THE PCCA BLOG

USP–NF and U.S. Pharmacist Featuring Proprietary PCCA Bases

Wed, 21 Apr 2021 13:54:23 GMT

By Maria Carvalho, PharmD, MRPharmS, PhD, Manager of PCCA Science

United States Pharmacopeia 43 – National Formulary 38

The United States Pharmacopeia (USP) was created over 200 years ago and, combined with the National Formulary (NF), is now the global leader in setting standards that help ensure quality and safety in medicines. It includes monographs for substances, products and compounded preparations. Monographs for compounded preparations describe formulas (ingredients and quantities), specific directions to correctly compound the particular preparation, packaging and storage information, labelling information, pH, beyond-use dates based on stability studies, and detailed assays (in the majority of monographs). The USP Compounding Compendium is a separate publication that includes sections from USP–NF that are relevant specifically for the practice of compounding.¹

The latest versions of the USP (43^rd edition) and NF (38^th edition), as well as the corresponding USP Compounding Compendium, have recognized the importance of several proprietary PCCA bases by including a total of five monographs in their official texts that use them as vehicles. The PCCA bases perform consistently with formulations for patients needing extended stability data, and these monographs provide further validation of the versatility of our bases in compounded formulations. This USP–NF recognition is of great value for compounding pharmacists in the U.S. and worldwide who demand the highest quality standards for their compounded formulations. The same rigorous testing used for USP Compounded Preparation Monographs is performed on all of our FormulaPlus^™ formulas, which are available to PCCA members with Clinical Services support.

The PCCA bases featured in the official compendia are in the table below.

*USP–NF* Compounded Preparation Monographs with PCCA Bases ¹
Monograph	Proprietary PCCA Base	Page Number(s)
Clindamycin Hydrochloride Compounded Oral Solution	SuspendIt^® (PCCA #30-4825)	481
Doxycycline Compounded Oral Suspension, Veterinary	Fixed Oil Suspension Vehicle (PCCA #30-4316)	495–497
Estriol Compounded Vaginal Cream	Emollient Cream^™ (PCCA #30-3168)	499–500
Ondansetron Compounded Topical Gel	Lipoderm^® (PCCA #30-3338)	539
Phenytoin Compounded Topical Gel	Spira-Wash^® Gel (PCCA #30-4678)	547–548

U.S. Pharmacist

U.S. Pharmacist is a monthly journal dedicated to providing pharmacists with peer-reviewed clinical articles relevant to the full spectrum of pharmacy-practice settings. The journal includes an open-access column on pharmacy compounding written by contributing editor Loyd V. Allen, Jr., PhD, RPh. Proprietary PCCA bases have been featured in this column as well, namely VersaBase^® Cream (PCCA #30-3641), Lipoderm (PCCA #30-3338) and PracaSil^®-Plus (PCCA #30-4655) (see table below). The most recent publication, dated January 19, 2021, discusses a formula with baclofen, clonidine HCl, gabapentin and ketamine in Lipoderm. Lipoderm is described in this publication as “an elegant alternative to traditional Pluronic Lecithin Organogels (PLOs), having a smooth and creamy feel rather than the tacky feel of PLOs. It contains a proprietary liposomal component that may increase the permeation of a variety of actives. Lipoderm is a stable system that does not separate upon refrigeration and has great resiliency in the presence of ionic substances.”² These independent formulas also provide further validation of the versatility of our bases in compounded formulations.

Compounding Formulas with PCCA Bases Published in U.S. Pharmacist
Publication Date	Formula	Issue
September 15, 2017	Progesterone 50 mg/Gm in VersaBase Cream	U.S. Pharmacist vol. 42, iss. 9, p. 47–48
November 20, 2018	Sertraline 4 mg/0.1 mL in Lipoderm	U.S. Pharmacist vol. 43, iss. 11, p. 47–48
October 16, 2019	Clotrimazole 2%, Ibuprofen 2%, Metronidazole 2%, Nifedipine 0.2%, and Dexpanthenol 3% in PracaSil-Plus	U.S. Pharmacist vol. 44, iss. 10, 48–CV
January 19, 2021	Baclofen 2%, Clonidine HCl 0.2%, Gabapentin 10%, and Ketamine HCl 5% in Lipoderm	US Pharmacist vol. 46, iss. 1, p. 44-45

For more information on the science behind PCCA’s proprietary bases, please consult the corresponding technical reports at pccarx.com/science. PCCA members can also contact us at PCCAScience@pccarx.com.

Maria Carvalho, PharmD, MRPharmS, PhD, is the Manager of PCCA Science. She is a certified pharmacist in Portugal and the United Kingdom with a PhD in pharmaceutical compounding from the University College of London (UCL). Maria has worked in community pharmacy, hospital pharmacy and the pharmaceutical industry in Europe and the United States. She was a teaching assistant at the UCL School of Pharmacy (UK) and an invited teacher at the University Fernando Pessoa (Portugal). Maria has authored and co-authored many scientific publications, including the book Compounding Practices in Europe (ISBN-10:149236925X).

References

1. United States Pharmacopeial Convention. (2020). United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

2. Allen, L. V., Jr. (2021). Baclofen 2%, clonidine HCl 0.2%, gabapentin 10%, and ketamine HCl 5% in Lipoderm. U.S. Pharmacist, 46 (1), 44–45. https://www.uspharmacist.com/article/baclofen-2-clonidine-hcl-02-gabapentin-10-and-ketamine-hcl-5-in-lipoderm

Upcoming Changes to PCCA Formulas per the New USP <795>, <797> and <800> (Part Two)

Wed, 06 Nov 2019 14:52:00 GMT

By Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development

As I wrote in the first part of this article, on June 1, 2019, the United States Pharmacopeial Convention published revisions to the compounding Chapters <795> and <797> in the United States Pharmacopeia and National Formulary, which were set to become official on December 1. However, USP later announced that they would postpone that official date because of pending appeals to certain parts of the revised chapters. The revisions in USP <795> and <797> affect the beyond-use date (BUD) that can be applied to compounded formulations, among other standards.

Even though the date when the revised chapters become official is postponed, our Formulation Development department is working on updates to our formulas to be compliant with the new USP standards. We will complete these updates within our formulation database when we are notified of the new official date and contents of the Chapters <795> and <797>, and they will go into effect in our database on the day that they become official. Therefore, it will be important for PCCA members to download the latest versions of PCCA formulas after the date that the new chapters become official (which has not been announced yet), as there will be changes that should be noted and documented for master formulas.

Therefore, we wanted to announce what these future changes will look like. Below is a summary of the formula changes based on the latest version of USP Chapter <797> as it is written currently. We will make further changes as needed based on the appeals outcome, and we will announce those changes as well.

Changes Related to USP <797>
Sterilization Procedures
Section 10 of the revised USP Chapter <797> discusses sterilization and depyrogenation for compounded sterile preparations (CSPs). The method of sterilization plays a role in establishing the BUD for CSPs. The chapter establishes two categories for CSPs: aseptically processed, which are sterilized by filtration, and terminally sterilized, which are sterilized by steam heat (autoclaving) or dry heat. We will update PCCA formulas to reflect these compounding processes and provide specific instructions to render the preparations sterile.

BUDs
Section 14 of USP Chapter <797> discusses the parameters for establishing BUDs for CSPs. Table 11 of the chapter covers the parameters in detail, but the BUDs are based primarily on factors that affect the achievement and maintenance of sterility (risk of microbial contamination). The chapter assumes that CSPs will remain chemically and physically stable within the container-closure systems used. Chapter <797> does not provide specific direction on chemical stability, but requires that compounders consider the chemical and physical properties of the drug and/or its formulation as well as the compatibility of the container-closure system with the finished preparation. Since establishing a BUD per these new guidelines depends on multiple factors, our sterile formulas (outside of FormulaPlus formulas) will no longer assign a specific BUD, but will rather provide the relevant guidelines for compounders to determine the maximum BUD they will be able to assign based on whether sterility testing was performed and passed and the temperature at which the preparation will be stored.

According to USP Chapter <797>, a multiple-dose CSP must additionally pass antimicrobial effectiveness testing in accordance with USP Chapter <51>. After the multiple-dose CSP is dispensed, and upon initially entering or puncturing the container for the first time, “the multiple-dose container must not be used for longer than the assigned BUD or 28 days if supported by antimicrobial effectiveness testing results (see <51>) on the CSP, whichever is shorter.” As an alternative, compounders may dispense the preparation in smaller, sealed, single-use, sterilized and depyrogenated container-closure systems.

According to the new guidelines as they are currently written in USP Chapter <797>, there are no means to extend a BUD beyond the dates listed in Table 11. However, PCCA’s data on our sterile FormulaPlus formulas is still a valuable resource. Since USP <797> does not address chemical stability, these studied formulas provide documented chemical stability and therefore ensure the chemical and physical stability of the preparation. We have 12 sterile FormulaPlus formulas, and several are bracketed studies allowing for a broad range of active ingredient concentrations. PCCA members can view these in the FormulaPlus master list.

Given the significant changes in pharmacy compounding recently, it is as important as ever to ensure that compounders comply with the latest standards. We hope that the updates we will make to our formulas when the new USP <795> and <797> become official — as well as the change we’ve implemented for compliance with USP <800> — will help them do just that. If PCCA members with Clinical Services access have questions about any of these changes, they can contact our Clinical Services department.

Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development, received her pharmacy degree from Mercer University in Atlanta, Georgia, in 1995. She currently is involved with and oversees the development and implementation of new formulas at PCCA. She had more than six years of compounding experience with pharmacies in Georgia and Florida prior to joining the PCCA staff in 2004. Her areas of interest include women’s health, veterinary and pain management compounding.

A version of this article previously appeared in PCCA’s members-only magazine, the Apothagram. PCCA members can find a more detailed description of these formula changes in the Fall 2019 issue.

Reference
United States Pharmacopeial Convention. (2019). General chapter <797> pharmaceutical compounding — Sterile preparations. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.

Upcoming Changes to PCCA Formulas per the New USP <795>, <797> and <800> (Part One)

Mon, 04 Nov 2019 15:26:00 GMT

By Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development

On June 1, 2019, the United States Pharmacopeial Convention published revisions to the compounding Chapters <795> and <797> in the United States Pharmacopeia and National Formulary, which were set to become official on December 1. These revisions affect the beyond-use date (BUD) that can be applied to compounded formulations, among other standards. On September 23, USP announced they were postponing the official dates of the revised chapters due to pending appeals to certain revisions of both chapters. With the revised chapters becoming official at some point in the near future, our Formulation Development department is hard at work planning updates to all of our formulas to be compliant with the new USP standards. We will complete these updates within our formulation database when we are notified of the new official date and contents of the Chapters <795> and <797>, and they will go into effect in our database on the day that they become official. Therefore, it will be important for PCCA members to download the latest versions of PCCA formulas after the date that the new chapters become official (which has not been announced yet), as there will be changes that should be noted and documented for master formulas.

Even with the delay in these standards, we wanted to announce what these future changes will look like. Below is a summary of the formula changes based on the latest version of USP Chapter <795> as it is written currently. We will make further changes as needed based on the appeals outcome, and we will announce those changes as well. Since USP Chapter <800> will become official on December 1, I have also highlighted a formula change that we have already implemented for PCCA formulas that contain an ingredient designated as a hazardous drug by the National Institute for Occupational Safety and Health. In the second part of this article, I summarize the formula changes we are planning to make based on the latest version of USP <797> as it is currently written.

Changes Related to USP <795>
Updated BUDs
Section 10.3 in the revised USP Chapter <795> sets parameters to consider when establishing BUDs for compounded nonsterile preparations (CNSPs). It states, “BUDs for CNSPs should be established conservatively to ensure that the preparation maintains its required characteristics to minimize the risk of contamination or degradation.” Following the guidelines shown below, we will update the BUDs of all PCCA formulas for CNSPs (excluding FormulaPlus™ formulas, which have extended BUDs compliant with USP <795>). We will also update the storage requirements listed in the formulas to comply with the chapter.

USP <795> established the BUDs listed below based on a CNSP’s ability to maintain chemical and physical stability and suppress microbial growth. The BUDs require packaging the CNSPs in tight, light-resistant containers. USP determined the BUDs by assessing the susceptibility to microbial contamination and the potential for active ingredient degradation in a CNSP through its water activity (Aw). Reduced water activity greatly assists in active ingredient stability and the prevention of microbial growth. Therefore, USP considers preparations with water activity above 0.6 (Aw > 0.6) to be aqueous and preparations with water activity equal to or less than 0.6 (Aw ≤ 0.6) to be nonaqueous (anhydrous). As a reminder, the BUDs below were established in USP <795> as it is currently written, and they may change depending on the outcome of the pending appeals.

Maximum Default BUDs in the New USP <795>

Non-preserved aqueous dosage forms: 14 days in refrigerator
Preserved aqueous dosage forms: 35 days at controlled room temperature or in refrigerator
Nonaqueous dosage forms: 90 days at controlled room temperature or in refrigerator
Solid dosage forms: 180 days at controlled room temperature or in refrigerator

USP Chapter <795> has also provided ways to extend BUDs beyond those listed above. If the United States Pharmacopeia and National Formulary has a compounded preparation monograph for the CNSP, the BUD must not exceed the one specified in the monograph. PCCA has quite a few of these formulas documented for our members review within our formulation database. They are cross-referenced and searchable by “USP monograph.”

Another means of extending a BUD up to a maximum of 180 days is by conducting a stability study using a stability-indicating assay for the active ingredient(s), the CNSP as a whole, and the type of container-closure that will be used. Additionally, Chapter <795> states that an FDA-registered laboratory should perform an antimicrobial effectiveness test (covered in USP Chapter <51>) when extending the BUD of a CNSP. In other words, the stability study must include assays for each of the individual active ingredients within the specific compounded formula and in the specific container noted, plus USP <51> testing.

This is where PCCA’s FormulaPlus program is so valuable: We have done all of this testing for PCCA members and have published over 135 nonsterile FormulaPlus formulas with extended BUDs. Many of these are bracketed formulas that allow compounders to use the data for a broad range of active ingredient concentrations and many formula options. FormulaPlus formulas are denoted in our database with the “BUD Study” designation and the FormulaPlus Symbol. PCCA members can view the FormulaPlus master list for the complete list of FormulaPlus-studied formulas.

Adding Physical Description
Sections 7.1 and 7.2 in the revised USP Chapter <795> list requirements for master formulation records and for compounding records. One of the noted items to document is the physical description for the final CNSP. We are adding this description to our formulations to help our members with these requirements. We will add physical descriptions to the majority of our existing formulas, and these will be included in all PCCA formulas in the future.

Changes Related to USP <800>
To help PCCA members comply with the requirements established in USP General Chapter <800>, we have added a note to all PCCA formulas that use an ingredient designated as a hazardous drug by the National Institute for Occupational Safety and Health. The note indicates that one or more ingredients in the formula is designated as a hazardous drug, and it also states that USP <800> provides guidelines for handling such substances.

If PCCA members with Clinical Services access have questions about any of these changes, they can contact our Clinical Services department.

A version of this article previously appeared in PCCA’s members-only magazine, the Apothagram. PCCA members can find a more detailed description of these formula changes in the Fall 2019 issue.

Reference
United States Pharmacopeial Convention. (2019). General chapter <795> pharmaceutical compounding — Nonsterile preparations. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.

What the Proposed USP <795> Revisions Mean for BUDs

Mon, 12 Nov 2018 16:45:00 GMT

By Dylan Herr, Eagle Business Development Specialist

The content below was based on an earlier proposed version of USP General Chapter 795. However, USP has since released a newer version of the chapter. To see our most current content about the new version of the chapter, please read our blog post Proposed Changes to USP 795. "

On March 30, 2018, the Compounding Expert Committee of the United States Pharmacopeial Convention published proposed revisions to USP chapter <795> Pharmaceutical Compounding – Nonsterile Preparations. The revised chapter was open to public comments until July 31, 2018, and is expected to become official on December 1, 2019. Major revisions to the chapter include, but are not limited to, the following:

Removal of information specific to the handling of hazardous drugs; compounders were instructed to refer to USP chapter <800> Hazardous Drugs – Handling in Healthcare Settings
Addition of specific guidelines related to requirements for personnel training, evaluation, qualification, hygiene and garbing
Addition of minimum frequencies for cleaning and sanitizing nonsterile compounding areas and equipment
Removal of categories for nonsterile preparations based on the complexity of compounding processes
Addition of specific guidelines on complaint handling and adverse event reporting
Changes to the allowable beyond-use date (BUD) in the absence of stability information for nonaqueous dosage forms and for preserved aqueous dosage forms
Expansion of requirements for assigning BUDs for compounded preparations in the absence of stability information¹

Assigning BUDs

Of the proposed revisions, the expansion of requirements for assigning BUDs in the absence of stability information has the most potential to affect the way that compounders practice pharmacy. The current USP chapter <795> only requires that “when assigning a BUD, compounders shall consult and apply drug-specific and general stability documentation and literature when available.”² To meet this requirement, many compounding pharmacies use peer-reviewed journal articles and other literature references in order to provide a scientific justification for extended BUDs.

The revised chapter, however, states that BUDs may be extended past the maximum BUD by type of preparation in the absence of CNSP-specific stability information (as outlined in Table 3) “if there is a stability study (published or unpublished) using a stability-indicating assay for the specific API, CNSP (compounded nonsterile preparation), and container-closure that will be used.”¹ The inclusion of these requirements will make finding peer-reviewed journal articles and other literature references more challenging, as many of them are not formulation or container-closure specific.

Stability-Indicating Methods
Additionally, the revised chapter requires the use of a stability-indicating assay for stability studies. Historically, many compounding pharmacies have collected data to support extended BUDs for their formulations by having a contract analytical laboratory test the potency of the preparation at certain time-point intervals over the proposed BUD. This type of potency-over-time testing, however, does not meet the requirements of a stability study and of the revised USP <795> chapter, as it is not conducted using a stability-indicating assay to measure the potency of the active ingredient(s). While all stability-indicating assays measure the potency of an active ingredient, not all potency testing methods are stability-indicating.

One of the primary differences between a potency test and a stability study comes down to the analytical testing method used. While a potency testing method is reliable at quantitatively determining the concentration of a drug in a preparation at the time of compounding, not all potency testing methods are capable of separating the intact drug from its degradation products. As a result, these other substances could potentially mask or simulate the analytical behavior of the intact drug, resulting in an inaccurate concentration of the active ingredient. Results from this type of testing cannot be interpreted to determine that the product is stable over time, as there may have been degradant products or changes in the concentration of the active drug that were present, but not detected.

As a comparison, a stability-indicating assay is a potency testing method that is specifically developed and validated to differentiate between the active ingredient and the presence of other substances, such as impurities, degradation products and excipients. A stability-indicating assay is typically developed by forcibly degrading the compounded preparation through exposure to conditions known to produce decomposition, such as light, heat, oxidation, acids and bases. The stability-indicating assay is then validated in the presence of the resulting degradation products, which provides assurance that any increases or decreases in the active ingredient represent actual changes in the concentration of the drug.

Conclusion
All of this means that the requirements for extending the BUDs of nonsterile compounded preparations will likely become more stringent on December 1, 2019. We recommend that compounding pharmacies start developing strategies for establishing extended BUDs for their preparations now so as not to interrupt patient access to compounded medications.

PCCA has already invested the resources in their FormulaPlus™ program to provide members access to formulations with extended BUDs that have undergone testing using stability-indicating assays. PCCA members can access the complete list of FormulaPlus formulations here.

Furthermore, at Eagle, not only can we develop, validate and execute stability-indicating assays for most sterile and nonsterile compounded preparations, but we also offer consulting services on all aspects of testing and regulatory compliance. If you have questions about any of these matters, please contact us at 800.745.8916.

A version of this article was originally published the Summer 2018 issue of the Apothagram, PCCA’s quarterly, members-only magazine.

References
1. United States Pharmacopeial Convention. (2018). <795> pharmaceutical compounding –Nonsterile preparations [In-process revision: General chapters]. Pharmacopeial Forum, 44(3). Retrieved from http://www.usppf.com/pf/pub/
2. United States Pharmacopeial Convention. (2017). <795> pharmaceutical compounding –Nonsterile preparations. In United States pharmacopeia and national formulary (USP 41st ed. & NF 36th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.