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By PCCA
From research and development to testing and updating, our 9,000+ formulas are far more than a list of ingredients and procedures. We have developed a robust system to ensure that we create and maintain formulas that provide PCCA members with what they need to compound high-quality, pharmaceutically elegant customized medications for their patients — all while complying with the latest standards in pharmacy compounding. But what does that look like? What’s in a PCCA formula? Let’s take a look at the work our Formulation Development team puts into every formula and what that ultimately means for PCCA members and their pharmacies.
Developing a PCCA Formula There are many ways it can begin. A compounder receives a prescription from a physician and would like assistance with the formulation. Or there is a shortage of a commercial product in the industry that compounders can help with. Or our clinical compounding pharmacists notice a trend or a significant patient need. Or we develop a new base, and our Research and Development, Clinical Services, and Formulation Development departments work together to determine new formulas for it based on research and clinical need. Regardless of where it started, every potential formula is entered as a request in our formula management system, the custom-built software that hosts our formula database, in which we’ve invested over $500,000. Then our Formulation Development team gets to work.
This is the genesis of a PCCA formula, one that will, if everything goes as planned, join the others in our database — over 9,000 of them representing almost 40 years of development and centuries of combined pharmacy, chemistry and laboratory experience across multiple teams involved.
Once someone submits a request in our formula management system, the Formulation Development team reviews it and takes many factors into consideration:
While researching each formula request, they may look at the United States Pharmacopeia and National Formulary, The Merck Index, Martindale, Trissel’s Stability of Compounded Formulations, the Handbook of Pharmaceutical Excipients and other references. This initial research period involves Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development, as well as our scientists, pharmacists and formulation specialists.
If the request is feasible based on the many considerations they take into account, one of our formulation scientists, pharmacists or specialists reviews all of the information again, and then they compound it in the lab, carefully documenting the procedures, calculations and any relevant findings, such as the preparation’s appearance, pH and the time it took to prepare. This typically includes three to four lab trials and about three hours of lab time per formula, though simple formulas could require only one half-hour compounding trial, and complex ones could take over eight hours of lab time across several trials. Regardless, they record their notes in our formula management system, which contains all of the information from the initial request and research to the final formula.
Once they complete the preparation, the Formulation Development team observes it for an amount of time determined by the default beyond-use date (BUD) allowed by USP. For example, they will observe a preserved aqueous topical formulation for 35 days. The maximum allowable default BUD for this type of preparation indicated in the current USP General Chapter <795> is 30 days, and it’s 35 days in the new version of the chapter that becomes official on December 1, 2019. Depending on the type of preparation, the team monitors for changes in physical characteristics, such as precipitation, discoloration, redistribution upon agitation, separation, crystallization, hardening, pH and others. If they do not observe any changes, they assign the appropriate BUD, and the formula then proceeds to the final review process.
During final review, the Formulation Development team triple-checks the formula. That is, every aspect has to be approved without any changes by three separate team members, including Melissa. The team reviews the original formulation research; regulatory status; clinical need and use; all lab-trial notes, calculations and procedures; and any other accompanying information. The team also reviews the BUD listed in the formula again to ensure that it complies with the applicable USP standard. If the team needs to make any changes during the final review, the triple-check process begins again. Once three of our Formulation Development team members approve the formula and all supporting information, then it is submitted for publication in PCCA’s formula management system. When it is published, it is available on the PCCA Members-Only Website.
Stability and Preservative Testing Our Formulation Development team also submits our most popular formulas for stability testing to extend their BUDs beyond the standard ones determined by USP. This is what we call our FormulaPlus™ program. FormulaPlus formulas are studied using a stability-indicating assay method over the course of a period of time at refrigerated and room temperature. The assay also undergoes method development and validation, a costly process ensuring that it works appropriately to indicate the stability over time of the preparation within the study conditions.
Due to the recent changes in USP General Chapter <795>, we are also subjecting all of our FormulaPlus formulas to USP <51> antimicrobial effectiveness testing. Also known as preservative efficacy testing, this validates the preservative system in a formulation. Most of our FormulaPlus formulas have already been tested according to USP <51> standards and passed, and all of them will be tested by December 1, 2019, when the new Chapter <795> goes into effect.
When our formulas have passed all of this testing, they are indicated in our formula database with the “BUD Study” designation in the title and accompanied by the FormulaPlus symbol: . We also add the report of the stability-indicating assay results to the Members-Only Website so that compounders can keep a copy of it for their records if they use the corresponding formula. A link to the report is available in each FormulaPlus formula. We currently have over 140 such formulas with extended BUDs, and we study more every year.
PCCA members can view all of our formulas with extended BUDs in the FormulaPlus master list.
Recently, our Formulation Development team has also begun to develop and submit bracketed formulas for FormulaPlus testing. These allow compounders to use a single formula to create a number of compounds with extended BUDs as long as the active ingredient in each compound is within the range of strengths listed in the formula. We currently have over 35 bracketed formulas with extended BUDs in our formula database, and we will continue to develop more in the future.
Revising and Updating PCCA Formulas As any experienced compounder knows, it’s necessary to change formulas from time to time. This is why our Formulation Development team also meticulously maintains our formula database, ensuring that all of the individual formulas are up to date and that PCCA members have access to the latest information about them.
Under certain circumstances, such as when we need to change a chemical supplier, we may need to make adjustments to existing formulas that contain that chemical. Furthermore, if an ingredient in a formula is no longer available and we do not have a viable replacement for it, our Formulation Development team will retire the formula from the database. The team also monitors lot-specific formulas, and when the lot of the chemical listed in the formula expires, they retire the formula from the database as well.
At the top of a PCCA formula, one of the first things the compounder will notice is the version number. Currently, PCCA Formula #12956 (a bracketed FormulaPlus formula with estriol and estradiol in VersaBase® Cream) is in version six, for example. The version number may represent changes to the procedures or ingredients, or it may indicate additional notes or literature citations being added. Regardless, whenever Formulation Development makes a change to a PCCA formula, the formula’s version is automatically updated in the formula management system. This is why we encourage our members to check our database when using a PCCA formula to ensure that they are always using the latest version.
Sometimes, Formulation Development will also remove formulas due to regulatory changes. When the FDA made its initial ruling for the 503A Bulk Drug Substances list in early 2019, in which it indicated that tranilast was not going to be included on the list, our Formulation Development team identified all of our tranilast formulas for human use. When the FDA’s final ruling went into effect on March 21, 2019, the team had already removed all of those formulas from our database to ensure that we were not providing formulas that no longer complied with regulations.
Also on The PCCA Blog: FDA Guidance Explained: Compounding with Bulk Drug Substances.
Similarly, the new and updated USP General Chapters <795>, <797> and <800> affect formulations, and we are updating formulas to comply with these changes. For example, the new Chapter <795> changes how default BUDs are assigned and which types of compounds receive which BUDs, so Formulation Development will update the BUDs for every PCCA formula that these changes affect by December 1, 2019, when the chapter becomes official. Formulation Development is also updating all PCCA formulas that contain ingredients included on the National Institute for Occupational Safety and Health’s list hazardous drugs (known commonly as the NIOSH list). The updated formulas indicate that they contain hazardous drugs, which will help compounders with USP <800> compliance.
All of this formula and database maintenance ensures that PCCA members have access to formulas that comply with the latest standards in the pharmacy compounding industry. It’s also a testament to the dedication and diligence of our Formulation Development department. In 2018 alone, they developed 431 new formulas — including 22 new FormulaPlus studied formulas — and updated over 8,000 existing formulas.
What PCCA Formulas Mean for PCCA Members What all of this means for PCCA members is saved time, money and stress as well as reduced risk for their pharmacies and patients. Every PCCA formula they use has been researched, compounded, observed, reviewed, approved and (when necessary) updated by a team of experienced formulation scientists, pharmacists and specialists, representing hours of work as well as lab space and materials. When it comes to FormulaPlus formulas, we’ve taken care of stability and preservative efficacy testing, saving members thousands of dollars per formula, and potentially tens of thousands of dollars for complex formulations. For bracketed formulas, the cost savings double.
So what’s in a PCCA formula? A lot. And we want to make sure everything that goes into it is scientifically sound and of high quality to save our members time and money, to reduce risk for their pharmacies, and to promote safety and efficacy for their patients.
A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.