Following the discussion in Part 1, which covered Pharmaceutical Packaging – Quality by Design, this part will look into Procedures, which is also a Critical Design Element (CDE) besides Equipment and Facility. Without procedures, the ‘State of Control’ is impossible to achieve. For instance, equipment will not be maintained in the ‘qualified status’. As another example, material and personnel flow through the facility layout is designed to achieve a unidirectional flow. If the procedure is not in place, or the procedure is not fully executed, then the flow is not necessarily guaranteed.
Operations
Built on the foundation of equipment and facility, operations consist of two critical aspects – Process and Procedure.
The process should adequately consider Control and Monitoring, including online monitoring as well as In Process Control (IPC) based on Risk Assessment. For an automated packaging line, it’s a critical input to equipment design. If the monitoring sensors or IPS station is omitted at the beginning, it would be rather difficult to correct, once the equipment is built.
Procedures shall be established around the process, equipment and facility. Specifically for packaging operations, line clearance and batch reconciliation could be much more tedious than a bio Drug Substance (DS) operation, considering the number of units, and the quantity and types of various packaging materials involved. A careful examination of the area and equipment shall be conducted to ascertain the line clearance prior to the start of the operation. The 5S principle (Sort, Set in Order, Shine, Standardize and Sustain) seems extremely relevant for the packaging operation – only when things are in order, errors will be reduced. Also, the LEAN approach – the more complex the system or procedure is, the easier it is for human mistakes to occur.
Precautions should be observed for certain packaging lines with both the IPC Station and Reject Station. The units from these two stations should be carefully managed (registered and reconciled) to ensure there is no mix-up. Also, the IPC units and rejected units are managed to prevent their mix up with the normal units.
It is a regulatory requirement that for each product, pack size and type, approved Packaging Instructions shall exist. These will either include the critical information, i.e. product pharmaceutical form and strength, all packaging materials, packaging operation description and IPC details etc. or bear a reference.
Assure quality throughout the lifetime
If the criteria discussed earlier are fulfilled, then quality should have been built into the product. Now it’s left to the Quality Control Unit to confirm that the desired quality has been achieved against pre-defined specifications (of the raw material, intermediate and finished product). On the contrary, if quality wasn’t built into those elements, then regardless of how many QC checks are performed, the quality of the end product will not be achieved. As mentioned in Part-1, quality should not be assured by testing, but be built into the design – to begin with the end in mind.
The analysis methods shall be sufficiently verified or validated for the specific product and on a specific site, using qualified QC lab equipment. As the data generated from the analysis testing is critical for releasing the product to patients, Data Integrity is crucial for QC testing. Data is actually the only thing QC provides. Procedures shall be in place to ensure that all test results are registered and managed, any OOS/OOT shall be investigated.
The testing results shall be reviewed with ‘metadata’ rather than isolated test results from a certain lab instrument. Metadata describes the structure, data elements, inter-relationships and other characteristics associated with the data. An example of metadata may include the time/date stamp of the activity, the operator ID, the instrument ID, processing parameters, sequence files, audit trails and other data required to understand data and reconstruct activities. This will allow the reviewer to understand the full ‘content and meaning’ of the testing results.
The QC test starts from the raw material, through the entire manufacturing process and will be extended to the whole product shelf life – the ongoing stability programme. The product quality shall also be monitored through the Annual Product Quality Review and the Complaints and Recall process.
Distribution
When the product is out of the manufacturing facility, it is not the end of the journey yet. The whole supply chain needs to be monitored to assure the quality of the product when it reaches the patients.
The Guidance on Good Distribution Practice laid out the requirements or expectations with similar principles of GMP, i.e. there shall be an effective quality system, personnel shall be trained and qualified, the validation programme shall be established and maintained as an ongoing process, and data integrity shall be assured. Every party in the supply chain must understand their responsibilities and the risks to product quality, and thus, to patient safety. Imagine – the drug manufacturers spent all their efforts producing bio injectables with perfect quality, however, the distributor failed to maintain the storage temperature, or worse, failed to recognize the failure of temperature control. The patient’s life could be put on the line.
If the distribution is outsourced to a third party, it is important that the manufacturer perform an adequate assessment and audit of the third party, and establish a Quality Agreement.
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With 15 years of experience in the global pharmaceutical industry, predominantly in Process, CQV, Process Automation and Project Management, Shanshan has held both Consultant and End User roles. With increasing involvement in the GMP remediation and GMP audit projects, she has been building in-depth compliance knowledge as well as interaction with authorities globally.
