cgmp 503b outsourcing

503B drug compounding facilities came into being as a result of the signing of the Drug Quality and Security Act (DQSA) in 2013. It marked a major transformation in the way that drug products are compounded in the US. One of those changes was the establishment of Section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C), which created what is formally known as the 503B Outsourcing Facility (although sometimes known as '503B pharmacy'). [1] 

These specialized drug compounding facilities serve a critical need along the patient care continuum; functioning between traditional compounding pharmacies that accommodate patient-specific prescriptions and conventional drug manufacturers.  503B outsourcing facilities can quickly supply sterile and non-sterile preparations in large batches to hospital pharmacies, ambulatory surgery centers (ASC), and other health care systems. 

Because they function much like pharmaceutical manufacturers, these unique compounding facilities are required to follow all applicable current Good Manufacturing Practices as designated by the Food and Drug Administration (FDA). The legal precedent for cGMP is established under the Code of Federal Regulations (21 CFR Parts 210 and 211). [2] 

In this article, experts at Fagron Sterile Services provide a breakdown of cGMP 503B outsourcing regulations and describe how these high regulatory standards establish mechanisms that ensure patient access to drug products that are safe and of high quality. 

FDA Guidance Documents  

Since the passing of the DQSA in 2013, FDA has issued a number of Final and Draft Guidance Documents in relation to human drug compounding, both for traditional pharmacies (known as 503A pharmacies) and 503B outsourcing facilities. 

In January of 2020, FDA issued a revised draft guidance document on cGMP 503B outsourcing requirements for Human Drug Compounding Outsourcing Facilities under Section 503B of the FD&C Act. [3] The document is the result of extensive and lengthy collaboration between key stakeholders in the human drug compounding industry, including regulators, compounders, and health care professionals. Multiple sub-sections of cGMP processes as stated in this revised draft guidance document  can be divided into four basic categories: professional ethics and expertise, environment, process, and labeling. 

Professional Ethics and Expertise

Central to the successful implementation of cGMP in 503B Outsourcing facilities is the cGMP Mindset. This is a desired attitude of vigilance and adherence to detail that must be first fostered by organizational leadership. Only then can it be embraced by all employees and incorporated into the company culture. [4] 

"I would also add honesty and transparency, specifically, with business ethics and quality operations. Do what you say, and say what you do – interestingly, this is also a fundamental of cGMP. Additionally, cGMP experience and subject matter expertise with 21 CFR Parts 210 and 211 are crucial."

Quality assurance activities should be conducted by trained employees that have no other organizational responsibilities. This policy helps to preserve impartiality and independence in judgement. The quality assurance unit is responsible for conducting record reviews of compounding operations annually at minimum. [5] 

FDA recommends that, as a part of their document review activities, the quality control units must confirm the appropriate documentation of items such as:

  • Environmental monitoring
  • Personnel monitoring 
  • Water system testing
  • Batch release testing
  • Media fills
  • Adherence to procedures and proper aseptic techniques
  • Failures in validation or stability testing 
  • Process deviations [6] 

Environment

cGMP requires that the facility design be conducive to safe manufacture, packing, processing, and holding to minimize contamination of sterile and non-sterile drug products. When processing sterile drug products, cleanroom air quality should be at ISO level 5 or better (International Organization for Standardization). Facility designs should accommodate best practices to prevent contamination from adjacent rooms due to lower air quality. The adjacent rooms must also comply with required ISO levels. [7] 

Environmental monitoring must take place on an on-going basis to minimize any potential for contamination. For ISO 5 aseptic processing environments, evaluation of temperature, humidity, pressure cascades,  particulate monitoring (viable and non-viable), and other quality metrics must occur during each production shift. These measures are critical in controlling microbiological growth. For secondary drug compounding areas, evaluation is required weekly. [8, 9, 10] 

Although cGMPs describe important elements of a suitable drug compounding environment, it is left up to the 503B compounder to gauge potential microbial contamination of active pharmaceutical ingredients (API) or other materials. A well-designed one-way flow of traffic of personnel, equipment, and supplies combined with appropriate pressure cascades must be used to minimize chances for cross-contamination. It should be noted that ongoing air quality sampling should occur during the initial studies but also during dynamic operations to assure an environmental state of control. [11, 12]  

Process

In cGMP-compliant 503B outsourcing facilities, processes for cleaning, disinfecting, and sanitizing are foundational and critical to patient safety. The suitability of cleaning agents and sanitization must also be confirmed by knowledgeable personnel. It must be documented by either Certificates of Analysis (COA) or published literature that they are effective for the specific types of surfaces. Even expiration dates of all cleaning and disinfectant solutions must be closely monitored and discarded if needed. [13]

There are special considerations for sterile compounding. If during processing, a problem should occur and cannot be immediately corrected, production should be stopped and potential impacts and causes of the problem be evaluated. [14]

Process controls are required when manufacturing any drug product. Any deviations from standard operating procedures during batch production are documented (to be evaluated by the quality control unit) and justified. These strict process control parameters are intended to yield batches of non-sterile and sterile products that meet acceptable standards of identity, strength, quality, and purity. Assurance that a batch of compounded drugs are successfully attained through process validation is necessary. [15]

The change control process is another key element of cGMP that is overseen primarily by the quality assurance unit. The focus is on the controlled and coordinated management of change to prevent unintended consequences; as well as to provide a procedural framework with which to work towards continuous improvement.  A formal change control process is critical to analyzing, documenting, and implementing changes in manufacturing procedures. Any proposed or actual changes are evaluated by representatives of the appropriate professional disciplines.  Prior to any distribution to the public, they must be fully aware of those changes and consider how the final drug product could be affected. [16, 17, 18]

21 CFR Part 211 requires that drug products be tested prior to distribution. It further emphasizes that the quality control unit be accountable to make sure release testing occurs. [19] Minimum qualifications for release testing include:

  • Identity and strength of active pharmaceutical ingredients (API)
  • Purity
  • For products purporting to be sterile and/or nonpyrogenic (not heat or fever-producing), a limit on bacterial endotoxins
  • That multiple-dose sterile drug products are assured to have the appropriate specifications that maintain antimicrobial effectiveness, thus maintaining quality and purity for each dose. [20]

Laboratory testing  must be conducted on components, in-process materials, and finished drug products. The laboratories can be in-house or external to the 503B outsourcing facility. They are required to utilize appropriate laboratory controls to ensure the quality of non-sterile and sterile compounded drugs. It should be noted that, even if laboratory controls are outsourced, the quality control unit of the 503B compounder is responsible for approval or rejection of final compounded drug products. [21]

Labeling

Accurate and clear packaging and labeling is an excellent safeguard in avoiding mix-ups throughout the compounded drug manufacturing process. It is also of paramount importance when health care providers administer sterile or non-sterile drugs to patients. Packaging should be designed to minimize manipulation by the health care provider and to communicate beyond-use-dates (BUD), dosage, and warnings. [22, 23]

In its guidance document, FDA has communicated several aspects of packaging and labeling that must be implemented, including:

  • Containers, closures, etc. must provide adequate protection against foreseeable external factors in storage/shipment that could cause contamination
  • Adequate controls must be established in examination of labels to prevent mix-ups
  • Adequate separation between labeling and packaging of different drug products to avoid mislabeling
  • Establishment of appropriate controls of filled containers that are stored unlabeled
  • Packaging records document results of examination of labels and include copies/specimens of labels used.
  • Labeled finished drug products must be examined prior to release. [24]

Conclusion

Current Good Manufacturing Practices for 503B Outsourcing Facilities is now considered a premier standard and has been adopted globally. The adherence to cGMP is another reason why the term '503B outsourcing facility' is more accurate than '503B pharmacy,' and thus is more closely aligned with the production activities of conventional drug manufacturers. It should be noted here that traditional 503A compounding pharmacies are not required to follow cGMP (although they are bound by other state and federal regulatory standards). In fact, some drug compounding industry experts suggest that incorporation of some cGMP principles into United States Pharmacopeia (USP) may be of benefit to safe patient care. [25] 

A report by the Office of the Inspector General on 503B Outsourcing Facilities found that most hospitals obtain their compounded drugs from FDA registered outsourcing facilities. As a rationale, they sited compliance requirements of cGMP and the occurrence of regular FDA inspections. As one pharmacy expert stated, "If I was a pharmacy director, I would be hesitant to purchase from a non-registered facility. [page 9] [26]

"I believe that partnering with outsourcing facilities improves the safety and reliability of medication use and optimizes the use of health system, hospital and ASC resources. Patient safety is enhanced using ready-to-use products with enhanced labeling, extended dating that is backed up by real data, tailored and individualized dosing, and extensive product testing before release." 

Fagron Sterile Services offers independent ISO 5 classified aseptic processing environments, industry leading automation, advanced environmental monitoring and FDA/DEA inspected quality testing labs, as well as top-tier customer service, streamlined shipping and 24/7 mobile friendly web shop access.

Contact Fagron Sterile Services today to set up a consultation.

References

[1] Congressional Research Service (2018, January 5) [R45069]. Drug Compounding: FDA Authority and Possible Issues for Congress, Retrieved from: https://www.everycrsreport.com/files/20180105_R45069_7e75552a7633b1082fc1f861fa60a867c60afea7.html.


[2] Code of Federal Regulations:  CFR Part 211.  TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES

SUB CHAPTER C--DRUGS: GENERAL -  PART 211 CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS. [Current as of April 1, 2019]. Retrieved from: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211&showFR=1&subpartNode=21:4.0.1.1.11.1.


[3] FDA. (2020, January). Current Good Manufacturing Practice—Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act Guidance for Industry. Retrieved from:  https://www.fda.gov/media/88905/download.


[4] Kastango, E.S., Douglass, K.H. (2014). Quality standards for large scale sterile compounding facilities. Clinical IQ. Retrieved from: http://www.clinicaliq.com/wp-content/uploads/2015/06/clinicaliq_compounding-quality-standards.pdf.


[5] FDA. (2020, January). Current Good Manufacturing Practice—Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act Guidance for Industry. Retrieved from:  https://www.fda.gov/media/88905/download.


[6] Ibid.


[7] Ibid.

[8] The FDA Group (n.d.). The importance of CGMP to the safety of compounded drugs:  How current good manufacturing practices (CGMP) offer a reliable remedy to poorly compounded drugs. [White Paper]. Retrieved from: https://cdn2.hubspot.net/hubfs/1706982/White_Papers/The%20FDA%20Group%20-%20The%20Importance%20of%20CGMP%20to%20the%20Safety%20of%20Compounded%20Drugs.pdf.


[9]  American Society of Health System Pharmacists [ASHP]. (n.d.) ASHP guidelines on compounding sterile preparations. Drug distribution and control: Preparation and handling. American Journal of Health -System Pharmacists. 71:145-66. Retrieved from: https://www.ashp.org/-/media/assets/policy-guidelines/docs/guidelines/compounding-sterile-preparations.


[10] FDA. (2020, January). Current Good Manufacturing Practice—Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act Guidance for Industry. Retrieved from:  https://www.fda.gov/media/88905/download.


[11] Ibd.


[12] Kastango, E.S., Douglass, K.H. (2014). Quality standards for large scale sterile compounding facilities. Clinical IQ. Retrieved from: http://www.clinicaliq.com/wp-content/uploads/2015/06/clinicaliq_compounding-quality-standards.pdf.


[13] FDA. (2020, January). Current Good Manufacturing Practice—Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act Guidance for Industry. Retrieved from:  https://www.fda.gov/media/88905/download.


[14] Ibid.


[15] Kastango, E.S., Douglass, K.H. (2014). Quality standards for large scale sterile compounding facilities. Clinical IQ. Retrieved from: http://www.clinicaliq.com/wp-content/uploads/2015/06/clinicaliq_compounding-quality-standards.pdf.

[16] Institute for Safe Medication Practices [ISMP] (2013-Rev. 2016). ISMP Guidelines for Safe Preparation of Compounded Sterile Preparations.  Retrieved from: https://www.ismp.org/sites/default/files/attachments/2017-11/IVCGuidelines.pdf.

[17] FDA.  (2006). Guidance for Industry: Quality Systems Approach to Pharmaceutical CGMP Regulations. Retrieved from: https://www.fda.gov/media/71023/download.

[18] World Health Organization [WHO]. (2007). Quality assurance of pharmaceuticals: A compendium of guidelines and related materials (Vol. 2). Retrieved from: https://www.who.int/medicines/areas/quality_safety/quality_assurance/QualityAssurancePharmVol2.pdf.

[19] FDA. (2020, January). Current Good Manufacturing Practice—Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act Guidance for Industry. Retrieved from:  https://www.fda.gov/media/88905/download.

[20] Ibid.

[21] Ibid.

[22] Ibid.

[23] Kastango, E.S., Douglass, K.H. (2014). Quality standards for large scale sterile compounding facilities. Clinical IQ. Retrieved from: http://www.clinicaliq.com/wp-content/uploads/2015/06/clinicaliq_compounding-quality-standards.pdf.


[24]  FDA. (2020, January). Current Good Manufacturing Practice—Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act Guidance for Industry. Retrieved from:  https://www.fda.gov/media/88905/download.


[25] Kastango, E.S., Douglass, K.H. (2014). Quality standards for large scale sterile compounding facilities. Clinical IQ. Retrieved from: http://www.clinicaliq.com/wp-content/uploads/2015/06/clinicaliq_compounding-quality-standards.pdf.


[26] Murrin, S.  Deputy Inspector General for Evaluation and Inspections. (2019, June). Most hospitals obtain compounded drugs from outsourcing facilities, which must meet FDA quality standards. Office of Inspector General (OIG).  Retrieved from: https://oig.hhs.gov/oei/reports/oei-01-17-00090.pdf


Fagron Sterile Services. (n.d.) How Ambulatory Surgery Centers (ASCs) Can Benefit from Pharmaceutical Outsourcing Facilities: 8 Questions Answered. Retrieved from: https://drive.google.com/file/d/1pJH26rhA5lxmEK8QroJ60auNstw0VGGk/view

Sean Jones, MBA
Director of Marketing at Fagron Sterile Services, with more than a decade of experience within the pharmaceutical and healthcare industries.