Due to the increased number of manipulations they undergo compared with commercial drugs, compounded drugs have more opportunities to become contaminated. The United States Pharmacopeia (USP) provides guidelines that instruct compounding pharmacies on best practices to avoid contamination. On November 1, 2022, the USP published its latest revisions to its compounding chapters <795> and <797>, which respectively govern how non-sterile (nasal sprays & irrigations, topicals, orals, suppositories) and sterile (injectables, intraocular, intrathecal) compounding is performed.1 [BS1] These changes were made based on advancements in science and will impact how compounded drugs are prepared and how their safety is ensured. The USP is aware that it will take time for compounders to implement the changes and recommendations within these guidelines and has extended the official deadline to November 1, 2023. The regulations are complex and may be confusing to both prescribers and patients alike, so this blog post will provide some clarifying information about what to expect and what to look for when obtaining compounded medications.
Summary of changes to USP chapters <795> and <797>
Each step in the compounding process poses a potential contamination risk that may jeopardize a patient’s health. The 2012 meningitis outbreak at the New England Compounding Pharmacy, which killed more than 100 patients, highlights the importance of ensuring that compounded medications are prepared according to the strictest standards. In this outbreak, the source of the contamination was fungal matter from unopened vials, highlighting that even the most overlooked location may harbor microbes. Although this is the most extreme example, the USP has updated its compounding chapters to provide stricter procedures governing activities inside compounding labs to help prevent similar incidents. The most recent guidelines include updates to BUD assignment, staff training, and cleaning and sanitizing procedures.
Changes to BUD Assignment
Most of the changes in USP guidelines involved changes to the beyond-use date (BUD) assignment to strike a balance between patient safety and timely access to compounded medications. In our previous blog post, we summarized methods to assign a BUD based on the latest USP guidelines.
The water content of a medication affects its susceptibility to microbial contamination and hydrolytic degradation. The revised chapters introduced the concept of water activity (aw) to clarify what preparations are “water-containing”. Although compounders are not required to measure aw, chapter <1112> provides examples of non-sterile preparations and their water activity to help assign an appropriate BUD as follows:
Non-preserved aqueous dosage forms (aw ≥ 0.60) = 14 days
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Preserved aqueous dosage forms (aw ≥ 0.60) = 35 days
Oral liquids (nonaqueous) (aw < 0.60) = 90 days
Other non-aqueous dosage forms (aw < 0.60) = 180 days
Category 1, 2, and 3 CSPs
In 2019, the USP changed how compounded sterile preparations were categorized in terms of their microbial contamination risk level from low-, medium-, and high-risk levels to Category 1 and Category 2 to better reflect how they are compounded and the timeframe within which they are expected to be used. In the latest revision, no changes were made to Category 1, but changes were made to the BUD assignment for Category 2 CSPs, and Category 3 was introduced.
The revised USP <797> chapter extended the BUD for aseptically-prepared Category 2 CSPs using only sterile ingredients at room temperature to help facilitate patient access. It also introduced facility and engineering controls and additional surface sampling requirements (as noted below) to help mitigate risks of inadvertent contamination to help support this extended BUD.
Category 3 CSPs were also introduced, which have more stringent standards for personnel qualifications, garbing, and environmental monitoring frequency (as will be discussed below). Additionally, USP provided guidelines for extending the BUD up to a maximum of 180 days when sterility and stability tests have been performed.
For sterile CSPs, the immediate-use provision was extended from one hour to four hours from preparation to administration to strike a balance between ensuring CSP quality and the immediacy of delivering a drug. This was based on the four to six hour lag phase of microbial growth.
Any type of manipulation to a conventionally manufactured commercial drug is considered compounding, including adding flavoring. Because of this, USP simultaneously published a supplemental document to USP <795> to help clarify how to assign a BUD when flavorings to conventionally manufactured nonsterile products.
The importance of staff training
Contaminants—either microbial or particulate—can come from almost anywhere, but the most dangerous and frequently found microbial contaminants during compounding are derived from humans. Therefore, the USP has modified its guidelines for personnel training and competency evaluations to ensure that compounding pharmacy staff are adequately trained to minimize contamination risks. To adapt to the new guidelines, staff training should be expanded and properly documented. Technicians and pharmacists should be tested for knowledge and competency via quizzes, tests, and hands-on evaluations while on the job. Hands-on tests should be recorded and saved for accountability and should be available upon request during inspections by state boards of pharmacy and/or the FDA.
Microbes can be transferred from humans’ bodily fluids and hair found on body piercings, jewelry, and even headphones! Because of these contamination risks, there are strict garbing competency requirements for compounding. Importantly, these changes now apply to anyone involved in compounding, including whoever is supervising the compounding. Remember organic chemistry lab, where lab-appropriate attire was required or a student would be sent home? Similar but much stricter garbing requirements apply to compounding pharmacy staff because humans are the primary source of microbial contamination. Particularly for Category 3 CSP preparation, there must be no exposed skin in the buffer room, i.e., complete head-to-toe coverage.
Garbs should also be sterile, low-lint garbs and must be re-sterilized after laundering. These regulations only apply when Category 3 compounding is being performed, but they must be followed at all times wherever and whenever Category 3 compounding is being performed.
In the revised chapter, gloved fingertip and thumb samplings should be taken for aseptic manipulation to assess microbial contamination and garbing competency evaluations. The garbing competency evaluation has to be completed “no fewer than three separate times initially” and only once during subsequent evaluations. There should be zero colony-forming units (CFUs) on the gloved fingertips. For Category 1 and 2, these tests should be repeated every six months, while Category 3 should be tested every three months.
Aseptic Manipulation Competency
Microbes are everywhere, and aseptic manipulation is performed to minimize the chance that they will enter sterile compounded medications. Because of how quickly they—and any microbes they carry—enter systemic circulation after administration, sterile medications have stricter requirements. To ensure that compounding staff have adequate aseptic manipulation competency, evaluations should be completed once initially and then once again for all follow-up evaluations. The USP now requires obtaining a work surface sample with a maximum of 3 CFUs before performing aseptic compounding and then again every 6 months for Categories 1 and 2, and every 3 months for Category 3. USP <797> also requires that the supervising pharmacist be trained and demonstrate competency in aseptic manipulation, core skills, and garbing every 12 months.
Environmental Monitoring and Sampling
Microbial and non-microbial filth may contaminate various surfaces in compounding pharmacies. For USP <797> Category 1 and 2 compounding, surface and air sampling recommendations remain unchanged. However, due to the introduction of Category 3 CSPs, additional guidelines have been provided, which include weekly hood surface sampling at the end of each batch and monthly air sampling, and at least 30 days before beginning Category 3 compounding. Microbial identification needs to be performed only if CFUs are above the specified limits (note that this may vary depending on state regulations).
The USP has different requirements for cleaning, depending on the type of compounding being performed. For non-sterile compounding per chapter <795>, daily cleaning and sanitizing of surfaces in the non-sterile compounding area must be performed at the beginning and end of a compounding activity/shift. In contrast, sterile compounding performed according to <797> requires only daily surface cleaning. This higher frequency for non-sterile compounding is because more particles are typically generated during non-sterile compounding compared with sterile compounding.
So how will these changes impact patients?
These changes were made to strike a balance between ensuring patient safety and timely access to compounded medications, particularly in lengthening the BUD assignment for some categories and creating even stricter compounding requirements for others. However, by and large, these changes should otherwise not affect patients, aside from increasing the safety of compounded medications. However, this is only true if the compounding pharmacy implements these changes properly. Patients trust their prescribers to source medications from reputable and reliable sources, so prescribers should take several steps to ensure that their compounding pharmacy is providing safe medications.
Confirm Licensure and Credentials
Federal law states that compounding must be performed by a licensed pharmacist in a state-licensed pharmacy or federal facility. However, since compounded formulations are not overseen by the FDA, this task falls upon individual state boards of pharmacy, each of which has its own set of regulations. Make sure your compounding pharmacy is legitimate by confirming the credentials and licensure of both the pharmacy and its pharmacists. Most state boards of pharmacy host an online database where such licensure can be verified.
Check for Form 483 Inspections and Warning Letters
The FDA occasionally conducts observational inspections of compounding facilities and may issue a Form 483 if they notice any potential regulation violations. This form precedes a more serious warning letter and may indicate serious safety concerns with compounding facilities. The FDA hosts a website that prescribers can check to see [BS1] if a compounding firm has received a Form 483 or warning letter, as well as other relevant news about their compounder.
Ensure API and excipient safety
According to the FDA’s FD&C Act regulations, APIs must be sourced from an FDA-registered facility. As we showed previously, there are potential risks when APIs are sourced from non-registered facilities. Each API should come with a safety data sheet (SDS) that lists all of its hazards. Although compounding pharmacies should strive to also source their excipients from FDA-registered facilities, this may not always be possible. Therefore, the USP has provided general guidance on what a certificate of analysis (CofA) should include, some of the most important of which are:
- Name of the excipient/API
- Batch number
- Date of manufacture
- Expiration date
- Stability statement
- Any performed analyses, their results, and acceptance criteria
- Identity of authorized individual and the date of their approval
Prepare for the changes now!
Although the USP’s official date for these changes isn’t until November 1, 2023, the time to begin implementing them is now. It will take time to develop new SOPs and train staff on any new procedures. Additionally, new equipment may need to be ordered, which might require budgeting considerations. Pharmacies should give themselves plenty of time to make sure their staff is comfortable and compliant with any updated protocols.
Why choose VLS Pharmacy and New Drug Loft?
VLS Pharmacy stays on top of any changes to USP guidelines to ensure we are fully compliant and prioritize patient safety. As a 503A pharmacy specializing in sterile and non-sterile compounding, we will support you and your patients by creating safe, individualized, and effective pharmaceutical therapies. All formulations are compounded with high-quality pharmaceutical-grade APIs sourced directly from PCCA, the leader of superior-quality APIs because they test each lot against the certificate of analysis (C of A), USP, EP, NF, FCC, ACS, and PCCA standards. We assign our BUDs by relying on our considerable expertise and following the latest USP <797> and USP <795> guidelines as well as USP <800> guidelines for hazardous drugs.
For men and women at any age, feeling healthy, conﬁdent, and comfortable is of the utmost importance. Your patients’ needs will change with each life stage. As such, they require an adaptive and personalized treatment plan. By working with a trusted compounding pharmacy like VLS Pharmacy and New Drug Loft, you are expanding the possibilities for successful and sustainable care.
Although the guidelines in this blog post are a great start to assist prescribers in understanding changes to USP <795> and <797>, it is not intended to be a comprehensive guide. For the latest updates and complete guidelines, we encourage prescribers and pharmacies to consult the USP Compounding Compendium (which is now available exclusively online), as well as their state’s board of pharmacy.
Reach out to our team to learn about best practices and to partner with our experts on custom compounded medications for your patients. All medications from VLS Pharmacy and New Drug Loft are prepared in a lab that follows safety and quality standards per our status as a 503A pharmacy.
(1) 2022 Revisions to USP General Chapters to 795 and 797 https://go.usp.org/2022_Revisions_795_797 (accessed Dec 8, 2022).
(2) Recognition of USP Compounding Standards | USP https://www.usp.org/compounding/legal-considerations (accessed Dec 8, 2022).
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