Flexible packaging is a relatively low cost and eminently suitable solution for the packing of APIs, drugs or vaccines, argues Benjamin Kepp, of flexible packaging specialist Bischof + Klein
Fulfilment of regulatory compliance, according to European or US Pharmacopoeia, is usually the main focus of pharmaceutical packaging companies, along with the necessary documentation and traceability for all quality-related items. But when using flexible packaging, further requirements need to be met - the cleanliness of high-purity bulk material has to be protected, as well as the cleanliness of the production area.
The requirements for cleanliness in facilities producing pharmaceutical and medical products continue to get stricter. Furthermore, the gap between the requirements for materials for hospital use and those for the pharmaceutical industry grows ever wider.
The cleanliness required for pharmaceuticals, especially for sterile active pharmaceutical ingredients, drugs or vaccines, is pushing new limits. As a consequence, high-purity packaging that protects the products is a prerequisite throughout the process and supply chain.
Particles are one of the key contamination issues, as not only can stray particles act as carriers for microbiological contamination, such as yeasts, moulds and germs, but administrations such as the US FDA or European EMEA have also implemented several rules and guidelines on procedures for protecting products and premises against such contamination.
regulations for premises
One example is the FDA's Industry Guidance on Container Closure Systems for Packaging Human Drugs or Biologics. The packaging material, or so-called Container Closure System (CCS), should be manufactured in accordance with cGMP requirements, included in the 21 CFR, parts 210 and 211. Specifically, 21 CFR 211.42(b) declares that "The flow of components ... through the building ... shall be designed to prevent contamination". The accompanying 21 CFR 211.80(b) declares further that "Components ... shall at all times be handled and stored in a manner to prevent contamination".
Similar requirements are defined in the FDA's Industry Guidance for "Sterile Drug Products". The manufacturing process has to be "designed to minimise exposure of sterile articles to the potential contamination hazards" (Part IV.E) and "microbiological and particle monitoring", including air, equipment, components, products and operational activities, has to be in place (Part IV. general).
EU GMP guidelines deal with the manufacturing process and premises in the same manner. A "minimal risk of causing contamination of materials or products" (Chapter 3.1) should be provided and particulate contamination of the end product, especially for sterile ones, should be minimised and also recontamination should be avoided. EU GMP Annex 1, positions 48, 53 or 67 give just a few examples.
This establishes the demands for high-purity packaging, both primary and secondary. According to GMP 13.A, the function of packaging is to "protect against light, oxygen, contamination, mechanical damage and humidity." The Guidance for Container Closure Systems for Packaging Human Drugs and Biologics requires a CCS that should provide the dosage form with adequate protection from factors that "can cause degradation in the quality"
A drug product can also suffer "an unacceptable loss in quality if is contaminated by dirt" (Part B.1.a). For the secondary packaging it asks for "an additional measure of microbiological protection" (Part B.4). Both of these include contamination of any kind - particles or bio burden.
flexible solutions
When it comes to the demands of high purity, clean packaging, flexible packaging, such as clean films and bags, could be a suitable and comparably cheap single-use solution.
Flexible packaging offers a well established logistical advantage in that a large number of units occupy a relatively small space, leading to cost savings in storage and transportation. Packaging materials made out of polypropylene (PP), polyethylene (PE) or other barrier laminations with PE are thermosealable to themselves - which means that container and closure can be made out of the same material.
Considering the above-mentioned regulatory requirements, flexible CCS offer three further advantages:
Contamination protection: Sealable packaging materials provide a tamper-evident closure as required in FDA 21 CFR 211.132. Closed by thermo-sealing, they provide protection for a bulk product against microbiological or particulate contamination. To protect the cleanliness and thus the quality of the product in compliance with regulatory requirements, the packaging should be as clean as possible with regard to particulates or bioburden. Particle and microbiological monitoring of the manufacturing process of packaging is mandatory to comply with this claim, and the need for cleanroom production is self-evident.
Protection from batch cross-contamination: In the majority of cases, flexible packaging is used as a disposable. Due to its single-use application cross-contamination is not an issue and the high costs for cleaning and cleaning validation for reusable containers or closures can be saved.
Protection against contaminating the cleanroom environment: As mentioned above, many legislative aspects are designed to protect the production area and all processes. Surprisingly, this is often not transferred to the packaging material, although it is a key driver to prevent contamination. Whether a packaging material is used as a primary, secondary or tertiary packaging or even as a waste bag, if the usage takes place under cleanroom conditions or even sterile environment, the films or bags have to be on the same cleanliness level.
Inadequate materials with regard to particle shedding or even micro-biological burden on the inside or outside have an impact on quality of the production environment.
The required level of cleanliness of the product and the need to avoid contamination determines the packaging requested. Sterile products require sterile packaging and products manufactured in a cleanroom class, require the same cleanroom class for the packaging materials.
Sterile or non-sterile active pharmaceutical ingredients, drugs or vaccines are processed in an environment that requires enormous financial investment to both build and run. Cleaning, disinfecting, properties of surfaces, stainless steel devices or garments are all under surveillance with regards to their impact on the quality of the product. Often the packaging material is the last link of the chain and, thus, always under price pressures, no matter what the total amount that has been spent on the whole drug producing unit.
The FDA Center for Drug Evaluation and Research requires that the packaging is included in every New Drug Application, and it seems that there is a growing trend for FDA inspections of plants to be packaging-orientated.. It is worthwhile, therefore, to be prepared from the beginning to use a suitable packaging material that provides full protection for highly sensitive goods.