DESC:FIELD OF THE INVENTION
The present specification relates to use of inert product transfer tubing in the manufacturing of pharmaceutical injectable products.
BACKGROUND OF THE INVENTION
In general, the manufacturing process of any pharmaceutical injectable product employs multiple components such as plastic tubing, gaskets, filters, intermediate storage containers, tank liners and the like, in various phases of production viz. generation/synthesis, processing, purification, intermediate storage. The primary material of construction of such components is rubbers, plastics, glass, metal, and paper components. The essential requirement of such components is compatibility with drugs, solvents and other excipients used in the manufacturing process.
It is well known in the art that materials coming into direct or indirect contact with a drug product have potential to leach substances and cause contamination. This may affect therapeutic effectiveness, stability, impurity profiles and physical properties like smell, taste or color of the finished drug product.
Silicon product transfer tubings are one of the plastic tubings, widely used in the manufacturing process of pharmaceutical injectable products. Silicon encompasses a large number of compounds based on polydialkylsiloxanes; amongst them the most common are the trimethylsilyloxyterminated polydimethylsiloxanes. Silicon is a trace element that constitutes about 27.6% of earth’s crust in the form of silicon dioxide.
It is known in the art that silicon traces are readily extracted from silicon material by ethanol. The studies carried out by Jenke et.al., showed the presence of large predominant peaks attributed to a homologous series of polymethylsiloxanes, when contacted with ethanol.
Ethanol is highly hygroscopic and reactive for polymeric surfaces. Prolonged contact of ethanol with silicon results in leaching of silicon oil in finished product. Once injected in human body, these globules can occlude blood vessels and cause embolism (blockage of blood vessels), infection and serious injuries such as scarring and permanent disfigurement, stroke and death. Silicon is present as oil globules and can form clusters resulting particle size increment, which can potentially obstruct the small capillaries of the pulmonary microvasculature.
An objective of the present specification was to avoid leaching from silicon product transfer tubing that may occur during manufacturing of pharmaceutical injectable products employing ethanol. The inventors while addressing the problem surprisingly found that replacing conventional silicon product transfer tubing with inert product transfer tubing provides better control over leaching phenomenon.
SUMMARY OF THE INVENTION
The present specification relates to a manufacturing process for pharmaceutical injectable products employing ethanol as one of the solvents, wherein the process comprises use of inert product transfer tubing.
DETAILED DESCRIPTION OF THE INVENTION
The present specification relates to use of inert product transfer tubing in the manufacturing process of pharmaceutical injectable products employing ethanol as one of the solvents.
Critical Quality Attribute (CQA) is a physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution, to ensure the desired product quality. The identified CQAs of carmustine for injection are: description, pH, reconstitution time, moisture content, impurities, particular matter, container closure integrity, bacterial endotoxin, and sterility. These CQAs are identified based on the relevant knowledge gained during the product development.
Fluoropolymer based inert product transfer tubings are commonly used in pharmaceutical manufacturing process of injectable products. With few exceptions, fluoropolymer product transfer tubing can handle virtually any corrosive chemical in use today. The well known fluoropolymer tubings include Fluorinated ethylene propylene, Sani-Tech® Ultra-HP, DuPont Teflon®, Polytetrafluroethylene, and PharmaFluor FEP.
Fluorinated ethylene propylene (FEP) product transfer tubing are: chemically inert with low permeability, lowest coefficient of friction of any solid material, made without plasticizer, which can leach into critical streams, and free of conflict minerals. It can be used with virtually all industrial solvents, chemicals, and corrosive materials, even at elevated temperatures. It does, however, react with fluorine, molten sodium hydroxide, and molten alkali metals.
Sani-Tech® Ultra-HP hose is a multi-layer silicon hose product with an inner FEP liner constructed using the same raw material as FEP tubing. The inner FEP fluoropolymer liner of Sani-Tech® Ultra-HP is a highly chemically resistant material, made without plasticizers or oils, the liner has an extremely low level of extractables, maintaining the integrity of even the most sensitive fluids. Highly pure materials combined with robust quality controls allow Sani-Tech Ultra-HP to function at optimum levels during bioprocessing applications.
DuPont Teflon® fluoropolymer resins are fully florinated molecules forming continuous non-reactive surfaces. Because of its durability and chemical resistance it was found suitable for many pharmaceutical or biochem process. It can be used for a wide range of chemicals such as strong mineral acids, inorganic bases, inorganic oxidizing agents, salt solutions, aldehydes, chlorocarbons, organic acids, anhydrides, aromatics, alcohols, ketones, esters and fluorocarbons.
Polytetrafluroethylene (PTFE) resin is fully fluorinated fluoroploymer tubing, widely used as a pressure tubing for general chemical applications such as delivery of natural gas and mineral oils, toxic gas monitoring and paint, varnish or adhesive delivery lines. It also serves numerous applications in automotive, electrical and appliance market.
PharmaFluor FEP is a fluoropolymer product transfer tubing which is chemically inert, ultra-pure, biocompatibile, non-cytotoxic, non-pyrogenic and non-hemolytic, low sorption, fully autoclavable and sterilizable. It is utilized in sterile filling and dispensing systems, diagnostic equipment, general laboratory use, cell and tissue culture transport, analytical and process equipment in biotechnology, pharmaceutical and environmental fields.
Silicon content is a CQA that influences the quality of pharmaceutical injectable products employing ethanol as one of the solvents during their manufacturing process e.g. carmustine for injection. On prolonged contact with product transfer tubing made of silicon, which is used for conveying the product during manufacturing process, caused leaching. The presence of higher level of silicone in product vial impacted clarity of reconstituted solution and the sub-visible particle count. The leached silicon is detected as oil globules and can form clusters of larger particle size. Eventually, it was observed that the major source for silicon particles in finished drug product was due to leaching of silicon product transfer tubing used in manufacturing process.
In the present specification, the aforementioned CQA was replaced with inert fluorinated ethylene propylene product transfer tubing, so as to control the silicon content in finished drug product e.g. carmustine for injection.
The silicon content and clarity of reconstituted solution was checked in different lots of carmustine for injection, initially and during stability. The observations are summarized in Tables 1 and 2.

The Table 1 data with silicon product transfer tubing shows the presence of higher level of silicon in product vial, thus impacting the clarity of reconstituted solution. Thus, it is essential to control the silicon content in drug product to reduce the risk of higher sub-visible particle count in drug product.

The data from Table 2 illustrate that silicon content is less than 50 ppm in batches with FEP product transfer tubing, whereas it crossed 100 ppm in few batches with silicon product transfer tubing.

Ideally, silicon content in batches with FEP product transfer tubing was expected to be nil. However, the traces of silicon indicate the possibility of contribution from container-closure system (glass vials and rubber stoppers are known to leach metallic impurities including silicon). There is no increasing trend of silicon content in batches with FEP product transfer tubing subjected to stress conditions over a period of time.
The following examples further illustrate the invention, but should not be construed as in any way limiting its scope. In particular, the processing conditions are merely exemplary and can be readily varied by one of ordinary skill in the art.
Table 1: Silicon content in different lots of carmustine for injection with silicon product transfer tubing
Lot No. Clarity of reconstituted solution Silicon Content (ppm)
1 Clear 35.6
2 Clear 36.1
3 Clear 40.9
4 Clear 37.9
5 Clear 40.2
6 Clear 40.2
7 Clear 37.9
8 Clear 50.9
9 Clear 39.3
10 Clear 58.9
11 Clear 77.3
12 Very slightly hazy 148.6
13 Very slightly hazy 336.9
Table 2: Silicon content for batches of carmustine for injection with Silicon product transfer tubing and FEP product transfer tubing
Sr. No. Name of sample Batch No. Mfg. date Age of sample Silicon content
(ppm)
Batch with silicon tubing
1 Dehydrated alcohol injection DHAA2001 Aug-12 64 months 68.40
2 Dehydrated alcohol injection DHAA2002 Aug-12 64 months 93.20
3 Dehydrated alcohol injection DHAA2003 Sep-12 63 months 115.80
4 Carmustine for Injection CMAA1005 Aug-11 76 months 44.50
5 Carmustine for Injection CMAA1003A Mar-13 56 months 56.20
6 Carmustine for Injection CMCA3004 Apr-13 55 months 160.40
Silicon content for batches with silicon tubing Mean 89.80
Minimum 44.50
Maximum 160.40
Batch with FEP tubing
Dehydrated alcohol injection DHAA5003A Apr -17 08 months 24.80
Dehydrated alcohol injection DHAA5004A Apr-17 08 months 37.90
Carmustine for Injection CMCA7006 Oct-17 Initial; bulk 4.00
Initial filled vial; bulk 12.60
Middle filled vial; bulk 12.90
End filled vial; bulk 11.20
Finished product; Initial 25.50
Finished product; kept at stress condition 55ºC; Upright for 48 hrs 20.10
Finished product; kept at stress condition 55ºC; inverted for 48 hrs 10.10
Finished product; kept at stress condition; autoclaved at 121ºC for 10 min 9.10
Carmustine for Injection CMCA8002 Jan-18 Bulk solution before filtration 0.54
Primary filtration 1st flush 12.19
Primary filtration 2nd flush 1.64
Secondary filtration 1st flush 2.99
Secondary filtration 2nd flush 2.05
Start of filling 15.16
Mid of filling 14.58
End of filling 16.68
Finished product 14.23
Silicon content for batches with FEP product transfer tubing Mean 13.07
Minimum 0.54
Maximum 37.90

,CLAIMS:1. A manufacturing process for pharmaceutical injectable products employing ethanol as one of the solvents, wherein the process comprises use of inert product transfer tubing.
2. The manufacturing process according to claim 1, wherein the inert product transfer tubing is based on fluoropolymer.
3. The manufacturing process according to claim 2, wherein the fluoropolymer based inert transfer tubing may be selected from fluorinated ethylene propylene (FEP), Sani-Tech® Ultra-HP, DuPont Teflon®, Polytetrafluroethylene, and PharmaFluor FEP.