Scientific Approach to Compounding Quality Preparations
In 2020, the FDA began teaching boards of pharmacy how to apply Current Good Manufacturing Practice standards to the compounding pharmacy setting. Restore Health Consulting observes that some state pharmacy regulators are increasingly emphasizing scientific justification for certain aspects of compounding operations, particularly in higher-risk settings. In other words, reliance solely on checklist-based compliance may not fully address all quality risks identified during inspections. Compounding pharmacies and hospital health systems are increasingly encouraged to consider approaches that emphasize building quality into systems, rather than relying solely on end-product testing. As described in a recent Pharmacy Practice News article, quality and scientific justifications are frequently emphasized by regulators and inspectors when evaluating compounding practices. Here are ten categories commonly discussed in quality-focused frameworks that may help promote product quality and patient safety:
Personnel
People are arguably a company’s most important asset. Defining who does what and who reports to who in an organizational chart along with associated job descriptions helps personnel understand from a legal standpoint which role is allowed or not allowed to do certain functions. Applying this basic principle at a compounding facility helps the pharmacy stay compliant with regulations. Furthermore, if personnel are assigned roles that complement their education, experience, and qualifications, it improves the quality of the operation as a whole if all of the players know their role so they can best work together. Organizations can implement structured training programs to clarify training and competency expectations for defined roles. Personnel are commonly expected to demonstrate proficiency or qualification in SOPs applicable to their assigned roles.
Facility
The act of compounding sterile preparations correctly relies on the proper functionality of the cleanrooms and surrounding facility. If there are problems with the facility, it will be nearly impossible to consistently and reliably reproduce compounds. Primary and secondary engineering controls are designed to support consistent product quality when they function as intended. Air movement patterns, air changes per hour, velocity, particle counts, pressure differentials, temperature, relative humidity, etc. are typically evaluated against defined industry standards or facility specifications. The rooms must be constructed of the proper materials. The layout must make sense to limit cross-traffic between and within critical environments, to separate material flow from personnel flow when possible, etc.
Many facilities choose to work with engineers and consultants experienced in cleanroom design to reduce the risk of design deficiencies or rework. Once cleanrooms are installed, facilities perform verification, certification, and/or validation activities consistent with their risk profile and regulatory expectations.
For those compounding sterile products in an aging facility, it important to stay current with the preventative maintenance programs. Study the certification reports. Watch the unidirectional airflow patterns in the dynamic smoke studies and confirm there are no weak points or turbulence demonstrated anywhere near the critical site or aseptic working area. Operating cleanrooms beyond their studied capacity may introduce additional risk and should be evaluated carefully.
An environmental monitoring (EM) program provides clues as to whether control of the cleanroom is maintained or if there are underlying problems that need to be addressed. The EM program needs to be designed well. Selecting the appropriate site locations, determining the frequency of sampling, detailing the process of sampling, incubation operation/temperature/duration must make sense for the kind of media and type of microbes you expect to recover, knowing how to properly read media results, and setting the appropriate alert and action limits for colony forming units (or CFUs) found after incubation are all important components of a functioning environmental monitoring program at a compounding facility.
Clean and disinfect the cleanroom properly and routinely and as per industry standards. USP has helpful information such as cleaning from top to bottom, furthest to closest, cleanest ISO area to dirtiest area, etc. The areas surrounding the cleanroom from the kitchen and bathroom to the warehouse and dispensary as well as the offices must have sufficient custodial procedures in place to keep surrounding areas clean and tidy. It is also necessary to have a proper pest control program as part of the quality built in concept. The presence of pests in the facility is considered an insanitary condition by the FDA and it’s a sign of either poor construction, engineering, procedures, quality culture, or house-keeping.
Equipment
Facilities typically maintain SOPs addressing the operation, calibration or qualification, maintenance, and documentation of equipment. The more detailed they are, the less mistakes are made, which translates to reduced waste, complaints, and costs. The operation procedure must adequately describe how to use the equipment. The equipment calibration program must include the frequency. Calibration documentation is commonly maintained and reviewed as part of equipment management programs. The preventative maintenance of equipment should be detailed in a document and include directions for routine maintenance tasks and frequencies, as well as how to clean the equipment, how often and with what.
Materials
There has been a general lacking in the qualification of compounding pharmacy material suppliers in the past. This has resulted in several recalls in compounded preparations and compromises in patient safety. It is not enough to buy from a supplier that “everyone uses.” Supplier qualification programs can be used to reduce the risk of material-related defects. Setting company specifications for the critical supplies an organization purchases is especially important for facilities compounding sterile preparations from non-sterile starting materials.
Process Controls
Production and process controls are the heart of any company engaged in compounding pharmaceutical preparations. Common SOP categories referenced in quality-focused compounding programs include:
Gowning and hand hygiene procedures
Operating procedures (e.g., compounding procedures for each compounding process, aseptic technique, material transfer, cleanroom behavior, etc.)
Equipment/utility SOPs used for the operation of equipment
Visual inspection procedures
Labeling and packaging procedures
Quality attribute inspection of the final product
Cleaning and disinfection
Environmental and personnel monitoring
Quality/Compliance (e.g., managing complaints, auditing, release of a batch or approval of a prescription compound, handling out-of-specification results, etc.)
Labeling and Packaging
There are five main elements to proper labeling procedures: security, selection, printing, application, and reconciliation. Organizations typically implement controls intended to reduce the risk of mix-ups. If your organization lacks appropriate packaging and labeling controls, it is advised to audit these processes to assess whether or not your system assures the prevention of mix-ups and erroneous labeling and packaging as this can contribute to waste, complaints and costs.
Holding and Dispensing/Distribution
Once a compounded preparation is made and labeled, it must be reviewed and approved. There is a short period where the compound is on hold waiting for the pharmacist approval. As such, facilities may implement controls to prevent compounds from being dispensed prior to pharmacist review or release. For batched compounds produced in 503Bs or pharmacies for multiple patients, it will be held in quarantine until product release testing is complete and passing.
Shipping and delivery procedures must be defined as applicable. Policies such as delivery cycles and order by deliver by, needs to be ironed out. Shipping validations help organizations understand if the way compounds are shipped or delivered meets specification for storage during transit. Shipping and delivery processes are often evaluated, verified, or validated to assess whether storage conditions during transit support product stability.
Laboratory Controls
Quality attribute testing can be defined based on formulation, risk, and intended use. Quality control testing procedures and specifications must be clearly defined.
If a third-party laboratory is employed for stability studies or production batch release, they should be qualified like material suppliers are (with a survey, audit, inspection review, etc.). Their analytical methods must be developed and specific to the product. Analytical methods should be validated for their intended use. USP provides guidelines for the validation of several analytical methods. Facilities may establish specifications and release criteria to support decisions regarding dispensing or release of compounded preparations.
Documentation
Document control and security practices can be implemented to manage SOPs, records, and reports. The generation or update of SOPs, master formulas, protocols, compounding records, reports, etc. should ideally follow a change control process. A good records management system assigns numbers for each controlled document, tracks their revisions and approvals over time, etc. and are retrievable for review in a secured physical location or electronic manner.
Returned or Salvaged Drugs
A rework procedure is helpful for organizations that intend to allow preparations that don’t initially meet specification to be salvaged. A returned drug product procedure is also helpful for organizations to follow in instances where a drug product is returned. Returns may happen from time to time due to poor quality, but they may also happen for other reasons including refusal upon shipping/delivery, etc. Having this procedure in place can help an organization reduce the propensity for returns if the reasons they are returned for are investigated, corrected, and prevented.
Does Your Facility Produce Quality Preparations?
If you’re ready to bring quality to the center of your compounding operations, consultants at Restore Health Consulting can help you design a robust quality management system to promote patient safety and regulatory compliance.
Disclaimer:
The practices discussed in this article reflect quality-focused frameworks and inspection trends and are not intended to define mandatory requirements or the sole means of regulatory compliance.