Application of Non-PVC Film in Sodium Bicarbonate Injection

- Wu Chunming, Sealed Air (China) Co., Ltd.

Abstract: The application of Non-PVC film in sodium bicarbonate IV solution is described in this article, including the
compatibility of related drug and packaging material, selection of appropriate packaging system and introduction of
application by China's enterprises.
Key Words: Sodium Bicarbonate IV Solution; Non-PVC film; Compatibility of Related Drug and Packaging Material;
High Barrier Packaging System;

1. Background
Sodium bicarbonate injection is a sterile solution of sodium bicarbonate in water and is indicated in
the treatments of metabolic acidosis and alkalinization of the urine, and can non-specifically treat
certain drug intoxications, such as by barbiturate overdose, salicylate poisoning or methanol
poisoning. It is a common first-aid medicine, and no substitute is found currently at home or
abroad.
Due to its slight alkalinity, sodium bicarbonate injection sets high requirements on chemical and
thermal stability of packaging materials directly in contact with it. Therefore, relevant medical
regulatory authorities have established very strict regulatory and licensing requirements for
packaging materials which directly contact sodium bicarbonate injection. In a developed country
such as the USA, the US Food and Drug Administration has so far only approved (borosilicate)
glass bottle to be the container for sodium bicarbonate injection. Similar to China, Japan has
approved three packaging materials: non-PVC multi-layer co-extrusion film, polypropylene bottle
and glass bottle (mainly borosilicate), but has set stringent requirements for medicine compatibility
tests, outer packages barrier system and filling process.
Non-PVC film was first developed by Sealed Air in 1980s and applied to IV solutions. Before that,
packaging materials for IV solution had undergone rapid development from early glass bottle, to
later PVC bag, and plastic bottle mainly made of polyacetadehyde which emerged at a similar
time.
Non-PVC film was officially introduced to China by Sealed Air in 1998 and this began a new
chapter in the history of non-PVC soft bag for IV solutions. After years of autonomous choice and
development of the market, non-PVC soft bag has captured a major market share in China IV
solution industry, resulting in a situation of tripartite confrontation with glass bottles and plastic
bags.
Due to its advantages other than safety and compatibility of drug products, the non-PVC infusion
bag has strengths on the market and gains its popularity. First, the infusion bag can be emptied
autonomously during infusion to avoid secondary pollution caused by introduction of ambient air.
Secondly, it is lightweight, impact resistant and unlikely to fall for convenience of transportation.
Thanks for its superior safety and chemical stability, the application of Non-PVC film is greatly
extended, from routine IV solution in the earlier phase such as glucose injection and sodium
chloride solution, to current electrolyte injection, nutrient injection and injection for treatment with
high added value. Among others, sodium bicarbonate injection is one of the emerging typical
applications.
Introduction of Author: WU Chunming Senior Technical Specialist, Medical Application Department, Sealed Air
(China) Co., Ltd.

However from a deeper perspective, the fact that part of immediate packaging materials for
sodium bicarbonate solution were changed from glass bottle to Non-PVC film is derived from
relevant game paradox of market and regulation. From the perspective of market, sodium
bicarbonate filled in glass bottles was previously made of inferior soda-lime glass, so the bidding
price was forced down, even much lower than the cost of a qualified borosilicate glass bottle made
in China. Different types of imported or domestically-made borosilicate glass bottle with price
lower than Non-PVC film are the optimal option for packaging sodium bicarbonate filled in glass
bottles. From the perspective of regulation, although the Circular of the General Office of the State
Food and Drug Administration on Strengthening the Supervision and Administration for
Pharmaceutical Glass-packed Injection Drugs issued by the State Food and Drug Administration
(SFDA) in November, 2011 (SYJBZ [2012], No.132) doesn't mention that current soda-lime glass
is not applicable to sodium bicarbonate solution, undoubtedly, the concern for the safety and
package compatibility of acid, alkaline or ph-sensitive drugs couldn't be a more obvious signal. It is
easy to understand why Non-PVC film has rapidly gained popularity in the area of sodium
bicarbonate injection in recent years in light of the two points above.

2. Applications
Before introduction of applications, it needs to be clarified that there are two mainstream Non-PVC
film products in the market, that is, five-layer co-extrusion film and three-layer co-extrusion film.
The Sealed Air M312C product is typical of the former one, while many companies produce
versions of the latter one with similar performance.
Theoretically, soda-lime glass is not applicable to sodium bicarbonate injection because in the
case of long-term exposure to sodium bicarbonate injection with slight alkalinity, metal ions such
as Ca2+, Mg2+ in the soda-lime glass will be detached, form so-called "white dots", and
compromise the clarity of products. In layman's terms, poor compatibility of drug and packaging
material will adversely affect the safety of terminal application, which is not acceptable.
However, the focus of Non-PVC film for sodium bicarbonate injection is completely different.
According to published technical literature, for sodium bicarbonate injections which are packed in
Non-PVC film and glass bottles, sterilized in normal process and stored under acceptable
conditions for a period of time (for example, one month), items such as the content of sodium
bicarbonate solution, visual impurities, bacterial endotoxins, insoluble particles and sterility test
meet the requirements of Chinese Pharmacopeia. The main difference between two products is
that regardless of three-layer film or five-layer film, pH of sodium bicarbonate solution packed in
Non-PVC film will increase and go beyond acceptable range (7.5~8.5), typically reaching 8.5~9.0.
That is to say, for sodium bicarbonate solution packed in Non-PVC film, the attention should be
paid to how to control the pH of the end product in an acceptable range as well as keeping the
compatibility of drug and packaging material.
Then, why does the pH of sodium bicarbonate solution packed in Non-PVC film increase? It is
because sodium bicarbonate solution stored under acceptable conditions will dissociate into
HCO3- and Na+ easily, and HCO3- will further release gaseous CO2 (chemical equation: HCO3- =
CO2 + OH-), produce OH- and increase the pH of solution. To decrease the balanced reaction
forward, sufficient gaseous CO2 are filled to maintain a dynamic equilibrium during preparing and
filling sodium bicarbonate.
Introduction of Author: WU Chunming Senior Technical Specialist, Medical Application Department, Sealed Air
(China) Co., Ltd.

Unfortunately, during long-term storage of sodium bicarbonate injection, due to the inherent CO2
permeability of Non-PVC film, CO2 inside the bag will easily permeate the barrier, break the
balance of CO2 inside the bag, and indirectly promote HCO3- breakdown reaction, leading to the
increase of pH of sodium bicarbonate injection.
To inhibit the escape of CO2, it is required to add an outer packaging system with high CO2 barrier
value, which is generally a bag, made of plastic. It is referred to as outer package in this article.
Based on years of application experience in the industry, if the CO2 barrier property can stably
reach < 1.0 CC/m224h0.1MPa, the pH of sodium bicarbonate solution packed in non-PVC soft
bag will remain in acceptable range during its lifecycle.
Undoubtedly, there are some points which shall be emphasized when using the high barrier
packages, for instance, outer package shall be added and CO2 shall be filled before sterilization,
and then the package is vaccumized and sterilized. In the case of adding outer package after
sterilization, some irreversible breakdown reactions may occur without the protection of high
barrier outer package during sterilization, resulting in a significant increase of pH after sterilization,
which even goes beyond the acceptable range (pH 7.5-8.5). In addition, filling CO2 before
vaccumization is to add CO2 between inner and outer packages, so HCO3- breakdown reaction is
inhibited due to the high concentration of CO2 between inner and outer packages.
Finally, a point worth emphasizing is that successful application of non-PVC soft bags in sodium
bicarbonate solution in China is mainly based on M312C five-layer co-extrusion film and M712
high barrier outer package produced by Sealed Air.

3. Analysis Summary
If nothing unexpected happens and outside of certain specific applications (for example, products
with one-month shelf life), it is likely that in next few years, soda-lime glass bottle for sodium
bicarbonate solution will be replaced by Non-PVC film. A portion of them may be substituted by
borosilicate glass bottles where the high cost-performance ratio is worthwhile.
For any individual pharmaceutical packaging, the market always prefers it to be safe and
economically viable.

References
1. ZHOU Na, ZHOU Renjin, The Compatibility of Multi-layer Co-extrusion Film Used for
Sodium Bicarbonate Injection, Guangzhou Chemical Industry Vol. 39, No.4 2011;
2. ZHAO Xueshen, DING Mei, The Compatibility of Multi-layer Co-extrusion Film Used for
Sodium Bicarbonate Injection, Qilu Pharmaceutical Affairs Vol. 25, No.3 2006;

Introduction of Author: WU Chunming Senior Technical Specialist, Medical Application Department, Sealed Air
(China) Co., Ltd.