Tony Cundell, Ph.D.- Microbiological Consulting, LLC
Introduction
A sterile compounding pharmacy can elect to register with FDA as an outsourcing facility under section 503B of the Federal Food, Drug, and Cosmetic Act, as added by the Drug Quality and Security Act, Pub. Law No. 113-54 (November 27, 2013). The advantages gained with registration include longer production lot sizes made without a pre-existing physician’s prescription as required by a section 503A compounding pharmacy and improved access to interstate sales. Although 503B outsourcing facilities are exempt from some labeling requirements and are not subject to new drug applications and approvals, they are subjected to compliance with the current Good Manufacturing Practices (cGMP) regulations contained in 21 CFR 210 and 211, which contain requirements for facility design, training and qualified staff, control of incoming components, aseptic processing, air quality, environmental monitoring, and related requirements designed to ensure the quality of the finished drug product. In addition, they must report serious adverse reactions to the agency and provide details of the products manufactured semi-annually. The 503B outsourcing facilities will be subject to regulatory inspection for GMP compliance, follow-ups to adverse inspections, and, if necessary, for cause.
This review article is directed towards 503B outsourcing facilities strengthening their quality systems as the first step in meeting cGMP requirements.
Growth of 503B Outsourcing Facilities
As of 1 June 2022 there were 76 registered outsourcing facilities in 30 states listed on the FDA website (https://www.fda.gov/drugs/human-drug-compounding/registered-outsourcing-facilities). The top ten States where these facilities are located are Florida (9 sites), Texas (8), New Jersey (6), New York (5), California (5), South Carolina (4), Arizona (3), Colorado (3), Connecticut (3), and Pennsylvania (3). Of concern to the author, 17 of the 76 registered facilities (22%) currently have not been inspected, probably due to travel restrictions during the COVID-19 pandemic, and churn, as some facilities cease operation exiting the list, and new facilities being added to the list.
FDA Inspection Outcomes
What has been the overall outcome of these cGMP inspections? To be frank, it has not been good. As reported in the January 2022 issue of Pharmacy Purchasing and Products (Diorio, 2022), 110 facilities have been inspected and 1,788 Form 483 inspectional observations issued with an average of eight observations per facility. The total number of inspection days was 2,039 with average of nine of days per facility using an average of two investigators. This record supports the view that the transition from a sterile compounding pharmacy regulated by a State Board of Pharmacy, with the lead pharmacist responsible for the quality and safety of compounded sterile preparation to 503B sterile product outsourcing facilities regulated by the U.S. Federal Food and Drug Administration, with an independent quality control unit responsible for cGMP compliance, has not been easy. The 503B outsourcing facilities have been constrained by both a lack of resources and experience with what is essentially pharmaceutical manufacturing.
The top ten FDA Form 483 observations in 503B outsourcing facilities from 2015 through 2019, in descending order, are summarized in Table 1 (Diorio and Thomas, 2019).
Benchmarking Against the Pharmaceutical Industry
How does this FDA inspectional history compare to that of the total pharmaceutical industry? Lynn (2022) published a review of FDA Form 483 observational trends over the past 23 years using data obtained from a commercial FDA Inspection database (Redica Systems, Pleasanton, CA), with special emphasis on the recent period from 2018 to 2021. He remarked how little the frequency of observations had changed over this time period, making the current emphasis on quality management systems even timelier.
Based on this analysis, the top ten broad 483 observational issues in descending order were as follows:
- Quality Systems/Deviations/Investigations
- Quality Systems/Quality Unit Inadequacies
- Laboratories/General Requirements/Controls
- Products/Records and Reports
- Laboratories/Stability Programs
- Facilities and Equipment/Maintenance
- Production/Sterile Products/Media Fills
- Laboratories/Routine Testing
- Facilities and Equipment/Design/Sterile Processing
- Production/Process Validation
Drilling down, in the area of Quality Systems, the range in percentage of observations for 2018, 2019, 2020 and 2021 by issue were as follows:
- Quality Unit inadequacy 30 to 40%
- Deviations/Investigations 25 to 30%
- Unqualified personnel 10 to 15%
- Records and Reports 8 to 12%
- Complaint Management 5 to 10%
- Audits 2 to 6%
- Agency notification 2%
- Change Control 2%
- Corrective action and Preventive Action (CAPA) 1 to 2%
Core Standard Operating Procedures for Inclusion in a Quality Systems Manual
The author of this article believes that the key to improved cGMP compliance is strengthening your Quality Management System. The regulators share this view. To provide guidance to assist with cGMP compliance, the FDA has published the 2020 Draft Guidance For Industry Current Good Manufacturing Practices – Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the F, D & C Act.
In December 2019, the FDA established the Compounding Quality Center of Excellence (COE) to work with outsourcing facilities to improve the quality of compounded drugs. This action may be viewed as a proactive step by the FDA that should be helpful to the 503B outsourcing industry. According to the FDA website, the COE supports the industry through training, market research, and outreach in the form of an annual conference (See https://www.fda.gov/drugs/news-events-human-drugs/2021-compounding-quality-center-excellence-virtual-conference-culture-quality-09142021).
Quality System
What are the major elements of a Quality System? They are as follows:
- Responsibilities of the Quality Control Unit
- Site training program: job descriptions, training curricula, skill training, SOP training, and retraining
- Production and laboratory equipment validation, calibration and preventive maintenance
- Sampling, transportation, receipt, storage, retention, and disposal
- Method validation and qualification testing
- Out-of-specification result investigations and corrective action and preventive action (CAPA)
- Quality metrics reporting program
- Customer complaint investigation
- Qualification of contract testing laboratories
- Stability testing program
- Preparation for external audits
- Response to Form 483 observations and warning letters
Figure 1 shows the hierarchy of documentation within a Quality System.
Details of the Quality Systems
Critical elements of the Quality System with reference to the GMP requirements are briefly discussed in this section.
Quality Control Unit
The quality control unit (QCU) in a 503B outsourcing facility is defined in 21 CFR 211.22 Responsibilities of quality control unit that states:
a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.
(b) Adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to the quality control unit.
(c) The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.
(d) The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed.
Critical to this GMP function is the independence of the individual leading the QCU within the 503B outsourcing facility. The ownership and management of the facility will most likely have to adjust and recognize the authority of the QCU. In a smaller organization this individual may have other assigned responsibilities whereas the FDA expect they play an exclusive role.
Personnel Training
Critical is the training and experience of the management and staff within the 503B outsourcing facility. 21 CFR 211.25 Personnel qualifications states:
a. Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee’s functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with cGMP requirements applicable to them.
b. Each person responsible for supervising the manufacture, processing, packing, or holding of a drug product shall have the education, training, and experience, or any combination thereof, to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess.
c. There shall be an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each drug product.
What would be expected is written job descriptions detailing the title of the position, description of the duties, and the educational qualifications and experience required to hold the position. Each staff member must have training curriculum listing the standard operating procedures and job aids associated with their position and their training must be current before conducting the manufacturing or testing activity. This training documentation must be available for inspection by external auditors.
Equipment Validation, Calibration and Preventive Maintenance
Production and laboratory equipment must be properly installed, validated, calibrated, operated, and maintained.
According to the 2011 FDA Guidance for Industry - Process Validation: General Principles and Practices the foundation for process validation is provided in 21 CFR 211.100(a), which states that “there shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess...”
USP general informational chapters <1229>Sterilization of Compendial Articles and <1058>Analytical Instrument Qualification provide useful information on industry practice on sterilization processes and laboratory testing respectively.
Out-of-Specification Investigations
Compounded sterile preparations will be subject to release testing, e.g., identity, potency, bacterial endotoxin and sterility testing. 21 CFR 211.165 Testing and Release for Distribution states:
a. For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Where sterility and/or pyrogen testing are conducted on specific batches of short-lived radiopharmaceuticals, such batches may be released prior to completion of sterility and/or pyrogen testing, provided such testing is completed as soon as possible.
b. Drug products failing to meet established standards or specifications and any other relevant quality control criteria shall be rejected. Reprocessing may be performed. Prior to acceptance and use, reprocessed material must meet appropriate standards, specifications, and any other relevant criteria.
The 2022 FDA Guidance For Industry - Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production provides the Agency’s current thinking on how to evaluate out-of-specification(OOS) test results. For purposes of this document, the term OOS results includes all test results that fall outside the specifications acceptance criteria established in drug applications, drug master files(DMFs), official compendia, or by the manufacturer. If the laboratory investigation clearly reveals a laboratory error, the test may be considered invalid and the OOS results rejected and assay may be repeated. However, if no laboratory error is found the result stands and the batch would be rejected. Product failures are subject to manufacturing investigation to determine the probable cause of the failure and Corrective Action, Preventive Action (CAPA) is instituted.
This guidance applies to chemistry-based laboratory testing of drugs regulated by CDER. It is directed toward traditional drug testing and release methods. For microbiological testing, the reader is referred to the 2022 PDA Technical Report No. 88 Microbial Data Deviation Investigations in the Pharmaceutical Industry for general guidance.
Product failure investigations and follow-up CAPAs are examined closely by FDA investigators during GMP compliance inspections so your program must be based on written procedures, be technically sound, investigations comprehensive, the CAPAs effective, and the entire program well documented.
Since the implementation of the New Inspection Protocol Project (NIPP) inspections in October 2018, 75 inspections were conducted using this data handling protocol (2021 FDA Office of Pharmaceutical Quality Report). The top ten questions (Table 2) in terms of the number of 483 observations in descending order were as follows:
These 483 observation categories reflect continuing weaknesses in the quality system within the inspected companies.
Other Related Areas that Must Be Defined in a 503B Outsourcing Facility’s Policies and Procedures
In addition to the quality system, the standard operating procedures (SOPs) describing manufacturing, and chemical, physical and microbiological testing that you may expect to find in a 503B outsourcing facility are listed below.
Manufacturing
- Facility layout and personnel and material flow
- HVAC Systems – temperature and humidity, space pressurization, HEPA filter maintenance and certification, air velocity, and air cleanliness
- Cleaning and sanitization of the production area
- Aseptic processing
- Personnel hygiene
- Use of Personal Protection Equipment
- Media fill program
Chemical and Physical Testing Program
- Identity testing
- Potency testing
- Osmolality
- Special gravity
- Viscosity
- pH measurement
- Water content
- Appearance
- Container closure integrity
Microbiology Testing Program
- Microbiological examination of non-sterile drug substances and products
- Microbial enumeration and tests for specified microorganisms
- Sterility Tests
- Validation of alternative methods
- Microbial characterization, identification and strain typing
- Cleaning and sanitization of the QC microbiology laboratory
- Bacterial endotoxin assay
- Bioburden monitoring of water for pharmaceutical use and in-process samples
- Biological Indicator testing
- Environmental and water monitoring program
- Antimicrobial effectiveness testing
- Use of Personal Protection Equipment
- Laboratory safety program
Conclusions
The transition from being a sterile compounding pharmacy to an outsourcing facility is challenging. The author hopes that this brief review of the role of strong quality systems in the state of cGMP compliance in 503B outsourcing facilities is useful to the industry.
References
- Diorio L. T. D. 2019 Due Diligence Drives 503B Compounder Selection. Pharm Purch. Prod. 16(2): 2-4.
- Diorio, L.T.D and D. Thomas, 2022 Trends in Regulatory Actions for 503B Compounders Pharm. Purch. Prod. 19(1): 18-22
- Lynn, S. J., 2022 A discourse on pharmaceutical cGMP FDA Form 483 Trends Amer. Pharm. Rev. 25(4): 72-78
- 2021 FDA Office of Pharmaceutical Quality Report on the State of Pharmaceutical Quality Fiscal Year 2021 pp28
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