When changing packaging, the first thing to consider is registration: the process of acquiring approval to market a product. This is a genuine challenge for every pharmaceutical manufacturer, but there are other more 'hidden' difficulties to be aware of.
What is packaging?
To understand the challenges in changing pharmaceutical packaging, we first will have a closer look at packaging. Packaging, from a handling perspective, is a means to protect products from deterioration during storage transport to and reception by the intended client, but also from outside influences like air, water vapour, micro-organisms and other contaminants. By using packaging, a product will also get a more uniform shape, making it easier to ship and store and, because it is covered, impossible to identify from the outside.
Registration of pharmaceuticals
Pharmaceutical products require registration. Registration is the process of acquiring approval to start introducing a product into a specific market. It is a detailed summary containing extensive information about: the active substance, the raw materials, batch sizes, equipment used, production parameters, the potency, clinical trial information, the packaging format and other relevant product specifications.
When looking in detail at the packaging section of a registration file, every pharmaceutical product bought at a pharmacy is registered in the format in which it is delivered: from the cardboard box and its print to the plastic type and shape of the primary packaging and the way it is produced. When it comes to registration, packaging and its design are dynamic. Changes to the container may influence important tests (such as a stability test), shelf life and other factors.
The registration file
Before making changes to a pharmaceutical or its packaging, the manufacturer needs to acquire approval from the relevant authority (this could be the FDA or another agency depending on the market that they wish to enter). The registration file is a dynamic document that can change during the life cycle of a pharmaceutical product. All changes, major or minor, to the production and presentation of a product need to be registered. The government of every country in which a product is marketed will only allow distribution after reviewing this file. All changes have to be documented and submitted separately per market. Submitting changes can also lead to audits with a strong focus on the involved product.
Effect on APIs
Manufacturers producing raw materials such as active pharmaceutical ingredients (APIs) also have to deal with registration. Any change made to an API can also affect a final product, so both registration files need to be updated. This includes changes to primary, secondary and/or tertiary packaging such as bags, drums, bulk containers and cardboard boxes.
Case study
As we explained before, there are more elements besides legislation that play a part in changing packaging. To uncover all possible aspects, we will discuss a business case of a fictional company that manufactures a very demanding (sterile) product.
The manufacturer in point uses approximately 100 small containers filled with 1kg of sterile active ingredients to formulate a batch. Adding the API to the formulation process is done manually: an operator empties the containers in a formulation vessel, which is placed in a sterile booth.
To improve this process and reduce manual handling, a new larger container is required that will allow the processing of the same amount of API with fewer manual interventions and less risk of contamination. The manufacturer therefore decides to increase the capacity tenfold resulting in a 10kg container and reduction of manual interventions from 100 to 10.
The API is registered, which means changing packaging will necessitate changing the registration file. If the registration file is included in the registration file of the final product (e.g. the lot sizes of raw material), that document will also have to be modified.
Stability testing
Another chapter of the registration file concerns stability testing: usually a representative sample is required for stability testing. In most cases a number of containers are kept aside (annually) for stability testing so there is no discussion about its representativeness. In our case, with the new container, 10kg would be a significant product loss (because this cannot be processed and thus sold), but a smaller sample size might not be representative. The API is sterilised after filling and sterilising a small and a large amount may have different results.
Logistics and processing
Change of dimensions and capacity can also influence the way a product is shipped and how it can be affected during transport, intermediate storage or handling (e.g. damage or decay).
There are two other activities in each process beside transport: formulation and processing.
All steps in the process need to re-considered. In our case, the process involves a lot of manual handling. The containers are moved between different areas using carts. Switching to a different capacity probably also means changing to carts that are more suitable for the handling of the larger containers.
During formulation, the containers are lifted manually. So what about Health & Safety or ergonomics? Lifting 1kg is considered safe and will not cause injury, but lifting 10kg from the ground to processing height is not a sustainable solution for routine operations. Our formulation area needs a mechanical lift to handle the containers. The lift (and possibly other tools) should be made of pharmaceutical grade stainless steel, which will increase the budget. A similar lift is needed in the processing area, where sterile conditions apply. And then there is the question of whether the current installation is suitable to be equipped with new tools.
This case shows that changing packaging can have a severe influence on all aspects of the production process and requires thorough analysis. To avoid high unexpected project costs, a multi-disciplinary impact assessment has to be performed on the product flow during the concept phase, in which a packaging developer or manufacturer should be involved in the earliest possible stage.
The authors
Kin Chun Cheung is a QbD consultant with affinity to validation and engineering and has an extensive experience with big and smaller pharmaceutical/biotech firms from plant design and built to equipment modifications.
Dominiek Rossillion is a QbD consultant with experience in product/packaging component qualification, validation and cGMP regulations at companies like Pfizer and Schering-Plough.
John Nuyens is QbD consultant with strong experience in QA and compliance he gained his experience with big references like J&J, Pfizer and Genzyme.
All participants are involved in different projects and training programmes internally for the pharmaceutical QbD consultants and externally for clients.
