The complex world of compounding labs

The American Pharmacist’s Association (APhA) defines compounding as “the creation of a pharmaceutical preparation—a drug—by a licensed pharmacist to meet the unique needs of an individual patient (either human or animal) when a commercially available drug does not meet those needs.” Compounded drugs allow physicians to customize doses, delivery methods, and ingredients especially for their patients’ needs. For instance, if a commercially available drug is available only in tablet, a compounding pharmacy can create a liquid form for a patient who may have trouble swallowing. 

In the US, pharmacies are governed by The National Association of Boards of Pharmacy (NABP), which was founded in 1904 to assist the state boards of pharmacy by creating standards for education and licensing. The organizations membership includes 50 United States state boards of pharmacy, as well as the boards in District of Columbia, Guam, Puerto Rico, the Virgin Islands, 10 Canadian provinces, and The Bahamas. In the US, each state pharmacy board has their own standards, so if compounded drugs are shipped over state lines, the compounding pharmacy must ensure the standards within the destination state are met. 

Standards that govern medicines, dietary supplements and foods are published by The United States Pharmacopeial Convention (USP). The USP quality standards for medicines are published in “General Notices” and “General chapters”. However, the USP has no role in enforcement, which is provided by the FDA and other government authorities and accrediting bodies. Three key standards for compounding pharmacies include:

• USP 795 Pharmaceutical Compounding – Nonsterile Preparations
• USP 797 - Pharmaceutical Compounding – Sterile Preparations
• USP 800 - Hazardous Drugs—Handling in Healthcare Settings

However, some compounded drugs are not FDA approved, meaning that the FDA does not verify the safety, efficacy, or quality of the final product. This is because, typically, compounded drugs are not manufactured in large amounts for broad commercial sale. 

Changes in compounding regulations

In October 2020, the FDA released a Memorandum intended to address interstate distribution of compounded drugs and complaint investigation by a state regulator relating to compounded drugs distributed outside the state. As of February 2022, the FDA has suspended  the standard MOU published in October 2020.

"During the rulemaking process, FDA will not enter into new agreements with states based on this standard MOU. FDA does not expect states that have signed the standard MOU to carry out the activities described in the MOU. In addition, the standard MOU will be updated based on the content of a final rule, and FDA intends to announce a new opportunity for all states to consider and sign the updated standard MOU."

See updates on FDA.gov: “Memorandum of Understanding Addressing Certain Distributions of Compounded Drugs (MOU)” 

The FDA had already extended the period before it would begin enforcing the statutory 5 percent limit on distribution of compounded human drug products to out of the state locations. The agency will further extend the period during which they will not enforce the statutory 5 percent limit. Currently, the FDA encourages pharmacies, consumers, and state regulators "to submit information on serious adverse events and serious product quality issues related to compounded drug products."

The vital role of compounding pharmacies

It’s important to understand the reason for compounded drugs. As stated, the delivery method of the drug may be problematic for some patients. In addition, some drugs contain common allergens in the commercially available drug formulations. For instance, certain dyes which, while harmless for most people, are still common enough so that compounding pharmacies need to be able to create a version of the drug without that substance. 

Compounding pharmacies in the US can be accredited by the Pharmacy Compounding Accreditation Board (PCAB). Pharmacies accredited by PCAB are regularly surveyed and submit documented proof that they meet PCAB quality standards, including: 

•    Chemicals must be obtained from trusted suppliers
•    Pharmacists and technicians receive ongoing education 
•    Facility design meets related standards of decontamination
•    USP <795>, USP <797>, and USP <800> standards are met or exceeded
•    Accredited pharmacies meet PCAB’s “Principles of Compounding”

Compounding pharmacies must also adhere to standards of USP be able to prove adherence in a survey by an accreditor. 

The National Association of Boards of Pharmacy (NABP) works collaboratively with the FDA and state pharmacy boards. Pharmacies seeking to ensure they reach the highest standards in compounding can voluntarily take part in the NABP’s Verified Pharmacy Program (VPP) inspection program, which aids in compliance with state pharmacy board requirements, verifies pharmacy data, assists with meeting licensing standards, and demonstrates compliance to current US Pharmacopeia standards for nonsterile and sterile compounding. Over the years, more US state pharmacy boards are requiring 3rd party inspections, as the program provided by the NABP. To maintain accreditation, a pharmacy has to initiate a survey of their operations every three years. 

Compounding Pharmacy Types

Compounding is an increasingly complex web of compliance, standards, and accreditation. In general, the two main types of compounding include sterile and non-sterile.  Sterile compounding is used for drugs that will be injected, administered through IV, or directly into the eyes.  Non-sterile compounding medications typically include oral dosages like pills and liquids, or topical treatments. 

In recent years, the FDA has further categorized pharmacies according to what they can produce and how much they distribute. Compounding pharmacies are now divided into two sectors: 503A and 503B. 

Briefly, 503A compounding pharmacies use prescriptions for a specific patient. These pharmacies are focused on agility and specificity in production and are required by state boards of pharmacy to comply with USP and other guidelines. They dispense only for out-patient use, compound only in small batches, and are (ideally) enabled to control production costs to ensure the compounded drugs are accessible to patients. These pharmacies do not function as large-scale manufacturers and do not need to comply with cGMP.

In contrast, 503B compounding pharmacies are drug outsourcing facilities that manufacture in larger amounts to distribute. This type of compounding pharmacy does not have to wait for a single-patient prescription in order to manufacture a drug. They focus on known formulations that are not commercially available. Because 503B pharmacies act more like a manufacturer and distributor, they are regulated and inspected by both the FDA and by the state board of Pharmacy. The compounded drugs typically take time to create but are known to be in-demand and therefore, often kept in stock by healthcare facilities for in-patient use. To control the costs of these compounded drugs, 503B pharmacies can produce and distribute in larger batches.  

Although the FDA doesn’t directly regulate 503A compounding pharmacies, they can call upon state pharmacy boards or the NABP to inspect to gather data if there was ever any cause for concern. 

On the whole, it is inaccurate to say that compounding pharmacies are not federally regulated, because: 
1.    State boards of pharmacy ensure all compounding pharmacies follow state regulations for pharmacy practice, which are aligned with USP standards.
2.    The FDA regulates 503B compounding pharmacies, as well as all active pharmaceutical ingredients that are used in both 503A and 503B pharmacies.
3.    The Drug Enforcement Administration regulates the handling and distribution of all controlled substances.
    
In the US, state boards set out regulations that are similar to the environmental monitoring and data integrity expectations of cGMP. For instance, critical parameters in clean suites, such as temperature, humidity, differential pressure, particulate, are all monitored and alarmed. Clean suites are maintained according to appropriate certification levels. Compounding pharmacies that produce cytostatic drugs, parenterals and other sterile products must operate a qualified and validated clean room. 

Reducing risk in compounding pharmacies

Many compounding pharmacies, both 503A and 503B, use the Vaisala viewLinc monitoring system to record, alarm and report on their critical parameters like temperature, relative humidity, and differential pressures. In past, compounding labs might use basic thermometers. Under survey, this could bring questions about calibration, expiry dates, records, or gaps in temperature data. 

Many compounding labs now use systems like viewLinc to minimize risk and ensure their drugs are manufactured in controlled conditions, with recorded, inerasable data, and connected to 24/7 alarming for out of specification conditions. For instance, if a power outage occurs, pharmacies must ensure that expensive inventory is maintained under the correct conditions. 

The Vaisala mapping system can also be used to perform qualifications of rooms and chambers, such as refrigerators, freezers, and cold rooms.

Both the viewLinc monitoring and mapping systems use data loggers that record information at the point of measurement, as well as in the system’s server, so that data is never lost and cannot be changed. Easy access to these records, along with calibration data for the sensors, makes compliance and accreditation simple and efficient, with reports that can be customized, but not altered, either accidentally or deliberately.