Profitability through Simplicity: November 2018

Sunday, November 25, 2018

Simplified Roadmap for ANDA/NDA Submission and Approval will change Pharma Landscape

FDA’s New Drug Application (NDA) and Abbreviated New Drug Application (ANDA) approval paths in their present form are complex cumbersome maze and from my perspective need lots of luck and flawless interpretation of FDA’s needs for a first pass perfect submission and acceptance. FDA has suggested that it is working on a plan to lower the review and approval time ⁽¹⁾for priority drugs. If FDA can reduce the time for priority drugs, it can also do the same for every other drug. Simplification is needed ^(2,3,4). Considerable effort on part of companies and FDA would also be needed. If accomplished, companies and patients could realize the following benefits.

1. Lower approval time will lower regulatory costs and improve affordability.

2. With faster approval companies will be able to have additional revenues.

3. Drugs would be available to the patients sooner than the current times.

Pressure has been and is being exerted by the general population on regulators ⁽¹⁾and legislators to reduce the approval time. For the drug safety regulators need to review the necessary information.

Form 356H ⁽⁵⁾seems simple, but meeting every requirement one has to follow 21CFR314 ⁽⁶⁾and that is a challenge. From my perspective the current process ^(6,7)is cumbersome and complex. It seems to be fraught with what I call considerable legalese, extensive intellectual complexities and ambiguities. An average person will require lot of explanation, hand holding and simplification to complete the necessary requirements.

I have my own perspective of how the ANDA approval process can be simplified and still meet what is required by FDA and other regulatory entities. My proposal most likely would be taken as oversimplified version but could be a starting point to revamp 21CFR 314 ^{(5, 6, 7)}. ANDA Submission ⁽⁷⁾has only 38 pages but due to included references is no different from its longer version⁽⁵⁾. 21CFR 314 ⁽⁵⁾should be reviewed and simplified every so often e.g. every five years or less to meet the changing needs of pharmaceutical landscape. It should be part of FDA’s internal “continuous improvement” process. It could be considered a living document creating a “quality by design (QbD)” product. If the suggested simplifications are pursued and ultimately adopted, the NDA/ANDA approval would be much simpler than what we have and companies would realize the above suggested benefits.

Information submitted and the filing process might not be any different from what it is today but would be much simpler step by step process as it can be easily understood by any one who is completing the application. No special expertise might be required.

Today’s process as stated earlier requires considerable knowledge of the maze and how to comply. Many current “what if’s, dos and don’ts” of the legal maze need to be simplified and eliminated. It is my conjecture that information needed by FDA will give companies a clear definition and total command of everything one needs to know about the drug. With 90 day or less approval time companies would have incentive to do a quality filing. In FDA’s vocabulary I would call such filings “a QbD filing”. Today’s NDA/ANDA filings are a “Quality by Analysis (aggravation) QbA” filing. This needs to change.

In Table 1 I have attempted a simple skeletal outline which could be used by the regulators to create an extremely clear and concise road map that could be precisely followed by a company for a complete application from the start. Filing requirements for NDA and ANDA fillings process would be simplified if each had their own their road maps. Elements of the road map from regulators would clearly define what they need and the industry needs to submit for a complete submission from the start. FDA or other regulators would review the submitted information for completeness and make necessary decisions to have the submitted filing granted in 90 days or less.

I would not be surprised that many who are associated with regulatory filings and their processes would say “filing simplification can’t be done”. Effort would be needed. Change is inevitable and a necessary reality. We have that capability especially when we can send a human to the moon and brought him back safely.

In my efforts to figure out how simplification can be done I reviewed perspective of others ^{(9, 10)}. These are interesting and should be reviewed by FDA to create the best and the simplest process. I am sure there are other ways also. Each perspective illustrates some of the challenges. They take us through the maze and could be used for simplification. Page 15 of reference 9 has a simple flow chart (road map) that could be used as a simplified process diagram for ANDA and NDA approval. FDA personnel should be familiar with Ishikawa and other logic diagrams. Such diagrams could be used to create new or be updated to improve filing and approval process. Reference 10 articulates the path via a written document.

Again, FDA has to clearly spell out in details what information is necessary and needed from a company so that its ANDA/NDA application can be approved in 90 days or less. Spelling out the needed information and its simplification is FDA’s job as it is the most knowledgeable authority to define what is needed for approval. Based on my reading parts of CFR314 there are just too many “what ifs, dos and don’ts.” Understanding the maze can be a challenge. An Ishikawa Diagram ⁽⁸⁾or a similar logic diagram would be of great help.

Company can take whatever time they needed for the initial submission. Once the company submits its application and FDA receives the submitted application that day becomes DAY ONE.

In my ANDA/NDA review and approval path design each submission from the filing date gets two paths at FDA and they run parallel as illustrated in Table 1 and it looks very simple in its format and it is.

ANDA/NDA Approval Application
Inspection Path:	Application Review Path:
Based on the submitted application it is assumed that it is complete and no additional information is needed. FDA sets up the mechanism for an inspection date for the applicant site. Time period for the inspection has to be between Day 45-60 from the date of submission. These dates could be changed or cancelled based on FDA’s Application Review Path. It is important to make companies aware of the timetable so they are prepared for the inspection. This should be spelled out in the FDA road map. If FDA informs the company of its completed application, company has to make every arrangement for such the inspection. If company does not agree to such inspection in the time window, future NDA and ANDA applications of the company should not be accepted for a prescribed time e.g. ONE year. This stipulation assures that the companies filing for approval are legitimate companies.	FDA starts the application review. If FDA does not see any discrepancy or the missing information within the first thirty days, submitted application should be deemed complete. FDA informs the company and the inspection date details that started date ONE is firmed up. If any of the submitted application is deficient or has missing information or an explanation/clarification is needed, FDA informs the company within the thirty days or sooner from the Day One date. FDA has to detail what all it needs for a complete application. Company has to submit the information to FDA for completeness in the next thirty days to retain its inspection date between 60-75 days from the original submission date. If the company cannot complete and submit the needed correction/s, application goes back in the queue and the 90 day process with no fee starts all over again. More than one FDA rejection should be deemed as a failure and no submission for the same drug should be accepted for the next two years from this company. If the company does file for the same drug it will have to pay necessary fees again. If FDA does not send any company any feedback in the first 30 days, the submission would be considered complete. If FDA does not approve the submission after 90 days, it will have to explain in writing its reasons. If FDA does not respond in any form, the submission would be considered approved and not subject to any reexamination for some time e.g. one year. However, this does not relieve company of meeting FDA's quality standards.

Table 1

Two parallel paths should lead to a process that will be fast and could result in 90 day or less time approval. Again if FDA chooses Ishikawa or similar process paths my conjecture is that Form 356 and CFR314 will become clearer and simplified. Resulting impact on the pharma landscape would be beyond our imagination.

One of the most challenging tasks for filings these documents is understanding and overcoming mountain of acronyms and clauses one has to deal with in submitting the necessary and needed information. Understanding the alphabet soup is daunting. Simplifying them would be a challenge and could be resisted by some as it could impact their business.

Again, FDA has to start, lead and complete the simplification process as they know what all is needed for a safe product. FDA could test simplification hypothesis internally using one selected group to compile and fill the needed information simulating submission and other selected group to review and critique the submitted information for completeness and approval. It would be a simulation of the filing and a review process. How much time the two processes take would be an excellent gauge of what all is needed to create a 90-day approval process. As stated earlier filing group can take whatever time they need but the reviewing group will have to complete the approval/disapproval task in ninety days.

I would not be surprised if FDA has already done such simulation but most likely have not publicly shared the results of the exercise. If they have not done it, that suggests that they most likely did not have a 90-day approval process in mind. Maybe it is time.

Reference 9, is an FDA presentation, has very interesting information about the number of approved, backlog and received ANDAs. These numbers raise a question and it is “Are the global companies filing ANDAs for the same drug and using FDA approvals to market their products in countries other than the United States and overburdening developed country regulatory system?” If so, such practice has to be stopped. Another question with so many filings is “Are the US PBM’s (pharmacy benefit managers) using FDA’s approval system to weed out companies to their advantage and maximize their profits, by artificially creating competition and dumping companies that do not meet their profit criterion”.

If the above 90-day road map can be promulgated and adopted my conjecture is that the pharma landscape will change. This is discussed in an upcoming post.

In any manufacturing or service process of continuous simplification is a must. It should be mandatory even for every regulatory ANDA/NDA filing and approval process. Opportunities exist. Improvements will lower prices and should improve new and generic drug availability and affordability. Better affordability should also improve revenues. It would be an overall win for humanity and there is nothing wrong with that.

Girish Malhotra, PE

EPCOT International

1. Testimony of Drs. Woodcock, Marks and Shuren

2. Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months? Profitability through Simplicity

3. ANDA (Abbreviated New Drug Application) / NDA (New Drug Applications) Filing Simplification: Road Maps are a Must. Profitability through Simplicity

4. What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity

5. APPLICATION TO MARKET A NEW OR ABBREVIATED NEW DRUG OR BIOLOGIC FOR HUMAN USE, Form 356H

6. 21CFR Part 314 Applications for FDA Approval to Market a New Drug, FDA

7. ANDA Submissions – Content and Format

8. Ishikawa Diagram

9. Ya, Dr. Naiqi, Deputy Director, Division of Chemistry IV Office of Generic Drugs, Generic Drugs – Application and Regulatory Review, Accessed November 14, 2018

10. Sullivan, Thomas: FDA ANDA Submissions Content and Format of Abbreviated New Drug Applications, Policy & Medicine, May 6, 2018 accessed November 10, 2018

Wednesday, November 7, 2018

Quick Review of Chemicals Related Process Development, Design and Scale up Considerations

Chemical engineers and chemists are the Picasso, the Michelangelo, the Zaha Hadid or the Gaudí or other artisans of their process designs. Their designs are emblematic of their learning, creativity and imagination. They use their training including their capabilities to exploit mutual behavior of chemicals and creatively extend equipment performance to design excellent economic processes.

Process development from the laboratory to a commercial operation goes through many similar steps. There is a process we all are aware of and go through, some cited ^(1,2,3). However, it is always good to re-visit the process and brush up on what we have learnt and are practicing ⁽⁴⁾. Such reviews lead to creativity sparks and eureka moments to do better. Learning never ends and has been covered by many to cite.

Below is a quick review from the lab to commercial path and steps we took and have since continuously improved. Steps are simple but as said earlier need to be revisited and improved. There is not enough space to cover everything. Please don’t be offended if I have overlooked few things. There is no financial involvement or remuneration from the companies cited. They are just examples.

Most of us go through all or some variations of the following generic steps.

1. Commercial value of a chemical or formulation product is identified.

2. A cost analysis is done and compared to any similar product on the market. If the cost and performance are better than the existing product/s, commercial value is explored/developed. If there are no similar products companies work fast to establish their foothold.

3. Product’s synthetic/formulation route is developed on paper, costed and explored in a laboratory.

4. Time is spent to come up with the best operating conditions and the highest yield. Process is optimized. Additional cost analysis is done while the process development work is underway.

With each positive in the above, race accelerates to commercialize the product. In process development subtle simplification steps can be overlooked. They can have significant impact on the product’s success. List is long but I am sharing some of the key steps that I have practiced. I am sure there are other ideas that are used.

Raw Materials:

Well accepted common practice in the lab is to get the raw materials from known research supply companies. For the initial steps, this might be alright but for the long-term success, it is of utmost importance to source the raw materials from commercial producers. Raw materials from the research supply companies are expensive and too pure to give any credible data and value for a commercial product. By getting the raw materials from commercial producers not only the developer company establishes a relationship and a long-term value but is also dealing with real raw materials that give us a dose of reality to develop an optimum and economic process.

Acquisition of raw materials is different for batch and continuous process. Raw materials of batch process can be acquired when needed but for every continuous process they have to be available all the time. In either case raw materials don’t have to be tested prior to use if the laid-out needs are clearly defined and there is trust in supplier’s quality. Any deviation in raw materials from the established standard can spell significant financial loss especially for the continuous process.

Physical State:

We all know that each raw material has its established physical properties and has its own specific behavior towards other chemicals including reaction by-products and products. How we understand these nuances and capitalize on their mutual behavior is critical for process development. Even with this acknowledged, still there are challenges we have to deal with.

Physical state of each raw material and each reaction has value. We need to think how the raw materials, intermediates and the product will be handled in a commercial plant. They influence every processing step and disposal.

Of the three states, liquids are the easiest to handle as they can be poured, metered and pumped with ease. Solids can be weighed but their handling in the lab vs. bulk can add their own challenges especially when the solids are hazardous. Hazard and handling can be somewhat improved or reduced/eliminated if the solid can be used as a liquid (solution or melt). Dilution to improve handling lowers process productivity. Economics has to be considered.

Reaction products, if liquid, have a hidden value. If their melting point is compatible with the process operating temperature, reaction product can replace or minimize solvent use, there by improving process productivity. Most of us overlook this simple nuance but who recognize it, know its value.

Raw materials that are gaseous at room temperature are best handled as liquid. Their use in the laboratory as liquid is limited and safety precautions are needed for safe handling. Their use in a commercial plant can be done well if the gas is metered in as a liquid. Exotherm of such reactions can be absorbed as the liquid converts to gas. An interesting example is ammonia as liquid vs. ammonia as 35.6% solution. Productivity and process conditions are significantly different in each case.

Solids have their own nuances and also can create challenges. If the reaction can be carried out as a melt it can minimize or eliminate solvent use and improve process productivity. However, due to volume of material to be handled and produced such opportunities are generally limited to continuous processes.

Hazardous chemicals require extremely careful handling. Batch vs. continuous process most likely will require different handling equipment and process. What might work for a batch process might not work for continuous process and vice versa. If hazardous solid raw material can be dissolved in a solvent or suspended as a uniform slurry, their metering can be better managed and controlled. Inert thickening agents like the kind that are used in the coatings industry can be used to create a pumpable uniform slurry. This is an unconventional approach and minimizes productivity loss that can happen due to excessive solvent needed for dissolution. Concept sounds simple, but can be a challenge. Ideas like this might seem farfetched. When they work they are called innovation.

Solids when blended to create uniform powder behave very differently due to their densities, particle size, shape, viscosity, angle of repose, mixing characteristics ⁽⁵⁾and processing conditions including temperature etc. As discussed later, they effect equipment design and selection for a batch or a continuous process. As suggested earlier what might work for a batch process might not work for a continuous blending process.

Intermediate reaction products, if solid can create challenges. Their solvency in a solvent of choice facilitates the process. They can be solid and will have to be handled in a manner that will maximize process productivity.

Liquids due to their mutual miscibility or lack of it can create opportunities e.g. in separation. Lack of miscibility can be changed by using different solvents. Many do not recognize and as explained later one can capitalize on this solubility and their density differences. Different solvents can facilitate processing, improve process productivity and have financial and environmental impact. It is most productive if one additional solvent besides water can be used in the process. Disposal costs are thus limited. More than one organic solvent used in the same process add complexity and cost to the process. Experience of the chemist and chemical engineer and their ability to recognize such subtleties matter.

Physical and Chemical Properties:

Once we know and understand different properties of chemicals, we can capitalize on their mutual behavior to create a process architecture that is economic and optimum for the needs. First time I saw physical and chemical property data details, their value did not register till I needed the information for process design and debottlenecking. They were a godsend.

As has been discussed, physical and chemical properties are the building blocks of every process. Many of the physical and chemical properties may not be readily available. Some can be obtained from product suppliers and also retrieved from different chemical databases(too many to cite). Getting some of the mundane information e.g. solubilities, specific heat, viscosity, heat of formation etc. can be a challenge. If some of the values are not available they have to be developed. Solubilities in different solvents or different temperatures are not available from databases and they might have to be generated the old fashion way. Azeotropic behavior along with solvent miscibility/immiscibility is of values can be used to advantage.

Harnessing and creatively manipulating physical properties of solids to produce a consistent blend, that will not be prone to separation, can change the solid formulation landscape, especially for pharmaceuticals. Effort that is very different from what has been considered/tested and practiced would be needed. Some could say that it would be “impossible” to come up with a solution where separation can be minimized. However, I would say “we would be significantly challenged”. Formulators will have to think and step outside their comfort boxes.

If we come up with a viable solution, my conjecture is that formulated products that have over trillion sales dollars per year could be impacted. Success could result in continuous formulation of many products especially pharmaceuticals (operating 7,140 hours operation per year per product per dose) would become a reality. We should see significant cost reductions, improved profitability and increased affordability. Existing equipment can be easily used. Few examples are referenced^{(1, 2, 3, 4)}.

Reaction kinetics can be manipulated to simplify design and process yields i.e. process economics. It can be of significant advantage. Raising the reaction temperature by about 10 ⁰C, a simple quirk, doubles the reaction rate is of considerable value and works. It improves the whole process, design and economics.

Equipment Design:

A critical element in the process design is the volume of product that needs to be produced. Product volume is the fundamental building block and a critical differentiator between a batch and a continuous process. Product costs, process economics and ROI of the investment depend on product demand.

Combination of unit processes and unit operation make processes that produce the needed quality products. Physical and chemical properties of chemicals involved influence process design. Many books have been written on the subject. However, how different equipment and configurations can be creatively used depends on process designer’s imagination. They are difficult to write and only can be documented after their successful use to produce products. Many are considered proprietary. Volumes have been and can be written to document creative applications. Some examples ⁽¹⁾are discussed.

Engineers/inventors at various equipment manufacturers, based on the needs they perceive for their customers, create and design different equipment and applications. However, the designed equipment could and does have value in other process applications that are not on their radar. Many times such uses and applications are not obvious. Engineers, do recognize their value and use them to simplify their processes. Selling application of such cross-fertilized equipment and their value internally takes out of the box thinking and sometimes skunkworks. Such innovations are considered proprietary and least documented.

Plate and Frame heat exchangers e.g. Alfa-Laval ⁽⁶⁾and others provide versatility of not only a heat exchanger but as a compact micro-reactor. Unknown to the suppliers we used such heat exchanger in early seventies with exceptional success. Creativity and imagination are needed to capitalize on such possibilities. Different breed of tubular heat exchangers ⁽⁷⁾that are not used in the chemical industry are available and provide excellent possibilities of not only heat exchange but reaction space also. Such exchangers are significantly less expensive than the micro-reactors that are being tested in different laboratories and may be used in very specialized processes. Their use is ROI dependent.

In certain applications, mostly due to tradition, high speed dispersers of high horse power are used. They pose their operating challenges. Inline dispersers ⁽⁸⁾are economic, available and can be used. In certain applications they deliver similar results. They also provide significant operating flexibility e.g. a batch to continuous process conversion. One has to figure out their applicability and value. These along with an inline eductor can be used for dissolution and dispersion.

As mentioned earlier, density differences of liquids can simplify processing. Value of density differences and hydraulics is of value in the design of gravity phase separators (decanters). If used thoughtfully, they can eliminate investment in exotic process controls that are generally considered a first option. I have seen decanters with fancy process controls but many become an operating bottleneck if their design is not understood by operating personnel. A decanter⁽⁹⁾based on specific gravity and hydraulic balance, if properly designed, is a simple and poor man’s elegant device. Most of the fancy process controllers (investment) disappears.

Process Design:

Mass balance of every chemical reaction is important as it gives us the knowledge of what to expect. Information can be used to exploit mutual behavior of chemicals in process design, optimization, and waste disposal. Sometimes the reaction side products can pop surprises due to their toxicity and hazardous nature. They have to be dealt with. Scale up from lab to pilot plant gives us a better picture of how the process will behave chemically and physically. All of the generated information along with product volume can be readily used to commercialize a batch or a continuous process. However, many a times what works in the lab does not necessarily work in the pilot plant and scale up to a commercial plant. Changes have to be made and that is where the experience is put to test.

In every manufacturing situation there are two kinds of processes: Batch or Continuous. Each has a well-established definition^{(10, 11)}. Routes are product volume and time dependent and there are no two ways about it. At times many forget the time element part of the continuous process. Time is an essential part of the definition. Batch processes are time interrupted. In continuous process, there is no stop and go except for the designated downtime for preventive maintenance and any production hiccups.

There are few other very striking differences in the two routes. Since batch processes are stop and go, intermediate product after every step generally by force of habit is sampled, tested and the process corrected if out of spec. Intermediate sampling is an addiction and extends batch processing time. Stoichiometry deviation in reactive and formulation batch processes can happen if the operating instructions are not followed precisely. This generally results in lower overall yield and a financial loss. Such processes producing quality by analysis could also be called quality by aggravation (QbA).

Stoichiometry in continuous reactive as well as formulation processes cannot deviate from design parameters. Designed process has to produce expected product quality every instant of the operating time. Compared to batch processes continuous processes are not at all forgiving to any deviations. Excursions outside the specifications can be an economic disaster. Uniform distribution of components in formulated products is very critical especially in formulations. Thus as stated earlier complete command is a must. Product quality has to be built in the process design and cannot be tested in.

Companies have to select the process to be used based on their business, short and long-term strategy, competition and expected return. Since each process, batch or continuous, is an independent route to produce the product, scale and method of execution of same unit process and unit operation can be different. Engineers and chemists are creative and do their best. We have to recognize that the equipment selected for a batch process can be retrofitted to produce many other products. However, such luxury does not exist for any continuous process as their design is product specific.

Process controls based on process logic can make some changes within the designed limits in the stoichiometry but still the resulting product cannot deviate outside the product quality expectations. Today’s process controllers and logic are extremely robust and sophisticated to deliver the designed quality product. As said earlier if the product volume is there, continuous processes are generally method of choice.

Batch and continuous processes have their own nuances of product supply and inventory. How they are handled and managed impact cash flow and cannot be overlooked. Manufacturing folks at times have to simultaneously wear many hats: manufacturing, accounting, marketing and purchasing.

It is also important for the creators and the designers of process to document their thinking, rationale and the design basis. This includes mass and heat balance, equipment selection rationale and design calculations etc. It might be considered a mundane task but is a gift for the upcoming engineers and chemists. They would know how, what and the why of the design. This information comes in handy for trouble shooting, debottlenecking, filings and discussion with any regulatory authority. First time I had to document my design basis, rationale and calculations, it seemed to be a pointless exercise. However, was thankful for it being available when I needed the information for the task at hand and later work by others.

In the annals of chemistry and chemical engineering there are many cases where equipment, physical and chemical properties have been married to create very simple and elegant designs and simplify existing batch and continuous processes. Chemists and chemical engineers at every company are the innovators and creators ⁽¹²⁾, and as stated earlier are the Picasso, the Michelangelo, the Zaha Hadid or the Gaudí or other artisansof the most innovative technologies and economic processes. Imagination and creativity are the two gifts they have and exploit. We have to let them do the best they do.