BRUCE LEE = ARTIST + PHILOSOPHER + REGULATORY CMC STRATEGIST?
Lee Jun-fan (Chinese: 李振藩; November 27, 1940 – July 20, 1973), known professionally as Bruce Lee, was a Hong Kong-American actor, director, martial artist, martial arts instructor, and philosopher. He was the founder of Jeet Kune Do, a hybrid martial arts philosophy drawing from different combat disciplines that is often credited with paving the way for modern mixed martial arts.
But what if Bruce Lee was part of the CMC management team at an emerging biotech company today, having to encounter the constant pressure of raising funds, building a creative and effective team, and keeping ahead of the competition, while focusing on ensuring a viable and effective clinical development strategy to keep the product moving forward, when the odds of clinical success were against him.
How would Bruce Lee develop and implement a viable and effective chemistry, manufacturing and controls (CMC) regulatory strategy? An effective CMC regulatory strategy that is critical to ensure that neither the manufacturing process nor the control testing of the product imposes any potential unacceptable human safety risk.
1. DEMONSTRATE IMPRESSIVELY
“The key to immortality is first living a life worth remembering”. – Bruce Lee
No feat of martial arts is more impressive than Bruce Lee’s famous strike, the one-inch punch. Lee was able to land an explosive blow that could knock opponents from just a single inch a way. So, when you demonstrate your skills make sure to impress others and no one will forget you!
Today emerging biotech management is responsible for more than signing off on a checklist or having the staff generate a standard operating procedure on quality systems. Management must demonstrate strong and visible support for the CMC regulatory systems and process and ensure its implementation throughout the organization.
To carry this out effectively, management must first gain a dear understanding of the relevant CMC regulatory compliance issues and evolving expectations, and then ensure that an effective quality risk management plan is appropriately and proportionately applied (especially in Phase 1).
2. EXPRESS YOURSELF
“Always be yourself, express yourself, have faith in yourself, do not go out and look for a successful personality and duplicate it.” – Bruce Lee
Don’t go out and try to duplicate successful people, you can learn from them, but always be yourself. People will see through you if you try to fake it, so focus on being you and you will be able to connect with people on a deeper level.
Probably nothing is more embarrassing (or more damaging to a company's financial valuation) than being placed on a clinical hold in development due to a CMC safety risk when trying to initiate, or in the midst of a clinical study.
It is recognized that modifications to the method of preparation of the new drug substance and dosage form, and even changes in the dosage form itself, are likely as the investigation progresses. The emphasis in an initial CMC submission should, therefore, generally be placed on providing information that will allow evaluation of the safety of subjects in the proposed study. The identification of a safety concern or insufficient data to make an evaluation of safety is the only basis for a clinical hold based on the CMC section.
The pathway for CMC regulatory strategy is well defined at Phase 1 but management needs to understand that FDA's comments on CGMPs at Phase 1 do not apply if the CMC strategy is to use the Phase 1 investigational drug product batches in Phase 2 or Phase 3 clinical trials.
By applying quality risk management (risk assessment and risk control) and following available published guidance, management, can ensure that an effective CMC regulatory compliance strategy is in place, even at Phase 1. Management has the ultimate responsibility to protect the process to protect the product to protect the patients.
3. HAVE FAITH IN YOURSELF
“The doubters said, “Man cannot fly,” The doers said, “Maybe, but we’ll try,” And finally soared in the morning glow while non-believers watched from below.” – Bruce Lee
Don’t let doubts take over your life and have faith in your abilities, because you can! You must believe in yourself when no one else does!
The proverbial Quality by Design (QbD) is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based upon sound science and quality risk management. Emerging biotech management is well advised to invest in process science and process characterization and really get to know the manufacturing process and its outcome.
But this investment should be made wisely of course. Understanding the science does not come cheap. Facing today's tight financial environment and the reality that only about 50% of drug products that transition from Phase 2 into Phase 3 make it into the marketplace, management must be selective in how limited time, resources and money are invested.
The goal is to increase the level of manufacturing process knowledge and understanding, not just to generate volumes of scientific data. Beware of the alternative? Famously known as Quality by Chance (QbC), is a very risky option!
4. EXPLOIT OPPORTUNITY
“A good martial artist does not become tense, but ready. Not thinking, yet not dreaming. Ready for whatever may come. When the opponent expands, I contract. When he contracts, I expand. And when there is an opportunity, I do not hit, it hits all by itself.” – Bruce Lee
We need to become yes – people (almost). Say yes when you perceive these prompts. Say yes to new life. Say yes to experience. Don’t say yes to everything, though, saying yes to every opportunity will burn you out completely. Trust your gut, it will take you down the path that is right for you.
The transition from Phase 2 clinical trials (studies to evaluate the effectiveness of the drug for a particular indication in patients) to Phase 3 clinical trials is a major milestone for an emerging biotech company, An effective regulatory strategy is critical at this stage to ensure that all CMC activities necessary for eventual market approval are being planned for and any identified CMC impediment is under discussion with the regulatory agency.
Want to avoid CMC regulatory delays? Seek out regulatory agency advice. This sounds easy, but for some management it also sounds threatening. What if the regulatory authority wants much more to be done than is currently scheduled? What impact would that have on the corporate-determined marketing submission date?
Management must understand that it is not about a company believing that it knows more about its process and product than the regulatory agency; it is about involving the regulatory authority as a team member. Since the regulatory agencies ultimately controls the drug product's fate, it can only be an advantage for a company to ensure that the reviewer profoundly understands the science behind the manufacturing process and product.
The management team needs a reality check for their CMC regulatory strategy at this transition from Phase 2 to Phase 3, and the regulatory agency can provide it. See the value of CMC-focused End-of-Phase 2 (EOP2) meetings and consider these meetings a “critical opportunity”.
5. BE CONFIDENT
“All of the time people come and say; ‘Hey Bruce, are you really that good?’ I say, ‘Well, if I tell you I’m good, probably you will say I’m boasting. But if I tell you I’m no good, you know I’m lying.’” – Bruce Lee
Confidence is the key to success in every area of life. If you are not confident, others won’t believe in you. And if you are not confident right now, don’t worry confidence can be learned, it comes with practice – the more you practice in a particular area the more confident you become!
The completion of Phase 3 clinical trials brings confidence, along with completing the definition of the manufacturing process and product, and is a major milestone for any emerging biotech company. Activities now focus on preparing the appropriate marketing application (the New Drug Application (NDA) for small molecules and the Biologics License Application (BLA) for all other biotech products).
The goal of this submission from a CMC perspective is to provide enough information to permit the respective regulatory agencies to determine whether the methods used in manufacturing the drug and the controls used to maintain its quality are appropriate and adequate to ensure the drug's identity, strength, quality, purity and safety.
By the end of Phase 2 studies, the company has devoted considerable time, expertise and expense to understanding the science of how the drug product works in humans and how to clinically administer the drug product to maximize its medical benefit and minimize its medical risks. But have similar resources been expended to understand the science of how the drug product can be manufactured consistently to yield the desired quality with confidence?
6. BE LIKE WATER
“Empty your mind, be formless, shapeless – like water. Now you put water into a cup, it becomes the cup, you put water into a bottle, it becomes the bottle, you put it in a teapot, it becomes the teapot. Now water can flow, or it can crash. Be water, my friend.” – Bruce Lee
It is the complete and unconditional acceptance of the self. Where the self itself melts and becomes formless, fluid and flexible. When you attain that state, you are water!
Manufacturing process changes are inevitable, and even desired, during clinical development, whether for scale-up to increase capacity; to improve process consistency, quality or safety; or for reduction in cost of goods. However, demonstrating product comparability following such manufacturing process changes can become challenging.
The desire to quickly fix everything at this late stage (make the process more robust and commercial) is frequently the result of discovering holes in the scientific understanding of the manufacturing process itself during the preparation of the Common Technical Document (CTD) – marketing application. Additional process improvements may be desired at this late stage, but they must be entered cautiously.
7. CREATE YOUR ART
“Though, Jeet Kune Do is not thousands, or even hundreds of years old, it started in around 1965 by a dedicated and intensified man called Bruce Lee. And my martial art is something that no serious martial artist can ignore.” – Bruce Lee
Jeet Kune Do, abbreviated JKD, is an eclectic and hybrid style fighting art heavily influenced by the philosophy of martial artist Bruce Lee, who founded the system in 1967, referred it as “non-classical”, suggesting that JKD is a form of Chinese Kung Fu, yet without form. What we can learn from Bruce Lee is that we can create our own art. Don’t be afraid to break the rules and to use your creativity!
The Art of continual improvement. An example in a commercial manufacturing process is the refinement of product specifications as additional manufactured batches provide greater knowledge. At the time of submission of the marketing application, all too frequently there are limited manufactured batches available to set specification limits. Some emerging biotech companies are now filing their submission based upon experience with 10 or fewer manufactured batches.
During the submission review, the emerging biotech company negotiates with regulatory authority reviewers for a “proposed interim specification” based upon the available but limited manufactured batch experience. Upon obtaining marketing approval, and after a specified number of commercial batches have been manufactured, the regulatory agency requires the company to re-evaluate the interim specifications. If the manufacturing process is adequately controlled, this re-evaluation should lead to tightening of the specifications, yielding better control over the consistency of the manufacturing process.
Each will require time and resources to correct if the regulatory agency believes the company's CMC regulatory strategy is not enough. By having the issues identified at an EOP2 meeting, the company has adequate time to respond to those concerns. Regulatory agencies do not expect a company to agree with them in every instance, but they do expect thoughtful consideration and a scientifically justified response pointing towards data.
An investment in the process with science rather then hand waving will pay off in improved manufacturing process control for later clinical stages and commercial production. Management needs to encourage communication and teamwork with the regulatory authorities. It is an Art. Meetings between the company and the regulatory agencies can help provide assurance to the company that there will be no major CMC strategic surprises that could significantly delay the approval and marketing of the product.
8. COMMIT FEARLESSLY
“I fear not the man who has practiced 10 000 kicks once, but I fear the man who has practiced one kick 10 000 times.” – Bruce Lee
Focus on getting better and improving every single day. Step by step, day by day – but it requires commitment and if you don’t commit you won’t reach your full potential! So, stay on track and grind every day.
Management pressure keeps things moving forward at an emerging biotech company that must stay ahead of its competition but should not lead to rash decisions. The urge to fix everything at a late stage needs to be tempered with caution regarding the risks of proving product comparability after the process improvements.
Commit fearlessly, but avoid rushing to file the marketing application. A premature submission may meet a preset corporate target, but it can lead to longer review times in the end. Management's goal should not be the application filing date but the marketing application approval date.
9. DON’T THINK, FEEL
“Don’t think. FEEL. It’s like a finger pointing at the moon. Do not concentrate on the finger, or you will miss all of the heavenly glory.” – Bruce Lee
To think, you tend to examine. To feel, it’s more instinct. To feel, means to be aware. To think, means to assess. If you just feel you won’t have any prejudices. Your culture and everything that your “world” has taught you is not in practice. Sometimes common sense is wrong. If you would just feel the situation (in fighting for example) you might come to a different conclusion than if you were to think. It means to be sensitive. To unlearn what you have learned. That’s why he said, “don’t think, feel”.
Corporate deadlines are set and publicly announced, and then the pressure is on for the CMC team to meet the timeline for submission of the marketing application.
The FDA product approval system permits the agency to issue a “refusal to file” letter declining to review a submission if there are major gaps in CMC information (such as the lack of full description of the manufacturing methods or uncorrected deficiencies that were communicated to the applicant before submission of the application). Or worse after months of review, an “approvable letter” informing the company that it has completed its review of the application and determined that there needs to be resolution of minor deficiencies, which are identified in such letter further delaying approval.
A premature marketing submission may meet a corporate target, but it can lead to significantly longer review times. One CMC senior reviewer offered this advice on knowing whether your company is ready to file: “If you have to ask, ‘Can we submit the [fill in the blank] section of the application [fill in the length of time) after we submit the application?', you are not ready!”
10. TAKE ON THE BEST
“If you always put limits on everything you do, physical or anything else, it will spread into your work and into your life. There are no limits. There are only plateaus, and you must not stay there, you must go beyond them.” – Bruce Lee
You are the only person that has control over your life, and you hold the keys to success. You are the one in charge and you have the power to either make it or break it. You’ve probably heard countless times that you only have one life, one opportunity and that life is relatively short thus, you need to live to your fullest and while that is cliché it’s true. So, don’t be afraid to dream big and as Bruce Lee said – In great attempts it is glorious even to fail.
Emerging biotech management needs to be the advocate of continual improvement at the company and at any contract partners. The relationship with the contract manufacturing partner(s) must be nurtured. The people involved-their competency, training, and cooperation-are the key element to the success or failure of managing any novel or complex manufacturing process and product. Nurture the relationship by communicating both good and bad performance; by being honest about the goals, both written and perceived; and by not over promising on any deadlines that need to be met or the amount of product to be manufactured.
As the expanded body of manufacturing knowledge and data occurs with the contract partner, management should ensure that continual process improvement and control is evaluated and given an appropriate response. As management you establish the corporate CMC regulatory culture, and those below you on the organizational chart follow your lead. What would Bruce Lee say?