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Pharmaceutical Compounding

The process of pharmaceutical compounding refers to the mixing of drug and other ingredients by a licensed pharmacist, normally under the guidance and regulation of state and federal authorities. All pharmacists are trained in basic compounding but there are pharmacists employed by specialty pharmacies who perform extensive compounding all day.

Besides following the rules and regulations set forth by the governing agencies, pharmacists also follow the standards established by professional compounding organizations. These excellence standards address the quality, purity and strength of the ingredients used to complete the final compounding products. There are separate sets of principles created for sterile and non-sterile preparations.

In this course, we will review the basic guiding criteria used for compounding. All the material contained herewith is intended for general information purposes only. Due to the nature of the subject, regulatory agencies may revise practices periodically. Visit the USP-NF, FDA as well as your local State Board of Pharmacy’s websites for detailed regulatory compounding practices.

What is Compounding?

Compounding – There are two versions of the legal definition of compounding. One by the Food and Drug Administration (FDA), the next by the United States Pharmacopeia (USP). The first, by the FDA, section 503A of the Food Drug &Cosmetic Act which basically states a compounded product must meet the following criteria in order to be considered a compound under section 503A:

  • Product is prepared for a specific patient under the order of a physician.
  • Product is prepared in a facility approved by the governing State Board of Pharmacy, within a state that coordinates with FDA under Memorandum of Understanding (MOU).
  • Compounded human drug product is prepared by a licensed pharmacist or physician.
  • All products are compounded in compliance with the standards set by United States Pharmacopeia (USP), and within established quantity limits.
  • All ingredients must be manufactured by companies that are registered at and approved by the FDA.
  • Final product must not represent an exact duplication of an already existing commercial product, or product that was withdrawn from the market for safety concerns.
  • USP has a broader definition of compounding: “…preparing, mixing, assembling, altering, packaging, and labeling of a drug, drug-delivery device, or device in accordance with a licensed practitioner’s prescription, medication order, or initiative based on the practitioner/patient/pharmacist/compounder relationship in the course of professional practice.”
  • The main differences being that the preparation of a medication by a pharmacist according to the packaging directions, is considered a compound by USP but not by the FDA. Therefore, if the pharmacist is preparing a medication following manufacturer’s instructions, and does not deviate from those directions, then the product is not bound by the FDA section 503A guidance.
  • To clarify, the FDA does not consider a drug that was mixed or reconstituted using package instructions, a “compound”. Its definition further extends to say that a compound may also refer to the combining, mixing, or altering of ingredients of a drug by another person working under the specific supervision of a licensed pharmacist, to make a medication to satisfy the individual needs of a particular patient.

Types of Compounding

When a patient needs two compounded medications, an intravenous drug and a topical medication which must be tailored to their needs, under what conditions must the durgs be compounded? Do they require different precautions because of the method of delivery? Yes, because of the mode of administration, the IV drug requires a more sterile preparation. While mixing the topical product in non-sterile conditions would be generally acceptable. Thus, there are two major types of compounding practices, sterile and non-sterile compounding.

Sterile Compounding – requires producing a drug in a virus, bacteria, or other infectious microorganism free environment. This kind of compounding is reserved for use of drugs which are to be given by ophthalmic administration, injection, inhalation, or intravenous route. By using sterile compounding techniques, the risk to introduce infectious particles from these products is significantly reduced.

Non-sterile Compounding – still refers to the producing of a medication in a clean environment but it does not have to be completely devoid of microorganisms. Oral medications such as tablets, capsules and liquids are made under non-sterile compounding. Topicals like creams, ointments, and suppositories also fall under this compounding category which already have a reduced risk of causing an infection.

Why are Sterile and Non-Sterile Compounding Necessary?

Millions of prescriptions are compounded every day in hospitals, specialty pharmacies and other pharmacies/facilities. There are many reasons why an individual may need a compounded drug. Sometimes a patient needs a drug that contains a dye or excipient which causes them an allergic reaction. A compounding pharmacist can prepare a formulation of that same drug using the active ingredient while excluding those unnecessary elements in the formula suspected of causing the allergy.

When an elderly person or a small child has a problem swallowing a medication that is not available in liquid, once again, a pharmacist can produce a liquid form using the active ingredients. Thereby significantly improving compliance and ensuring a better patient outcome. Even if a baby needs a unique strength of a drug that is currently not commercially available, the pharmacist can create this exclusive dose and also alter the flavor by using flavoring additives. Making the new formulation for the infant more desirable and palatable.

Patients in hospitals often have special needs for tailored medications. Therefore, hospitals perform inhouse extensive compounding to produce compounded drug for immediate need and can stock for anticipated demand.

Dangers of Compounded Drugs

Compounded drugs are not considered to be FDA approved drugs. As per guidance from the FDA, drugs which are compounded, are not thought to have equal quality, safety, or efficacy as their approved counterparts. Unfortunately, sometimes the use of compounding can increase a patient’s exposure to serious health risks.

The main reasons why a compound is associated with greater risk of harm are as follows:

  • Pharmacist or pharmacy technician makes an error in preparation, such as, selecting the wrong ingredient or measuring incorrectly.
  • Pharmacist or pharmacy technician does not follow proper preparation technique (sterile or nonsterile).
  • Pharmacist or pharmacy technician use inadequate or inappropriate ingredients (damaged, expired, etc.)
  • Pharmacist or pharmacy technician work with faultily sterilized equipment.
  • Pharmacist or pharmacy technician use inadequate sanitary maintenance practices.
  • Pharmacist or pharmacy technician do not use proper or adequate quality controls.

Of course, when compounding, it is the pharmacist and pharmacy technician who are responsible for delivering a safe and effective product to the patient.

Dangers of Compounded Drugs – Cases

It is crucial to recognize the impact to the patient when failing to produce a safe and effective product. The following cases represent instances where something went seriously wrong during compounding. The resulting devastation includes permanent harm to the patient, damage to the reputation and standing of the pharmacy, and uncertainty to the future of the pharmacist.

Dallas, TX. 2017 – An intravitreal injection made from the combination of triamcinolone and moxifloxacin was compounded by Guardian Pharmacy Services and used in the eyes of 43 patients. The various adverse events reported included general vision and night vision impairment, color perception loss, considerable reductions in vision field and vision acuity.

Upon the conclusion of the FDA’s investigation, it was found that the compounding pharmacy had used preservatives even though they had labeled their product PF (preservative free). The issue was caused by the degradation of these excipients which contaminated the resulting batch. The clinic’s use of outdated product was discovered to have also contributed to this issue.

Check your Knowledge Question and Scenario 1

Check your Knowledge Question and Scenario 1 – Answers

Dangers of Compounded Drugs – Cases cont.

New York City, NY. 2016 – This case involved an IV flush that was used at an oncology clinic whose patients had an implanted vascular access port. They had received this flush which is a compounded product containing saline, heparin, vancomycin, and ceftazidime. Records show that 38 patients received the IV combination. Six of which had passed away before the investigation began, 3 refused to participate in the evaluation leaving 29. Screening found that the blood of the patients was contaminated with a fungal infection. Two of the patients died during the investigation, and those testing positive for the fungal infection were treated accordingly.

Final analysis determined that the clinic failed to meet CDC infection control standards. Additionally, the clinic neglected to follow required procedures for sterile medication compounding and the handling of hazardous drugs. The clinic had the solution compounded under poor conditions, it had been stored in the refrigerator and accessed multiple times for a period of four to eight weeks. This is what, it was ultimately concluded, contributed to the development of the contaminant.

Framingham, MA. 2012 – New England Compounding Center (NECC) was the focus of this investigation. They produced a preservative-free methylprednisolone acetate injectable that was used to reduce pain and swelling in people’s backs and joints like the knee, shoulder, or ankle. The compounded product included about 14,000 units and was distributed to multiple states. Because of NECC’s substandard compounding practices, and laxed safety measures, their steroid product developed mold and caused over 750 people to become sick with a fungal infection. It was reported that over 60 people lost their lives as a result of the contaminated product.

The inquiry concluded that the NECC failed to maintain a proper clean room for compounding. The center was filling false prescriptions under fake names like “Coco Puff”, “Chester Chetah”, “Harry Potter” and others. They used these phony prescriptions to continue to operate as a compounding pharmacy regulated by the FDAs (503A) and not have to be subjected to the more stringent rules under the agency’s Current Good Manufacturing Practice (CGMP), which is in place for mass drug production.

As of recently, there have been fourteen people prosecuted for their role in the NECC’s attempt to deceive the government and the public. The owner, also a pharmacist, is serving a nine-year prison term for multiple related felony charges. The pharmacist-in-charge was sentenced to eight years. Both also await trail in Michigan for second-degree murder, in response to those patients that perished.

A positive change did come about from the NECC case. Today, the United States has more clarity and a better approach for the regulation and oversight of pharmacies that provide compounding services. The FDA now has uncontested authority to not only regulate but take necessary action against those violating the rules. This positive change came in the form of legislation following the NECC incident. In 2013, Congress passed the Drug Quality and Security Act (DQSA). As a result, pharmacies compounding in bulk and shipping out of state must register as outsourcing facilities under the FDA. This brings them directly under FDA oversight and makes them subject to inspection. It also requires them to operate under the more stringent regulations of the Current Good Manufacturing Practices (CGMP).

Pharmacy Compounding Regulation

Establishing the Standards

As an original, major part of the professional duty, pharmacists have been compounding for over a hundred years. This obligation has evolved throughout time, slowly becoming what it is today: A serious commitment to satisfy the special needs of the patient by providing a unique, compounded product that meets safety and quality standards.

Compounding is a task that must be accomplished while following evidence-based standards of purity control, sterile processing, and quality assurance. The known authority in setting these standards is the United States Pharmacopeia (USP). A private, nonprofit entity responsible for the identity, strength, and quality of drugs, supplements and food additives used in compounding.

Since 2000, the USP has been involved in creating and publishing quality standards for the purpose of ensuring the safety of the employees working on the compounded preparations and that of the patients who receive the final product.

Chapter <795> and <797> of the USP were established as a template for compounding procedures pharmacies can follow and for use by the regulating agencies for the purpose of enforcement. The USP standards for compounding are the most stringent guidelines found. USP is world renown and works in collaboration with foreign pharmacopeias and other organizations to help create trust in medications throughout the globe. USP standards are recognized today in 140 countries.

Chapter <797> – in this chapter, are the USP’s national standards for processing, testing, and verifying compounded products that were prepared under sterile conditions. The guidance provided refers to the prevention of contaminants and other variables in sterile products. The recommendations are geared toward both hospital and community pharmacies and applies to all who is involved in sterile compounding whether, pharmacists, pharmacy technicians, doctors, nurses, or others.

Chapter <795> – This chapter contains similar information from the <797> chapter, but it is primarily directed to non-sterile products. It defines the different compounding classifications which include simple, moderate, or complex. The ‘beyond use date’ and stability indicators are also discussed, some of which will be discussed later.

Chapter <800> – The standards outlined in this chapter are designed to promote the safety of compounding employees. Here, USP creates quality and procedural standards for the handling of hazardous drugs. The purpose is to minimize exposure of the person doing the compounding, veterinarians, veterinary technicians, pharmacists, pharmacy technicians, and all others. It also takes into account the patient’s safety and affords specific provisions for environmental protection.

State Oversight – State Board of Pharmacy

The primary oversight for compounding pharmacies comes from the State. The State Board of Pharmacy is responsible for creating the rules that govern pharmacy compounding practices. It is also accountable for enforcing these same regulations.

The State Boards use USP standards as the benchmark to meet. All pharmacies must comply with the recommendations for compounding set forth by the USP as well as comply with all other rules established for the practice. Some of which include:

  • All pharmacy staff must have a current license or certification to practice pharmacy.
  • Compounds are produced in a licensed facility in an approved environment.
  • All drugs and ingredients are kept under secure storage.
  • Records are maintained properly and securely.
  • There is adequate purity/stability testing and storage of compounded product.
  • Compounds are being produced on the order of a physician.

Pharmacies are monitored through regular and surprise inspections for compliance. Unfortunately, due to the large volume of pharmacies, the number of Board visits are few and far between.

Check your Knowledge Question & Scenario 2

Check your Knowledge Question & Scenario 2 – Answers

Federal Regulation – Food and Drug Administration (FDA)

Once again, compounded drugs are not approved by the FDA. They are not evaluated for quality, safety, or efficacy. In order for a drug produced by mixing, adding, or altering ingredients to be considered a compound, it must be ordered by a physician. The FDA has strict rules differentiating between compounded drugs and manufactured drugs.

According to the FDA, compounding is reserved for a smaller facility that prepares product as per the request of a doctor and production is maintained on a lower scale. Here, the enforceable standards include section 503A of the Food, Drug and Cosmetic Act. However, the mass production of medications is considered manufacturing.

Therefore, a facility producing mass quantities of drugs must follow the more stringent Current Good Manufacturing Practice standards. Furthermore, all ingredients used by either compounding pharmacies or drug manufacturers must be FDA approved.

The Drug Quality and Secure Act of 2013, which came in response to the numerous incidents of contaminated compounded products, gives the FDA the opportunity to exercise undisputed authority over compounding pharmacies.  To oversee and take action against violators.

Compounding Control Substances

Drug Enforcement Administration (DEA) – is the oversight agency for the compounding of control substance ingredients. Some of these controlled substances include narcotics like hydrocodone and oxycontin. Benzodiazepines used for anxiety or sleep like diazepam or lorazepam also fall under the controlled substance category, among many others. In the Pharmacist’s Manual – An Informational Outline of the Controlled Substances Act, pharmacy compounding is addressed. The DEA outlines expectations for compounding pharmacies.

National Institute for Occupational Safety and Health (NIOSH) – is a government agency that falls directly under the Centers for Disease Control and Prevention (CDC). Their primary mission is to protect workers. Through research, studies, and guidance, they promote the safety and health of the worker. The NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings is a comprehensive list that includes the name of the drug, reason for being categorized as hazardous, and the American Hospital Formulary Service (AHFS) classification.

Occupational Safety and Health Administration (OSHA) is a governmental agency that reports to the United States Department of Labor. It is responsible for protecting the safety and health of workers by ensuring proper working conditions. This is accomplished by establishing standards and enforcing them through training, instruction, and outreach. Although fines may be issued if failure to take corrective action occurs.

They created the Hazard Communication Standards (HazCom). It provides information that helps identify hazardous chemicals. Manufactures of chemicals are required to assess their products, provide labels along with informational sheets that give the hazard data. All workers must have access to these data sheets so that they are aware of how to manage hazardous chemicals properly.

OSHA safety regulations apply to all pharmacies including community, hospital, and specialty pharmacies. Institutions are required to maintain a safe work environment and employees must be appropriately trained to handle hazardous drugs.


 

Pharmacy Accreditation Services

Accreditation Commission for Health Care (ACHC) – is determined to help healthcare providers, reach, and maintain the highest standards. They operate under the standards created by the U.S. Pharmacopeial Convention (USP) guidelines.

Pharmacy Compounding Accreditation Board (PCAB) – is the specific accreditation agency under the ACHC that will send out an experienced inspector to a compounding pharmacy be it a mail order, community, or hospital pharmacy, to conduct a comprehensive evaluation of compounding practices. The extensive assessment includes facility requirements, employee training and procedural practices. In order to maintain accreditation, institutions must be surveyed regularly, within predetermined intervals.

Accreditation is a voluntary status a compounding pharmacy provider selects to have to demonstrate their willingness to uphold the highest standards and their commitment to substantially lower the risks related to compounding drugs. It also helps them remain compliant with all state and federal requirements, ensuring them a greater probability of passing inspections.

The Joint Commission (TJC) – has specifically the Medication Compounding Certification for compounding providers. The accreditation process provides assistance and tools to help a compounding pharmacy maintain compliance with the United States Pharmacopeia (USP) standards.

The focus is on the employees, the facility environment, and the final product produced. Attention is given to whether the pharmacy staff is properly trained and demonstrate appropriate use of personal protective equipment while following required aseptic procedures. The facility is inspected to ensure airflow and buffer requirements are met and that recommendations for cleaning, documenting and storage are followed. Compounding products are randomly checked for sterility, beyond use dates, and proper labeling.

This accreditation is very significant especially to hospitals. A gold seal from the TJC represents the health organization’s commitment to maintaining high safety and quality of care. Thereby reducing the inherent risk of error due to inadequate care. Providers that lose their TJC accreditation are in danger of losing the privilege of providing services to commercially insured patients.

Other Pharmacy Compounding Organizations

Professional Compounding Centers of America (PCCA) – is an organization that is committed to education, support, and training for compounding pharmacists. They also provide resources on compounding chemicals, devices, and equipment. They hold an annual International Seminar where compounders can meet and connect to discuss emerging trends.

Alliance for Pharmacy Compounding (APC) – is an advocate organization that lobbies Congress, the FDA, and other regulatory agencies on behalf of compounding pharmacies/pharmacists. Their mission is to preserve the right of the patients to have access to unique, life altering compounded products and to protect the ability of compounding pharmacies to conduct business successfully and ethically.

Compoundingtoday.com – is a website that provides complete and detailed information required to maintain a successful compounding pharmacy. It is produced by the International Journal of Pharmaceutical Compounding. It is an excellent site for compounding tools and resources often used in daily compounding activities.

Some of these organizations require memberships. Anyone that finds themselves working in a pharmacy that performs extensive compounding may greatly benefit from the support and resources of these organizations.

Required Compounding Training 

Non-sterile Compounding

Training for non-sterile compounding is less stringent than that for sterile compounding. It does not require an extensive course of 20/40 hours as in sterile compounding. It does require written education, practical training, and demonstration of competency. There is also required continuing education to learn and maintain refined techniques.

A pharmacist is responsible for:

  • Checking and authorizing drug components, containers, closures, labels, and everything else related to compounding.
  • Reviewing compounding documentation for accuracy.
  • Performing during and final compounding checks to prevent mistakes.
  • Making sure all compounding equipment is properly cleaned and maintained.

 

A pharmacist technician is expected to:

  • Have the proper training, education and demonstrate the competence required to complete non-sterile compounding.
  • Receive continuing education in accordance with the type of compounding they perform.
  • Compound only under the direct supervision of a licensed pharmacist.

Additional Sterile Compounding Training Requirements

The pharmacy staff training requirements for a compounding pharmacy is delegated by the State Board of Pharmacy where the pharmacy is located. The succeeding information is taken from the Texas State Board of Pharmacy compounding rules.

For the most part, the compounding knowledge prerequisites included have both written and practical experience training requirements. The compounding technician must be evaluated for competency which is assessed through demonstration in both written and experiential testing. All training must be kept documented, and it must include knowledge and skill in the following categories:

Media fill testing is the method used to assess pharmacy personnel’s technique and competency for aseptic manipulation of created sterile preparations (CSP). This evaluation will determine if the ability to fill, transfer and handle tasks free of contamination is sufficiently present. Specific repeat competency testing requirements are mentioned on the next slide.

The expectation is for the pharmacist-in-charge to establish continuous compounding competency testing for all pharmacy staff. It should include in-service education, hands on training both written and practical, and media-fill testing. There are requirements for the minimum number of times these education exercises and competency evaluations should occur, they include:

The managing pharmacist is considered responsible for continually providing supervision and guidance to minimize error and reduce the risk of contamination. If multiple technicians are being monitored, it is recommended to perform consistent during compounding checks rather than just final checks.

Check your Knowledge Question & Scenario 3

Check your Knowledge Question & Scenario 3 – Answers

Assessing Aseptic Technique

Aseptic technique is a significant factor in maintaining sterility in sterile compounding. It is the process of preventing microorganisms like viruses and bacteria from developing in a compounded preparation. The reason to use aseptic technique is to protect the patient from getting an infection from a contaminated compounded product. Every employee that prepares compounded sterile preparations (CSP), should be observed, and reviewed by pharmacy management at least once a year. Regular inspections should be performed and must include at a minimum observation of the following characteristics of aseptic technique:

Compounding Terms

It is important to recognize the definition of the following terms in order to ensure adequate comprehension of sterile and non-sterile compounding rules.

Compounding area – a critical area designated International Organization for Standardization (ISO) Class 5. Here vital sites are subjected to unidirectional high-efficiency particulate air (HEPA)- filtered air.

Clean room – a room with controlled directional air flow filtered by HEPA to meet a specific particulate cleanliness class. The microbial quantity for air, surface and staff is tested and verified to meet specific ISO classification.

Beyond-use date (BUD) – a date that indicates when a compounded product should not be used after. This date is established based on the date the compounded preparation was produced.

Aseptic technique – using proper hand hygiene, dress, and movement within a sterile clean room for the purpose of maintaining the sterility of equipment, vials, containers and syringes in the compounding area.

Compounded preparation – an either sterile or non-sterile product that is compounded in a licensed pharmacy following an anticipated or given order from a licensed physician.

Critical site – an area which includes section of fluid surfaces like beakers, vial septa, injection ports or it has openings like needle hubs or ampules that have exposure and greater risk of direct contact with air, moisture, or physical contamination.

Engineering controls – devices designated primary, secondary, or supplemental used in the reduction of staff exposure to chemical hazards and for protection of compounded sterile preparations (CSP) from contamination. Some examples include biological safety cabinets (BSC), closed system drug transfer device (CSTD), retracting syringe needles and safety interlocks.

High efficiency particulate air filtration (HEPA) – Filtration device that has a minimum particle collection efficiency of 99.97% for removal of particles with a diameter of 0.3 micrometers or larger.

Laminar airflow workbench (LAFW) – a working area designed with a laminar airflow system that complies with the ISO requirement for Class 5 or better sterile environment for compounding. It is comprised of a unidirectional HEPA filtered airflow system.

Master formulation record (MFR) – official, detailed documentation of the formula (or recipe) of a compounded product. It normally includes the name, strength and dosage form. It also contains the calculations needed for preparation, instructions for the mixing of ingredients and packaging, storage and BUD information.

Personal protective equipment (PPE) – items used for the protection of compounding staff from hazardous exposures. These include items like face shields, masks, goggles, respirators, gowns, and gloves.

Quality assurance – a process of methods, activities and controls that assures all highest quality levels and operational standards are constantly met.

Quality control – refers to the taking of samples, analyzing them for purity and accuracy of strength, and documenting the results to verify requirements have been fulfilled prior to releasing the final product.

Compounding record (CR) – an official record of the compounded preparation. The CR contains specific information about the compound and its production step by step process.

Repackaging – actually transferring the contents of a conventionally manufactured product from its original container, to a secondary, normally smaller one.

Media fill test – the use of a sterile microbiological growth medium, instead of a drug solution, for the purpose of assessing if the aseptic methods are appropriate to avoid contamination during an actual drug production.

Safety data sheet (SDS) – a detailed description of a hazardous chemical product which contains specific information required by regulating agencies. It used to be called the material safety data sheet.

Stability – the degree to which a compounded product preserves the same properties and characteristics within a specified period of storage and use.

Sterilization – the use of physical and chemical processes to destroy or eliminate microorganisms. Some of these include under pressure steam, hydrogen peroxide gas plasma, ethylene oxide gas, dry heat and other liquid chemicals primary used in healthcare settings.

Active pharmaceutical ingredient (API) – a substance or mixture of substances that is used in a drug compounding preparation as the main ingredient and that is expected to produce pharmacological activity that may affect the structure or function of the body.

Consistent training of personnel is essential for any compounding pharmacy. It is crucial to confirm that all pharmacy staff possess the knowledge and understanding of all compounding terms. There are more terms associated with compounding. Some will be discussed later as they relate to the subject at hand.

International Organization for Standardization (ISO) class

The ISO designation refers to the airborne particulate cleanliness class. The intensity of cleanliness indicated by the most amount of allowed particles per cubic meter of air in a particular atmospheric environment. The ISO class is used to reference the type of class a clean room or clean area is required to have.

The above table represents the most updated classifications. It also contains the only three classes addressed in the Texas State Board of Pharmacy sterile compounding rules. Check with your state board of pharmacy for specific ISO class requirements in your area.

Compounding Environment

There are different environment requirements for sterile and non-sterile compounding. The specifications for a sterile drug preparation area are more stringent and quite detailed. On the other hand, the compounding space for non-sterile production requires minimum planning depending on the amount of compounding done.

Non-sterile preparations

Sterile preparations – Clean room

For high-risk preparations, everything listed in the previous slide for the low to medium risk preparations plus:

Check your Knowledge Question & Scenario 4

Check your Knowledge Question and Scenario 4 – Answers

Engineering controls

Primary Engineering Controls – refers to a machine or space that should offer an ISO Class 5 environment for critical site exposure during sterile compounding procedures. Examples of these devices include biological safety cabinets (BSC), compounding aseptic isolators (CAI), compounding aseptic containment isolators (CACI) and laminar airflow workbenches. These devices are designed to safeguard the compounded sterile preparation from both microbial and cross contamination.

Secondary Engineering Controls – any room or area that leads to a primary engineering control. Examples are the anti-areas and buffer areas (clean rooms). According to the state board rules, these rooms or areas must be at least an ISO Class 8 or safer (lower number like a 5 or a 7).

These ISO classifications requirements for primary and secondary controls are recommendations found in the United States Pharmacopeia – National Formulary (USP-NF). These are the guidelines the board of pharmacies follow when creating their rules and regulations.

HEPA Filtration

In clean room environments, particulate matter is a major cause of contamination. These can include skin cells, dust, strands, virulent microorganisms, and other airborne fragments. They can cause both an impure compounded sterile preparation and a serious infection to a patient.

A high efficiency particulate air (HEPA) filter is a type of pleated air filter. It is expected to remove at least 99.97% of bacteria, dust, mold, pollen, and other airborne particles that are 0.3 microns in diameter.

Currently, the State Board rules, the FDA and the USP have specific requirements for HEPA filtration placement in a clean room. In the case of the ventilated cabinet, the requirement is to have inward airflow to protect the compounder, downward HEPA filtered laminar airflow to save the compound’s critical sites, and for environmental protection, a HEPA filtered exhaust.

HEPA filters are not designed to remove gasses, odors, or chemicals. This is why NIOSH requires the HEPA filter exhausts. It prevents the pharmacy staff from exposure to harmful gasses while still protecting the environment.

Microbial Contamination Risk Levels

A categorization assigned to a specific type of sterile compounded preparation corresponding to its potential to be introduced with contaminants during the compounding process is called microbial contamination risk level.

All risk levels below are as outlined under USP chapter <797>, Pharmacy Compounding – Sterile Preparations. There are basically five different risk levels, these are: for immediate use, low risk, low risk with a BUD of 12 hours, medium risk and high risk.

Immediate Use Compounded Sterile Preparations – to be used for immediate or emergency patient care. Examples include compounding during cardiopulmonary resuscitation, treating in the emergency room, preparing agents used for diagnostic testing, when compound is urgently needed, and delay may harm patient. In order for a compound to qualify under this category, all of the following standards must be met:

Microbial Contamination Risk Levels – cont.

Immediate Use Compounded

Sterile Preparations

Low-Risk Level Compounded Sterile Preparations – are compounds that have been compounded using ISO Class 5 aseptic manipulations or better air quality. These preparations are compounded using only sterile devices, ingredients, and components. Examples of compounded preparations that fall under this category are single volume transfers using sterile syringes/needles, into other sterile containers or administration devices. Below are the required standards that must be met.

Storage

Low-Risk Level Compounded Sterile Preparations with 12h or less BUD – These compounds are prepared for a particular patient, following a doctor’s order. To meet this classification, the subsequent conditions must be met:

Low-Risk BUD < 12h

Medium-Risk Level Compounded Sterile Preparations – are compounded under low-risk circumstances plus one or more of the conditions listed below. Examples of medium risk compounds include parenteral nutrition fluids which requires multiple aseptic manipulations, filling infusion device/reservoirs of injection with three or more products, filling of infusion devices/reservoirs of injection using sterile drug solutions which are to have prolonged administration (in temperatures of 25o to 40o C/77o to 104o F).

Storage

               

An important point to consider, is that there are other factors to take into account besides risk levels and engineering controls before calculating beyond use dates (BUD). For instance, if according to Trissel’s handbook (Stability of Compounded Formulations), a drug whose stability is only 6 hours after mixing with a solution, the beyond use date cannot be 12 hours regardless of what primary engineering control was used or which ISO Class cleanroom compound was prepared in.

Check your Knowledge Question and Scenario 5

Check your Knowledge Question and Scenario 5 – Answers

High Risk Level Compounded Sterile Preparations – are compounds that were produced under the conditions listed below. Examples of high-risk level compounds include those prepared using sterile ingredients exposed to air quality above ISO Class 5, for over 1 hour, utilizing non-sterile drug powders to mix into solutions, using non-sterile devices to mix sterile ingredients, using bulk product without checking for contamination or adulteration between uses.

High Risk Level

Storage

High Risk Level

The compounding of high-risk compounds still require the identical ISO Class as those used in low and medium risk. The main reason a final compounded sterile preparation is considered high risk is because non-sterile ingredients were used during production.

Basically, ISO classifications help determine a compounded sterile preparation’s risk level. There are other factors that also assist in establishing the risk level such as the number of commercially manufactured packages used, whether sterile or non-sterile ingredients are used, if sterility tests will be conducted or not, and the number of entries performed on a single container.

BUD, Packing and Labeling for Non-Sterile Compounded Products

Non-sterile compounds prepared at the pharmacy must be packaged in tight, light resistant containers. The pharmacist is to determine the beyond use date (BUD) by considering the following criteria:

 

  • Active ingredient’s chemical and physical properties.
  • Whether preservatives or stabilizing agents were used.
  • Which compounded dosage form was produced.
  • What storage containers were used and the conditions it was under.
  • Whether there is scientific data or reference data available.

 

The reason compounded preparations should be dispensed in a tight, light resistance container is to prevent UV light from degrading its contents. If stability data is not available, the following beyond use dates must be used.

  

  • Liquids and Solids (nonaqueous) – BUD should be 25% of remaining manufacturer’s expiration date (from drug used as active ingredient) or six months, whichever occurs first.
  • Formulations containing water – having used solid ingredients, BUD should be not more than 14 days if refrigerated (2o to 8o C / 36o to 46o F).
  • All other formulations – BUD should be whatever the doctor indicated for therapy duration or 30 days, whichever occurs first.

 

After a compounded product has been properly packaged, it must be labeled. The following information should be included on the label for a non-sterile compound.

  • Full name of patient
  • Name of Doctor
  • Name, address, and phone number of the pharmacy.
  • Prescription number
  • Official name of drugs/ingredients in compounded preparation and quantity.
  • A statement indicating that the drug was compounded (can be on auxiliary label).
  • A beyond use date.
  • Pharmacist’s name or initials 

A patient must receive a written information sheet about the drug/active ingredients used to compound. Patient must be counseled by pharmacist on the name, strength, how to use or take compounded product, how to store it, when to discard it, any possible side effects, how long it will take to notice efficacy, and answer any patient questions. There are also documenting requirements for non-sterile compounding that will be discussed in an upcoming slide.

Packing, Labeling and storage for Sterile Compounded Products

In sterile compounding there are many different types of packaging and repackaging. Below are some examples.

Pharmacy bulk packaging – refers to a sterile preparation container which holds a parenteral solution that is divided up into several single doses. It is meant to be used in admixtures for intravenous infusion. It must be labeled “Pharmacy Bulk Package–Not for Direct Infusion.“

Prepackaged Units – these are reduced quantities of drugs that are considered better suited for facility or institutional distribution. The label for each unit dose must include:

  • The brand or generic name of the drug, including the strength and dosage form.
  • The facility or institution’s lot number.
  • The expiration date of the drug.
  • The drug quantity in the new package.

 

Documentation of prepackaging should include all of the following information:

  • The brand or generic name of the drug, including the strength and dosage form.
  • The lot number assigned by the pharmacy or facility.
  • The name of the manufacturer that originally packaged the drug. 
  •  The lot number of the original manufacturer.
  • The original expiration date from the manufacturer.
  • The quantity per packaged unit.
  • The total number of packages.
  • The packaged date, and any new expiration date if assigned.
  • The pharmacist on duty’s initials.

Sterile preparations produced for anticipated use

The following labeling requirements are for sterile compounded products that are produced in anticipation of future use:

Storage is a major factor in determining and maintaining stability as well as in preserving the accuracy of an assigned beyond use date. The temperature, more specifically, of where a compound will be stored is more of the driving force in ascertaining beyond use dates. There is temperature monitoring check requirements once daily. This must be documented in a temperature log and maintained with other pharmacy records. USP has standard temperature ranges as follows:

  • Temperatures between 20o to 25o C (68o to 77o F) is considered controlled room temperature.
  • Temperatures between 8o to 15o C (46o to 59o F) is considered cool temperature.
  • Temperatures between 2o to 8o C (36o to 46o F) is considered cold or refrigerated.
  • Temperatures between -25o to -10o C (-13o to 14o F) is considered frozen.

  

Storage also includes the segregation of controlled and hazardous drugs. These types of drugs should possess additional security measures to prevent access to unauthorized individuals. They should be maintained in cabinets which are either locked by a key, numeric combination, or other electronic methods.

Documentation Requirements

Documentation requirements for sterile compounded preparations are slightly more extensive than non-sterile compounds but they share some common requirements. There are two main work data sheets that must be completed for each compounded preparation. These are the Master Formulation Record (MFR) and the Compound Record (CR).

It is important to maintain precise records of the formula of the compound (MFR), and how exactly the compound was prepared (CR). Although one form details specifically what was used to compound such as in a recipe and the other the procedure for the compounding, there are some overlapping information in the two forms.

All documentation must be kept in electronic form or hard copy so that a board inspector may have reasonable access to it. The time for record retention corresponds to the general period mandated for all pharmacy records. The next slide contains exactly what information is required on each form.​

Master Formulation Record (MFR) – must be completed by the compounder and have the initials of the approving pharmacist. An MFR contains all the required details for compounding the specified compound. The MFR always should include updated information and contain proper rationale and reference if any changes are made. All pharmacy staff must be notified of any changes in order to ensure compounding preparation quality and safety. A more complete MFR would contain the following information.

  

  • The name, strength, and dosage form of the compounded preparation.
  • The formula of the compounded product.
  • An actual physical description of the final product.
  • A list of the names and quantities of all the ingredients used.
  • Full instructions for the preparation process of the compound, including the supplies used, equipment and each step taken for the completion of the compound.
  • The beyond use date and the data used to determine it.
  • Any quality control methods used such as checking pH, vision inspection, filtering etc.

Compounding Record – also needs to be completed by the person doing the compounding and requires signature or initials of approving pharmacist. To be clear, USP requires the forms to be completed but do not have specific guidance on exactly what should be on the forms. For best practices, and for the sake of completeness, it is recommended to provide the following details.

The purpose for completing the MFR and the CR forms is to create a systematic method of going back to evaluate and replicate what was done during the compounding process. By creating this record, the details included can be used as reference for the next time this formula or compounded preparation needs to be mixed. This will increase the chances of producing a higher quality drug in a faster, more expedient manner.

Check your Knowledge Question and Scenario 6

Check your Knowledge Question and Scenario 6 – Answers

Continuous Quality Improvement (CQI) in Compounding

It is the pharmacist’s responsibility to have a secure and effective process in place to deliver a safe and accurate product to the patient. As with the dispensing of manufactured drugs, the best manner to accomplish this is to have a continuous quality improvement program.

A CQI is designed to evaluate errors that happen during the review, preparation, or dispensing of compounded medications. It is meant to address these errors and prevent the likelihood of repeating the same mistakes.

The Pharmacy State Boards recognize and require the need for a continuous quality improvement program in the pharmacy because it is in the best interest of public safety. A review of processes, systems, the technologies used, and any training or training gaps is included. The requirement is to perform a self CQI evaluation quarterly that shall be non-punitive.

The purpose for a Continuous Quality Improvement (CQI) program is to make sure that each compounded preparation produced is made safe and will remain stable until it’s beyond use date. This can only be accomplished through regular self-evaluation and consistent amendment to procedures to reflect changes of faulty processes.​

Standard Operating Procedures Requirements

A Standard Operating Procedure (SOP) is a written account of specific operational standards derived from either regulatory, law or business sources. It helps in ensuring the systemization of daily work processes so that daily tasks are performed properly and in the same manner.

According to state board rules, the requirement is to have written standard operating procedures for all significant process performed in compounding. These SOPs will assist in maintaining accuracy, safety, quality, and consistency in the process of compounding. This will also ensure accountability and a basis for the need to provide continuous training. The areas to which SOPs must be established and applied are:

 

  • Specifications for the facility and its maintenance.
  • Detailed information of equipment including cleaning, calibration, log readings, etc.
  • A complete evaluation of the compounded product, preparation processes, ingredient storage, etc.
  • Personnel requirements such as no open lesions, rashes, undesired garments, etc.
  • Quality Assurance procedures.
  • How to manage compounded product recalls.
  • Procedures for packaging and storing compounded products.

 

Active Learning

Unfortunately, it is difficult to find a source that provides extensive material on sterile compounding. Most information out there is either presented as a general, abbreviated summary, or as a narrow focus on a major component of compounding. It is not often that you find a gem that can be used as comprehensive review information as well as a resource for future inquiries like the one I stumbled into while researching this topic.

Below is a link to the University of Florida College of Pharmacy’s free home study manual on sterile compounding available online. It is probably the most expansive, detailed resource I have ever found. It touches on every single aspect of sterile compounding from the law to compounding calculations. A training section on aseptic techniques includes all types of sterile manipulations through specific detail, demonstrated with colorful photographs. It is an excellent resource to have.

Perhaps most crucial, is to abide by all the laws, regulations, and safety procedures to avoid serious consequences associated with product contamination. This can be accomplished with continuous education to remain current and compliant as required by law. I once heard a pharmacy manager ask his compounding technician, “Are you comfortable enough with your final product that you would gladly have your mother use it?” What about you? Are you?

https://education.lp3network.com/system/files/Sterile%20-%20Home%20Study%20Manual_1.pdf​

Conclusion: Maintaining USP Standards

Now a days, there is an increasing demand for compounded products, due to shortages, manufacturer backorders and other reasons for delayed production. Pharmacies are more engaged than ever to remain an integral part of that market. Therefore, compounding standards are required to produce safe and effective preparations.

A compounded drug can only reach the desired goals of purity, strength, and sterility from the direct methods employed to produce it. This remains the main reason why it is important to use the highest standards in production. The guidelines that have been created by USP which have been established through significant experimental study, are the standards for compounding recognized by the regulatory agencies, pharmacy state boards and the FDA. Their thorough recommendations cover every aspect of compounding.

Great care must be given to the designing of the compounding area which would require the use of easily cleaned materials for ceiling, floor, walls, and surfaces. Using the proper cleaning disinfectants is also critical in preventing contaminants from thriving and ruining the preparations. Environmental controls like HEPA filtration and airflow direction must be properly maintained. Furthermore, creating the proper ISO and risk-levels necessary to appropriately compound in accordance with all laws and regulations is essential.

Utilizing methods to test for purity and accuracy is another vital step in the adequate delivery of the safety and efficacy of a compounded product and is an essential part of the compounding process. Additionally, a vigorous personnel training program to ensure proper aseptic technique and a way to regularly evaluate skill set can be paramount.

While the charge of complying with all the requirements of USP compounding standards seems complex, expensive, overwhelming, and impossible to attain, compliance can be achieved through a systematic and organizational approach. Ultimately, it is the responsibility of compounding facilities and their personnel to observe all the established compounding rules and regulations and act in the patient’s best interest.

References

  • Texas State Board of Pharmacy. Texas State Board of Pharmacy Board Rules. March 12, 2021. §291.131 Pharmacies Compounding Non-Sterile Preparations, & §291.133 Pharmacists Compounding Sterile Preparations. https://www.pharmacy.texas.gov/files_pdf/TSBP%20Rules_MASTER%20FILE.pdf. Accessed May 2, 2021.
  • Food and Drug Administration. Pharmacy Compounding of Human Drug Products
  • Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance. June 2016. https://www.fda.gov/media/94393/download. Accessed April 27, 2021.
  • Becker S, Jinga LI. USP compounding standards: Prepare with care: Know the current standards. American Nurse Today. 2019;14(2):19. Accessed April 26, 2021. http://search.ebscohost.com. ruby.uhv.edu/ login.aspx?direct=true&AuthType=ip,uid&db=ccm&AN=134881490&site=eds-live
  • Kastango ES. Blueprint for Implementing USP Chapter 797 for Compounding Sterile Preparations. Vol 62. Oxford University Press / USA; 2005:1271. Accessed April 26, 2021. http://search.ebscohost.com. ruby.uhv.edu/login.aspx?direct=true&AuthType=ip,uid&db=syh&AN=17268827&site=eds-live
  • Lee LD. Compliant compounding. Meeting USP 797 pharmacy regulations. Health facilities management. 2010;23(2):36-39. Accessed April 26, 2021. http://search.ebscohost.com.ruby.uhv.edu /login.aspx?direct=true&AuthType=ip,uid&db=mdc&AN=21638948&site=eds-live
  • Hung JC. USP general chapter <797> pharmaceutical compounding-sterile preparations. Journal of nuclear medicine: official publication, Society of Nuclear Medicine. 2004;45(6):20N. Accessed April 26, 2021.http://search.ebscohost.com.ruby.uhv.edu/login.aspx?direct=true&AuthType=ip,uid&db=mdc&AN=15181114&site=eds-live.
  • Kastango ES, Bradshaw BD. USP chapter 797: establishing a practice standard for compounding sterile preparations in pharmacy. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2004;61(18):1928-1938. doi:10.1093/ajhp/61.18.192
  • Wilson, M., PhD. (2016). Sterile compounding pharmacies: States that do and do not require compliance with USP versus FDA 483s. Therapeutic Innovation & Regulatory Science, 50(3), 279-303. doi: http://dx.doi.org.ruby.uhv.edu/10.1177/2168479016636417
  • Traynor K. Pharmacists Prepare for New Compounding Standards. American Journal of Health-System Pharmacy. 2019;76(23):1886-1888. doi:10.1093/ajhp/zxz260
  • U.S. Food & Drug Administration, FDA’s Investigation into Guardian’s Compounding Triamcinolone-Moxifloxacin Drug Product. Updated July 5, 2018. https://www.fda.gov/drugs/human-drug-compounding/fdas-investigation-guardians-compounded-triamcinolone-moxifloxacin-drug-product. Accessed April 28, 2021.
  • Vasquez AM, Lake J, Ngai S, et al. Notes from the Field: Fungal Bloodstream Infections Associated with a Compounded Intravenous Medication at an Outpatient Oncology Clinic — New York City, 2016. MMWR Morb Mortal Wkly Rep 2016;65:1274–1275. DOI: http://dx.doi.org/10.15585/mmwr.mm6545a6. Accessed April 28, 2021.
  • U.S. Food and Drug Administration. January 31, 2018: New England Compounding Center Pharmacist Sentenced for Role in Nationwide Fungal Meningitis Outbreak. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/press-releases/january-31-2018-new-england-compounding-center-pharmacist-sentenced-role-nationwide-fungal. Accessed April 28, 2021.
  • U.S. Food and Drug Administration. December 20, 2019: Two Former Pharmacists at New England Compounding Center Sentenced in Connection with 2012 Fungal Meningitis Outbreak. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/press-releases/two-former-pharmacists-new-england-compounding-center-sentenced-connection-2012-fungal-meningitis. Accessed April 29, 2021.
  • Egervary A. Fungal Meningitis Outbreak Rocks U.S., Pharmacy Today. Nov 2012. Volume 18, Issue 11, P50-51. https://www.pharmacytoday.org/article/S1042-0991(15)31626-1/fulltext
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  • Occupational Safety and Health Administration (OSHA). Hazard Communication. https://www.osha.gov/laws-regs/regulations/standardnumber/1910/191
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  • Drug Enforcement Administration (DEA). Pharmacists Manual – An Informational Outline of the Controlled Substance Act. https://www.deadiversion.usdoj.gov/GDP/(DEA-DC-046)(EO-DEA154)_Pharmacist_Manual.pdf. Accessed April 30, 2021.
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