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 predicts that state pharmacy regulators will soon be expecting compounders to scientifically justify every facet of the operation. In other words, following a checklist of standards won’t be good enough. Compounding pharmacies and hospital health systems will need to have quality built in, not just tested in, to their systems. As described in a recent Pharmacy Practice News article, quality and scientific justifications must be at the center of every compounding practice. Here are the 10 categories a compounding operation must master to 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. There should also be a robust training program in place that details the training and competency requirements for each job description. Personnel must demonstrate proficiency or qualification in SOPs applicable to their job description to promote the quality of compounds produced.
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 such as the ISO 5 and ISO 7 environments must work as intended so that quality products are consistently produced. Air movement patterns, air changes per hour, velocity, particle counts, pressure differentials, temperature, relative humidity, etc. must all meet defined industry standards or 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.
Contracting with engineers and consultants specialized in cleanroom design and construction for compounding facilities is critical to avoiding costly and time consuming rework projects. Once the cleanrooms are installed, it is also important to validate them.
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. Don’t stress the cleanrooms beyond the studied max capacity.
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
SOPS must exist for the operation, calibration/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 certificates must also be available. 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.” Each supplier should be properly qualified to avoid compound 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. The main SOP categories a facility needs to have to promote quality built in are as follows:
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. Each organization must have appropriate controls in place to prevent 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, there must be controls in place for preventing compounds from going to the floor or being dispensed without prior pharmacist approval. 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. It is very important to validate the shipping/delivery process so that products remain stable during transit and for the duration of the assigned BUD, otherwise there is a potential for the rise in waste, complaints, and costs.
Laboratory Controls
Quality attribute tests (e.g., pH, weight, appearance, visual inspection, sterility, endotoxins, potency, etc.) must be specified as to when, how and what is to be tested for a given formulation or circumstance. 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. Finished compounded preparations should only be dispensed or released if they meet the appropriate specifications.
Documentation
There needs to be control and security for handling various documents. 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.