Valensa International announced Non-GMO Project has been awarded to Valensa’s Organic Spirulina, Chlorella and Microalgae products.

Bergstrom Nutrition, manufacturer of OptiMSM®, a branded form of methylsulfonylmethane (MSM), recently published an article detailing how the small intestine absorbs MSM, particularly in relation to sulfur.

Alkemist Labs is pleased to announce a move to a new facility with over four times more space to expand capacity and accommodate continued growth.

Outside influences have shown strong correlations with what lives inside our bodies, and researchers are just beginning to understand how these environmental factors may affect the makeup of the gut microbiome.

NutraIngredients is pleased to announce the shortlisted finalists for the 2020 edition of the NutraIngredients Awards ... with the winners to be announced in the first online awards ceremony next week (May 13th).

Older adults who consumed large amounts of flavonoid-rich foods were two to four times less likely to develop Alzheimer's disease and related dementias over 20 years compared with people whose intake was low, in a study of 2,800 people.

Equal pay, migrant workers, and maternal health are the issues highlighted by the finalists of the inaugural APEC Healthy Women, Healthy Economies Research Prize.

Ministers address developments in the global economy and take action to safeguard the region’s growth.

Broaden opportunities for people and ensure more inclusive growth across the Asia-Pacific, urged the 2020 Chair of APEC Senior Officials, host of the Asia-Pacific Economic Cooperation in 2020.

Research Promoting Women’s Health to Receive $20,000 Prize

Regional cooperation key to containment and rebound

Medical supplies and personal protective products are facing barriers worldwide

From : Communities>>Regulatory Open Forum
Yes, I think there were some previous posts where people uploaded Word versions you can get; just need to look around a little. ------------------------------ Richard Vincins RAC Vice President Global Regulatory Affairs ------------------------------

From : Communities>>Regulatory Open Forum
Great! Thanks Anna --------------------------------- Anna Alonzi MD Sr. Regulatory Associate Newtown PA United States ---------------------------------

From : Communities>>Regulatory Open Forum
Yes, exactly i asked same

From : Communities>>Regulatory Open Forum
This message was posted by a user wishing to remain anonymous Why not use Adobe to fill out the form?  You will need it to compile the submission anyway.

From : Communities>>Regulatory Open Forum
This message was posted by a user wishing to remain anonymous Hello, Does anyone know how long FDA's EUA process takes for approval compared to a 510k.  EUA seems to ask a lot of the same information that a 510k requests so not clear on what the benefits are or if it's worthwhile.  I assume you will eventually have to achieve traditional market clearance at some point. Any insight would be most appreciated. Thank you.

From : Communities>>Regulatory Open Forum
This message was posted by a user wishing to remain anonymous When this was first issued we printed it out, filled in the answers with careful handwriting and then scanned it back in - which seemed to be perfectly acceptable. Since then we've converted their form to a fillable PDF.​

From : Communities>>Regulatory Open Forum
Hello,  I can see many unapproved combinations of Minoxidil as topical solution like minoxidil+ Azelaic Acid; Minoxidil + Finasteride; Minoxdil+ niacin+retinol+caffeine that are available online for sale in US but these drug products are not approved by FDA as visble from USFDA website.  Can anyone explain that is there any mechanism or guideline to allows to sell such unapproved drug products online in US and also in EU? Or is this totally illegal practice?  Thanks Ankur RAC

From : Communities>>Regulatory Open Forum
Hi, Ankur - Some may be "legal," others not. It's a big industry, and it is fair to be cynical. Combination products for sale that have not been approved-as the combination-by FDA are just that, unapproved drugs. I assume you checked for the approval status in FDA's "Orange Book" (https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm). Even if both active pharmaceutical ingredients in a 2-drug mixture were approved separately on their own, it does not mean the combined product is approved for [More]

From : Communities>>Regulatory Open Forum
Hi, Willard - The Product code RHP won't show any 510(k)s because that is not a match for any regulated medical device. You can see the classification in the "Radiation Emitting Electronic Product Codes" page (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD_RH/classification.cfm?PCD=RHP), where it also notes that for this Product Code, there are no applicable standards for these "UV Lamp, Germicidal" products.  If it were a medical device, it might fall under FDA's classification for certain [More]

From : Communities>>Regulatory Open Forum
These are all unapproved new drugs. Many people who have very limited knowledge of our OTC drug system, assume that if it is sold OTC, it is a monographed drug and they can change the formulation. They do not know that there are two types of OTC drugs allowed-compliance with a monograph or NDA. Minoxidil is one and chlorhexidine antiseptic wash is another. ------------------------------ David Steinberg,FRAPS President Steinberg & Associates, Inc. Pompton Plains NJ USA 609-902-8860 -------------- [More]

From : Communities>>Regulatory Open Forum
The only  possible way I can see any of these products being legally marketed in the US without going the OTC NDA route would be if the ingredients  other than Minoxidil are considered "inactive" and have some purpose (other than their active ingredient purposes) in the formulation.  That said, this might work for the last combination in your listing because all of these can and are often used in OTC products as inactive ingredients with understood and current reasons for existing in a formulation [More]

From : Communities>>Regulatory Open Forum
This message was posted by a user wishing to remain anonymous For device-lead drug combination products, is there any difference in the quality (grade) of API used compared to a pure drug product? The cGMP guidance for combination products does not seem to specify, and since drug claims cannot be made on device-lead drug combination products, it was not clear what quality of drug is required. Thank you!

From : Communities>>Regulatory Open Forum
​I doubt FDA would have any willingness to change the requirements or expectations for a drug product based on whether it is in a strictly drug product versus in a combination product.  The fact also that there is not a published allowance for this is further evidence that FDA expects that the drug will meet the requirements as expected for drug products without providing any allowed changes or classes of changes.  Remember, FDA expects that drug products meet specific requirements.  Things like [More]

From : Communities>>Regulatory Open Forum
Hello, The EUA is much faster than the 510(k) process.  However, the EUA intended uses are only authorized during the state of emergency.  Once the state of emergency ends so does your authorization for the EUA intended uses.  The 510(k) clearance is permanent and authorizes the product with its cleared intended uses, to be put into interstate commerce. Hope that helps. ------------------------------ William Coulston PMP, MS, RAC Quality & Regulatory Manager San Antonio TX United States -------- [More]

From : Communities>>Regulatory Open Forum
Annie: Thank you for sharing this news.  I am curious whether the Board considers this a limited exception or a potential new normal option going forward? Scott ------------------------------ Scott Bishop Houston TX United States ------------------------------ ------------------------------------------- Original Message: Sent: 04-May-2020 08:50 From: Annie O'Brien Subject: New: Take the RAC Exams Online this Summer! The RAC board has been working hard to find solutions offering more flexibility [More]

From : Communities>>Regulatory Open Forum
Yes, you will need to achieve a 510(k) clearance after the emergency use has been officially ended by the FDA as William mentions.  Much of the information is the same, but the review process is intended to be expedited.  If you want to continue selling the product in the United States after the emergency use, you should really submit a 510(k) now; while the virus issue may continue for a few months it will take a few months for 510(k) clearance.  And if you have an EUA Approval this really is not [More]

From : Communities>>Regulatory Open Forum
Good morning, Willard. In the U.S., disinfectants fall under the jurisdiction of both the FDA and EPA.  The agencies have an MOU in place to better define there roles.  Accordingly, devices that are  intended for "trapping, destroying, repelling, or mitigating any pest or any other form of plant or animal life (other than man and other than bacteria, virus, or other microorganism on or in living man or other living animals). . ." are defined as "pesticide devices", under  FIFRA section 2(h),.    Pesticide [More]

From : Communities>>Regulatory Open Forum
These types of products and combinations you mention are all unapproved drugs and unapproved combinations.  Unless the specific combination is approved or listed in an OTC monograph, it is a new drug and requires a NDA to market it.  Minoxidil is a Rx to OTC switch product so it requires a NDA or ANDA to market this drug in the US, even as a OTC drug.  Thus any combination with minoxidil is a new drug. In the past the FDA has also specifically stated that combining different types of products (drug [More]

Is data integrity music to your ears?  Ours, too!

ALCOA, GAMP, Part 11, GIGO, we cover it all.
(Sung to the tune of Simon and Garfunkel's "The Sound of Silence.")

By Laurie Meehan

“I can’t get the IWRS to assign a kit number.”

“My ECG reports take forever to come back from the Core Lab.”

“The eCRF won’t let me create a new subject.”

“This stupid machine is blinking an error code again.”

Sound familiar?  Sprinkle in some colorful adjectives and it probably does -- these problems are common enough at clinical research sites.  Equipment and systems have become increasingly technical and specialized, and study site staff has had to contend with more technology than ever before.  And because of the proliferation of niche vendors who provide the new tech, sites have had to deal with more vendors than ever before, too.  



And how are problems like these typically resolved?  Someone at the study site works his/her way through a list of maybe 20 or more vendor contact numbers, places a call, navigates a series of menu options, and hopefully gets directed to someone who can help.  And that assumes the site calls the right company; with tightly integrated systems, it’s not always obvious in which vendor’s system the problem lies.  This is frustrating for sites.  It takes time.  It costs money (since “vendor wrangling” is seldom sufficiently covered in the budget).  And it keeps study staff from doing what study staff does best – run the study, work with the study volunteers, and keep them safe.

So what’s the solution? 

Hint: It’s Not Training
Calm down.  Of course, adequate training on equipment and systems is important. But training doesn’t solve every problem.  Training doesn’t keep equipment from malfunctioning.  Training doesn’t ensure vendors deliver what and when they’ve promised.  Training can’t anticipate every situation nor address an unusual site circumstance.  And training doesn’t turn people into infallible little machines; we make mistakes.  And so, in all these cases, we’re back to site personnel interacting with perhaps scores of vendors, by phone or email, all over the world.

The Solution: a Single Point of Contact
Q: How do you help sites interact with dozens of vendors?
A:  You don’t.  You do it for them.  Establish a single point of contact within the Sponsor* organization for a site to call when vendor issues arise. 

Why is this a good idea when the expertise to resolve the issue lies with the vendor?  Why is this a good idea when the introduction of a middleman may result in some inefficiencies?

Excellent questions.  Here are our responses. 

• Better Vendor Oversight.  When sites filter their vendor issues through the Sponsor, the Sponsor can more easily track vendor performance.  Are there vendors that provide low-quality solutions, are repeatedly late, or difficult to deal with?  At best, these vendors are wasting time and money, and aren’t good for business (let alone site relations).  At worst, these vendors are jeopardizing subject safety or study data integrity, and require immediate Sponsor intervention.

• Better Site Oversight.  When sites filter their vendor issues through the Sponsor, the Sponsor can more easily track site performance.  Are there sites that routinely use equipment and computer systems incorrectly?  (Yes, now’s the time for that training.)  Are there high-performing sites that are able to work independently?  This information has always been important, but in an RBM paradigm, it’s essential.  Adaptive monitoring plans rely on on-going site performance measurements so Sponsors can adjust resources accordingly.  A reduction in monitoring visits means less opportunity to assess a site’s comfort level with study technology.  The corollary of “if it ain’t broke, don’t fix it” is “if you don’t know it’s broke, you can’t fix it.”

• Ability to Identify Pervasive Problems. After the third or fourth site reports the same problem, it’s clear that this is not an isolated occurrence.  Knowing that, the Sponsor can work with the vendor to resolve the problem before other sites experience the same troubles.

• Better Functioning Sites.  We have a saying: “The Site Comes First."™  In our experience, all things being equal, Sponsors that put their sites first -- make things as easy as possible for the study coordinators -- get the best results.  They also build the good relationships that keep the best sites coming back to work on future studies.

• Better Functioning Vendors.  The efficiencies for the vendor here are clear.  Who wouldn’t rather interact with a single point of contact than field individual calls from multiple study sites?  Plus, with far fewer players, miscommunicating both problem descriptions and problem solutions is less likely to occur.  The Sponsor contact and the vendor contacts will eventually settle into common terminology and build a history regarding past issues and resolutions.

What Do You Think?
We know that not everyone espouses this idea, and we recognize there are probably other effective processes out there.  Sponsors, how do you help your sites deal with multiple vendors?  Sites, do you have experiences and/or suggestions you can share?  (Be kind, anonymize!)  Leave a comment here, visit our website, or send us an email.




____________________
*When we use the term “Sponsors” in this post, we’re including CROs that take on Vendor Management responsibilities on behalf of Sponsors.

Protocol trumps practice. This principle seems clear enough, but complying with it is not always as straight-forward as it sounds. Years of practicing medicine has reinforced the way a physician responds to medical situations. But do these responses run counter to the investigational plan? Can a site’s commitment to standard of care affect its ability to meet enrollment targets?


There’s a lot to consider.



What’s Your Standard of Care?
When deciding whether or not to conduct a particular study, a PI needs to verify that the protocol is aligned with practice norms. For example, an early phase trial might exclude a medication that is part of a practice’s routine therapy. Is the study placebo-controlled? Does it feature a specific comparator drug? Will it include a washout period? Any of these elements could present enrollment challenges or preclude a site from accepting a study at all. Responsible sites want to make thoughtful decisions about study suitability; they want to provide realistic enrollment estimates. Sponsors want this too, and can help sites do both these things by providing them a sufficient level of detail about protocol procedures as early as possible.


The Road to Deviations is Often Paved with Good Intentions
Therapeutic misconception – a well-documented phenomenon in clinical research – occurs when a study participant “fails to appreciate the distinction between the imperatives of clinical research and of ordinary treatment.”* Study participants are not alone in this. Researchers blur the distinction themselves when they conduct procedures that are consistent with clinical care but deviate from the protocol. This may be particularly true for PIs who recruit participants from their own practices. An endocrinologist might ordinarily reduce dosage for a particularly diminutive patient. A pulmonologist would often skip a scheduled chest x-ray she felt wasn’t needed to avoid exposing her patient to unnecessary radiation. An orthopedic surgeon may decide his patient needs more recovery time than usual before attempting her first walk. In a clinical care setting, these decisions are sound, made in an individual patient’s best interest. In a clinical trial, if they differ from the investigational plan and haven’t been approved by the Sponsor, they’re protocol deviations.**

It May be Par for the Course, But It's Still an AE
Specialists who have experience treating particular conditions are also familiar with the complications that ordinarily accompany them. A nephrologist, for instance, knows that a patient with end-stage renal disease frequently experiences bloat from a buildup of fluid between dialysis sessions. Though useful for a doctor treating patients, this knowledge can actually work against a doctor running a trial. How? A PI may fail to report a stomach ache as an AE because it’s so typical, so expected. “Bloat is common for renal patients. If I recorded every GI incident, I’d be recording AEs all day.” At its surface, this PI’s argument sounds reasonable, but what if the study drug itself is contributing to the participant’s discomfort? In order to assess the drug’s gastrointestinal effect, the PI must document the frequency and severity of all GI events.

Lab values that are either above or below normal range are also prime candidates for AE underreporting. “Of course the participant’s liver enzyme is high – we’re testing a cholesterol drug.”

The Importance of Study Oversight
Any GCP course worth its registration fee will discuss the distinction between standard of care and the study protocol. In practice, the distinction is not always as obvious as training sessions might suggest. This is where well-trained CRAs come in. As site monitors, CRAs are in a position to catch deviations that result from lapses into standard of care. Reading through progress notes, a monitor can ensure that any untoward medical event has been reported as an Adverse Event. They can verify that procedures conducted by the PI and site staff are compliant with the protocol. Then, by reviewing which types of data must be collected and emphasizing the importance of following certain protocol procedures, monitors can take the opportunity to re-educate study personnel and help them avoid these common pitfalls.

_______________________________________________________________________
* Lidz CW, Appelbaum PS (2002) The therapeutic misconception: problems and solutions. Med Care 40: V55-V63.

**Andrew Snyder of the HealthEast Care System wrote a thoughtful piece describing the compatibilities that do exist between clinical care and clinical research. His arguments provide a useful counterpoint to the issues we’re raising here. https://firstclinical.com/journal/2017/1707_Research_vs_Care.pdf

A version of this article originally appeared in InSite, the Journal of the Society for Clinical Research Sites.

    WARNING LETTER

VIA UNITED PARCEL SERVICE
SIGNATURE REQUIRED

December 1, 2018

Mr. Kris Kringle, Owner
Santa’s Workshop, LLC
1225 Santa Clause Way
North Pole, Arctic Circle
 
Dear Mr. Kringle:

The U.S. FDA inspected your manufacturing facility, Santa’s Workshop, LLC at
1225 Santa Claus Way, North Pole Arctic Circle, from April 2 to April 20, 2018.

This warning letter summarizes significant violations of CGMP regulations for finished product. See 21 CFR, parts 210 and 211. During our inspection, our investigators observed specific violations including, but not limited to, the following.

CGMP Violations

1.    Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of product has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions (21 CFR 211.25(a) and 211.28).

Many members of your Enterprise Labor Force (ELF) unit lacked sufficient prior experience for designing and assembling (b)(4). At the time of our inspection, no ELF members had received training on CGMPs, and most were unaware of their responsibilities in the areas of cleanliness and proper attire. Hands and faces were often coated with chocolate, and bells on hats and shoes prevented protective apparel from attaining a proper fit. More generally, factory staff demonstrated an undisciplined, almost gleeful disregard for quality procedures. On three separate occasions, at critical stages of the manufacturing process, floor workers erupted into spontaneous song and dance.



Your written response of May 18, 2018 is inadequate because it does not address these training and experience deficiencies. While endearing, the ability to “sit on a shelf” or “live in a hollow tree” does not constitute acceptable manufacturing experience. Candy coating does not qualify as protective covering. And sticking one’s hands in a nearby snowdrift is not a recognized sanitation procedure. “Pure as the driven snow” is not a thing. Especially with all those reindeer knocking about.

2.    Your firm failed to maintain a system by which the distribution of each lot of product can be readily determined to facilitate its recall if necessary (21 CFR 211.150(b)).

Product distribution records were incomplete and, in the event of a recall, would be insufficient to identify all product recipients.

Your written response of May 18, 2018 is inadequate. Santa’s Own Procedures (SOPs) are insufficient to capture the information required to conduct a thorough recall.  Mr. Kringle may well know which customers are naughty and which are nice -- who’s good, who’s bad, who’s sleeping, and who’s awake, but this information is not written down and, in the opinion of our investigators, would be of limited value if it were.

3.    Your firm failed to store product at an appropriate temperature to ensure the identity, strength, quality, and purity of the products are not affected (21 CFR 211.142(b)).

Entire sections of the facility lacked effective air conditioning, resulting in destruction of all (b)(4) warehoused in two large storage rooms. A third inadequately cooled room was not in use, and except for some miscellaneous items – a couple hunks of coal, a corncob pipe, and a large, oddly sad puddle of water – the room was all but empty.

Your written response of May 18, 2108 was inadequate. FDA isn’t really sure what to do with “that old silk hat we found” in your response package.

4.    Products failing to meet established standards or specifications and any other relevant quality control criteria shall be rejected. Reprocessing may be performed (21 CFR 211.165(f)).

While not strictly a violation of 21 CFR 211.165(f), the rejection and quarantining procedures your firm follows for products that fail to meet established criteria is concerning. While it’s appropriate to reject a (b)(4) that swims, a (b)(4) with square wheels, a (b)(4) that shoots jelly, and a (b)(4) that rides an ostrich, exile to a remote island ruled by a flying lion is, in a word, extreme. Your firm also rejected and exiled a (b)(4)-in-a-box for what was almost certainly an easily remediated labeling problem; reprocessing would have been a more appropriate course of action. Also, we just have to know. Seriously. WHAT WAS WRONG WITH THE DOLLY???

5.    Your firm failed to establish adequate acceptance criteria for sampling and testing necessary to assure that batches of product meet appropriate specifications as a condition of their approval and release (21 CFR 211.165(d)).

Sampling procedures consisted of pulling each finished batch of (b)(4) out of a hot oven, taking a few nibbles, and declaring it “Jingle-icious.” Testers would frequently adulterate samples by submersing and saturating them with milk. These procedures are totally without scientific rigor. Furthermore, sampling was not restricted to members of the Quality Control Unit, but was extended to the entire plant floor. At times, sampling frequency was so high that there was very little, if any, of (b)(4) left to distribute. (On a personal note, our investigators would like to express their appreciation for the opportunity to participate in the testing activity. All the batches they sampled exceeded the strictest statistical quality control criteria, excepting the fruitcake, which could have benefited from additional stability testing and an earlier expiry date.)

Conclusion

Violations in this letter are not intended as an all-inclusive list. Typically the manufacturer is responsible for investigating violations, determining their root causes, and preventing their recurrence. However, in this case we’re going to make an exception. Though your methods and procedures are unconventional and frequently out of compliance with regulations, they are not wholly without merit. Our investigators have never experienced such a high level of workplace morale -- some calling it “downright merry” – and believe it warrants further observation. Investigators have suggested a series of mutually consultative visits to your workshop. Music, dance, batch samples, reindeer games, and the occasional adulterated eggnog are highly encouraged.

Sincerely,
/S/
Holly Bush
Division Director/OPQO Division I
North Pole District Office

Guest Blogger: Greg Weilersbacher
Founder & President, Eastlake Quality Consulting

All companies outsource. It’s a humbling fact that you simply can’t do it all yourself. This often has to do with resource allocation; your company may allocate dollars to build and sustain some activities in-house while choosing to contract higher-cost operations to qualified suppliers who already have the expertise and equipment. 

You may outsource the manufacturing of tablets, sterile injectable, or topical dosage form, or the GMP release and stability testing of your product. Once the production and testing is complete, the product may need to be stored under controlled temperature and humidity conditions and then distributed to locations around the globe. The Contract Development and Management Organizations (CDMOs) who execute these critical operations are of paramount importance to your company’s success. Choosing the right suppliers will also help to minimize stress-induced headaches throughout your organization. Here are the top five ways to get the most out of a supplier audit.



1.  Come to the Audit Prepared
This seems obvious. However, more often than not, quality auditors step into the supplier’s lobby without doing their homework. Ask yourself the following questions: Why am I auditing this supplier? Is this supplier new to my company or one that we have used before? If used previously, have I read over the audit observations as well as the supplier’s responses and do I understand them? Which audit observations do I suspect would be the most challenging for the supplier to address and which are most important to my company’s requirements for this product? Have I reviewed previously executed production batch records and testing data and are there issues that need to be resolved? Are their deviations and CAPAs to follow up on?

Your understanding the supplier’s work proposal is of great value in refining the scope of the audit. Ask yourself:  Which of our products may be manufactured and tested here and which strengths (e.g., potency) will be produced? Which equipment is likely to be used? For a tablet production, the equipment train could include balances, blenders, roller compactor, spray dryer, solvent-rated oven, comils, tablet press and tooling, gravity feeder, coating systems, de-duster, weight sorter, metal detector, tablet counter, etc. This list of equipment will assist you in requesting equipment records during the audit. 

2.  Stay On Point
Proper audit planning will help to keep the audit organized and adhere to the audit timeline. In advance of the audit, provide the audit host with a list of the technical, lab, and manufacturing staff you wish to speak with and the records you need to review. A well-organized host will have this available for your review. Stick to your audit agenda. This is critical. The best way to derail your progress is to spend precious time chasing down minor issues while glaring problems get little to no attention. Continually refer back to the audit agenda and remember to keep the content of your audit report in mind while executing the audit.


3.  Know Your Technical Expertise and Limitations
Many auditors have led previous lives in the laboratory or in manufacturing while others started their careers in quality assurance and may have little technical background with regard to equipment, manufacturing processes, GMP utilities and laboratory testing. Know your limitations and if necessary strengthen them by hiring an expert consultant to assist you during the audit.

A common problem area that is at best glossed over and at worst completely ignored during an audit is the CDMO’s compliance with GMP utilities requirements. All too often, this is due to the auditor’s lack of understanding of the operation, inputs and outputs, validation parameters, and periodic testing and maintenance requirements for utilities such as HVAC, clean or pure steam, purified water and WFI systems, autoclaves, clean compressed air, nitrogen and other gases used for operating equipment or used during processing activities in manufacturing. Typically, these areas are also less well understood by the CDMO’s employees and as a result noncompliance abound. 

Some GMP utilities may be connected to the facility’s building management system, while others may be stand-alone equipment. In either case, the CDMO should have records of alarms (e.g., out of specification or out of range conditions), an acknowledgement of each alarm by designated staff members, and documentation of corrective actions. The last item is key. This is where the execution of quality systems tends to fail. Make a point to request documentation of corrective actions for each utility alarm. 

Additionally, purified and WFI water systems along with gases, such as clean compressed air and nitrogen, require periodical sampling/testing at each point-of-use. Verify that the timelines (monthly, quarterly, or annual) for sampling and testing were performed as directed by the CDMO’s procedures. These timelines are typically not well adhered to. A clear understanding of all the operations of the supplier’s GMP utility management process will keep your thoughts clear during the audit and help identify areas that are in need of improvement. 

4.  The Auditor’s Job is to Identify the Good and the Bad (Not to Win the Debate)
An important goal of a supplier audit is to identify the supplier’s strengths and weaknesses and come away from the audit with a compliance assessment that your company can use to make important decisions. It is of no value to your company if the goal of the auditor is to show the supplier how much he or she knows by debating the fine points of compliance. GMP auditors with decades of experience generally avoid this competitive exchange as it is unproductive. Rather, it is more important to the spend the necessary time identifying compliance issues, making them known to the audit host in a professional manner, and taking detailed notes that assist in writing the audit report. Your company’s senior managers need to know the supplier’s good and not-so-good points; detailing all of these provides the greatest value. 

5.  Interview the CDMO's Lab Staff, Manufacturing Operators, and Shipping/Receiving Personnel
CDMO’s quality systems are generally written by managers and directors who have many years of industry experience. It is of utmost importance that staff members who execute these systems understand them if your company’s product is to be manufactured, tested, stored, and distributed in a compliant manner. Request to speak with manufacturing staff members who work on the production floor and are likely to work on your product. Ask them about the process they would follow to conduct lines clearance, charge powders to a blender, operate a spray dryer, use a comil, set-up of a tablet press, inspect tablets, use metal detectors, etc. Compare the information they provide to the CDMO’s SOPs to determine if the staff understands their jobs. Listen for phrases such as “I usually do it this way…” or “it’s a different every time but I typically set up the equipment like this…” These phrases reveal a lack of control and adherence to procedures. 

The Take Away
The audit itself lays the foundation for a relationship with the supplier and the take-away message should address the following questions: Will the supplier work to resolve the issues I’ve identified? Am I confident that the supplier will immediately notify and involve my company’s representatives when deviations occur during production or testing? Do the supplier’s quality systems and records meet my company’s requirements and those of regulatory agencies? How confident am I that the supplier will produce and/or test a quality product that my company can stand behind? Is the supplier simply a pair of hands or are they committed to be my partner in this product’s success? The answers will provide you with a comfort level in making the decision to move forward with the CDMO or to look to the their competition.  

*********************************************************************************

A version of this article was first published in Outsourced Pharma.

 About the Author
Greg Weilersbacher is the Founder and President of Eastlake Quality Consulting, a GMP consulting firm based in the Southern California area. Over the last 25 years, he has held director and vice president positions leading Quality Assurance, Quality Control, Analytical Chemistry, Materials Management, GMP Facilities, and Product Manufacturing in biotech and pharmaceutical companies. His unique experiences and technical background have led to the manufacture and release of hundreds of solid oral, sterile, and biologic investigational products to clinics in the U.S. and abroad. Email Greg at weilersbacher.greg@gmail.com.

Over the years, attendees of MAGI Clinical Research Conferences have collected a set of practical, actionable suggestions for improving clinical trials. More than eighty such tips appear in the July 2019 edition of Journal of Clinical Research Best Practices*.  In this post, Polaris auditors weigh in on some of their favorite MAGI suggestions. Surprising no one, they also were eager to share some of their own.

Our Favorites Tips from MAGI

So how does a clinical trial tip earn a spot on our exalted Faves List?  First, it must be something we don’t see too often, or not as much as we’d like.(If most organizations already do a useful thing, it doesn’t really qualify as a helpful tip; it’s really just a common practice.) Second, the effort to implement the tip can’t be too onerous. If a practice requires too much interdepartmental coordination, change management, training, money, or resources, it’s not a tip. It’s a full-blown initiative.

So here they are. Each tip from MAGI attendees is in bold font. Our accompanying commentary is in plain text:

• To help ensure quality study conduct, clinical sites should prepare protocol-specific quality checklists for each study. We’ve written about quality checklists from the auditing perspective before. They’re not a panacea, certainly, but that doesn’t mean they can’t be very useful.
  
  
• After study close-out, sponsors and CROs should consider holding conference calls with groups of sites to capture lessons learned. This in turn could be used to improve training, SOPs, SIVs, etc.
  
  
• As a recruitment aid, clinical sites should create pocket-sized, laminated study cards that list the inclusion/exclusion criteria for a study.  Site staff members can keep these cards in their lab coat pockets and quickly refer to them when treating a patient who could be a potential subject.
  
  
• CROs should share risk assessments and mitigation plans with Sponsors. We agree, but would also encourage CROs to keep the sites involved and aware of risks so they can anticipate them and proceed accordingly.
  
  
• Sponsors/CROs should ensure proper qualifications of vendors prior to executing contracts. It’s hard to argue with this logic, but we don’t see it as much as we should. Too often qualification audits come after the paperwork has been signed. Should the audit uncover noncompliance or quality risks at the vendor site, it’s much harder to get the vendor to make necessary changes after the contract is in place.
  
  
• CROs should align 3rd party contracts with the Sponsor/CRO contract and the Clinical Trial Agreement. Yep.

Additional Tips from Polaris QA/Compliance Auditors

The MAGI list of clinical trial tips brought others to mind that we wanted to share. We applied the same criteria to these suggestions as we did to the MAGI contributions: (1) not necessarily rare, but not as common as it could be, and (2) not overly complex or expensive to implement.

• When evaluating outsourcing partners and clinical sites, Sponsors and CROs should make sure to look at personnel turnover rates. Frequent turnovers may suggest underlying problems that could jeopardize study conduct and quality.
  
  
• Sponsors and CROs should make sure their Monitoring Report templates are consistent with the Clinical Monitoring Plan (CMP). For example:
  
  
• The CMP calls for a focus on a particular set of critical variables, but the report template only has a place for recording that 100% SDV was completed. This means that there’s no way to document that the monitor put special emphasis on anything.
• The CMP requires bi-direction review of study data – a confirmation that what is in the CRF can be verified in the source, and all pertinent data in the source can be found in the CRF – but the report template only allows for the former to be documented.
  
  
• Every member of the site team has valuable input. It’s important to include the study PI, CRC, pharmacist, and other key personnel in the discussions. In 2017, we wrote an article about the important, yet often overlooked, input that the pharmacist on site can provide.
  
  
• There are many reasons that trial participants leave a study, many of which can’t be remedied with improved site practices. But sites that demonstrate they value the participation of their study volunteers, and honor the time they’re spending and contribution they’re making, tend to have better retention results. To that end:
  
  
• To help participants schedule their time, sites can prepare calendars that include all study visit dates and indicate the activities and procedures they entail. (This, of course, needs to be approved by the IRB).
• When participants arrive, they shouldn’t have to sit in a waiting room or empty exam room; they should be seen immediately so they don’t feel their time is being wasted.
• Sites can provide beverages and light snacks to their study participants who especially appreciate them immediately after a fasting blood draw (protocol permitting, naturally). It’s a small courtesy, and not difficult to do. Whose day isn’t brightened by a proffered nosh?**

Uh oh. Now we got you all thinking about mini muffins and cheddar popcorn. Go ahead. Grab a treat. We'll talk later.

________________________________________________________________
 * Journal of Clinical Research Best Practices, July 2019

** Proffered Nosh™ would be a really great name for a restaurant. Or a fictional Scotland Yard Inspector -- legendary for his wit, brilliance, wine pairings, and fashion sense.

• Independent Data Monitoring Committee recommended continuing ongoing Phase 3 trial only in the more advanced “critical” group with Kevzara higher-dose versus placebo and discontinuing less advanced “severe” group

- Libtayo decreased the risk of death by 32.4% compared to chemotherapy

Objective responses seen in 29% of patients with locally advanced basal cell carcinoma (BCC)

US-based drugmaker Mylan and partner India-based biologicals specialist Biocon have announced the launch of their pegfilgrastim biosimilar, Fulphila, in Australia. The drug can be used to treat neutropenia (a lack of white blood cells) in cancer patients.

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