Dr Bettine Boltres, Product Manager Pharmaceutical Tubing, SCHOTT AG gives an introduction on the different packaging options and their requirements
It is not easy being a primary packaging material for parenteral drugs these days. And not less complicated is the job of the pharma company. How to find your way through the jungle of regulatory requirements and ever increasing demands of the lately developed drugs? This article gives an overview of the different packaging options and their requirements.
From all packaging materials, primary packaging for parenteral drugs has the highest quality standards. According to the European and the US regulations, “equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements” 1, 2. This regulation applies to all materials that are in direct contact with the drug product including metals, glass, and polymer. The European (Ph. Eur.) and United States Pharmacopeia (USP) define a pharma container as being in direct contact with the drug product. The container shall be designed in a way as to protect the drug product from environmental influences and minimise the loss of the product. 3, 4 Except for when ampoules are used, the packaging consists of several components, like the container, a stopper, a plunger, a needle, etc. The FDA Guideline on Container Closure Systems for Packaging of Human Drugs and Biologics defines the whole Container Closure System (CCS) as a combination of all these individual components that contribute to the stability and quality of the drug product 5, p. 2.
Primary packaging for parenterals can be either made of glass or polymer. Using glass there are two different possibilities depending on the specific requirements: Molded vials or bottles are made by filling a gob of glass into a mold and blowing or pressing it into its final shape. Tubing containers are produced in a two-step process where first the tubing is drawn and secondly the container is formed from the tubing by using heat and forming tools.
The development of various different types of glass based on scientific principals was started over a hundred years ago, when the basic recipe for the borosilicate glass was developed. From these the borosilicate glasses have developed as the standard packaging material for pharmaceutical purposes.
According to the current USP and Ph. Eur., borosilicate glass contains significant amounts of boric acid, aluminum oxide, alkali metal oxides and alkaline earth metal oxides. With a high hydrolytic resistance, this glass is classified as a Type I glass and is recommended to be used for packaging parenteral drugs. On the other side, by increasing the amount of alkali and alkaline earth metal oxides in the glass composition a soda-lime glass is created. With an only moderate hydrolytic resistance this glass is classified as Type III and recommended to be used rather for preparations, not for parenteral administration 4, 3.
Within the past years the pharma market was driven by an increased development of biopharmaceuticals, such as monoclonal antibodies, recombinant proteins, vaccines, blood- and plasma-derived products, etc. These drugs usually pose higher requirements on the container in terms of extractables and leachables, hydrolytic resistance, pH stability, etc. than the traditional drugs. As a consequence, regulatory agencies brought stricter and more individual quality controls into focus which can be seen from the increasing number of publications. This is why, now a known material like glass with a long history, is looked at in a new light.
While choosing a primary packaging for their drug product the pharma company has to evaluate several quality criteria. Helpful guidelines are found in the Ph. Eur., USP and Japanese Pharmacopeia (JP). An overview of some important chapters is given in Table 1
In the meanwhile, for parenteral products there are in general five possible packaging options, as shown in Table 2. Which container shape and which packaging material to choose exclusively depends on the requirements of the drug product. The different quality aspects that have to be considered along the development process are discussed as follows:
Chemical resistance
Within the chemical stability, an important measure for the suitability of glass for pharma containers is its resistance against water attack (hydrolytic resistance). There are two test methods to assess this, which are the glass grains test and the inner surface test. They are described in the international standards ISO 719, ISO 720, ISO 4802-1, ISO 4802-2 and the Ph. Eur., USP as well as JP6, 7, 8, 9, 4, 3, 10. Hereby, the Ph. Eur. and the USP are aligned whereas the JP testing method is different. A very important difference is that in the Ph. Eur. and USP, the classification is done into Type I and III according to their hydrolytic resistance, whereas in the JP the result of the test is ‘pass’ or ‘fail’.
Glass tubing manufacturers in various regions of the world supply three different sub-types of borosilicate glasses for use in the pharma industry. Although all three are Type I glass, the hydrolytic resistance drops slightly from one type to another. At the same time, the coefficient of thermal expansion (CTE), a measure of the volume and length expansion of glass when subjected to a temperature change, increases. Based on the value of this coefficient, borosilicate glasses are classified as 3.3·10-6 K-1, 5.0·10-6 K-1 and 7.0·10-6 K-1, whereby the hydrolytic resistance decreases from 3.3·10-6 K-1 to 7.0·10-6 K-1. Borosilicate glass of 3.3·10-6 K-1 poses some challenges on the converting process whereas borosilicate glass with a CTE of around 7.0·10-6 K-1 offers lower hydrolytic resistance. Given these aspects, borosilicate glass 5.0·10-6 K-1 is the ideal compromise of a high chemical resistance and convenient to convert. Thus it is used as a standard all over the world.
Extractables and leachables
Over the past years the biologically developed drug formulations growing in the areas of therapeutic proteins, vaccines and monoclonal antibodies exhibit much higher sensitivities towards any foreign substances and changes in environment than the chemical drugs do. Additionally the liquid formulations containing surfactants, salts and chelating agents coupled with ever lower drug levels placed a global focus on the interactions between the formulation and the packaging material and thus the whole CCS. Determination of potential extractables and leachables became part of the process validation when filing new drug applications. The composition of glass has always been widely known and official. So in the interaction of the drug with glass packaging, the amount of extractables and leachables has to be determined rather than their nature.
Transparency
The transparent nature of glass permits a proper visual inspection in a fast and cost-effective manner. Equally, the filling volume and the level of contamination can be checked. After storage, a discoloration or the occurrence of glass particles can be detected.
Light protection
Within the growing field of biologics but also among the known drugs there are substances that are very sensitive to light and which decompose when subjected, especially, to UV-light. For these cases, coloured glass can be used, which is supplemented with either iron and titanium or iron and manganese. Still, this type of glass remains transparent enough to allow for visual inspection. In order to ensure the safety of the drug the allowed amount of light passing through the glass is specified. Here the requirements are different when comparing Ph. Eur., USP and JP. The JP is the only one specifying the transmittance through the glass wall in the visible range (590-610 nm).
Permeability
Apart from being light-sensitive, there are also drugs that are sensitive towards oxygen and water vapour. For ensuring the quality and efficacy of these drugs a tight CCS (Container Closure Integrity, CCI) is crucial. The structure of glass does not allow for any gases or pyrogens to travel through it and into the drug product. The helium permeation rate is somewhere around 10-10 mbar·l/s which is insignificantly low especially because helium is a third of the size of oxygen.
But, not only are harmful substances prevented from contaminating the product but, in addition, it is impossible for the contents of the intact container to leak out.
Sterilisation
Glass has a very stable structure which is kept even when confronted with high temperatures as e.g. 330°C in the depyrogenation tunnel. Exceeding this temperature glass generally stays stable up to 500°C. Only then a very slow deformation starts. Hence, temperature applications are in general not critical for glass.
Freezing
On the other side glass also keeps its structure when exposed to very low temperatures. This makes it suitable for lyophilization and freeze/thawing. In these applications attention has to be paid not to exceed the temperature shock resistance of the glass. This value is given by a combination of composition, CTE and wall thickness of the container wall. Generally it can be said that the lower the CTE the higher is the temperature shock resistance. Due to the low thermal conductivity of the glass temperature needs some time to pass through the glass wall. If a hot glass container is in direct contact with a cold metal it might happen that at this particular contact spot the temperature shock resistance is exceeded which then leads to a thermal shock crack. For the CTE 5.0·10-6 K-1 tubing container e.g. a container with a wall thickness of one mm takes a temperature shock of 200°C.
With this variety of requirements and container options it is not always easy for a pharma company to find the right solution for their new drugs. Here it is always recommended to be in close contact with the container suppliers, carefully evaluate the options on the market and by using the many regulatory advisories to choose on a case-by-case basis.
References:
1. European Comission of Glass, “Good Manufacturing Practices, Medicinal Products for Human and Veterinary Use,,” 2010.
2. US Government Printing Office, “Equipment construction,” CFR, Code of Federal Regulations, Food and Drugs, Title 21, p. Part 211.65, 2010.
3. USP 36 NF 31, Chapter <660> Containers – Glass, United States Pharmacopeia, 2013.
4. Ph. Eur. 8.4, Chapter 3.2. Containers, European Pharmacopeia, 2014.
5. FDA, „Guidance for Industry. Container Closure Systems for Packaging Human Drugs and Biologics,“ 1999.
6. ISO719, Glass – Hydrolytic resistance of glass grains at 98°C – Method of test and classification, International Organization of Standardization, 1985.
7. ISO720, Glass – Hydrolytic resistance of glass grains at 121°C – Method of test and classification, International Organization of Standardization, 1985.
8. ISO4802-1, Glassware – Hydrolytic resistance of the interior surfaces of glass containers – Part 1: Determination by titration method and classification, International Organization of Standardization, 2010.
9. ISO4802-2, Glassware – Hydrolytic resistance of the interior surfaces of glass containers – Part 2: Determination by flame spectrometry and classification, International Organization of Standardization , 2010.
10. JP XVI, Testing for Glass Containers for injections, Japanese Pharmacopeia, 2011.