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GMP News No. 436
16 July 2004
Inspection FindingsRegarding Change Control
Documentation of changes – a matter ofcourse, but not done!
Not least because of the great number of official inspections, thetopic 'GMP-compliant documentation in pharmaceutical engineering' hasbecome the focus of attention. In this context, special focus has beenplaced above all on the topic of changes as well as the control of changesand their documentation.
Change control systems should be an integral part of the qualitymanagement system of each company. Their task and aim is to ensure thatall announced or requested changes are carefully checked and completelydocumented and authorised.
The first step in the handling of changes concerning engineering is toclassify them with regard to their GMP relevance. This should beaccompanied by a risk analysis. There is no guideline specifying themethods and documentation for doing this, and consequently every companyhas developed its own approach.
A frequent problem is the handling of changes in an ongoingqualification phase (e.g. during IQ or OQ). Here it is crucial thatequipment supplier and pharmaceutical manufacturer agree on the samechange control procedures and keep to them as well.
In connection with the change control of equipment, the question isoften asked which kind and scope of requalification are required.Sometimes it is even unclear whether requalification is necessary at allwhen one has a change control system and no critical changes have beenmade. Important factors for answering this question are preventivemaintenance, recalibration and statistical process control. Therefore,change control in pharmaceutical engineering is one of several methods toensure a continued validated status.
The official inspections mentioned above and their results show thatdocumentation in the field of engineering is mostly considered to be amatter of course; however, in the end it often turns out not to have beendealt with in a GMP-compliant way.
In the following you can see an excerpt from the originalquotations of warning letters issued in Fiscal Year 2003. Here someexamples for the topic 'Written Procedures; Deviations':
Changes to written procedures are not drafted, reviewed and approved bythe appropriate organizational unit and reviewed and approved by thequality control unit [21 CFR 211.100(a)] and [21 CFR 820.40(b)]. …
Deviations from written production and process control procedures arenot justified. [21 CFR 211.100(b)] and [21 CFR 820.100(a)(2)].Specifically, a deviation from the approved procedure … "SterileFiltration of Product" was not appropriately recorded and justified.The process was changed to include in each of the […]nozzles used in theaseptic filling of saline solution in room […] with no assessment of theimpact of the change on sterile finished products.
Failure to follow your procedure related to your Change Control Programas required by 21 CFR 211.100(a). For example, many instances werereported as lacking the required signatures prior to the implementation ofa change requested.
The inspection revealed inadequate process validation ofdrug manufacturing (as required by 21 CFR 211.100, 211.110(a), and211.110(b)), failure to follow Standard Operating Procedures forchange controls and process validation (as required by 21 CFR 211.100(b) and211.22(d)), ...
Specifications for the GMP-compliant documentation of changes can befound in Annex15 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....