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Pharmaceutical Manufacturing and Packing Sourcer

A Question of Use


The majority of new drug developments are coming from the biopharmaceutical sector. Growth due to the contribution from these drugs is in the double-digit region and is predicted to increase further over the next decade.This non-reversible trend is linked to the resolution of human DNA, which has resulted in drugs with a highly selective action and increased potency (1,2).

Many newly developed biopharmaceutical drug candidates have the potential to be successful products in the healthcare market. However, the increasing volume of investment necessary to develop one candidate to an efficient treatment for patients carries manifold risks which have led to a reduction in the number of new drug applications (NDAs) during the past decade.At the same time, expectations of efficient treatments in terms of low side effects have increased significantly, putting even more pressure on the biopharmaceutical industry.



The major challenges in protein and peptide production include reproducibility, easy scale-up and process robustness. In addition to being safe and efficient, the drug has to be applied in the right way for the patient to experience its therapeutic effect. Delivering a protein as a parenteral therapeutic is a complex challenge and involves investigations on stability, pharmacokinetics and bioavailability, all of which are potential sources of failure.

Although peptide and protein drugs have a limited shelf-life in solution, most biopharmaceutical drugs are launched as injectables because they cannot survive the oral administration route. Therefore, parenteral packaging components for biopharmaceuticals play a major role in the phase of developing the drug delivery concept, as they can have a significant influence on the stability of the respective drug product formulation. In a nutshell, the specific properties of biopharmaceuticals mean that they require more sophisticated container closure systems and glass, as the conventional material for syringes sometimes reaches the limits of its capabilities. Plastic polymers such as polyethylene and polypropylene as an alternative material to glass for packaging components are well established in various areas of application, such as solid and ophthalmic preparations, as well as infusions. These polymers are not ideal candidates for injectables due to their lack of transparency after sterilisation and their limited gas barrier properties.

Polymer Usage

There are two examples of plastic polymers in the class of polyolefin compounds, which can be used for primary packaging components and permit the long-term storage of a liquid drug product. One is cyclic olefin copolymer (COC), a copolymer of a sixmember cyclic carbon hydride with polyethylene.The other is cyclic olefin polymer (COP), a polymer based on a five-member cyclic carbon hydride polymerised by metathesis reaction. Superior properties compared to polyethylene or polypropylene are high transparency, low level of organic extractables – being typical for plastics – and no extractable metal ions. The question is why these plastic compounds have not yet conquered the sector of primary packaging for parenterals?

The reasons for this lack of universal use include limited experience in the environment of the regulated pharmaceutical industry and long drug development times. In contrast, the Japanese pharma market has already been using parenteral plastic vials and syringes produced from COP for many years now. Another is cost pressure because high quality polymers like COC and COP are rather expensive compared to glass. Finally, there is a difference in the processing of plastic vials on standard glass vial filling lines because they cannot be introduced using the conventional method via the traditional depyrogenisation oven.

The complexity and sensitivity of biopharmaceuticals has changed the picture and makes the use of highend plastic polymers for parenteral containers an interesting solution for primary package of injectables.

Stability and Adsorption
There are various degradation mechanisms which affect the stability and availability of biopharmaceutical drugs, such as peptides or proteins, during storage in the final container. Several investigations have been performed to ascertain the level of adsorption of protein-like molecules on the surface of different materials used for primary packaging. It has been observed that adsorption is proportional to surface area and depends on the type of protein and formulation. Other publications claim that absorption is a very dynamic process of protein resorption occurring within 24 hours until equilibrium is reached. As a result, low concentrated protein-based drug formulations sustain degradation up to 50 per cent of the original concentrations. Bovine serum albumin (BSA) as a model protein showed moderate absorption of nine per cent (3). Even this ‘moderate’ loss requires a significant overfill as compensation with adverse effect on the efficiency of the manufacturing costs. Figure 2 (page 105) shows the product loss of BSA onto glass surface.



Proposals to reduce protein adsorption include the following measures:
  • The inclusion of high concentrations of an inert protein in the drug formulation to saturate the glass surface
  • The addition of carbohydrates, surfactants or amino acids to reduce interaction between container surface and protein
  • Silicone oil treatment of the glass vial surface to reduce the adsorption
At the same time it is reported that silicone oil droplets can cause aggregation of proteins (4). Last but not least, the correct selection of the container material also influences the stability of protein solutions. CJ Burke et al evaluated the protein adsorption properties of different materials such as glass, polyester, polypropylene and polyamide in an empirical study (5). The result of this study demonstrated that the correct selection of container material for each protein is essential to achieve minimisation of product loss by adsorption. Figure 3 shows an extract of a study where a comparative test of protein adsorption on type 1 glass vial and a multilayer COP vial was performed utilising BSA as a model protein.

The figure clearly shows the reduced adsorption level of BSA on the inner surface of the COP multilayer vial compared to the glass vial. Based on this, it seems important to include COP vials in drug container compatibility screening tests for novel protein-based biopharmaceuticals parallel to the glass vials – a notion supported by the work of Hoffmann-La Roche (6).

As shown above, it is obvious that the use of COP-based plastic vials can improve drug potency by reduced adsorption on the container surface and could save overfill of typically expensive biopharmaceuticals which should more than compensate for the higher costs for the COP plastic vial.

Metal Ion Release at High pH Values

Glass is composed of a set of inorganic oxides that forms a threedimensional structure during the manufacturing process. Parenteral drug solutions with with a pH value above seven attack the surface. Under such conditions the glass releases metal ions with potential adverse effect on the stability of sensitive biopharmaceuticals. In severe cases the attack on the glass surface can even cause flaking, which has led to an increased rate of recalls (7). One can easily imagine that a pH shift or released metal ions would be sufficient to cause an adverse effect on the drug, in that it would denature a protein in a biopharmaceutical formulation. COP-based vials are an ideal solution to problems experienced in connection with parenteral drug solutions with high pH-value.

Despite the superior compatibility properties commonly available, COP vials suffer from weak gas barriers, which can impact the shelf-life of oxygen-sensitive biopharmaceuticals. This weak barrier has forced the industry to add additional barrier bags as separate packaging components or freeze-dry in glass vials, which creates additional process costs and related investments for freeze-drying equipment. Very recently, multilayer plastic vials have been introduced with improved barrier properties (see Figure 4).

Thus, the main characteristics of the high-end cyclic olefine polymer are enhanced by high gas barrier properties without the loss of any advantages such as low adsorption tendency, no metal ion release, high transparency and high drainability. The drug contact surface area remains COP, which is known to be a very inert and clean material. The advantage of the multilayer design is the increased oxygen barrier and improved integrity when the container suffers from external impact or incidental drop due to the extremely high puncture resistance of polyamide which strengthens the structure. Regarding the gas barrier properties, measurements of the oxygen barrier of the new multilayer plastic vials demonstrated a barrier level which is superior to any available plastic material in use for parenteral pharmaceutical packaging.



Conclusion

The enhanced barrier properties of the multilayer plastic vial based on COP offer a new alternative to glass vials for sensitive biopharmaceuticals without the typical limitations of existing monolayer plastic vials made from PE, PP or the COC and COP.

The increased impact resistance of the multilayer design addresses concerns such as secure sterility of the filled injection solution during transport or storage or protection of hospital staff and patients against contamination of toxic drug solutions through accidental breakage. Comparing the impact resistance of glass and plastic vials, the result depends on the selected method and the plastic grade. Multilayer plastic vials based on COP show five to 10 times higher impact resistance compared to glass vials. Figure 5 shows the impressive impact resistance of the multilayer plastic vial, which remains intact even when the outer shell is broken. The punctureresistant polyamide layer of the multilayer structure prevents the liquid leaking and predestines multilayer vials for usage of cytotoxic drug solutions, for example for anticancer treatments. Higher break-resistance gives the biopharmaceutical production the opportunity to reduce production costs generated by breakage during filling and transportation. This aspect could be also a significant contribution to cost saving.

We expect that combined considerations, such as stability, throughout the shelf-life, safety during filling, transportation and handling will change the niche role of multilayer plastic vials as parenteral containers with superior properties addressing the specific functional requirements of sensitive biopharmaceuticals and will make drugs more efficient and safe in the long run.

References
  1. Biological Drug Delivery 2007-2012, Visiongain Ltd, London, UK
  2. Prefilled Syringes – 2009 Drugs, Devices and Disease Therapeutics, Greystone Associates, Amherst, NH, US
  3. Wu et al, Adsorption of proteins onto glass surfaces and its effects on the intensity of circular dichroism spectra, Analytical Biochemistry 177: pp178-182, 1989
  4. Jones, Latoya, Kaufmann, Allyn, Middaugh and Russell, Silicone oil induced aggregation of proteins, Journal of Pharmaceutical Sciences 94(4): pp918-927, 2005
  5. Burke CJ, Steadman BL, Volkin DB, Tsai PK, Bruner MW and Middaugh CR, The adsorption of proteins to pharmaceutical container surfaces, International Journal of Pharmaceutics 86: pp89-93, 1992
  6. Qadry SS, Roshdy TH, Char H, Del Terzo S, Tarantino R and Moschera J, Evaluation of COP vials for packaging protein-based parenteral formulations, International Journal of Pharmaceutics 252: pp207-212, 2003
  7. Bloomfield JE, Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, at the 2011 PDA/FDA Glass Quality Conference, Arlington, VA, 23rd to 24th May, 2011


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Wolfgang Dirk has a PhD in Chemistry from the RWTH University of Aachen, Germany. He has worked on hydroboronbased cage-structured molecules for cancer treatment, and held management functions at Schweizerhall Pharma GmbH and Indukern Chemie AG. Before joining Gerresheimer he worked for four years at West Pharmaceutical Services as Technical Support Manager for primary packaging components for parenterals. As new Product Manager at Gerresheimer Plastic Packaging, Wolfgang is focusing on the market introduction of the new multilayer COP vials and the development of the parenteral business.
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