Somerset House Consultants
Category: Product Quality
The incentive for this change came from a number of high-profile inspection failures and product recalls. Inspectors found that, over time, modifications had been made to manufacturing or testing procedures, specifications, equipment etc, which had not been incorporated into the regulatory approvals for the products.
The final version of the guideline was published in October 2005, and came into effect on 1 January this year. Medicines Inspectors will be looking for evidence that these reviews are being carried out and properly documented. Failure to do so will be highlighted as a deficiency in the inspection report, and could lead to action against the company and their Qualified Persons.
Companies that supply products to the USA will be used to providing Annual Product Reviews in the FDA format. The information required in the EU Product Quality Review is slightly different, so a separate document will be needed. The FDA review is intended to confirm that every batch of product released during the review period complied with the registered process and specification. The EU review concentrates on the quality systems and processes, to show that they continue to produce consistently good quality product. Inspectors will not expect to see reams of raw data, but the results of the analysis of these data and the implementation of appropriate process improvements.
The Product Quality Review can be used as part of a continuous improvement quality system to highlight where development resource can most effectively be targeted. It can:
- Decrease the risk of out-of-specification results
- Minimise the risk of rework/reprocessing
- Decrease downtime
- Increase productivity
- Decrease the risk of product recalls
- Meet all regulatory commitments/requirements
- Improve communication between production, engineering, quality and regulatory functions
The last point can be very important when activities such as production, distribution, stability testing or regulatory affairs are outsourced to other companies.
If the product is contract manufactured on behalf of the Marketing Authorisation holder, the Product Quality Review needs to be a joint activity between the MA holder and the manufacturer. In addition, the Qualified Person at the manufacturer must assess the final review document, to satisfy themselves that the process is in control, and that they can release batches for sale. This will require Technical Agreements detailing which company will be responsible for each aspect of the review, and the procedure for analysing data and producing the final document.
The review should cover the following:
Starting materials and packaging materials
Are they still being supplied by the source specified in the Marketing Authorisation? Has the specification changed, and is it appropriate to ensure the quality of the final product? Have the suppliers of active ingredients been audited to ensure that they comply with GMP? Have there been any problems with the suppliers, eg rejections of incoming batches?
Critical in-process controls and finished product results
Are these still the same as the ones in the Marketing Authorisation? Do the controls ensure that the finished product is of suitable quality? Are all test methods validated according to current standards?
How many batches were rejected during the review period? What investigations were carried out at the time? Were there any trends or similarities about the failures? Have any process changes been made to prevent recurrence?
Deviations and non-conformances
How many have occurred during the review period? What investigations were carried out, and what corrective and preventative actions were introduced to prevent recurrence? Were these actions effective? Was the Marketing Authorisation varied?
Changes to processes or analytical methods
Have these changes been properly authorised and validated? Has the Marketing Authorisation been varied to incorporate them? Have new or modified equipment or procedures been introduced that will require revalidation?
Marketing Authorisation variations submitted during the review period
This includes not only those that were granted, but also those refused, and those for third country (export only) dossiers. Does the Marketing Authorisation correctly reflect the manufacture and testing of the product? Why were variations refused; is more data needed?
Stability testing results
What are the results from routine stability testing of production batches? Do they still demonstrate that the product will meet the shelf-life given in the Marketing Authorisation? Are any adverse trends becoming apparent? (This may require additional statistical analysis of the results from all stability trials on the product). Are the tests and methods still appropriate for assessing the stability of the product? Do any changes to starting materials or processing methods mean that a full stability trial should be repeated?
Returns, complaints and recalls
How many of these have occurred during the review period? Were they adequately investigated, and what changes were implemented to prevent recurrence? Were these changes effective? Are there any trends to the complaints?
Adequacy of previous process or equipment corrective actions
Corrective and preventative action (CAPA) programmes will have been instituted to resolve problems arising during the review period, but did they fully achieve this? The Product Quality Review is a good time to confirm that CAPA programmes were appropriate, or to introduce further changes.
Post marketing commitments
Regulatory authorities often approve Marketing Authorisations provided that the MA holder commits to provide further information when available (eg samples of finished packs, ongoing stability data etc.). These are sometimes forgotten in the push to get a new product marketed and distributed. The Product Quality Review is a good time to confirm that these commitments have been fulfilled.
Qualification status of relevant equipment and utilities
Are utility systems such as HVAC, water or compressed gases still working appropriately? Have ongoing testing or monitoring results been reviewed for trends or failures? What investigations were carried out and were any corrective actions effective? Have any changes been made to these systems, and was requalification carried out?
Are there Technical Agreements with all suppliers and contractors, and are they up to date? Do they adequately reflect the activities and responsibilities of each party, and meet the requirements of the GMP guidelines?
Unlike the FDA Annual Product Review, there is no defined format for the completed report. The company is able to choose the format that is most appropriate for the product and the quality system.
Companies will need to establish where the information is currently held, and set up procedures and agreements to obtain it. While the final document must be assessed and signed off by the Qualified Person and the Marketing Authorisation holder, it would be acceptable to outsource the assembly and review of the raw data to an expert consultant.
Medicines Inspectors will be expecting to see the first Product Quality Review Reports, for a minimum review period of at least six months, during their inspections in 2006. Subsequent reports should cover the full twelve months review period.
It will require a significant resource to assemble, collate and review all of these data, but the cost savings from reduced batch failures and improved regulatory compliance should outweigh the cost of producing these reviews.