CMC Live - Chemistry, Manufacturing & Controls – Details, episodes & analysis

• 00:55 – Ed, Meranda and Brian welcome today’s guest, Mike Carroll, who speaks to his background in microbiology and product development  
• 04:28 – Mike talks about his involvement in the Parenteral Drug Association (PDA)  
• 07:51 – Lessons Mike has learned throughout his career and expounds on the relevance of PDA technical reports  
• 15:03 – The evolution of regulatory approvals in the pharmaceutical industry  
• 17:34 – Mike describes the influence of the PDA today, given the pandemic  
• 20:18 – Mike explains a typical day working in microbiology and quality control and assurance
• 23:11 – The pressure of working in pharmaceutical drug development and final comments from Mike  

“The PDA was kind of the bridge. It’s the Parenteral Drug Association – its focus is sterile injectable product. But it’s into all kinds of different things.” 

“The biggest things that are most frequently used in my case are the media fill, as Brian mentioned, and environmental monitoring.” 

“When you cite regulations from Europe, it used to be you would pull the British because they were gonna be the standard. If you could pass Brit, you could worry about anybody else at all; you were fine.”

“It’s an entire system that you’re trying to get where every little thing that fits into the process has been qualified and can be depended on. From the raw materials coming in the door to the viles, to the stoppers, to the machinery, the environment, the filters, the air quality and differentials – all of that stuff fitting together.” 

“With drug development, you’re not having a life depend on you. You’re having tens of thousands of lives depend on you.”

Design Space InPharmatics – LinkedIn

Design Space InPharmatics – Twitter

Edward Narke on LinkedIn

Michael Carroll on LinkedIn

PDA

• 00:54 – Ed, Meranda and Brian welcome a special panel of guests to break down today’s topic: Quality Management Systems (QMS) Explained!  
• 07:53 – The panel expounds on the timing necessary for QMS and what role the quality manual plays  
• 13:06 – The panel explains the Code of Federal Regulations (CFRs)  
• 17:30 – The panel defines Phase Appropriate as it pertains to QMS
• 23:12 – Identifying which guiding documents to follow  
• 27:29 – The value in having an experience quality professional  
• 31:54 – Why a quality agreement is necessary  
• 35:32 – The panel provides final words of wisdom on Quality Systems Management  

“Quality System Management provides an infrastructure for a company to ensure the quality of your drug product with patient safety in mind as its primary function.” 

“It helps determine and define management’s commitment to quality. Because if you don’t have senior management commitment, all could be lost.”

“To begin at the beginning, when you set up your QMS, you need to start with the procedures and processes that will reduce risk and help you prepare for your submission in the long run. That would come through managing your documents.” 

“Guidance documents are just an opinion. And they actually say that in the documents. So, you kinda try to do a combination of everything.”

“The biggest thing is that when you have somebody who’s experienced and they’ve been through various things like FDA audits or have worked with a very small company versus a very large company, they can differentiate what you really need right now.” 

Design Space InPharmatics – LinkedIn

Design Space InPharmatics – Twitter

Edward Narke on LinkedIn

Bettina Kaplan on LinkedIn

Susan Fasso on LinkedIn

Robbi Freisem on LinkedIn

Maria Arakil on LinkedIn

• 00:55 – Ed, Brian and Meranda welcome to the show David Blasingame who speaks to his extensive background as a process chemist as well as the advantages and disadvantages of manufacturing drugs in China  
• 10:20 – The importance of person in-plant activity and the White Coat Effect  
• 11:29 – David speaks to the issues he’s experienced with employee turnover  
• 17:11 – Facts and myths about America’s dependence on medicine from China, overcoming communications issues and the process of dealing with CMOs  
• 23:41 – David talks about the benefits of staying with the same drug substance manufacturer and expounds on the reasons why not every program is a fit for China  
• 31:55 – Ed, Brian and Meranda thank David for joining the show  

“One of the key activities for any oversight of manufacturing and any CMO is person in-plant activities.” 

“You better make sure you have an easy to manage process…easily transferable, and you really do have to budget to have a presence on that floor. All these things have to be factored into your decision to move into China.”

“If you’re looking for a commercial process that you might be able to take anywhere, I’m not necessarily sure that [China] is the place that you would go.” 

“We found it actually paid for itself in having somebody on staff who can speak the language because the communication style and the communication was very different than when we didn’t have one.”

“I think if you’re planning on doing manufacturing in China, plan on being hands on.” 

Design Space InPharmatics - LinkedIn

Design Space InPharmatics - Twitter

Edward Narke on LinkedIn

David Blasingame on LinkedIn

• 01:12 – Introducing a very spooky Halloween Special where Ed, Brian, Meranda and the rest of the DSI Team share stories of time spent in creepy labs and other scary situations
• 21:58 – Paul tells a story of working the graveyard shift at a hospital
• 25:06 – Valerie and Meranda share their own spooky experiences working in pharma
• 35:01 – An Excel Horror Story
• 36:06 – Ed shares a scary email story followed by Dave’s liquid ammonia experience
• 48:55 – Ed, Brian and Meranda thank everyone for joining the show and sharing their stories

“I’ve never tasted cherries as delicious as the ones that were being fed and rooted from the formaldehyde and sulfuric acid that was being pumped into the soil.” 

“You know it’s a bad day when the local news crew is sitting in the lobby when you walk in.” 

“I would have to go down and walk – this is in the middle of the night, no one around – walk down to the basement, past the morgue, through the boiler room, into this dark, dank, dusty place with like rats and dig through boxes for the records.” 

“I’ve scared myself. I was working late one night and we had liquid oxygen on site and every once in a while you’d get a hiss or a clank or something weird. And the warehouse was making an awful lot of noise one night so I was like, ‘Ok, I’m just gonna go home.’” 

“In the days before corporations had things like change control, and quality groups on site and so forth, Smith-Kline and others were organized as just a bunch of chemical operators. And that was it. There was no other functions on site.”

“Dave told a story about liquid ammonia and some scary situation there.” 

“I’ve actually been at a place where we did heavy duty analysis on bungie cords.” 

Design Space InPharmatics – LinkedIn

Design Space InPharmatics – Twitter

Edward Narke on LinkedIn

• 01:19 – Ed, Brian and Meranda welcome to the show Dr. Rick Offerman who speaks to his experience as a process chemist, the drug development process and what goes into selecting a solvent 
• 15:41 – The importance of selecting the right CMO partner 
• 19:05 – Questions that must be asked in the beginning of the drug manufacturing process 
• 23:14 – Dr. Rick breaks down best practices in cost-control 
• 30:16 – The importance of the project timeline 
• 40:13 – Dr. Rick takes a moment to recognize those who greatly influenced his career
• 46:23 – Ed, Brian and Meranda thank Dr. Rick for joining the show 

“A lot of CMOs are now going to a ‘one-stop shop’ type model. So basically they’ll say, ‘Yeah we’ll take you all the way from gram quantities right through commercial. We can do your API and your drug substance.’ But there’s still a lot of smaller shops out there that can do small scale pre-clinical work.”

“Cost is always a factor [in selecting a solvent] but it’s not the major one.” 

“You’re gotta have an integrated approach all the way through the system to understand the API that you’re producing, the impurity profile, the crystal morphology, the polymorphs, that sort of thing.”

“Realistically, when you look at the cost of an API as a percentage of a drug product, it’s usually fairly low.”

“If the analytical people aren’t up and ready to go, then when the chemists start running stuff in the hoods, how do they analyze it? We don’t have methods, so we’re kinda going on a wing and a prayer.” 

Design Space InPharmatics - LinkedIn

Design Space InPharmatics - Twitter

Edward Narke on LinkedIn

Rick Offerman on LinkedIn

• 01:16 – Ed, Brian and Meranda take a deep dive into analyzing CMC strategy and submissions
• 11:26 – Ed, Brian and Meranda discuss resources required for compiling CMC dossiers and the importance of understanding roles and responsibilities within this process
• 20:09 – Essential aspects of putting together an effective authoring team
• 25:25 – Brian speaks to the importance of respecting the experience of those that have been working on projects from the jump
• 28:28 – Ed, Brian and Meranda discuss what sponsors should know about CMC regulations to prepare for a marketing application

“I think the experience level of that regulatory point person during the submission is really critical.” 

“Oftentimes we find that clients are also looking for a submission to be a learning opportunity for their own people.” 

“When you’re preparing to undertake this preparation to write this, the first and probably the most critical step is to engage across disciplinary teams.”

“One of the things that I think is often a recipe for anxiety and stress is not understanding roles and responsibilities.” 

“One of the areas that’s really essential when you’re putting together your authoring team is to have somebody at the client that truly understands where the skeletons are.” 

“Over the years we’ve worked to build in efficiencies that take a lot of the guess work out of compiling the submissions.” 

“I think respecting the experience of the people that brought the project to this point is critical.”

“Planning is probably a better option than chance.”

“Typically what I would do if I was moving on from an IND and starting to develop an NDA, I would start from ground zero, making sure I at least have an outline chart with all of the ECTB sections outlined in that manner.”

“I think it’s important to note that the cost of doing an incomplete filing is monumental.” 

“Regulatory authorities are part of the team. They’re your friends. Seek advice, ask for their advice and also educate them.” 

Design Space InPharmatics - LinkedIn

Design Space InPharmatics - Twitter

Edward Narke on LinkedIn

Brian Lihou on LinkedIn

Meranda Parascandola on LinkedIn

• 00:59 – Hedley Rees joins the show to share his background in the pharmaceutical industry, his thoughts on Big Pharma and issues he’s observed with medicine coming to market
• 09:43 – Hedley speaks to the importance of designing supply chains strategically and why your supply chain is actually your value chain
• 17:51 – Hedley discusses outsourcing in the pharmaceutical industry
• 24:07 – Hedley provides his thoughts on Quality by Design (QBD), including changes that must be made to the process
• 39:22 – Hedley shares some of his upcoming projects
• 42:27 – Ed, Brian and Meranda thank Hedley for joining the show

“If they all beat together at the same time, instead of taking sixteen years for penicillin to come to market it would take maybe four years.” 

“The main point between strategic supply team management is you actually engage with the end user of your product the same way as Apple would or any company who really builds value into their products.” 

“The value that you add – the money you bring in – has got to be less than the cost that you incur in the business and then you obviously make a profit grow.” 

“In terms of procurement, the industry has outsourced this critical asset.” 

“The problem with pharma is that there is no competition because once you’ve got a patented molecule approved, the most that’s gonna happen is you get an oligopoly where two or three companies make blockbuster revenue.” 

“The body is the most complex, connected thing in the world.” 

“The other thing that people have noticed is that you can develop a drug now without being a pharma company.” 

Design Space InPharmatics - LinkedIn

Design Space InPharmatics - Twitter

Edward Narke on LinkedIn

Hedley Rees on LinkedIn

Hedley’s Book – Taming the Big Pharma Monster By Speaking Truth to Power

Hedley’s Blog PharmaFlow

Cutting Through the QBD Foliage, Aiming for the Roots Article

• 00:53 – Kyriakos Michailaros joins the show to share his background and expertise in the subject matter of drug product services 
• 02:59 – Kyriakos shares his thoughts on appropriate timing for a development report, the validation process and the importance of having your development report be a living document 
• 08:53 – Addressing risks and concerns as it pertains to drug development programs and what Kyriakos looks for in a comprehensive development report 
• 14:56 – Kyriakos speaks to the standards he looks for in development programs when determining dosage form and the value of efficient documentation
• 21:49 – The importance Kyriakos places on stability data and proper documentation 
• 30:03 – Kyriakos explains tablet friability, pan coating, the Ishikawa fishbone diagram and elaborates on the strangest dosage form he’s ever come across
• 40:02 – Ed, Brian and Meranda thank Kyriakos for joining the show 

“I think it’s never too early. Ideally you want to have the story of the development program pretty much summarized by the time you’re making an NDA submission.”

“A good development program is gonna do risk assessments at certain points along the way and assess what are the major concerns associated with developing this drug product.” 

“Particles tend to de-mix and segregate based on size.”

“Some reviewers, it seems, can be primarily box checking, take less of a holistic risk based approach, which has been the trend for some time now. I try to focus on what is actually important for this particular product and has that been explored appropriately.” 

“If you’re not gonna have a working development report, what you need to have is a working document repository with a file structure that can be easily followed so that you can go back and know what you have and piece together a report or a submission from that.” 

Design Space InPharmatics - LinkedIn

Design Space InPharmatics - Twitter

Kyriakos Michailaros on LinkedIn

Link to Hey Google, Tell Me About the Importance of Living Development Reports

• 00:46 – Daniel Torok joins the show to share his experience as a process chemist and collaborating with CMOs in the pharmaceutical industry 
• 07:54 – Daniel speaks to the importance of building trust in order to become an effective in-plant person 
• 19:59 – Daniel details best practices he utilizes for site visits 
• 24:15 – The information exchanged in a well-rounded site wrap up report 
• 28:47 – Daniel shares some facts, myths and stories about CMOs 
• 37:47 – Ed, Brian and Meranda thank Daniel for joining the show 

“The White Coat Effect is real. Even in a good facility it’s absolutely real. When operators find out the client is coming they behave very differently and the level of detail is much more.” 

“Probably the most touching was I spent a lot of time on an API facility on the East Coast and, on the last day, their process chemist said, ‘I want to thank you. You’re the first person in plant who’s ever actually helped me.” 

“I warn them, ‘I’m gonna be there when you don’t really want me there.’” 

“Just because you walk out the door of the plant and you go to the airport and get on the plane, it [the process] shouldn’t be done or finished for us.” 

“I think one of the myths people have is that a CMO absolutely knows their equipment all the time and the process is going to be run the same every single time.”

“It changes, it’s going to be fluid in this industry. Things happen. Things go wrong.” 

Design Space InPharmatics - LinkedIn

Design Space InPharmatics - Twitter

Daniel Torok on LinkedIn

• 00:44 – Ed, Brian and Meranda join the show to share their experiences in all phases of the pharmaceutical development industry
• 5:12 – The process of filing an Investigational New Drug (IND) and a New Drug Application (NDA) 
• 18:54 – What it means to have ‘rest-of-world awareness’ as you author an NDA 
• 22:37 – Ed, Brian and Meranda speak to the importance of storyboards and telling a story from the right perspective 
• 28:55 – Ed, Brian and Meranda break down the detailed development process, including the work that Design Space InPharmatics does 
• 39:28 – The document review process, timelines for submissions and tracking projects 
• 49:00 – Ed, Brian and Meranda conclude the podcast and thank the audience for listening 

“Filing an IND is important to get a trial started. And folks start clinical trials for a variety of reasons.” (05:43) (Ed)

“Out of academia we see a lot of this very little information filed into an IND, and then very little information generated up to the point where you get to a Phase Two or Three where you see efficacy data and then suddenly you have to file an NDA.” 

“It’s hard to become an expert. There’s no real training. I think a lot of it is just experience. It’s going into meetings with FDA when you don’t have all the data.”

“Make sure it looks good, because it does reflect on the actual data and content in there, just like anything in life.” 

“As the author goes through the process with the client, there’s still another piece. And that’s the publishing group.” 

“One way to alleviate that [stress] is to be able to give an update on any given subject or any given section at any given time.” 

Design Space InPharmatics - LinkedIn

Design Space InPharmatics - Twitter

Edward Narke on LinkedIn

Brian Lihou on LinkedIn

Meranda Parascandola on LinkedIn