CMC Live - Chemistry, Manufacturing & Controls

What We Covered00:55 – 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 assurance23:11 – The pressure of working in pharmaceutical drug development and final comments from Mike  Tweetable Quotes“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.”Relevant LinksDesign Space InPharmatics – LinkedInDesign Space InPharmatics – TwitterEdward Narke on LinkedInMichael Carroll on LinkedInPDA

Bettina Kaplan is the Head of Quality Assurance Services, Robbi Freisem and Susan Fasso are Senior Quality Assurance Consultants and Maria Arakil is a Quality Assurance at Design Space InPharmatics. Together, this talented panel of subject matter experts join Ed, Meranda and Brian to discuss all things Quality Management Systems. QMS are highly complex and many organizations struggle to implement them. They discuss a brief history of QMS, the timing required and guiding documents, such as the Code of Federal Regulations. They talk about reasons why quality agreements are necessary and the value in hiring an experience quality professional.

Jim Mencel is Senior Drug Substance Consultant at Design Space InPharmatics. With an extensive background in CMC management, Jim has a wealth of knowledge on the topic of process validation. Process validation is an integrated and mandatory process in the pharmaceutical industry to ensure all processes are in compliance with regulatory standards. In this episode, Jim provides his thoughts on the significance and science of process validation in the pharmaceutical industry as it pertains to drug substances. He discusses the evolution of batch documentation, expounds on PAR and CPP and stresses the importance of communication.

Shelli Connelly is a Senior Drug Product Consultant at Design Space InPharmatics. With over 20 years of long- term success in the pharmaceutical manufacturing industry, Shelli has expertise in pharmaceutical process validation, business development activities, strategic planning, and more. In this episode, Shelli shares her thoughts on filter validation, including what to do if you pick the wrong filter, how filter vendors represent the best resources and the importance of having a partner with experience in filter validation.

Edward Narke is a Principal and Regulatory Managing Director and Meranda Parascandola is the Head of Business Development & Marketing at Design Space InPharmatics. Today, Ed and Meranda discuss topics they’ve covered on DSI’s ongoing blog series, The Regulatory Odd Couple. They dive deep into the process of regulatory drug development, including the importance of having regulatory starting materials, building the quality overall summary and the role that excipients play in that process. Ed and Meranda share their thoughts on the analytical framework of API and other stages of pharmaceutical development.

Ed Narke is the co-founder, Principal and Managing Regulatory Director at Design Space InPharmatics. In this episode, Meranda and Brian are turning the tables on Ed and turning him from interviewer to interviewee. Ed touches on his hometown roots, his extensive background in CMC and drug development and lessons learned throughout his career. He expounds on his current role at DSI and the impact his team has had on the industry. Ed lists some of the many mentors-turned-friends he’s had the pleasure of meeting throughout this journey and thanks them for the life lessons they taught him. Finally, Ed talks about the importance of developing powerful, positive routines in order to navigate this virtual new normal in the remote world. Those who embrace change are more likely to experience accelerated growth and wind up ahead of the pack.

Paul Long is a Project Management Consultant at Design Space InPharmatics. Paul has supervised government regulatory pharmaceutical industries for over twenty years and has a wealth of business knowledge. He knows how to build and lead high-performing, cross-functional teams, how to prioritize and the importance of meeting budgets and targets. In this episode, Paul, Ed, Meranda and Brian discuss the benefits and challenges of virtual project management during the COVID-19 pandemic, integral project management tools and how project management fits into drug development and the overall CMC space.

What We Covered00:43 – Ed, Brian and Meranda introduce today’s 2020 Year-In-Review show and look back on learnings from Jim Mencel, Dave Adams and Daniel Torok10:11 – Ed, Brian and Meranda reflect back on their conversations with Rick Offerman, Les Mintzmyer and Dave Blasingame19:06 – Ed, Brian and Meranda talk about a recent panel discussion they held with other CMC experts21:00 – Ed, Brian and Meranda recap episodes featuring Kyriakos Michailaros, Bettina Kaplan and Colman Byrne31:06 – Ed, Brian and Meranda highlight a very special external guest, Hedley Rees who spoke with them about how to create a value chain37:39 – Ed, Brian and Meranda speak to their discussions with Judy Magruder and Catherine Bernard43:05 – Ed, Brian and Meranda wrap up this 2020 Year-In-Review, thank the listeners for their support in 2020 and look forward to what 2021 has in storeTweetable Quotes“One of the things that resonated with me on that particular podcast was how Dave [Adams] took a step back and said, ‘You really can’t underestimate the importance of the skilled technicians that actually run the process.’” “The reality is they still need that person-in-plant. So, I think what Dan [Torok] brings to the table is what a lot of clients look for. Some clients don’t have that infrastructure and they blindly trust the CMO – and sometimes not always to the right result.” “I think people are now realizing that they do need to take a lot of different factors into consideration when selecting their CMO and they might need that assistance from experts like us.”“If you know that you have properly identified and characterized the development history of your product, and its pitfalls, and its areas of concern – and you’ve explored those – it really makes for a much more robust filing that stands up to scrutiny.” “We had a special external guest, Hedley Rees, who talked a bit about supply chain and how to create a value chain.” “Our job as regulatory reviewers, strategists, authors, CMC experts, is to decipher what the data is saying.” “I think that’s the experience that Judy brought to bear is that holistic approach to a client’s program.” Relevant LinksDesign Space InPharmatics – LinkedInDesign Space InPharmatics – TwitterEdward Narke on LinkedInBrian Lihou on LinkedInMeranda Parascandola on LinkedInTaming the Big Pharma MonsterzcTR6b8N5mnoOKtALIZa

What We Covered01:03 – Ed, Brian and Meranda welcome to the show a panel of drug substance services experts, Daniel Torok, Dave Adams, Jim Mencel and David Blasingame who speak to trends they’ve observed in the landscape of API manufacturing 07:04 – The panel speaks to the types of drug manufacturing requests they’ve been seeing 14:42 – The panel expresses their shared concerns over the diminishing number of API manufacturing professionals in the United States 23:53 – The panel provides their thoughts on the immediate future of API manufacturing 30:04 – The panel discusses the current state of regulation 33:15 – Ed, Brian and Meranda thank the panel for joining the showTweetable Quotes“We’re certainly seeing a very rapid change in the API/CMO world. I think if you went out with an RFP maybe two years ago and you threw this RFP out to eight vendors, you’d have eight proposals back fairly rapidly.” “I don’t know how many of you guys have been involved in plant build outs and plant qualifications. It is not a slam dunk, especially when you’re trying to retrofit an existing site.” “The number of people in the U.S. who have manufacturing backgrounds in small molecules is just small and diminishing rapidly because all the jobs have been offshored.” “Good operators are worth their weight in gold.” “I think what has to happen [in the future of API manufacturing in the U.S.] is that the industry has to know that the demand is there.”Relevant LinksDesign Space InPharmatics – LinkedInDesign Space InPharmatics – TwitterEdward Narke on LinkedInDaniel Torok on LinkedInDavid Adams on LinkedInJim Mencel on LinkedInDavid Blasingame on LinkedIn

What We Covered00:54 – Ed, Brian and Meranda welcome to the show Amber Sheriff who speaks to her background as a regulatory affairs specialist in the pharmaceutical industry and the three procedures for obtaining market authorization in the European Union06:15 – What CMC drug development looks like in the EU and how it differs from the United States11:24 – Amber breaks down specifics of the centralized filing procedure in the EU15:49 – Amber provides insights on the impact of Brexit on CMC filing in the EU18:40 – Benefits and advantages of a decentralized or mutual recognition procedure23:28 – Amber speculates on the future of drug regulation, including collaborations between the FDA and the EU27:57 – Finals thoughts from Amber31:28 – Ed, Brian and Meranda thank Amber for joining the showTweetable Quotes“In principle, there are three procedures for obtaining market authorization in EU. One is the mutual recognition procedure. The second one is the decentralized. And then the third one is the centralized procedure.” “If you get an approval in Europe, there are testings that you have to do for EU.” “Effective planning is the key. Because then basically you know when you’re going to get approval and you’ll know when you will be able to market.” “So, what is happening now, people who have filed in the UK can no longer sell their products in EU because UK walked away from the European Union. So now they are setting up their own procedures because, by the end of this year, they will be fully separated from the European Union.” “The mutual recognition that is between the FDA and EU, I see that as becoming more and more the norm.” “Once you get the approval [in the EU], you get it in all twenty-seven countries, including Norway, Iceland and I think Lithuania.”Relevant LinksDesign Space InPharmatics – LinkedInDesign Space InPharmatics – TwitterEdward Narke on LinkedInAmber Sheriff on LinkedIn

What We Covered00:55 – 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  Tweetable Quotes“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.” Relevant LinksDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterEdward Narke on LinkedInDavid Blasingame on LinkedIn

What We Covered01:12 – 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 situations21:58 – Paul tells a story of working the graveyard shift at a hospital25:06 – Valerie and Meranda share their own spooky experiences working in pharma35:01 – An Excel Horror Story36:06 – Ed shares a scary email story followed by Dave’s liquid ammonia experience48:55 – Ed, Brian and Meranda thank everyone for joining the show and sharing their storiesTweetable Quotes“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.” Relevant LinksDesign Space InPharmatics – LinkedInDesign Space InPharmatics – TwitterEdward Narke on LinkedIn

What We Covered01:19 – 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 career46:23 – Ed, Brian and Meranda thank Dr. Rick for joining the show Tweetable Quotes“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.” Relevant LinksDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterEdward Narke on LinkedInRick Offerman on LinkedIn

What We Covered01:16 – Ed, Brian and Meranda take a deep dive into analyzing CMC strategy and submissions11:26 – Ed, Brian and Meranda discuss resources required for compiling CMC dossiers and the importance of understanding roles and responsibilities within this process20:09 – Essential aspects of putting together an effective authoring team25:25 – Brian speaks to the importance of respecting the experience of those that have been working on projects from the jump28:28 – Ed, Brian and Meranda discuss what sponsors should know about CMC regulations to prepare for a marketing applicationTweetable Quotes“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.” Relevant LinksDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterEdward Narke on LinkedInBrian Lihou on LinkedInMeranda Parascandola on LinkedIn

What We Covered00:59 – 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 market09:43 – Hedley speaks to the importance of designing supply chains strategically and why your supply chain is actually your value chain17:51 – Hedley discusses outsourcing in the pharmaceutical industry24:07 – Hedley provides his thoughts on Quality by Design (QBD), including changes that must be made to the process39:22 – Hedley shares some of his upcoming projects42:27 – Ed, Brian and Meranda thank Hedley for joining the showTweetable Quotes“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.” Relevant LinksDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterEdward Narke on LinkedInHedley Rees on LinkedInHedley’s Book – Taming the Big Pharma Monster By Speaking Truth to PowerHedley’s Blog PharmaFlowCutting Through the QBD Foliage, Aiming for the Roots Article

What We Covered00:53 – 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 documentation21:49 – 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 across40:02 – Ed, Brian and Meranda thank Kyriakos for joining the show Tweetable Quotes“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.” Relevant LinksDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterKyriakos Michailaros on LinkedInLink to Hey Google, Tell Me About the Importance of Living Development Reports

What We Covered00:46 – 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 Tweetable Quotes“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.” Relevant LinksDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterDaniel Torok on LinkedIn

What We Covered00:44 – Ed, Brian and Meranda join the show to share their experiences in all phases of the pharmaceutical development industry5:12 – 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 Tweetable Quotes“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.” Relevant LinksDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterEdward Narke on LinkedInBrian Lihou on LinkedInMeranda Parascandola on LinkedIn

What We Covered01:15 – Dave Adams joins the show to discuss his experience with active pharmaceutical ingredients (APIs) and provides examples of how he’s solved problems with APIs in the past09:41 – What Dave looks for in a comprehensive, well thought out development program and how he works and interacts with process engineers15:02 – Dave provides his thoughts on sourcing the highest quality raw materials22:53 – Dave discusses the pilot scale example and the critical role of development32:30 – Dave talks about the importance of presenting a CMO with a well-characterized process and establishing solid relationships with your client and CMO38:26 – Dave explains what tech transfer is and provides suggestions for how CMO’s can ensure they are receiving high quality raw materials42:46 – Dave speaks to the importance of tech transfer procedures and the role of process champions47:58 – Ed, Brian and Meranda thank Dave for joining the showTweetable Quotes“Manufacturing of APIs was very much a technical job, not a scientific process.” “In production, time is money. The longer it takes to run the process, the more it’s going to cost your company or the more that a CMO is going to charge you to manufacture your product.” “You need to very carefully scout your suppliers and make good agreements with what it is they’re going to be supplying to you.” “So yes, you need to investigate every ramification of development. And some of them might lead to surprises – you see in new impurities or new emulsion – and so you’re going to have more development.” “It helps to have somebody on your side who understands production and knows when you’re being taken advantage of and even upfront when you’re making your contracts.” “It is very important to have one process owner – process champion – one person who represents the process.” Relevant LinksDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterEdward Narke on LinkedInDave Adams on LinkedIn

What We Covered01:32 – Les Mintzmyer joins the show to discuss his background in biologics manufacturing, speak to CMO selection, and break down the RFP process 08:14 – Les speaks to the criteria he uses to identify the best CMO to work with and the importance of timely correspondence 18:59 – Lessons Les has gleaned from the RFP process throughout the years 24:34 – Challenges of communicating with foreign CMOs, including language and cultural barriers 32:15 – Les provides a brief overview of his experience in bio-pharmaceutical manufacturing 34:05 – Capacity and relationships in the CMO selection process 40:28 – Advice Les would give to those looking to potentially shift to a new CMO and why you should never place too much emphasis on a ‘name brand’ 43:35 – Ed, Brian and Meranda thank Les for joining the show Tweetable Quotes“If you put the effort into getting a very detailed and exact request for proposal written, then the CDMO that is reviewing the request can determine if they have the resources to actually accomplish the task that you’re looking for.”“The nice thing about having a good network is that you can certainly weed out the ones that you don’t want to be involved.” “Every company wants everything yesterday.” “Tell you what, the money they’ll spend on consultants early on is a drop in the bucket compared to change orders and change of scope and misunderstandings that occur later on.” “You can tell a lot about an organization if they’ll let you take a look at their regulatory history, for instance, and look at their maintenance history. Those are two really key things.” “Most of the CMOs, they’re not working at one hundred percent capacity. If they can get seventy or eighty [percent] they’re pretty happy.”Relevant LinksDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterEdward Narke on LinkedInLes Mintzmyer on LinkedIn

What We Covered00:43 – Colman Byrne joins the show to discuss his background in analytical chemistry and challenges he’s observed in analytical method development and validation10:27 – Colman’s recommendations for method development and validation plans15:04 – Colman speaks to the commonality of changing methods mid-stream 22:01 – Regulatory parameters that exist for analytical method development and validation for drug development 35:11 – Other physiochemical properties that can affect method development and the vital role that data plays in the validation process 48:32 – Ed, Brian and Meranda thank Colman for joining the show Tweetable Quotes“One of the difficulties is that when you’re starting off with a molecule, you know relatively little about it. And, over the course of the development project, as you go further and further through pre-IND to Phase 1, Phase 3 and eventually into commercialization, you’re constantly learning more and more about the molecule and about what can happen to it under different circumstances.” “It’s typically less expensive to develop a solid test method than it is to develop a drug substance manufacturing process or to go through and manufacture bunches of batches of drug products. And so, it is really a question of trying to spend the appropriate resources at the appropriate time.”“Typically, you’re looking at seven different parameters. The first one – one of the more important ones – is specificity, showing that you can, with a particular test procedure, separate out whatever you’re looking to quantitate with that test method.” “You don’t know and you can’t know everything upfront, right away. You’re always going to find more things out. Ideally, they’re not going to be bad things that you have to do a lot to resolve. But, sometimes, that’s what happens due to situations that are outside your control.” “You try to minimize the frequency in which you have these unfortunate learning experiences, but sometimes they’re unavoidable. And by focusing your development upfront and looking at the available information and the potential pitfalls, then you can minimize the possibility of having what we call these unfortunate learning experiences that will cost time and money and cause potential delays.” “A validation of a test method should be a smooth process because you should expect that you know everything that could possibly gone wrong and will have addressed those before you do the validation. A validation is ideally just a rubber stamp to show that you have done, under control conditions, all the work that’s needed to show that your data is accurate and precise and linear.” Relevant LinksAnalytical ServicesDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterEdward Narke on LinkedInColman Byrne on LinkedIn

What We Covered03:00 – Dr. Catherine Bernard joins the show to discuss her background in regulatory affairs within the pharmaceutical industry07:35 – Dr. Catherine speaks to some of the challenges associated with preparing a CMC dossier10:38 – Dr. Catherine speaks to the vital role project management plays in submissions and explains realistic timelines and target dates12:58 – Dr. Catherine talks about her experience with breakthrough designations and managing sponsor expectations20:59 – The importance of listening to regulatory agencies such as the FDA29:01 – Future trends in pharmaceutical regulation that Dr. Catherine foresees and one thing the audience doesn’t know about Dr. Catherine32:29 – Ed, Brian and Meranda thank Catherine for joining the showTweetable Quotes“You need to be very careful what you’re going to put in a dossier during the product development.” (08:07)“And that’s where the interaction with the FDA is critical. So, the sooner, the better. You need to be upfront when you go to those meetings with the FDA. However, you don’t ask a question for which you don’t want to hear the answer.” (09:04)“So, it’s not because you’re going to get a breakthrough or a fast track that you’re going to cut the corner and not have all the appropriate information that is required or expected by the FDA. However, what you could do is do a science-based or some justification that you could propose to the FDA to mitigate the risk and ensure that your product meets always the same quality and strength.” (17:52) “There are times where, as a consultant, you could provide the best of your knowledge, but then the sponsor will decide, ultimately, what to do and when to do it.” (27:00)Relevant LinksDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterEdward Narke on LinkedInCatherine Bernard on LinkedIn

What We Covered02:08 – Bettina Kaplan joins the show to discuss her background in quality assurance, compliance and auditing within the pharmaceutical industry09:43 – Trends in quality auditing that Bettina observed before the shutdown and strategies to ensure a successful audit12:48 – Bettina expounds on when it’s appropriate to have an expert, such as an analyst or a drug substance chemist, present during an audit14:42 – Bettina speaks to challenges that Covid-19 has posed to auditing and how she would prepare for a virtual audit19:48 – Risks and dangers associated with not having regular audits during Covid-19 and the importance of having flexibility as an auditor24:36 – Bettina discusses the evolution and growing acceptance of virtual audits in the pharmaceutical industry, including potential benefits and disadvantages30:05 – Ed, Brian and Meranda thank Bettina for joining the showTweetable Quotes“The person [auditor] needs to be able to communicate properly. So, build a rapport with the auditee. When you build that rapport, auditees tend to tell you more than just your basic questions.” “So, if you have to cover manufacturing, analytical and all the quality systems in one day to do a thorough audit, there’s no way you can do it with just one person. You need to have the other experts.” “The other issue is going to an audit. If you’re from a location like where I live, I have to be in quarantine for two weeks before I can even go into an audit. And then I have to be in quarantine for two weeks after. It’s not feasible. And there are a lot of states like that where we have personnel that need to be able to audit and they can’t.” “How do you get the site that you’re auditing to work with you? It’s showing them that you’re willing to work with them.” “A paper audit is never as effective as a virtual or on-site audit. A paper audit a lot of times can be used in conjunction with the on-site or virtual audit.” Relevant LinksLeadershipDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterEdward Narke on LinkedInBettina Kaplan on LinkedIn

What We Covered02:10 – Judy Magruder joins the show to discuss her background in early stage drug development and best practices for creating integrated product plans06:21 – Judy provides her insights on CMC and the importance of identifying effective ways of executing strategy shifts in this ever-changing industry13:09 – Other communication tools early stage companies can use to meet milestones14:39 – How to manage expectations and risks as a CMO or head of an early stage drug development company21:52 – Judy expounds on CMC regulatory challenges that early stage companies face and the importance of developing a plan26:58 – Ed, Brian and Meranda thank Judy for joining the showTweetable Quotes“Think big picture first and then all the minutia and the smaller, what I call micro-plans, come later. And, I think that when companies take the time to do that upfront and build a registration strategy, ya know, ‘What does the product need to look like when it hits the market,’ all the plans underneath that become that much more valuable and realistic.” “So, things change all the time. And so, whether you do a weekly meeting or a daily meeting or a sub-team, I just love that people know number one, what the change is because communication is the key. It’s so multi-disciplinary. All these different disciplines depend on each other, so communicating change in a succinct way is very important.”“There’s so many different ways to communicate what’s important, what’s the critical path, what are the milestones and what’s important to focus on today.” “It’s like anything in life. Unless you have a plan, there’s no guarantee you’re gonna get there. If you want to increase the probability that you’re going to succeed, you need a plan that shows how you’re gonna get there.” Relevant LinksInternational Council fo HarmonisationLeadershipDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterEdward Narke on LinkedInJudy Magruder on LinkedIn

What We Covered00:54 – James continues his discussion of expedited drug development programs, focusing on the importance of establishing regulatory starting materials07:34 – James provides best practices for working with clients who don’t want to approach the FDA proactively and curating fallback plans 11:45 – James speaks to strategies for establishing ideal regulatory starting materials 16:44 – James shares his thoughts on ICH Q11 20:39 – James expounds on the idea behind Quality by Design (QBD)28:53 – James provides some final thoughts on the process of establishing regulatory starting materials 34:10 – Ed and Miranda thank James for joining the showTweetable Quotes“It takes a fair bit of time to develop a package to support a regulatory starting material proposal to an agency. And the better packages are ones that are supported by data…The reason this is important is because the stronger your package is, the more likely you are to be successful in your proposal.” “I see this as like being an advanced scout watching another team play ball. If you can stand at the field and watch how they approach and do things, you’re prepared when you face that team yourself. And I think if you can approach the FDA and say, ‘Look, here’s what we have based upon the guidance. What do you think?’ I think you’re better off than waiting until you face them now and when you have to do it because you’ve run out of time and you’re really not prepared.”“One of the crux issues with choosing a starting material is the whole case you can make about how you purge the impurities from that point forward.”“I think it’s [the ICH Q11] is a great document. And I think that any process chemist should read it and understand what’s being looked for.” “What it really comes down to is you want to try to understand what’s making your process tick. If you get some new impurity, the process is telling you something. Where is it coming from? Sometimes you get impurities you can’t get rid of. How do you deal with an impurity that does not go away?” Relevant LinksInternational Council fo HarmonisationLeadershipProject ManagementAnalyticalDrug SubstanceDrug ProductRegulatoryQuality AssuranceBiologics & MicrobiologyFormulation & Clinical OpsDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterEdward Narke on LinkedIn

What We Covered00:23 – James discusses regulations and the importance of starting with big ideas when it comes to expedited drug development programs05:44 – Breakthrough designations that occur as a result of expedited drug development programs08:20 – When a sponsor should consider applying for expedited drug development11:14 – James speaks to his unique background and experiences with CMC including obstacles and challenges that CMC faces15:02 – What companies can do to get ahead of the curve when it comes to drug development18:10 – Ed and Miranda thank James for joining the showTweetable Quotes“When you are in a program that gets expedited, the attention is for the program to move quickly. And there are several ways in which it can move quickly. But almost all of them lead to a very shortened timeframe for CMC. So what it gets you is the FDA’s aware that there is stress on CMC.” “If you know you’ve got a receptor site – a validated model – some sponsors know from the outset they’re going to approach the FDA even before they go into Phase One because they have a receptor site model. And if they get a model that hits then they’re going to request some sort of expedited status.” “The first question to ask yourself is, ‘Can this process do the job?’ Because, if this program goes expedited, this process that I’m running right now may be the commercial process whether I like it or not.” Relevant LinksLeadership - https://dsinpharmatics.com/leadership/#leadershipProject Management - https://dsinpharmatics.com/leadership#projectmanagementAnalytical - https://dsinpharmatics.com/leadership#analyticalDrug Substance - https://dsinpharmatics.com/leadership#drugsubstanceDrug Product - https://dsinpharmatics.com/leadership#drugproductRegulatory - https://dsinpharmatics.com/leadership#regulatoryQuality Assurance - https://dsinpharmatics.com/leadership#qualityassuranceBiologics & Microbiology - https://dsinpharmatics.com/leadership#biologicsFormulation & Clinical Ops - https://dsinpharmatics.com/leadership#formulationDesign Space InPharmatics - LinkedInDesign Space InPharmatics - TwitterEdward Narke on LinkedIn

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