Lec 1- Compounded Pharmaceuticals: Key Steps

Key Points for Compounded Pharmaceuticals

• Compounded pharmaceuticals require a series of essential steps: Rx receipt and evaluation, dosage form design, infrastructure review, preparation, dispensing and counseling, and cleaning.

Need for Compounding

• Pharmaceutical compounding prepares tailored medications by combining, mixing, or altering ingredients to meet specific patient needs when commercially available options are insufficient.
• Reasons for compounding include allergies to inactive ingredients, dosage form limitations, unavailability of medications, the need for specific strengths or combinations, and palatability issues.

Indications for Pharmaceutical Compounding

• Compounding facilitates excluding non-essential allergenic ingredients like dyes, preservatives, or specific fillers.
• Alternate dosage forms can be created through compounding, such as turning pills into liquid suspensions, topical creams, or suppositories for easier patient use.
• Compounding enables adjusting medication strength for specific patient needs, especially in pediatric or geriatric care where standard dosages may be inappropriate.
• Medication that has been discontinued by manufacturers or is temporarily unavailable due to shortages can be obtained through compounding.
• Specific formulations, flavors, or dosage forms for animals, not commercially available, can be made via veterinary compounding.

Rx Receipt and Evaluation

• Prescription drug and intended dosage form evaluation is important.

Patient Evaluation

• Patient identity, indications, dosage, and allergies are verified to match the patient name.

Drug Evaluation

• Drug name confusion should be avoided with awareness of high-risk or alert drugs.
• Commercial availability should be examined to avoid unnecessary compounding, and drug/equipment compatibility, including packaging, Y-sites, and administration devices, should be verified.

Design Dosage Form

• Each dosage form design addresses pharmacology, pharmaceutics, and stability, with references checked and inactive ingredient functionality studied, leading to the drug's formula compounding.
• The Beyond-Use Date (BUD) is determined and therapy duration and expiration dates are checked.

Non-Sterile References

• Pharmacies use references such as Remington: The Science and Practice of Pharmacy (21st Ed., 2005), The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals (14th ed., 2006), and Trissel's Stability of Compounded Formulations (3rd ed.).
• Physical descriptions, solubility, molecular weight, pH, and stability considerations are examined.

Sterile References

• Dailymed.nlm.nih.gov and Micromedexsolutions.com are used for sterile compounding references.

Beyond-Use Date (BUD)

• BUDs contain DATE AND TIME, with the time starting when compounding BEGINS, not after the product is finished.
• The duration of therapy and expiration dates of all ingredients are checked.
• Quality control measures are enforced to minimize variations in products and check calculations, texture, color, precipitates, and leaking IV bags.

Sterile BUDs (USP <797>, Under Revision)

• Category 1 products have varying storage conditions for controlled room temperature (20°-25°C) and refrigeration.
• Category 1 products at room temperature have a BUD of ≤ 12 hours, and in the fridge, the BUD is ≤ 24 hours, following manufacturer's guidelines if the BUD is shorter.

Sterile BUDs (USP <797>, Under Revision) continued

• Category 2 product storage conditions depend on sterilization type.
• Aseptically prepared CSPs have time limits that depend on whether they are prepared from one or more non-sterile starting components.

Sterile BUDs (USP <797>, Current Version)

• BUDs for sterile preparations depend on the risk level.
• Immediate use products should be used within one hour.

Non-Sterile BUDs (USP <795>, Under Revision)

• Non-Sterile BUDs Under Revision depend on the type of dosage form.
• Solids have a BUD up to 180 days.
• Preserved aqueous formulations have a BUD up to 30 days and are stored at controlled room temperature (20-25°C).
• Non-preserved aqueous suspension, emulsions, gels, creams, solutions, and sprays have a BUD up to 14 days under refrigeration (2-8°C), and non-aqueous items last 90 days.

Non-Sterile BUDs (USP <795>, Current Version)

• Nonaqueous formulations: 180 days
• Water-containing oral formulations: 14 days
• Water-containing topical/dermal/mucosal liquids; and semisolid formulations: 30 days

Infrastructure Review

• Reviewing site equipment, facilities, utilities, and procedures is important.
• Hood certification, blower function, correct air quality, compounding area cleanliness, acceptable balance sensitivity, and minimum weighable quantity must be ensured.
• Dedicated machines, weigh boats, filters, and glassware are crucial.

Materials Review

• Drugs, inactive excipients, and packaging materials are examined to ensure ingredients lack microbial or other contamination or signs of instability and are within BUD.
• Ensure packaging materials are available and clean.
• Certificates of Analysis should be available for each component to verify its identity, purity, and quality.

Personnel Review

• Technician qualifications are reviewed, and trust is placed in their trustworthiness.
• There should be specialized personnel training with periodic retraining.
• Wear gowns, head coverings, and gloves, with each professional dedicated to the task.
• Compounding personnel should be adequately trained and competent in techniques, calculations, and quality control procedures, with ongoing continuing education.

Rx Preparation, Rx Label, Review, and Documentation

• The compounding procedure, labeling, and documentation must be executed.
• Labeling must comply with USP standards.
• Accurate records of the compounding process should be maintained, including ingredient lot numbers, equipment used, and quality control results.
• Comprehensive records of all compounding activities must be maintained, including prescriptions, compounding formulas, quality control results, and training records.
• Traceability should enable the tracking of ingredients, processes, and personnel involved in the preparation of each compounded medication.

Labeling (USP <795>)

• Assign an internal ID number, name, and amount/concentration of the active pharmaceutical ingredient.
• Labeling should clearly state dosage form, total volume, storage conditions, indication for use, route of administration, and any special handling instructions or warning statements, and includes the compounding facility's name, address, and contact info.

Labeling (USP <797>)

• Assign an internal ID number, name, and amount/concentration of the active pharmaceutical ingredient.
• Labeling should include storage conditions (if other than controlled room temperature), date prepared, BUD, use, and administration, as well as total volume, multi-dose information, and the compounding facility's name, address, and contact info.

Dispensing and Counseling

• Dispensing and patient or caregiver counseling are carried out, with special considerations for delivery.
• Verification of patient identity is necessary, as is counseling and training.
• Storage should avoid humid rooms, like bathrooms, and shaking is usually done before administering the medication.
• Pharmacists should counsel patients on proper use, storage, and potential side effects.

Cleaning

• Needles and syringes should be put into sharps containers, glass in glass containers, and special waste into identified containers, with general waste disposed of separately, and all equipment must be clean and dry.

What can go wrong?

• The team may get confused by names, the dosage form might be inappropriate, stability might have errors like an unstable solution, there could be unlabeled materials, and testing procedures might be omitted.
• Errors happen, such as formulation being commercially available, dosage form or flavor not being appropriate, calculation mistakes, pharmaceutics error, and incorrect or omitted information in the compounding procedure.

Types of Compounding

• Extemporaneous compounding involves preparing medications for immediate use based on a prescription.
• Anticipatory compounding involves preparing medications in limited quantities before receiving a prescription, based on anticipated need.
• Bulk compounding involves preparing medications in large quantities for future use.

Types of Pharmaceutical Compounding

• Sterile compounding involves preparing medications in an environment that prevents microbial contamination and is used for intravenous solutions, eye drops, and irrigations.
• Requirements for sterile compounding include strict adherence to aseptic techniques, use of specialized equipment like laminar airflow workstations, and stringent environmental controls.
• Non-sterile compounding involves preparing medications in forms like creams, ointments, solutions, and capsules.
• Requirements for non-sterile compounding include following established procedures and quality control measures to ensure the final product is safe and effective.

Compounding Environment

• Compounding requires a dedicated space separate from general pharmacy operations.
• Adequate lighting, ventilation, and temperature control are essential, with cleanliness and sanitation critical to prevent contamination.
• The compounding area should be clean, organized, and properly equipped to prevent contamination and ensure accuracy.
• Surfaces must be non-reactive, non-shedding, and easily cleanable, and temperature and humidity must be controlled to maintain the stability of drug products.

Equipment and Supplies

• Compounding requires specialized equipment.
• Use appropriate and calibrated equipment for accurate measurements and consistent product quality.
• Balances for accurate weighing must be calibrated regularly.
• Measuring Devices: Use appropriate devices such as graduated cylinders, pipettes, and syringes for precise measurement of liquids.
• Balances for accurate weighing.
• Mortar and pestle for grinding and mixing.
• Measuring devices (graduates, syringes) for accurate volume determination.
• Mixing equipment (stirrers, homogenizers) for uniform blending.
• Ointment mill for particle size reduction and uniform mixing of ointments and creams.
• Supplies include chemicals and ingredients of pharmaceutical grade, empty capsules, ointment bases, packaging materials.

Compounding Process

• Prescription review: Pharmacist verifies appropriateness, legality, and patient medical history.
• Accurate calculations ensure correct dosage and concentration.
• Select appropriate ingredients based on quality, stability, and compatibility.
• Accurate weighing and measuring of each ingredient using calibrated equipment.
• Combine in the correct order using appropriate techniques to ensure uniformity.
• Quality control: Visual inspection, weight verification, and pH testing ensure quality and consistency.
• Select appropriate packaging materials and label the medication with required information.
• Maintain records of compounding process, including ingredients, calculations, and procedures.
• Provide patients with information about the medication, including proper use, storage, and potential side effects.
• Follow a detailed compounding formula or recipe that includes the amounts of each ingredient, the order of mixing, and specific preparation instructions.

Quality Control

• Quality control measures are essential to ensure compounded medications meet quality standards.
• Visual inspection involves checking for particulate matter, discoloration, or other signs of instability.
• Weight variation involves assessing the uniformity of capsules or other dosage forms by weighing a sample.
• pH testing involves measuring the pH of solutions and adjusting if necessary.
• Implement quality control measures to verify the identity, strength, purity, and stability of the compounded medication.
• Assess the compounded preparation for any signs of physical instability, such as discoloration, phase separation, or particulate matter via visual inspection.
• Confirm that the final weight or volume of the compounded preparation is consistent with the expected value via weight or volume verification.
• Measure the pH of aqueous preparations to ensure they are within the acceptable range via pH Testing.
• Perform assays to determine the concentration of the active ingredient in the compounded preparation with potency testing.
• Sterility testing involves ensuring compounded sterile products are free from microorganisms.

Stability

• Stability refers to the extent to which a compounded preparation retains its properties within specified limits throughout its storage and use period.
• Factors affecting stability: Temperature, light, humidity, pH, and compatibility of ingredients.
• Stability testing is performed to determine the shelf life of a compounded preparation by evaluating its physical, chemical, and microbiological properties over time.
• Information on the chemical properties of the ingredients, the presence of preservatives, the storage conditions, and the type of container used, all affect stability.
• Proper storage involves storing compounded medications under appropriate conditions to maintain stability.
• An appropriate expiration date should be determined based on available stability data and considerations.

Documentation

• Accurate and detailed documentation is crucial for compounding.
• A compounding record should be kept of each preparation, including ingredients, calculations, procedures, and quality control results.
• Standard Operating Procedures (SOPs): Written instructions for specific compounding procedures to ensure consistency.
• Material Safety Data Sheets (MSDS): Information on the safe handling and storage of chemicals and ingredients.

Regulatory Considerations

• Compounding is regulated by state boards of pharmacy and the U.S. Food and Drug Administration (FDA).
• United States Pharmacopeia (USP): Provides standards and guidelines for compounding, including USP for non-sterile compounding and USP for sterile compounding.
• State regulations: Specific requirements for compounding pharmacies, including personnel qualifications, facility standards, and record-keeping.
• The U.S. Food and Drug Administration (FDA) oversees the regulation of drug manufacturing and compounding in the United States.
• Pharmacies and outsourcing facilities must comply with applicable regulations and standards to ensure the safety and quality of compounded medications.
• Regulatory agencies conduct inspections to assess compliance with compounding regulations and standards.

Regulatory Aspects

• Pharmacies and pharmacists are licensed and regulated within their respective states by State Boards of Pharmacy, which establish specific regulations for compounding practices.
• Section 503A addresses traditional pharmacy compounding, involving preparing medications based on a prescription for an individual patient.
• Section 503B pertains to outsourcing facilities which compound sterile medications in bulk for distribution to healthcare facilities.
• The United States Pharmacopeia (USP) develops and publishes standards for drug substances, dosage forms, and compounding practices, with chapters providing guidance on compounding aspects.

Sterile Compounding

• Sterile compounding prepares medications in an environment free from microorganisms.
• Utilized for intravenous medications, ophthalmic solutions, and injections.
• It requires specialized equipment and techniques, including a cleanroom (controlled environment with HEPA filters to remove airborne particles); a laminar airflow workbench (LAFW) or compounding aseptic isolator (CAI) to provide a sterile work area; and aseptic technique to prevent contamination of sterile products.
• Personnel training: Required to be trained and qualified in sterile compounding techniques.
• Quality assurance: Regular monitoring of the compounding environment and testing of finished products to ensure sterility.
• Sterile compounding should be performed in a cleanroom suite with controlled air quality and environmental conditions, with air cleanliness meeting specific ISO standards, such as ISO Class 5 for direct compounding areas and ISO Class 7 or 8 for buffer and ante-areas.
• Strict aseptic techniques, including proper hand hygiene, garbing, and disinfection of equipment and surfaces, should be used.
• Thorough hand washing with antiseptic soap followed by a sterile alcohol-based hand rub should be performed, wearing sterile gloves, gowns, masks, and shoe covers to minimize contamination risk
• Utilize sterile equipment and supplies, such as sterile syringes, needles, vials, and intravenous bags; sterilizing using appropriate methods like autoclaving or filtration.
• Sterility testing should be performed on preparations to ensure freedom of microbial contamination, incubating samples in growth media and monitoring for any microbial growth signs.
• Pyrogen testing should be conducted, using the Limulus Amebocyte Lysate (LAL) Test to verify that preparations do not contain excessive levels of bacterial endotoxins.

Non-Sterile Compounding

• Non-sterile compounding prepares medications that do not need to be sterile.
• Used for oral medications, topical creams and ointments, and suppositories.
• Requires a clean and organized compounding area.
• Personnel must follow proper hygiene and sanitation procedures, and quality control measures to ensure the product meets standards.

Quality Assurance and Control

• Quality assurance involves systematic monitoring and evaluation of compounding processes to ensure meeting established standards/requirements.
• Develop and follow detailed SOPs for all compounding aspects, including ingredient selection, compounding techniques, equipment maintenance, and quality control procedures.
• Compounding processes should be validated to demonstrate consistent production of acceptable quality, conducting studies to evaluate performance under different conditions.
• Compounding practices should be continuously monitored and improved based on quality control results, feedback from healthcare professionals, and emerging scientific information.
• Internal audits and inspections should be regularly conducted to identify deficiencies in compounding practices and implement corrective actions.
• System for reporting/investigating adverse events or medication errors associated with compounded medications should be in place.

Patient Safety Considerations

• Prescribers should provide clear and complete prescriptions including the medication name, strength, dosage form, and any necessary instructions.
• Healthcare providers should monitor patients for adverse effects or therapeutic outcomes.
• Patients and healthcare providers should report any adverse events or medication errors to the appropriate regulatory agencies.
• Risk management strategies should be implemented to minimize the potential for errors or adverse events in compounding practices.

Monitoring

• Healthcare providers should monitor patients for any adverse effects or therapeutic outcomes associated with compounded medications.

Advances in Pharmaceutical Compounding

• Automation: Automated compounding devices and technologies can improve accuracy, efficiency, and safety in compounding processes.
• 3D Printing: Three-dimensional (3D) printing technology can be used to create customized dosage forms with precise drug delivery profiles.
• Nanotechnology: Nanotechnology-based formulations can enhance the solubility, bioavailability, and targeted delivery of compounded medications.
• Personalized Medicine: Compounding plays a crucial role in personalized medicine by allowing the preparation of medications tailored to an individual patient's genetic makeup, disease state, and therapeutic response.
• Research and Development: Ongoing research and development efforts are focused on improving the stability, efficacy, and safety of compounded medications.

Compounded pharmaceuticals require careful steps, starting with Rx receipt and evaluation. Patient verification, drug evaluation, and dosage form design are essential. Compounding should only proceed if the product isn't commercially available.