile compounds• NECC: Fungal meningitis 68 deaths/700 injuries from fungal contamination• Endophthalmitis, blindness, eye loss:• Compounded bevacizumab (Avastin), trypan blue, cyclosporine, ceftazidime
Request sterility testing results
Ask pharmacist for method of sterilization:• Filtration:• Appropriate for solutions and will remove particulate• Inappropriate for suspensions and will remove active drug
• Autoclaving:• Active drug and excipients are heat stable?• Inappropriate for non‐aqueous liquids/solids• Must be able to generate steam in direct contact with drug in closed system
• γ‐irradiation:• Appropriate for solids and non‐aqueous liquids
Checklist For Success
Evaluate clarity for solutions• Particulate in solutions dependent upon:• Solubility• Sterilization method• Only filtration will remove particulate
Evaluate particle size for suspensions • <10 micrometers• Finger test• Reticule microscopy
Checklist For Success
Evaluate tonicity for intended use • Goal is isotonic• Acceptable range: 200‐600 mOsm/kg• Short excursions: 171‐1700 mOsm/kg• Hypotears: 230 mOsm/kg• 5% Sodium chloride ointment: 1700 mOsm/kg
• Methodology?• Osmometer• Sodium chloride equivalents
Checklist For Success
Evaluate final pH • Methodology?• pH paper • Solutions vs. suspensions
Evaluate buffer capacity• Hanks BSS:Drug 3:1• pH should be 6.5‐8 at 35C• If out of this range, compound will cause irritation, tearing, and flush drug out of eye
Checklist For Success
Evaluate viscosity enhancers for intended use • Ideally below 20 cP
Agent Maximum Concentration (%)Hydroxyethylcellulose 0.8Hydroxypropylmethylcellulose 1.0Methylcellulose 2.0Polyvinyl alcohol 1.5Polyvinylpyrrolidone 1.7
Agents used to increase viscosity of ophthalmic solutions and suspensions.
Summary
Approved ophthalmic drug products provide assurance of safety, efficacy, and quality.
Compounded ophthalmic preparations are not required to prove safety and efficacy.
Quality requirements for compounded preparations vary greatly from country to country.
Relative lack of oversight for compounding pharmacists requires due diligence on the part of the veterinary ophthalmologist to ensure patient safety.