October: FDA cGMP Quality News Briefing

What industry news have you been reading this month? At FDAzilla, we’ve compiled the most noteworthy articles we’ve come across in the weeks since our last update. This month’s picks include information from two conferences, surprising warning letters abroad and in the US, an explanation QSIT protocol, and stories of both exemplary and reprehensible strategies from companies dealing with in-house deficiencies. Take a look:

  1. Quality issues account for two-thirds of shortages (NOTE: You must select “Yes” in the pop-up window to read the article)  Recently at the Biopharma Ambition Conference, Dr. Michale Kopcha, Director of Pharmaceutical Quality with the FDA, spoke about the significant role quality control plays in causing drug shortages. Kopcha argues that updating technologies in the industry could decrease the frequency and number of drug shortages by reducing the amount of quality issues that are currently prevalent in pharmaceutical manufacturing. This article highlights some of Kopcha’s specific criticisms – for example, he notes that some current technology in manufacturing dates all the way back to World War II. It also reviews his suggestions for advancing technology, including his emphasis on the importance of partnership and collaboration between firms and the FDA to push the industry into the technological present.
  2. ISO 13485: Ex-FDA Official Kim Trautman Gives Advice on TransitioningHere’s another piece of advice from a recent conference – this time, it’s from Kim Trautman, medical device quality systems expert and former FDA official, who spoke at RAPS 2016 Regulatory conference on ISO 13485:2016. The ISO realized the revision to 13485:2016 this February, but has established a 3-year transition period to give companies time to adjust. — Trautman’s words of wisdom? Don’t use that extra time if you don’t need it. Switch to the new standards as soon as possible. None of us want to make the change, but if your company doesn’t start now, it will suffer later. The article reviews the details of ISO’s transition phases, and highlights the specific changes Trautman says your company should look out for as you switch to the new standard.
  3. Understanding the 4 Types of FDA Inspection:This article’s focus is on the inspection of medical device manufacturers, but is a good overview of inspection protocol for all sectors. Peter Ohanian of Halloran Consulting reviews the four types of FDA inspections — pre-approval, routine, compliance follow-up, and “for cause” – and explains when and how they occur. After this refresher, Ohanian dives into a detailed explanation of Quality System Inspection Technique (QSIT) to help you know how to prepare for and what to expect from your own FDA inspections. Did you know the FDA decides which firms to inspect based on risk classification? Can you name the four subsystems the QSIT identifies? Do you know what differentiates an abbreviated from a baseline inspection? If not, this piece might be worth a read.
  4. Does an FDA Import Alert Equate to an FDA Warning Letter?: The short answer to this question is “no” — but this article looks at the reasoning and nuance behind that response. For example, how strong is the correlation between Warning Letters and Import Alerts? GMP Quality Expert Barbara Unger has tabulated FDA data on Import Alerts and associated Warning Letters. This information, presented in three tables and a graph of raw data, is used to determine the statistical strength of the relationship.
  5. ‘The Rooms Had Never Been Cleaned': Two New FDA Warning Letters for Chinese Manufacturers:This article reviews warning letters recently issued by the FDA to Chen Fong Chemical and Hebei Yuxing Bio-Engineering, two Chinese API makers. The problem? Data Integrity and GMP violations – a common reason for FDA enforcement action, particularly in overseas plants. The FDA is issuing an increased number of Warning Letters to overseas manufacturers in general, with 16 of the 25 issued this year being addressed to firms in either China or India. Read this story for a list of the startling details from these Warning Letters, which include phrases like “leaks,” “insects,” “dirt,” and “microbial contamination.” Links to the original documents can be found at the end of article.
  6. FDA Warning Letters: Pests, Seafood HACCP Issues, Drug Residue: In case we’ve given you the impression that everyone getting in trouble with the FDA is based overseas, this article should clear that up. While it might be true that “rodent droppings” and “live insects” have recently been associated with manufacturers in India and China — this time it’s right here in the USA. Food Safety News covers warning letters recently issued to a multitude of local companies, including Chicago’s Indoor Garden, SuperValu Inc., Frontier japan Inc. (for their seafood importer in NYC), Arcadia Trading Inc., Varel Farms LLC, and Tensen Dairies LLC. The violations listed in this piece are gross in multiple senses of the word. For example, in Chicago, one of the FDA’s criticisms was an employee who “repeatedly wiped their nose with gloved hands and then returned to packaging the [finished vegetable product] without washing or changing gloves or washing their hands.” If you were disturbed by the insect boor holes in the last article, this should make you even more uncomfortable.
  7. J&J Warns Diabetic Patients: Insulin Pump Vulnerable to Hacking: How can a security defect in your product end with public praise from the FDA? It’s all about how you address the problem, and Johnson and Johnson’s approach to a recent cyber vulnerability is an exemplary illustration of how to handle similar situations. Reuters reports that J&J was made aware of a possible security hazard in their Animas One Touch Ping insulin pump earlier this year. According to J. Radcliff, the Rapid7 Senior Security Consultant who informed the company of the problem, hackers could potentially overdose diabetic patients due to the fact that the device’s remote control release feature is not encrypted or scrambled. What did J&J do about this? Neither J&J nor the FDA know of any attempted hacking attacks on the device. In fact, J&J described “the probability of unauthorized access” as “extremely low.” Nevertheless, after working with Radcliff to examine assess the risk, the company released letters to doctors and patients warning them about the threat and providing steps to prevent possible attacks. What did the FDA have to say about this approach? The FDA is currently developing formal guidance on how medical device makers should handle reports about cyber vulnerabilities. Apparently, this is exactly what they want. An agency statement published the day after J&J’s letter reads, “this is the proactive behavior the FDA has been looking to see.”
  8. FDA Warns Japanese Company for Impeding Inspection: If you pay attention, everyone teaches you something. Sometimes you learn what to do, and sometimes you learn what to avoid. If the last article showed us the ideal way to handle problems within your company, the actions of Nippon Fine Chemical Co. recorded here demonstrate the worst possible approach. During their inspection, employees — under the direction of management! — physically blocked inspectors from entering certain areas of the facility, refused to deliver their records, and would not allow the officials to take photographs. If the company was trying to avoid enforcement action by hiding their mistakes, they didn’t succeed. Instead, they compounded their problems by trying to conceal them. FDA issued a Warning Letter in which they found Nippon in violation of CFR 21 Section 351(j). Shipments from this facility will be refused until an inspection can be made successfully.
  9. FY 2016 Generic Approvals by FDA: A New Record Under GDUFA:The results are in: the FDA approved 159 more ANDAs (abbreviated new drug applications) in FY 2016 than it did in FY 2015 (and 242 more than in 2014). But does this indicate increased leniency toward new drug proposals? Nope. Instead, these numbers reflect an increase in the rate at which the FDA is reviewing applications. How do we know? The number of ANDA approvals rose this year only because the total number of response letters increased overall. In fact, the FDA sent more complete response letters in FY 2016 than in any other previous year. They issued 1,725 in total, which is up by 545 CRLs from 2015. This means that while the number of approvals increased this year, so did the number of rejections. This increased review rate is intentional – it’s a result of the FDA hiring almost 1,000 new employees this year to help fight the backlog of ANDAs the FDA has been working against since 2012. It’s also an area where the FDA hopes to continue improving. According to the GDUFA I performance goals for the coming year, the FDA hopes to “review and act on 90 percent of complete electronic ANDAs within 10 months after submission.”
  10. Teva’s Ranbaxy-like Mess Builds Up in MexicoIt’s been less than a year since Teva purchased Rimsa, a leading pharma manufacturing and distribution company in Mexico, but writers at PharmaCompass argue that parallels between this acquisition and the events we saw in the 2008 Ranbaxy debacle are already “strikingly” clear. To say the transition has not been smooth would be an understatement. Both parties – the former owners ofRimsa, Fernando Espinosa Abdala and Leopoldo de Jesus Espinosa Abdala, and its current owners at Teva – have filed legal complains against the other. The Abdalas claim that Teva is experiencing “buyers remorse” and is looking for ways to reverse the transaction “by any desperate measure.” The problems at Rimsa, which Teva listed in their 52-page complaint, resemble many of those found at Ranbaxy. PharaCompass has compiled a helpful table, found in the middle of the article, which summarizes the similarities between the two ordeals.

What recent events do you think are important to our industry? Is there a story we missed? Are there specific topics you’d like to see covered? Let us know in the comments!

Learn more about how FDAzilla can help you achieve your quality and inspection preparation goals: get 483s, Inspector Profiles, Enforcement Analytics, and GMP Regulatory Intelligence. Any questions? Contact me at tony@fdazilla.com.


What Has the FDA Been Focusing on for the Month of August?

We took a snapshot of the 13 warning letters the FDA sent to pharmaceutical companies last month.  Drug manufacturing violations ranged from failing to “maintain written records” to failing to wear “clothing appropriate to protect drug product.”

From pharmaceuticals in Brazil, India, China, and 6 US states, here they are (starting with the most recent):
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FDA cGMP Quality News Briefing: August-September

We’ve compiled August and September’s most relevant, important news for anyone concerned with Pharmaceutical Industry GMP and FDA inspections. Our top 12 picks are listed chronologically by publication date. Happy reading!

  1. 25 JulyAfter scandal, China begins vaccine inspections nationwide– Discovery of a blackmarket vaccine ring earlier this year was the impetus for China’s nationwide campaign to inspect vaccine purchasing. The $90 million scheme involved illegal purchase and distribution of non-refrigerated vaccines. — China has cracked down on their enforcement of sourcing and distribution, launched an investigation into the scandal, and added random checks to their regularly vaccine inspections, which will be overseen by China’s NHFPC.
  2. July/AugustThe Real Cost of Poor Data Integrity in Pharmaceutical Manufacturing (PDF) — In this whitepaper from Lanchman, James Davidson, PhD, explains just how much data integrity issues can cost your company. After this, he outlines and defends a “proactive approach to the assessment of risks to data reliability.” This is an important read for anyone in the pharmaceutical industry.
  3. 17 AugustFDA sends warning letters to 12 medical device companies — It’s important to note the incredible variety and uniformity simultaneously at work in this story. Violations were found at plants across a wide geographical spread: Italy, Germany, China, the Philippines, Argentina, the U.K., France, and the U.S.  Products made by these firms include items as diverse as surgical devices and dental floss. The takeaway? First, that violations can happen in any company, regardless of plant location or product type. Second: No matter how simple or complex the device, FDA inspectors will enforce the rules.
  4. 18 AugustWhat Does Getting a 483 or Warning Letter Really Cost You? — One Head of Manufacturing estimates that even a “moderately bad” warning letter costs his company $250,000, and we can understand why. Correcting from a 483 can include internal teams, external consultants, process redesign, and hundreds or thousands of hours dedicated to the recovery. All of those processes add up. Unfortunately, Warning Letters are even more costly — exponentially so: corrections run in the hundreds of millions of dollars, and that’s not to mention the hits companies take to reputation, drug approvals, and competitive response. 
  5. 30 AugustTheranos Halts New Zika Test After FDA Inspection —  The FDA inspected Theranos earlier this month in response to the company filing for emergency clearance on a Zika virus blood test called minilab. Sadly, it seems that Theranos by-stepped some important procedures in their rush to develop their new product. Inspectors found that some of the supporting data had been collected without implementing protocol approved by an IRB (Institutional Review Board). In response to these findings, Theranos volutnarily withdrew their request for clearance. They plan to collect additional data — this time under properly reviewed protocols — and resubmit their application. For their sake, let’s hope this round will involve a more dedicated attention to detail. The takeaway? Even for an emergency clearance, the FDA does not budge on patient safety. 
  6. 31 AugustFDA finds China manufacturing plant full of holes, chipped paint, and insects –Words like “lizards”, “falsified”, and “mold” catch the eye, but the keyword here is “management.” This article covers two instances of plants owned by Chinese companies receiving FDA enforcement action for violations of the most fundamental GMP standards. The problems stated here are so serious they are almost unbelievable. Stories such as these are significant in today’s global market. Remember: China controls 50% of the API market globally, and exports from China to the US grew 4% in just the last year. You can read the warning letter issued to one of the two companies here
  7. 31 AugustPharmaceutical Compounding: The FDA Is Not The Problem – Some concerning statistics: 65% of the 43 states that responded to a PEW survey indicated that they “did not mandate specific expectations for specialized training.” In 60% of these states, pharmacies are not required to report “serious adverse events or reactions related to sterile compounding.” 30% do not require a pharmacist license to work in pharmaceutical compounding. Given these facts, it might not surprise you to hear that the FDA is requesting more jurisdiction over the preparation of sterile drugs. The last section of the article outlines three recommended reforms for compounding pharmacy. 
  8. 1 SeptemberSterility Assurance and Cross Contamination – In this article, GMP Quality Expert Barbara Unger will guide you through 6 examples of 483s whose observations note problems with sterility assurance and cross contamination. This overview will help you understand the scope of these issues and the enforcement actions that can be linked to non-compliance. The main point? “FDA observations regarding problems in SA & CC include facility design and operations issues, training of operating staff, and deficiencies in media fill exercises.” Good to know.
  9. 7 SeptemberCDMO Pharmaceutics International gains $93M investment, new president — A consortium of investors, including Athyrium Capital Management, HIldred Captial Partners, and Pharmascience, signed a deal with Pharmaceutics International worth $93 million. In exchange, they will receive equity stake and debt refinancing. The article outlines how Pharm Int. will use these extra funds — they plan to focus on manufacturing and formulation. You can read a statement on these plans here. The company’s new executive is Michael Bogda. 
  10. 12 September: No expectations for China or India to join Inspection Co-operation Scheme — PIC/S currently has 49 members, 4 new applicants, and 3 pre-applicants. Many other nations —  including Armenia, Bulgaria, Nigeria, Saudia Arabia, Uganda, Vietnam, and Zimabwe — are showing interest in joining. Despite the importance of international cooperation and the fact that they supply most of the world with pharmaceuticals, officials say it is unlikely that either China or India will be joining PIC/S or the International pharma regulatory schemes (ICH) any time soon — But China has exhibited markedly more interest in joining than India. For China, obstacles to joining the PIC/S arise from administrative and political complications. Chinese politicians, not the CFDA, would have to make the decision to apply. In India, hesitation centers on the expensive of joining. Some argue that if India were to follow GMP standards in manufacturing, local patients in India would be unable to afford medication.
  11. 15 September: New Bills Would Require Drug Companies to Justify Price Hikes of More than 10% – The FAIR Drug Pricing Act, proposed by Tammy Baldwin, John McCain and Rep. Schakowsky, hopes to “expose the profiteering of drug corporations” by requiring increased transparency. If passed, the proposed bills would require manufacturers to submit a transparency and justification report 30 days before increasing the price of certain drugs by more than 10% of the current cost. The act would not keep companies from increasing prices, but would hopefully highlight problems leading to price gouging. The required reports would include info on net profits from the drug in question, marketing-advertisement spending, a justification of price increase, manufacturing, research, and development costs. All of this information would be made available to the public online within 30 days. You can find text of the bill  here.
  12. 22 September: FDA May Push Back Release of Biosimilar Interchangeability Draft Guidance – Have you been waiting for the FDA to finalize their definition of “interchangeability”? If so, you might be disappointed — the final publication year is now expected to be 2019 or 2020, and the FDA says the first draft will be produced by 31 December 2017. The article lists the FDA’s timeline for the publication of guidance drafts on other related topics, as well.

Is there a story we missed? How do you keep up with your industry’s news? Let us know in the comments!

Learn more about how FDAzilla can help you achieve your quality and inspection preparation goals: get 483s, Inspector Profiles, Enforcement Analytics, and GMP Regulatory Intelligence. Any questions? Contact me at tony@fdazilla.com.


3 Key Learnings from the PDA/FDA Joint Conference

by Barbara Unger, FDAzilla GMP Quality Expert and Editor-in-Chief of GMP Regulatory Intelligence

OVERALL:  This is the 25th anniversary of the PDA/FDA conference and many of the presentations provided evidence of the significant progress made in research and medicine during this time.  It was fascinating to stand back for a few moments to see just how far we’ve come.  The overall conclusion I take from the two days of the conference that I attended are:

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Sterility AssuranceandCross Contamination

Sterility Assurance and Cross Contamination

by Barbara Unger, FDAzilla GMP Quality Expert and Editor-in-Chief of GMP Regulatory Intelligence

Forms 483 Addressing Sterility Assurance and Cross-Contamination 

Along with data integrity, deficiencies in sterility assurance and the potential for product or API contamination identified during FDA inspections often lead to warning letters. Also many product recalls are based on lack of sterility assurance or less frequently on potential cross contamination.  Here we take a look at six forms 483 that include observations associated with sterility assurance and potential cross contamination.  These are certainly not meant to provide an all-inclusive view of the topic, but rather represent recent inspection observations in these areas to demonstrate the broad scope of the topic.  FDA’s flurry of inspections and enforcement actions against compounding pharmacies and outsourcing facilities focuses heavily of requirements associated with expectations regarding aseptic manufacture of sterile drug products. These sites are often also cited for the potential for cross contamination. Lack of sterility assurance and the potential for cross contamination, particularly by high potency compounds or sensitizing agents both have potentially serious consequences for patient safety.   Many compounding pharmacies and outsourcing facilities have recalled large numbers of products due to concerns about sterility assurance.  We include one example of this type of facility in the collection presented below.  Failure to complete adequate cleaning validation for multi-product equipment is often another source of potential cross contamination even when products do not include high potency compounds or sensitizing agents.

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These 3 companies got slammed by the FDA. (1)

The Story of 3 Consent Decrees

by Barbara Unger, FDAzilla GMP Quality Expert and Editor-in-Chief of GMP Regulatory Intelligence

A consent decree agreement is an agreement filed in the US courts formalizing a voluntary agreement between two parties.  Here we will address consent decree agreements between FDA and several pharmaceutical companies based on repeated failures to adequately address CGMP deficiencies.  It is not an action taken on the basis of a single form 483, or a single warning letter.  Generally, a series of events play out over time when critical inspection observations are not addressed and are identified in subsequent inspections.  Frequently one or more warning letters are involved.  Consent decree agreements often include fines, with the option for additional financial penalties if conditions to which the firm agrees are not met.  Often these firms are required to use a 3rd party consultants to perform lot release.  Firms operating under a consent decree agreement have largely lost their independence in GMP activities.  Unlike Corporate Integrity Agreement which have a defined duration, firms must petition to have the consent decree agreement condition rescinded.

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