Drug Compounding: Manufacturing Standards Announced for Outsourcing Facilities

by Akin Gump Strauss Hauer & Feld LLP
Contact

In late 2013, Congress passed the Drug Quality and Security Act (DQSA) in response to a deadly fungal meningitis outbreak linked to a sterile compounded injectable drug shipped across the country and responsible for more than 750 confirmed infections and 60 deaths. A key component of the DQSA is the recognition of a new type of drug compounding entity—outsourcing facilities—that can provide a source of high-quality compounded drugs for hospitals and providers. Unlike traditional state-regulated compounding pharmacies, outsourcing facilities are regulated by the U.S. Food and Drug Administration (FDA) and subject to manufacturing standards for the production of sterile compounds. This week, FDA released draft guidance explaining how the agency intends to apply current Good Manufacturing Practices (cGMPs) to these outsourcing facilities.

This guidance is important to outsourcing facilities (sometimes referred to as “503B” entities, based on the section of the Food, Drug, and Cosmetic Act under which they are regulated) and other entities considering establishing an outsourcing facility; hospitals and other providers relying on outsourcing facilities for their compounding needs; payors considering reimbursement and coverage policies concerning compounded drugs; and other participants in the pharmaceutical industry. The agency is developing proposed rulemaking on this topic, and comments should be submitted by interested parties as soon as possible.

cGMPs for Outsourcing Facilities

Although the DQSA itself does not provide that outsourcing facility cGMPs will deviate from the regulatory cGMPs for drug manufacturers, congressional negotiators, FDA and many stakeholders recognized that some variations would be needed. The interim guidance is designed to reflect the differences between outsourcing facilities, which produce smaller batches of customized compounds, often from finished sterile drugs, and conventional pharmaceutical manufacturers, which produce larger lots of standardized drug products that have been evaluated by FDA for safety and efficacy. The draft guidance also accounts for the differences among outsourcing facilities and provides for the tailoring of cGMPs to the nature of the facilities’ specific compounding operations. Ultimately, the cGMPs are designed to set minimum standards for outsourcing facilities, with a primary focus on ensuring sterility, strength and accurate labeling.

The interim guidance identifies the relevant sections of the regulations that apply to pharmaceutical manufacturers (21 C.F.R. parts 210 and 211) and explains how the agency will apply these rules to outsourcing facilities. These sections outline the expectations for outsourcing facilities and describe any variation from the rules as they apply to drugmakers. Specifically, these standards relate to:

  • Facility Design: laying out standards for processing and controlled areas, high-efficiency particulate air filters, and cascading air quality and pressurization for critical areas (set at ISO-5 classification in cleanrooms and ISO-7 in immediately adjacent areas)
  • Control Systems and Procedures: identifying the protocol and documentation requirements for sanitation schedules and methods, humidity and temperature controls, and air flow and pressure monitoring, as well as built-in alarms to detect deviations and response plans
  • Environmental and Personnel Monitoring: requiring well-defined systems for monitoring environmental conditions (i.e., air, surfaces, process, operation and personnel practices) in aseptic processing areas with alert limits and response plans, as well as scheduling and monitoring programs for personnel gowning and garbing
  • Equipment, Containers and Closures: requiring equipment, containers and closures to be tested to ensure adequacy for their intended use, including items that must be sterilized and depyrogenated before use
  • Components: setting controls over the source and quality of components, including the establishment of specifications (e.g., identity, strength, purity, particle size, sterility, bacterial endotoxin level) for components, with an emphasis on identity testing for nonsterile starting materials
  • Production and Process Controls: requiring written procedures for general production processes, batch records, hold times and in-process controls relating to sterile filtration and aseptic processes, as well as requirements to investigate any deviation from the procedures; process controls also include criteria for introductory training, mastery of department-specific techniques (e.g., simulating media fills), certification of mastery and recertification
  • Release Testing: mandating testing for each drug product for identity and strength, visible particles and sterility, as well as authorization from a designated quality control individual prior to release, subject to certain exceptions
  • Laboratory Controls: specifying analytical methods and equipment necessary for in-house or external laboratory determinations, including the maintenance of complete records of all tests
  • Expiration Dating: establishing specific and conditional expiration date criteria supported by reliable and specific stability-indicating test methods, as well as the substitution of beyond use dating as appropriate
  • Packaging and Labels: requiring packaging systems capable of ensuring the integrity of the product against foreseeable external factors until administration with adequate controls for issuing, examining and reconciling labels to prevent mix-ups
  • Quality Assurance Activities: mandating an independent quality control unit with individuals designated to handle failure investigations, written and oral complaints concerning the drug product quality, and possible adverse reactions.

In many instances, FDA indicates that it does not intend to take enforcement action against an outsourcing facility regarding a particular cGMP requirement if the facility relies on the assurances of certain third parties and fulfills additional obligations. For example, the requirements for testing starting components are moderated for components such as FDA-approved finished human drug products and ready-to-use, sterile single-use items. Similarly, FDA relaxes the cGMP requirements for release testing of very small batches, as well as compounded products composed solely of one or more FDA-approved drugs whose labeling specifies how to assign an “in-use time.”

With regard to testing starting components and laboratory testing prior to release, FDA has requested public comments on alternative approaches that would reduce the need for duplicative testing by multiple outsourcing facilities by instead relying on a drug master file containing specific information reviewed by FDA.

Next Steps in Compounding Implementation

The agency plans to promulgate specific cGMP regulations applicable to outsourcing facilities, but will use these draft guidelines for inspection and enforcement purposes in the interim. The draft guidance on cGMPs joins several other draft guidance documents that describe outsourcing facilities’ obligations regarding registration, product reporting and payment of fees. This cGMP guidance, however, was perhaps the most highly anticipated; many observers have suggested that potential registrants have been waiting to see the standards before registering with FDA.

As of June 27, 2014, 48 outsourcing facilities are registered. The DQSA directs FDA to inspect these facilities according to a risk-based inspection schedule. Since enactment, the agency has begun inspecting new registrants that do not have a prior inspection on record and has issued a Form-483 for observed cGMP violations for all but one of the 17 inspections it has conducted. FDA has asserted in press statements that these interim standards, combined with other recently announced rules, give the agency broad latitude to employ a risk-based enforcement scheme and to act swiftly if it identifies concerns about compounded drugs.

 

DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

© Akin Gump Strauss Hauer & Feld LLP | Attorney Advertising

Written by:

Akin Gump Strauss Hauer & Feld LLP
Contact
more
less

Akin Gump Strauss Hauer & Feld LLP on:

Readers' Choice 2017
Reporters on Deadline

"My best business intelligence, in one easy email…"

Your first step to building a free, personalized, morning email brief covering pertinent authors and topics on JD Supra:
Sign up using*

Already signed up? Log in here

*By using the service, you signify your acceptance of JD Supra's Privacy Policy.
Privacy Policy (Updated: October 8, 2015):
hide

JD Supra provides users with access to its legal industry publishing services (the "Service") through its website (the "Website") as well as through other sources. Our policies with regard to data collection and use of personal information of users of the Service, regardless of the manner in which users access the Service, and visitors to the Website are set forth in this statement ("Policy"). By using the Service, you signify your acceptance of this Policy.

Information Collection and Use by JD Supra

JD Supra collects users' names, companies, titles, e-mail address and industry. JD Supra also tracks the pages that users visit, logs IP addresses and aggregates non-personally identifiable user data and browser type. This data is gathered using cookies and other technologies.

The information and data collected is used to authenticate users and to send notifications relating to the Service, including email alerts to which users have subscribed; to manage the Service and Website, to improve the Service and to customize the user's experience. This information is also provided to the authors of the content to give them insight into their readership and help them to improve their content, so that it is most useful for our users.

JD Supra does not sell, rent or otherwise provide your details to third parties, other than to the authors of the content on JD Supra.

If you prefer not to enable cookies, you may change your browser settings to disable cookies; however, please note that rejecting cookies while visiting the Website may result in certain parts of the Website not operating correctly or as efficiently as if cookies were allowed.

Email Choice/Opt-out

Users who opt in to receive emails may choose to no longer receive e-mail updates and newsletters by selecting the "opt-out of future email" option in the email they receive from JD Supra or in their JD Supra account management screen.

Security

JD Supra takes reasonable precautions to insure that user information is kept private. We restrict access to user information to those individuals who reasonably need access to perform their job functions, such as our third party email service, customer service personnel and technical staff. However, please note that no method of transmitting or storing data is completely secure and we cannot guarantee the security of user information. Unauthorized entry or use, hardware or software failure, and other factors may compromise the security of user information at any time.

If you have reason to believe that your interaction with us is no longer secure, you must immediately notify us of the problem by contacting us at info@jdsupra.com. In the unlikely event that we believe that the security of your user information in our possession or control may have been compromised, we may seek to notify you of that development and, if so, will endeavor to do so as promptly as practicable under the circumstances.

Sharing and Disclosure of Information JD Supra Collects

Except as otherwise described in this privacy statement, JD Supra will not disclose personal information to any third party unless we believe that disclosure is necessary to: (1) comply with applicable laws; (2) respond to governmental inquiries or requests; (3) comply with valid legal process; (4) protect the rights, privacy, safety or property of JD Supra, users of the Service, Website visitors or the public; (5) permit us to pursue available remedies or limit the damages that we may sustain; and (6) enforce our Terms & Conditions of Use.

In the event there is a change in the corporate structure of JD Supra such as, but not limited to, merger, consolidation, sale, liquidation or transfer of substantial assets, JD Supra may, in its sole discretion, transfer, sell or assign information collected on and through the Service to one or more affiliated or unaffiliated third parties.

Links to Other Websites

This Website and the Service may contain links to other websites. The operator of such other websites may collect information about you, including through cookies or other technologies. If you are using the Service through the Website and link to another site, you will leave the Website and this Policy will not apply to your use of and activity on those other sites. We encourage you to read the legal notices posted on those sites, including their privacy policies. We shall have no responsibility or liability for your visitation to, and the data collection and use practices of, such other sites. This Policy applies solely to the information collected in connection with your use of this Website and does not apply to any practices conducted offline or in connection with any other websites.

Changes in Our Privacy Policy

We reserve the right to change this Policy at any time. Please refer to the date at the top of this page to determine when this Policy was last revised. Any changes to our privacy policy will become effective upon posting of the revised policy on the Website. By continuing to use the Service or Website following such changes, you will be deemed to have agreed to such changes. If you do not agree with the terms of this Policy, as it may be amended from time to time, in whole or part, please do not continue using the Service or the Website.

Contacting JD Supra

If you have any questions about this privacy statement, the practices of this site, your dealings with this Web site, or if you would like to change any of the information you have provided to us, please contact us at: info@jdsupra.com.

- hide
*With LinkedIn, you don't need to create a separate login to manage your free JD Supra account, and we can make suggestions based on your needs and interests. We will not post anything on LinkedIn in your name. Or, sign up using your email address.
Feedback? Tell us what you think of the new jdsupra.com!