Original Post Date: January 6, 2011
Author: John English
Everyone has their own way of starting the New Year. In my case, I was fortunate to catch an FDA colleague for a brief discussion. When I asked for an opinion about the large increase in Warning Letters posted in the last 15 months, the reply I got was – “When the new commissioner came in, I believe that she said “It’s all about Enforcement.” Warning letters are the measure of enforcement.” With those words fresh in my mind, I noticed the following item that appeared TUE morning in the CDER daily update. (Yes, it’s dated Monday but it wasn’t there late MONDAY afternoon)
• FDA Issues the following Warning Letters:
o Macco Organiques, Inc.
o Yuki Gosei Kogyo Co., Ltd.
o Synbiotics Limited c/o Ambalal Sarabhai Enterprises
There are several interesting parts to this. First, these weren’t “new letters.” All of them were “issued” last year! (OK, last month, actually, but still in December and not this week.) What else do they have in common? All of them are for ex-US API facilities in three different countries – Canada, Japan and India. This seems to show a clear focus on the issue of off-shore sourced API’s within the FDA-regulated area. Following up on those three, a fourth was posted on TUE – this API company (Klinge Chemicals Limited) is located in Scotland.
There is also some new focus point in two of the letters – the USP. Two of the companies had USP issues. Macco addressed that issue in a way that is simple, novel and one the FDA didn’t accept:
(Item 2) …In your response you indicate that your products will no longer have a United States Pharmacopeia (USP) claim on the label and that, therefore, you do not need to comply with the USP. We disagree with your response. These three APIs are all the subject of monographs in the USP …Removing the designation “USP” from your product labels does not eliminate the statutory requirement that your firm comply with the USP requirements. If your product fails to meet the standards of strength, quality, or purity in the USP, you may state on the label how your drug differs from these compendial standards. Either failing to comply with the USP compendial requirements or to state on the label how your drug differs from the compendial standards renders your drug adulterated under the Act.
Klinge has a similar problem but for a different reason. You may find it of interest.
(Item 3) …. the finished product assay determination and volumetric solution standardization procedures and calculation formulas do not at least meet the current USP standards. There is no assurance that the final result for all finished products released by your firm are within specification. The FDA investigator noted that your firm had no access to the USP.
Your response is inadequate because it failed to evaluate whether or not the lots of (b)(4) (API) that have been released were within specification according to USP monograph. …
The Synbiotics Ltd letter has a much different issue – they did not allow the investigator access to the site. Even ‘from a distance,’ the review did not go well:
On August 23, 2010, the U.S. Food and Drug Administration arrived at Synbiotics Limited, your manufacturing facility for active pharmaceutical ingredients (API), located at Plot Nos. 570, 571, 576A, Maitry Marg, Village-Luna, Tal Padra (Dt.), Vadodara, India, to conduct an inspection. YOUR FIRM DENIED OUR INVESTIGATOR ACCESS INTO THE FACILITY, and instead requested that the investigator remain in a business office located at Asence Pharma Private Ltd., Parshwa Pooja Complex, Akota, Vadodara, India. During August 23-27, 2010, information and limited documents provided to the investigator for review revealed significant deviations from Current Good Manufacturing Practice (CGMP) for the manufacture of APIs.
Let’s review one more common issue – both the Canadian and the Scottish firms were cited for issues with stability studies. In the case of the second firm, to quote the old song “Please don’t bother trying to find them, they’re not there.” Please consider the excerpt below:
2. Failure to establish a stability program to monitor the APIs manufactured at your facility.
For example, your firm has NOT COLLECTED or tested a batch of (b)(4) API IN THE LAST THREE YEARS. At least one batch per year of API should be tested as part of an ongoing stability program.
We acknowledge your response indicating that your outside contract for stability sample analysis was discontinued and that YOUR FIRM INTENDS TO PURCHASE EQUIPMENT and conduct stability testing onsite. However, you have not adequately addressed the specific issues cited on the FDA-483. Your firm failed to have written procedures that govern the stability program to address your annual commitment and analyses to be performed. …
Please note there are other issues covered – endotoxins for one and training for another but these are hopefully enough to encourage you to read them on your own. In the interest of getting this done, finally, all four letters do have this phrase in common:
Until all corrections have been completed and FDA has confirmed corrections of the deviations and your firm’s compliance with CGMP, FDA MAY WITHHOLD approval of any new applications or supplements listing your firm as an API manufacturer…..
Please note that the phrase is “may withhold?” If “enforcement” is the key reason for issuing a warning letter, what level of non-compliance is required to actually get a companies products refused entry? “Patience is a virtue” but please consider this observation, also taken from one of these letters as a measure of patience and inspection activity? (Oh yes, and ‘understatement!)
“We acknowledge that your firm is performing the second stage of qualification for this water system. However, this deficiency was brought to your attention DURING THE LAST FDA INSPECTION IN 2003. Your failure to correct then LEADS US TO QUESTION your commitment to manufacturing quality APIs.”
Please note that all highlights or font change are by this author. Specific references are available by request at John.T.English@prodigy.net or through this website firstname.lastname@example.org. In addition:
“Matters described in FDA warning letters may have been subject to subsequent interaction between FDA and the letter recipient that may have changed the regulatory status of issues discussed in the letter.”
John English is a consultant to the life sciences industry.
Original Post Date: December 17, 2010
Author: John English
Recent warning letters have contained two new trends and they have been repeated this week. The first is still rare but it is the inclusion of a cease to market order in the warning letter itself. The second is an enhanced FDA comment about what the letter does and doesn’t say about “your facility.”
Several times so far this year, FDA warning letters have included a ‘cease to market’ order. These orders have usually been for “off-shore” companies, although the last one referenced in this group was for a NY-based contract manufacturing company. Another warning letter has just been made available (14 DEC2010) for a domestic company that produces diagnostic assays, a CDRH regulated product. The text is quite to the point:
FDA requests that FIRM NAME immediately cease marketing, promoting, and distributing all in vitro diagnostic products that require PMA approval or 510(k) clearance without FDA approval or clearance. The adequacy of your corrective actions will be evaluated during our next inspection…..
It may be a coincidence that the other US-based example had issues related to testing as well but that one was under CDER. (Integrity of test results is certainly a key FDA focus point – whether the results are “traditional” or electronic.) This new letter also contains another item – it is one of two this week that includes a new ‘disclaimer’ if you like.
Warning letters usually contain a summary text that is similar to the following (also posted 14 DEC 2010):
Finally, you should know that this letter is not intended to be an all-inclusive list of the violation(s) at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA.
Recent letters have added the additional ‘disclaimer’ – which is not unprecedented, but it isn’t a common one. That said, it was also in two letters made available this week. The CAPITALS are my insertion:
The specific violations noted in this letter and in the lnspectional Observations, Form FDA 483, issued at the close of the inspection MAY BE SYMPTOMATIC OF SERIOUS PROBLEMS IN YOUR FIRM’S MANUFACTURING AND QUALITY ASSURANCE SYSTEMS. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance….
The new FDA focus on enforcement ties in with their attention to two key areas – the Quality and Manufacturing systems. It also points out the responsibility to take investigations seriously and make your CAPA system work:
“You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance.”
Many of you may observe that all of the above is quite basic and should go without saying, to use an old phrase. While I agree, the agency keeps saying it – and saying it more pointedly. The question should be therefore – is the industry listening? More specifically, since these letters are addressed to Senior Management, will there be additional efforts by FDA to question why quality activities are not carried through? Another letter posted this week (CDER product) includes this statement – the unsaid question is why is this happening. Again, the CAPITALS are my addition.
“Our inspection found your firm’s quality unit failed to adequately review batch records. The above major batch record deficiencies underscore the importance of appropriate quality unit oversight at YOUR firm……
YOU are responsible for investigating and determining the causes of the violations identified and for preventing their recurrence and the occurrence of other violations. It is YOUR responsibility to ensure your facility operates in compliance with all requirements of federal law and FDA regulations….”
Those of you who do the field level compliance work know who you are. The question is who has the authority to enable these efforts? And what steps are being taken to ensure the field level efforts are successful?
NOTE – Since these letters represent trends, the specific companies are not identified.
John English is a consultant to the life sciences industry.
Original Post Date: April 1, 2010
Author: Mindy Allport-Settle
Some things will never change when it comes to getting a new drug or medical device to a state of commercialization that includes profits beyond simple revenue. Regulatory approvals, mountains of paper work, clinical trials, research and development efforts that sometimes lead nowhere are only a few. Some things, though, are changing.
Most of the people who develop an idea for a new drug or medical device product have more than one idea — more than one viable target. Traditionally, we sift through our ideas and choose the one that seems like it has the best chance of success. Maybe that means it will treat the largest patient population or be the most appealing to a venture capital firm. What do we do with the ideas that don’t make that cut? We frequently abandon them — especially in favor of a target that has a higher dollar value down stream. Maybe we should be taking advantage of more of those ideas.
Two new entrepreneurial strategies for financing research and development efforts and eventually bringing flagship products to market have emerged over the last few years.
1. Commercialize first in countries outside North America and the European Union
While drug and medical device sales in the United States account for an average of 80% of a company’s revenue, ignoring the rest of the planet is a mistake. Many countries are eager to approve products for commercial sale with abbreviated clinical studies. The revenue might not be much, but it will provide additional patient data and might provide enough of a revenue stream to off-set the cost of U.S. commercialization efforts.
2. Develop a non-drug product that doesn’t require regulatory approval
OTC (over the counter) products are a multi-billion dollar industry. There are even countries that will brand their product with your name to provide you with products to help establish your brand.
One product that illustrates both of these concepts is Monster Be Gone / Monster Be Good™. This product addresses a very real and sometimes difficult to manage condition in pediatric-aged patients: fear of monsters. The revenue from this product alone would not support a company, but in combination with other similar products, the revenue can pay base salaries and facility costs. Being able to keep the lights on and paying salaries takes some of the fear factor out of the normal research and development cycle leaving the company a little more freedom to grow.
Mindy Allport-Settle is the CEO of PharmaLogika, Inc and is a consultant to the life sciences industry. She has worked extensively with the manufacturing development of traditional and non-traditional vaccine platforms.
Stringent Compliance Required in Pioneering Biotechnology, says Physician & Human Gene Therapy Researcher
Original Post Date: February 1, 2010
Author: Evan Scullin, MD
A clinical trial conducted at the University of Pennsylvania went horribly awry in 1999 when one of the gene transfer trial subjects, an 18 year old man named Jesse Gelsinger, spiraled into a devastating immune reaction and died as a result. Jesse suffered from ornithine transcarbamylase (OTC) deficiency, a rare genetic disease caused by the inexpression of a functional OTC gene, preventing the normal elimination of ammonia from the body. This deficiency results in a toxic build up of ammonia, a protein metabolite. For the gene transfer trial study, the team at the University of Pennsylvania utilized an engineered strain of the adenovirus, which causes the common cold.
In an April 2009 Article in Molecular Genetics and Metabolism, Dr James M. Wilson, the director of the clinical trial said, “It is clear now that the Clinical and Quality Assurance (QA) groups did not have the resources necessary to assure complete compliance for such a dynamic and complex protocol. They were asked to cover too much territory; each clinical research nurse oversaw as many as three gene therapy protocols at any one time, while the QA group, which numbered seven staff members at its peak, was responsible for most aspects of [Good Manufacturing Practice] GMP, [Good Clinical Practice] GCP, and [Good Licensing Practice] GLP compliance for up to seven active investigational new drugs. Support for these programs was provided primarily from grants and contracts that, individually, did not provide sufficient Clinical and QA resources to fully support specific protocols.”
Wilson said that insufficient Quality Assurance played a major role in the trial’s shortcomings along with a conflict of interest with a biotechnology firm, Genovo that had invested heavily in the treatment. By not rigorously considering the QA aspects of the trial, he said, patient safety had been placed at risk.
In a later interview in September 2009 with the journal Scientific American, the director of the trial, Dr. Wilson posed the question in an interview, “If the worst-case scenario played itself out—not the potential or likely, but the worst—would [going ahead with the study] be acceptable?” His answer to this question was — absolutely not. This central question, he says, would have been an excellent gauge as to whether his team was ready to proceed with the study. It would also serve as a solid cue to the industry as a whole today for evaluating whether all supports for a trial are in place before moving ahead, particularly in regard to Quality Assurance.
This specific case demonstrates the high importance firms must place on GMP, GCP, GLP toward preventing scenarios where patient safety can be compromised amidst powerful forces that often act on those studies. When companies have invested in research, clinical trials become high stakes endeavors. Companies want to develop solid products for the least in cost, but following short-cuts in testing and bringing those products to market threaten the very innovative products themselves, by casting a cloud over the specific technologies when things go wrong.
Aggressively pursuing new therapeutic technologies is important in order to bring effective cutting-edge treatment to patients, but this is only worthwhile when patient lives and interests are fully protected first. In the competitive world of scientific discovery – especially in the life-sciences, the industry must seek safety first before seeking return on investment. Life-sciences firms must consider good compliance practice as “routine” and as part of the cost of doing business in successfully developing and manufacturing new products for patients.
The following are Dr Wilson’s enumerated lessons learned from the failed project, as listed in the April 2009 article:
Lesson #1: The clinical protocol is a contract with the research subjects and regulatory agencies that must be strictly and literally adhered to.
Lesson #2: If you think about reporting – then do so!
Lesson #3: It is very difficult to manage real or perceived financial conflicts of interest in clinical trials.
Lesson #4: Informed consent may require objective third party participation
These lessons could apply to most any clinical study and would certainly serve as part of a helpful roadmap for innovative biotech and pharmaceutical endeavor in the decade ahead.
Molecular Genetics and Metabolism:
Dr. Evan Scullin is the Director of Business and Product Development of PharmaLogika, Inc and is a consultant to the life sciences industry. His work focuses on both domestic and cross-border pharmaceutical ventures and collaboration between medical institutions, governments and private firms.
Originally posted November 10, 2009
Some medical professionals are confused about the safety of the H1N1 influenza vaccine, commonly called the swine flu vaccine. Based on the newness of this particular strain of the flu, some doctors believe the vaccine is untested and therefore unsafe. Some of the patients most at risk for severe influenza complications are not receiving a vaccine that could help them.
In short, the vaccine is no more “untested” than the seasonal flu vaccine released every year. Counseling patients to avoid the vaccine might be as irresponsible as the parents who have “swine flu parties” to infect their children in much the same tradition as “chicken pox parties.”
While new technologies are being researched and developed, influenza vaccine production has changed very little since its discovery. In 1931, viral growth in embryonated hens’ eggs was discovered, and in the 1940s, the US military developed the first approved inactivated vaccines for influenza, which were used in the Second World War.  The current egg-based technology for producing influenza vaccine was created in the 1950s. 
In the U.S. swine flu scare of 1976, President Gerald Ford was confronted with a potential swine flu pandemic. The vaccination program was rushed, yet plagued by delays and public relations problems. Meanwhile, maximum military containment efforts succeeded unexpectedly in confining the new strain to the single army base where it had originated. On that base a number of soldiers fell severely ill, but only one died. The program was canceled, after about 24% of the population had received vaccinations. An excess in deaths of twenty-five over normal annual levels as well as 400 excess hospitalizations, both from Guillain-Barré syndrome, were estimated to have occurred from the vaccination program itself, illustrating that vaccine itself is not free of risks. The result has been cited to stoke lingering doubts about vaccination. 
While the substrate for all injectable influenza vaccines is the same, the inactivated virus used in the vaccine changes from season to season depending on what strain is present or anticipated in the population. The safety and efficacy of the H1N1 vaccine is statistically the same as the trivalent seasonal influenza vaccine. In layman’s terms, the swine flu vaccine is the same as the regular seaonal flu vaccine. Your chances of avoiding flu-realted complications are better with the vaccine than without it.
Mindy Allport-Settle is the CEO of PharmaLogika, Inc. and is a consultant to the life sciences industry. She has worked extensively with the manufacturing development of traditional and non-traditional vaccine platforms. Influenza Report article Vaccines by Stephen Korsman
 NEJM Volume 352:1839-1842 May 5, 2005 Number 18 articlePreparing for the Next Pandemic by Michael T. Osterholm
 The Sky is Falling: An Analysis of the Swine Flu Affair of 1976 by Joel Warner
It’s not easy to cross-reference FDA regs and guidance on the FDA website: CGMP Concise Desk Reference Needed
Originally posted November 9, 2009
The FDA website is designed to allow the user to search on terms only within the sections the user specifies. This means we frequently miss, or are not aware of, all of the regulations and guidance documents that apply to us in industry. The pocket CFR manuals available at conferences and training events are not easy to search and don’t include all of the information we need. This book fills in the gaps.
20% Bulk Discount $34.39 (http://www.pharmalogika.com/cgmplid.html)
Amazon.com list price $42.99 (http://www.amazon.com/Current-Good-Manufacturing-Practices-Pharmaceutical/dp/1449505236/ref=sr_1_1?ie=UTF8&s=books&qid=1257637926&sr=1-1)
“Current Good Manufacturing Practices: Pharmaceutical, Biologics, and Medical Device Regulations and Guidance Documents Concise Reference” (634 pages)
Included Reference Tools: