Disclaimer

All opinions are my own.

Thursday, May 23, 2019

Opportunities for Generic Pharma to Clear the Quality Stigma

Recently there has been significant press (1)in the United States about quality of generic drugs. India and China were singled out. Increased exposure (recalls and FDA citations) are par for the course. These are indications that issues of varying degree are there and they need to be addressed. Press in general looks for opportunities to get on the band wagon. It is ironic that many in press might not have any clue of what a drug is, how they are developed, costed or for that matter what the manufacturing processes entail but are riding the news horse. They have power of the pen. We must remember that negativity sells and influences. 

The current negativity unless harnessed is going to cause increasing damage and the publicity will not end soon. I consider this an opportunity for various companies to re-work/re-look the current business model/plans to see how and what can be done to improve the affordability of generic drugs to the largest global market while producing quality drugs. If nothing is done to excel in product quality eventually lack of action will come back and haunt generic pharma. 

होजायेगा(Ho Jaye ga) or 着什么急呀! (zháo shénme jí ya!) loosely translated what’s the hurryattitude must be shed. Quality must be delivered today as tomorrow never comes. If for any reason quality demanded by the customer is not respected and delivered, business in the long term will suffer. In this effort, it is possible that many egos may have to be shelved as lives are stake. Onus to correct perception of questionable quality, perceived or actual, is on the generic pharma companies.

Again, bottom line, the current negativity is an opportunity to harness and rein in the quality horse. Some costs may be there but done right they should be minimal or none and will be offset and will add to the bottom line. Long-term survival of generic pharma depends on quality and undeniably it must be their highest priority. First time quality should be the goal. It is well known that to re-work the product to achieve quality can cost as much as 40% (2, 3)that simply translates to lower profits. 

Presented is my perspective/perception which is based on the current landscape. There is no vested interest of any for-profit or non-profit entity. In addition, this is also not a solicitation or a recommendation but a suggestion that companies must overcome the prevailing negativity by using talent that can and does think out of the box and can resolve issues. Talent that can “walk the talk” rather than “talk the walk” is needed.

Acknowledgement and Capabilities:

Generics must acknowledge their quality issues internally and must take the bull by horns to fix the current negativity. Companies that are excelling need not worry but will have to stay the course and continuously improve. There will be internal denials and challenges that could be hard to swallow. That is to be expected. Change is needed. If anyone thinks that it is difficult and expensive to achieve quality, that notion needs to be challenged. They need to be asked “would they risk to take the medicines produced by their own company?”   

Chemists and chemical engineers are taught to produce quality the first time. It seems that somewhere between the university doors and plant floors, they faltered and have accepted and/or succumbed to the prevailing practices. I am not sure how they have lost their mojo. Doing right is cheap and fixing the wrong is costly and in pharma wrong can cost lives, an unacceptable occurrence. Again, lack of first-time quality is expensive (2, 3)

Frugality and creativity are the cornerstone of India’s ingenuity as exemplified by its extremely low-cost mission to Mars. Similar attributes are true for China. My question is why these traits are not being applied to pharma. 

What is needed for quality drugs? 

Most pharma plants operate are at about TWO Sigma level (3, 4), a significant opportunity to improve. This might not hold true for every company but based on publicly available information, fragmented manufacturing could be the root cause of poor quality. 

Even though drug manufacturing is understood, it is good to re-visit the process. Every produced drug is a two-step process. An active pharmaceutical ingredient (API) is formulated with inert excipients to produce a dispensable dose. Method of API manufacture is dependent on the chemistry and volume needed. Since APIs are toxins that kill the disease-causing bacteria they are used in minute quantities. Thus, small quantities of API are needed to meet the needs as exemplified by the fact ONE kilo of API will produce ONE million tablets of one milligram @ 100% conversion. Table 1 is an illustration of API needed and tablets produced per year for 50 million patients. Needed API could be produced at a single plant but formulation most likely would be done at more than one plant.

Patients
milligrams
#/yr.
API, Kilo/year
Tablets/yr.
 50,000,000 
1
365
    18,250 
  18,250,000,000 
 50,000,000 
10
365
  182,500 
  18,250,000,000 
Table 1: Theoretical API and Formulation needs 

If I were to produce the needed API (Table 1 Illustration) for 50 million patients it will produced at a single plant. Multiple lines at the same site or multiple sites would be needed for formulation. In today’s landscape multiple plants will produce it. Multiple plants or lines would be need for formulations. it is imperative that the product quality meet established specifications and follow cGMP. 

Table 2 (5 ,6, 7) is an illustration for some named drugs. Potential of products being perfectly same is unlikely but it is necessary that they meet the accepted specifications. 

Drug
Number of API Sites
Number of FDF Sites
Ciprofloxacin
22
536
Atorvastatin Calcium
44
865
Omeprazole
87
768
Modafinil
29
70
Metformin HCl
77
752
Metoprolol
41
338
Table 2: Number of sites for APIs and Formulations

Since most APIs are manufactured and formulated at many plants (Table 2), based on my experiences and I am sure of others, ensuing processes have significant cost variations. Due to lack of economies of scale most of the processes are not optimum. Global API demand of ciprofloxacin, omeprazole, modafinil, metoprolol can be fulfilled from a single plant. FDF facilities for these products could be lot fewer than the current number. API and FDF plants for atorvastatin and metformin can be significantly lower the current numbers. 

If a company is producing many products in the same equipment, cGMP issues can result. Short production runs test operating personnel’s metal. This can happen across the board for generic drugs. Combination of above can result in two sigma quality. Due to nature of the processes and method of execution, quality in current manufacturing methods is most likely tested in rather than built in, an expensive process (3,4). These processes also can be a leading cause of quality infractions. Companies who rely on “after the fact quality” aka “quality by analysis/aggravation” rather than QbD, could apply fundamental of process design which every designer of a chemical process is expected practice. They could explore methods to have command of their processes (8, 9). Internal resistance is very possible. Regulations also intervene to make such improvements.  

Another alternate to retain quality is through consolidation and taking advantage of economies of scale. Processes will be optimized. Quality will be consistent. Such processes will have significantly higher profitability than the current processes. Every chemist and chemical engineer knows and understands these fundamentals. It just behooves me why they don’t practice what they have learnt. Is it the corporate culture? As said earlier regulators do not facilitate process improvements either. 

Generic companies like any other profitable company have to continuously do self-evaluations of their operating and business practices and strategies. However, it seems not much has happened (10,11). Increasing 483s and recent issues e.g. valsartan are telling us that quality issues are persisting and things need to change.

USFDA due to repeated generic pharma quality issues could succumb to political and social pressure and could take significantly drastic stand of stopping import of these drugs. That would an unhealthy situation for the generic pharma and US populous. Health of Generic Pharma like any human patient is in their own hands. They can fool the doctor (FDA) some of the time but eventually when reality hits home, results can be pugnacious and difficult to handle. By ignoring quality generic pharma is playing with its own existence. Thus, it is in the interest of generics to stay on top of their quality game. 

Girish Malhotra, PE

EPCOT International 

  1. Eban, Katherine: Bottle of Lies, Harper Collins Publishers, May 14, 2019 
  2. Cost Of Quality: Not Only Failure Costs https://www.isixsigma.com/implementation/financial-analysis/cost-quality-not-only-failure-costs/
  3. Hussain, A. S.: Pharmaceutical 6-Sigma Quality by Design, The 28thAnnual Midwest Biopharmaceutical Statistical Workshop, Ball State University, Muncie, IN, May 23-25, 2005, Page 20, Accessed May 19, 2019
  4. Shanley, Agnes: Will the Pharmaceutical Industry Ever Get to Six Sigma? Pharmaceutical Technology, July 2017
  5. Malhotra, Girish: Impact of Regulations, Manufacturing and Pharmaceutical Supply Chain (PBMs) on Drug Shortages and Affordability Part 2, Profitability through Simplicity, April 3, 2019
  6. Berndt, Ernest R., Conti, Rena M. and Murphy, Stephen J: The Generic User Fee Amendments: An Economic Perspective, NBER Working Paper 23642, August 2017
  7. PharmaCompasshttps://www.pharmacompass.com 
  8. Malhotra, Girish:  Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
  9. Malhotra, Girish: Chapter 4 “Simplified Process Development and Commercialization” in  Quality by Design-Putting Theory into Practice co-published by Parenteral Drug Association and DHI Publishing© February 2011
  10. Malhotra, Girish: US FDA citations to Ranbaxy are an excellent opportunity, Profitability through Simplicity, September 17, 2008
  11. Malhotra, Girish: What do the Ranbaxy Citations Teach US? Profitability through Simplicity, February 4, 2014

Saturday, April 20, 2019

Considerations to Simplify Organic Molecule (API) Manufacturing Processes: My perspective

Organic chemical synthesis is a pathway chemists take/suggest to synthesize different organic chemicals. These are generally multi-step processes and are a road map of their thinking. Their processes are based on the laboratory equipment available to them. In the development of synthesis process many times tradition prevails. Chemical engineers use the laboratory road map to develop and commercialize an optimized process. 

I have randomly selected three patents and reviewed them. This should not be considered as criticism or questioning anyone’s knowledge. My discussion is based on what all I would consider and experiment to simplify and economize these processes. If anyone looks at the chemistries, they are like any other organic chemical but these create a product that cure illnesses and are called active pharmaceutical ingredient. 

Generally majority of these processes have to be reconfigured and economized before they can be commercialized. In certain cases, simplification can be a complex task and even can be out of reach. Still effort has to be made. 

There are certain process and design considerations that are necessary for an economic process. I mention few of these considerations but others might have additional considerations. Basic underlying thinking, at least mine, is how a process can be made economic, efficient and least burdensome on the environment. 

I have used the following considerations (1, 2) to simplify and commercialize chemical processes.
  1. How the chemical and physical properties can be exploited? 
  2. How the solvent use be minimized and/or eliminated? It impacts process productivity?
  3. Can the solvent use be limited to one in addition to water?
  4. How the conversion of each reaction step can be improved by applying chemical kinetics fundamentals?
Instead of reviewing each patent in totality, few steps are discussed to convey the thought process of how to simplify the whole process. 

PROCESS AND NOVEL POLYMORPHIC FORM OF VORTIOXETINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS US 2019/0002421 A1, Applicant Apicore US LLC, Somerset, NJ

Step 1: Preparation of 1-(2-nitrophenyl) piperazine 
To a solution of piperazine (224.0 gm) dissolved in methanol (600.0 ml) under an atmosphere of nitrogen, 1-chloro-2-nitrobenzene (100.0 gm) was slowly added while the temperature was maintained at 30.degree. C. The temperature of the reaction mass was raised to 70.degree. C. (70-100.degree. C.) and the contents maintained at this temperature for 24 hours (20-24 hours). After the reaction was complete the reaction solution was distilled under vacuum below 50.degree. C. Charged water (600 ml) and toluene (600 ml) into the crude. The pH of the reaction mass was adjusted to below 1.0 with hydrochloric acid. The organic layer and aqueous layer were separated. The aqueous layer was taken and the reaction mass pH was adjusted to 7.0-8.0 with sodium carbonate solution. The obtained aqueous layers were extracted with dichloromethane (300 ml and 150 ml), and the organic layer dried with sodium sulphate. The organic layers were collected and concentrated under reduced pressure at 45.degree. C. to furnish the title compound (120.0 gm) as brown viscous oil which was used for the next step without further purification. 

            
                                                              Reaction Step 1 Chemistry

Step 1 Analysis:

Table 1 lists each raw material. 1-chloro-2-nitrobenzene is considered the key staring material and in my analysis is used as the basis of the reaction stoichiometry. Based on reaction mass balance one mole of piperazine would be theoretically required for the reaction. However, in the described reaction more than four moles of piperazine is being used. This is excessive. If it is not recovered, would be a waste and will add additional burden on the effluent system. Such an excess also increases the manufacturing cost. Since the reactants and the product from this reaction step have high boiling points, reaction should be tried at the highest possible temperature to increase the reaction rate i.e. reduce the process batch time. I would also consider an environmentally and reaction friendly high boiling point solvent.

At 100% conversion one mole of 1-(2-nitrophenyl) piperazine (207 grams) would be produced. However, based on patent description only 120 grams of the product is produced. This is about ~58% yield. Three different solvents are being used. I consider them to be excessive and would make every effort to economize. 

I have not explored the chemistry in the laboratory but based on my experiences, I would consider using a single solvent that will work for each reaction step. Every step has to be re-configured to maximize yield, reduce the reaction time and improve process productivity. Use of excessive amount of low boiling solvent (methanol ~64.7 oC) not only lowers the productivity but also prevents speedier reaction i.e. lower batch cycle time, as has been mentioned earlier. 

Step 2: Preparation of 1-benzyl-4-(2-nitrophenyl) piperazine 
1-(2-nitrophenyl) piperazine (100.0 gm) was dissolved in DMF (200.0 ml) and toluene (500 ml) at room temperature. The contents were cooled to 0.degree. C. followed by addition of potassium carbonate (160.0 gm) and benzyl chloride (73.0 gm) while maintaining the temperature at 0.degree. C. The temperature was raised to 100.degree. C. (100-120.degree. C.) and the reaction mixture maintained at this temperature for 2 hours (2-4 hours). On completion of the reaction (monitored by TLC), the contents were brought to room temperature and slowly poured into ice water (1000 ml) with vigorous stirring. The organic layer was washed successively with water (2.times.400 ml), brine (400 ml), dried over anhydrous sodium sulphate and solvent removed under reduced pressure to furnish the title compound (140 gm) as thick orange oil. The product was used for the next step without further purification. 


Reaction Step 2 Chemistry 

Step 2 Analysis:

In this step again, large quantities of solvent are being used. Reactants are less than 20% of the reactant mass. This is not an effective use of reactor. Yield is poor also. I would go back to the bench and create the best conditions to improve productivity and yield. Potassium carbonate is being used in situ to neutralize the generated HCl. In a commercial process HCl can be neutralized using a caustic scrubber. I would also minimize benzyl chloride use e.g. to 5% excess.

If the laboratory process is commercialized, my conclusion is more money will be spent in remediation of the effluent rather than earned from the process. Reaction yield of the two-process step is dismal ~27%, extremely poor for any organic synthesis. 

My conjecture is that if the remaining steps are also carried out as outlined in the patent, and if each has a 90% yield per step, overall process would be less than 20%, an extremely poor and an uneconomic process. I would review each step to determine how the yield per step can be improved to better than 95% for a respectable overall yield. 

Apicore LLC
USP 2019/0002421
First two steps for Vortioxetine process

Step 1



Step 2


Chemical name
1-Chloro-2-nitrobenzene
Piperazine
1-(2-Nitrophenyl) piperazine

1- (2-Nitrophenyl) piperazine
Benzyl Chloride
1-Benzyl-4-(2-nitrophenyl) piperazine
CAS #
88-73-3
110-85-0
59084-06-9
100-44-7
199105-16-3
Chemical formula
C6H4ClNO2
C4H10N2
C10H13N3O2

C10H13N3O2
C7H7Cl
C17H19N3O2
Mol. Wt. 
157.5
86
207

207
126.5
297
MP, o C
31
108
131




BP, C
246
146
392


179
441
Grams
100
224


100
73

Moles
0.63
2.60


0.48
0.58

Moles/ mole 1-Chloro-2-nitrobenzene
1.00
4.10

Moles/ mole 1-(2-Nitrophenyl) piperazine
1.00
1.19

Theoretical yield, gm


207.00



297
Actual exp. Yield


120.00



140
% yield


57.97%



47.14%
Table 1: Stoichiometry of First two steps Vortioxetine USP 2019/0002421

Process for the Preparation of Vortioxetine: US 10,227,317 Assigned to Lupin Limited, Mumbai (IN)

Step 1: Preparation of S-(2,4-dimethylphenyl) ethanethioate


Reaction Step 1 Chemistry 

100 g of 2,4 dimethyl thiophenol was suspended in 500 ml of dichloromethane and added 94 gm of pyridine at 25.degree. C. Reaction mixture was cooled to 5-10.degree. C. and then drop wise added acetyl chloride (64 gm, 0.815 mole). Resulting reaction mixture was heated at 5-15.degree. C. for 1 hr. RM was monitored by HPLC. When reaction was completed cooled to RT, added water and stirred for 10-20 mins. Desired product was extracted with ethyl acetate twice. Combined organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to give oily mass as desired product (130 gm, 100%). 

Analysis Step 1:

Based on my training, using industrial stoichiometry fundamentals, the yield of ethanethioate is about 72% rather than claimed 100%. I am not sure of the basis for 100% yield. In addition, I would consider using a higher boiling solvent to speed the reaction. Generated HCl can be scrubbed and acetyl chloride condensed back to the reactor (3). In addition, I would consider significant reduction of amount of solvent used. I even question the use any solvent. Since the reaction product is a liquid, possibilities to lower or eliminate solvent do exist and should be explored. 

Step 2: Preparation of (2-bromophenyl)(2,4-dimethylphenyl) sulfane 


Reaction Step 2 Chemistry 

100 g of S-(2,4-dimethylphenyl) ethanethioate was suspended in 500 ml of degassed toluene. Then added Pd(dba).sub.2 (3.25 gm, 0.006 mole), rac-BINAP (6.4 gm, 0.01 mole), and sodium tert-butoxide (62.5 g, 0.65 mole) under nitrogen purging. Reaction mixture was heated to 45-55.degree. C. and then added 2-iodo-1-bromo benzene (165 gm, 0.583 mole). Reaction mixture was stirred at 90-100.degree. C. for 3 hrs. under nitrogen atmosphere. After completion of the reaction, it was cooled to room temperature and added 400 ml of water, and allowed to stir for 15-20 mins. Reaction mixture was allowed to settled and organic layer was separated and concentrated under reduced pressure to give thick viscous oil to give desired product (2-bromophenyl)(2,4-dimethylphenyl) sulfane (162 gm, 100%). 

Lupin Limited       USP 10,227,317
First two steps for Vortioxetine
Step 1
Step 2
Chemical name
2-4 dimethyl thiophenol
Acetyl Chloride
S-(2,4-Dimethylpheny) ethanethioate

S-(2,4-Dimethylphenyl) ethanethioate
2-iodo-1-Bromobenzne
(2-Bromophenyl)(2,4-dimethylphenyl)sulfane
CAS #
13616-82-5
75-35-6
94602-20-7
94602-20-7
583-55-1
960203-41-2
Chemical formula
C8H10S
C4H10N2
C10H12OS
C10H12OS
C6H4BrI
C14H13BrS
Mol. Wt.
138
78.5
180
180
283
293
MP, o C
9
BP, C
207
51.8
121
329
Grams
100
64
100
165
Moles
0.72
0.82
0.56
0.58
Moles/ mole 2-4 dimethyl thiophenol
1.00
1.13
Mole per
S- (2,4-Dimethylphenyl) ethanethioate
1.00
1.05
Theoretical yield, gm
180.00
293
Actual exp. Yield
130.00
162
% yield
72.22%
55.29%
Table 1: Stoichiometry of First two steps Vortioxetine USP 10,227,317
Analysis of Step 2:

This step using rationale mentioned earlier need to be optimized. Effort to reduce sodium tert-butoxide with less expensive base is necessary. I would review and explore alternate and simpler ways instead of the suggested expensive chemistry? In addition, stoichiometry needs careful consideration to minimize use of excessive amount of all chemicals. 

Process for preparation of levothyroxine and salts thereof: USP 9,932,295

This is an interesting patent. It uses oxidative properties of bleach in a reaction. Since the oxidative properties of bleach have been used in the past, I am wondering about the validity of this patent. Patent claims:

1.     A process for the preparation of Levothyroxine of formula (II) comprising iodination of compound of formula (III) with sodium iodide and sodium hypochlorite in the presence of an aliphatic amine. 

2.    The process according to claim 1, wherein said aliphatic amine is selected from the group consisting of methyl amine, ethyl amine, propyl amine, isopropyl amine, tert-butyl amine, diisopropyl amine, diisopropyl ethyl amine, n-hexyl amine, morpholine, triethylamine, and mixtures thereof. 

3.    The process according to claim 1, wherein said iodination reaction is carried out in suitable solvent comprising water, dioxane, methanol, ethanol, or mixtures thereof. 

In the suggested process two moles of sodium iodide per mole thyronine are needed. Bleach acts as the oxidizing agent. Some excess of sodium iodide is necessary but not the quantity mentioned in the patent. Quantity of bleach has to be optimized. For a commercial process, I would prefer water-based chemistry as they are commercial. This is suggested because at Sherwin Williams Chemicals in late sixties used a similar chemistry to produce isatoic anhydride from phthalic anhydride by a continuous process using bleach and sodium hydroxide after phthalic anhydride had been converted to phthalimide. Bayer AG was granted a USP 3, 687,951. 

Intent here is not to challenge the Lupin patent but present that substitution reactions using bleach and an alkali salt have been commercial for over fifty years. The outlined process can be economized and if executed properly Lupin using modular operation can produce global demand for Levothyroxine from a single plant that would require multiple plants to formulate. 

Syntheses proposed by chemists are a laboratory pathway to a product. However, optimization and careful pruning of the laboratory process is necessary to have an economic commercial process. There are many routes. Creativity and imagination are necessary in the simplification process. Careful exploitation of mutual social behavior of the chemicals and unit operations is necessary for creating an economic process. Underlying goal of the chemists and chemical engineers has to be that the commercial process they will create is their best ever and the most economic. It is a challenge because the product demand dictates the type of process they will create. 

Another factor which is latent is that how API manufacturing process impact our environment. We may not have the necessary empathy but we need to recognize that active pharmaceutical ingredients are organic chemicals that are toxins that kill disease causing bacteria, a living organism. We don’t know the toxicity of every chemical and other reaction byproducts. Thus, if we can minimize their presence in the environment, we will make a difference while curing illness. Their presence impacts mammal, aquatic and bird life.  

Girish Malhotra, PE
EPCOT International

Reference:

  1. Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
  2. Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, Vol. 119 No. 4 April 2012, pgs 63-66
  3. Communication with Dr. Charles Kausch, Senior Scientist, OMNOVA Solutions, Akron, April 16, 2019