Technical Discussions

Question : How does the USFDA define a facility?  If I register as a 503B outsourcing facility – can I also compound under 503A within the same facility? This has been a common question to FDA from outsourcing facilities and other stakeholders.  To answer this question the FDA issued the Draft Guidance: Facility Definition Under Section […]

Do you understand the sources of variation in your manufacturing processes?As described the FDA Process Validation: General Principles and Practices, the manufacturer should use the product and process knowledge as a basis for establishing an approach to control that is appropriate for the manufacturing process. This includes: • understanding the sources of variation• detecting the […]

User Requirements User requirements are just what the name implies.  They are requirements set by the end user.  These requirements express how a facility, equipment or process should perform in terms of the product to be manufactured, required throughput, and conditions in which product should be made.  User requirements provide information that serves as the […]

The final rule for implementation of a unique device identifier or UDI has been released and will be posted on the following FDA page on 9-24-13.  Additionally, the FDA has posted the Global Unique Device Identification Database (GUDID) draft guidance available here. The FDA has provided a summary of compliance dates for the UDI final rule. 1 year […]

Most regulated organizations are well aware of the need to deliver the core suite of planning, user requirement, functional and design specification, testing protocol, and summary report documentation required to complete a successful validation of their computerized system.  And they are very conscientious to adhere to the requirements found the first eight paragraphs of 21 CFR, Part […]

SISPQ Safety, Identity, strength, purity and quality.  Anyone working in the business knows that the firm must meet SISPQ as an expectation of quality and that meeting the current Good Manufacturing Practices (cGMPs) are a requirement to demonstrate SISPQ.  However, where is this requirement stated? As codified in 21 CFR 210.1(a): The regulations set forth in […]

Under the cGMPs the role/responsibilities of the quality unit are described in Subpart B Organization and Personnel, specifically 21 CFR 211.22. However, these roles/responsibilities are not always implemented or effective by pharmaceutical manufacturers.  As described in a recently posted FDA Warning Letter, the FDA cited a manufacturer of OTC products with significant failures of the Quality Unit.  […]

In the January 2016 Intergovernmental meeting on Compounding the FDA provided a response to the Nov 2015 meeting item concerning communication from FDA to the states when compounders resume operation.  The response to this item is provided from the USFDA site: FDA intends to provide the following information to states regarding the Agency’s recommendations to compounders to […]

Why are we concerned with Quality Risk Management (QRM) when planning, developing, and executing commissioning, qualification, and validation work?   The simple answer is time and money.  Pharmaceutical companies are under pressure to bring new therapies to market quicker and to do so at less cost, while still meeting the mandates of cGMPs which ensure […]

On July 28, 2015 the FDA posted the draft guidance on Request for Quality Metrics for public comment.  Industry has 60 days from the publication date in the federal register to submit comments.  The public comment period will end on September 28, which means there are approximately 3 weeks remaining to review the draft and provide your comments. […]

Subject matter experts (SMEs) are considered to be those individual stakeholders in a computer system who contribute their technical expertise to the system validation effort.  Among the SMEs are system software developers, infrastructure support providers, process engineers, process owners and others who share in the responsibility for design and configuration of the system. Our first […]

What makes for a successful 503B Outsourcing Facility? While undoubtedly there may be more elements that contribute to the overall success of the organization the three pillars described above are critical based on my experience in review of multiple Form 483s, Warning Letters, and discussions with pharmacy industry professionals.

FDA’s published draft guidance on data integrity, to clarify the role of data integrity in current good manufacturing practice (cGMPs) with both electronic and paper based records. Data integrity is defined as “refers to the completeness, consistency, and accuracy of data. Complete, consistent, and accurate data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate […]

Friedman (2011) USFDA presented at the Pharmaceutical Quality System (ICH Q10) Conference October/November 2011.  On slide 21, Chowdhury (2001) as cited by Friedman provides a comparison of common day events when operating at 3.8 Sigma meaning that you are getting it right 99% of the time.  This sounds really good—BUT  Chowdhury (2001) identified that getting […]

Among the observations cited in FDA Form 483 reports over the last ten years there are numerous documented findings were where software used as part of the production and/or quality system was not adequately validated for its intended use according to an established protocol. The ‘FDA’s General Principles of Software Validation – Final Guidance for […]

At the conclusion of the inspection, the FDA inspector will give the owner a FDA Form 483 which lists the firm, the dates of the inspection, and the observations made by the inspector(s). FDA will then provide an initial classification of the inspection based on the observations noted in the inspection, the investigator’s report, and […]

FDA has released final approved guidance addressing Insanitary Conditions at Compounding Facilities.  The guidance is available at this FDA link. This guidance provides specific examples of insanitary conditions identified during FDA inspections of 503A and 503B facilities in section IIIA for both sterile and non-sterile compounding. Some examples in the guidance include: In section IIIB the […]

As described in the Food Drug and Cosmetic Act (501(a)(2)(A)), a drug is deemed to be adulterated “if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health.”It is important to note that the drug does not […]

ICH Q9 provides a simple process flow of a typical risk management process.  This process includes risk assessment (risk identification, risk analysis, and risk evaluation) which leads to risk control (risk reduction and risk acceptance). Figure 1 below, extracted from ICH Q9 illustrates this process flow. Figure 1. Adapted from ICH Q9, Quality Risk Management, Nov […]

Governance, risk, and compliance or GRC is a term one in the pharma or biotech world might not hear all that often. It is a concept most often employed in financial, legal, and information technology divisions. “Governance” refers to the processes/procedures/activities used to manage the organization – such as management processes. This includes the GRC […]

Good Document practices are required by subpart J of 21 CFR 211.  The agency expects firms regulated by 21 CFR 210 and 211 to follow good document practices as this is the evidence that the API or Finished Pharmaceutical meets the Safety, Identify, Strength, Purity and Quality levels required of the cGMPs. A few days […]

Five things a Pharmacist should understand prior to writing that check for registration fees to the FDA for their brand new 503B outsourcing facility. Commissioning and Qualification Overview Planning Risk Management User Requirements Have a question on 503B’s feel free to contact Dr. Van Doel, or use our Contact Us page to send us your questions.

The FDA issued draft guidance July 12, 2013 for comment.  The comment period closed in September and FDA is currently reviewing industry comments prior to publishing a final rule. This guidance attempts to clarify unreasonable conditions when an owner, operator or agent causes the delay of an inspection this may cause the drug to be adulterated under section […]

What could happen when a medical provider knowingly submits claims to the government for reimbursement that are not correct?  For example, a compounding pharmacy compounds drug  that does not meet USP, is manufactured under insanitary conditions, or for 503B under manufacturing conditions that do not meet cGMPs? An interesting read is Justice Thomas’ majority opinion in […]

One of the key elements supporting commercial manufacturing of pharmaceutical or compounded products is the facility design.  This element is captured in the Drug cGMPs as subpart C Buildings and Facilities, and codified in 21 CFR 211.42 Design and construction features. Process Validation Guidance & Facility Design Facility Design is also a key element of the Jan 2011 […]

Do you do API’s?  Have questions?  If yes, you should check out – FDA’s Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients – Question and Answers. Per the intro section – Since the ICH Q7 Guidance was finalized, experience with implementing the guidance worldwide has given rise to requests for clarification of uncertainties due to the […]

FDA has issued the Data Integrity and Compliance with Drug cGMP final guidance on December 13, 2018.  The final guidance is available at the following link. As stated in the Introduction section of the guidance: FDA expects that all data be reliable and accurate (see the “Background” section). CGMP regulations and guidance allow for flexible and risk-based […]

In a recently posted FDA warning letter, the FDA cited a firm for failure to establish and maintain plans that describe or reference the design and development activities and define responsibility for implementation, as required by 21 CFR 820.30(b).  Items missing in the Standard Operating Procedure (SOP) included identifying who is responsible for the design […]

The Center for Drug Evaluation and Research (CDER) releases the CDER’s Program for the Recognition of Voluntary Consensus Standards Related to Pharmaceutical Quality Guidance for Industry draft guidance for comment. This proposed guidance will address how CDER will informally recognize volunatry consensus standards. Historically concensus standards have been recognized and required to be used through […]

Prior to starting commissioning and qualification activities, a plan should be developed. The plan may be commonly referred to as a Commissioning Plan, Commissioning and Qualification Plan, Qualification Plan or Validation Plan. The name changes based on the overall intent of the activity, but the documents all serve the same purpose – to help guide […]

If you are responsible for a cleanroom or a cleanroom environment then you need to know that ISO 14644-1 and -2 have reached Final Draft International Standard (FDIS) status and are out to the member states for final vote. According to some sources these new ISO standards could be contractually invoked as early as October […]

Question: Can I use my vendor’s Certificate of Analysis when making a pharmaceutical product or compounding a product as a 503B outsourcing facility?  Yes – BUT in accordance with 21 CFR 211.84(d)(1) and (2): (d) Samples shall be examined and tested as follows: (1) At least one test shall be conducted to verify the identity of each component of […]

As identified in the Integration of FDA Facility Evaluation and Inspection Program for Human Drugs: A concept of Operations published June 6, 2017 a for-cause facility inspection may be initiated: In response to a new registrant or a specific event or information that brings into question the compliance and/or quality of a manufacturing practice, facility, process or […]

ICH has released a new Questions and Answers: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients on 10 June 2015.  The Q&A document is intended to respond to the requests received by ICH for guidance concerning implementation of Q7. The document is 18 pages in length and the annex provides a cross-reference of the Q&A sections to […]

21 CFR 211.192 requires a thorough review of any unexplained discrepancy whether or not the batch has been distributed.  Lack of / or poor Alarm management was identified by the FDA during an inspection of a 503B Outsourcing Facility (Observation 2, Form 483). The firms Building Maintenance System had logged ~766 alarms since March 8, […]

As of November 13, 2015—54 facilities have been registered as Human Drug Compounding Outsourcing Facilities under Section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Nine of these registered facilities have not yet been inspected by USFDA. The balance of the registered facilities have been inspected by USFDA with 100% of these facilities […]