GMP News No. 436
16 July 2004
Regarding Change Control
Documentation of changes a matter of
course, but not done!
Not least because of the great number of official inspections, the topic 'GMP-compliant documentation in pharmaceutical engineering' has become the focus of attention. In this context, special focus has been placed above all on the topic of changes as well as the control of changes and their documentation.
Change control systems should be an integral part of the quality management system of each company. Their task and aim is to ensure that all announced or requested changes are carefully checked and completely documented and authorised.
The first step in the handling of changes concerning engineering is to classify them with regard to their GMP relevance. This should be accompanied by a risk analysis. There is no guideline specifying the methods and documentation for doing this, and consequently every company has developed its own approach.
A frequent problem is the handling of changes in an ongoing qualification phase (e.g. during IQ or OQ). Here it is crucial that equipment supplier and pharmaceutical manufacturer agree on the same change control procedures and keep to them as well.
In connection with the change control of equipment, the question is often asked which kind and scope of requalification are required. Sometimes it is even unclear whether requalification is necessary at all when one has a change control system and no critical changes have been made. Important factors for answering this question are preventive maintenance, recalibration and statistical process control. Therefore, change control in pharmaceutical engineering is one of several methods to ensure a continued validated status.
The official inspections mentioned above and their results show that documentation in the field of engineering is mostly considered to be a matter of course; however, in the end it often turns out not to have been dealt with in a GMP-compliant way.
In the following you can see an excerpt from the original quotations of warning letters issued in Fiscal Year 2003. Here some examples for the topic 'Written Procedures; Deviations':
Changes to written procedures are not drafted, reviewed and approved by the appropriate organizational unit and reviewed and approved by the quality control unit [21 CFR 211.100(a)] and [21 CFR 820.40(b)].
Deviations from written production and process control procedures are not justified. [21 CFR 211.100(b)] and [21 CFR 820.100(a)(2)]. Specifically, a deviation from the approved procedure "Sterile Filtration of Product" was not appropriately recorded and justified. The process was changed to include in each of the [ ]nozzles used in the aseptic filling of saline solution in room [ ] with no assessment of the impact of the change on sterile finished products.
Failure to follow your procedure related to your Change Control Program as required by 21 CFR 211.100(a). For example, many instances were reported as lacking the required signatures prior to the implementation of a change requested.
The inspection revealed inadequate process validation of drug manufacturing (as required by 21 CFR 211.100, 211.110(a), and 211.110(b)), failure to follow Standard Operating Procedures for change controls and process validation (as required by 21 CFR 211.100(b) and 211.22(d)), ...
Specifications for the GMP-compliant documentation of changes can be found in Annex 15 to the EU GMP Guide.
The Annex includes the following passage:
... All changes that may affect product quality or reproducibility of the process should be formally requested, documented and accepted. The likely impact of the change of facilities, systems and equipment on the product should be evaluated, including risk analysis.
A change control system should be built up
with the active participation of the Quality Assurance Unit. For this
reason, the topic of change control is part of the GMP Education Course
and FDA Compliance in Quality Assurance Units" in Milan from 6-8
Changes in API production are probably among the most difficult challenges. Therefore, several lectures are dedicated to this topic on 22 October:
Please click here if you would like to read more about the European API Conference.