◆ WHO publishes second Draft on the Revision of its Process Validation Guideline (08-Oct-14 ECA)
The second draft is considerably more stringent than the first one. The document is a bit of a mix of FDA’s Guidance on process validation and EMA’s process validation guideline where the terms used come from the FDA Guidance. Both documents are also listed under references. A few inconsistencies remain. The topics risk assessments, QRM, and risk-based approaches are seen in very different ways in the document. The chapter “background and scope” recommends a risk-based approach. Risk assessments are referred to as “should” requirements, QRM rather as “nice to have” (“when applying QRM…”). A flow diagram shouldn’t be only named as “may” requirement. Naming process validation under process design in the flow diagram for the process validation life-cycle (background/objective) is against the definition in the glossary according to which process validation include the whole life-cycle. Moreover, mentioning concurrent validation as an alternative to the life-cycle approach could be misunderstood.
It is astonishing that ICH Q10 hasn’t been referred to although some elements of this document (e.g. continuous improvement, product life cycle) have been used.
◆ New FDA Interim Guidance for Human Drug Compounding Outsourcing Facilities (08-Oct-14 ECA)
The FDA has recently announced that it will regulate this area in the future in accordance with the cGMP. Until appropriate regulations have been developed, the FDA has – in the meantime – expressed its expectations for this transitional period in a Guidance for Industry – Current Good Manufacturing Practice – Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act. This Guidance is based on the 21 CFR parts 210 and 211 with regard to cGMP. The FDA has tried to take into consideration the differences between industrial medicinal products manufacturing and compounding, and to adjust the specific aspects of the compounders. The FDA has announced that it will focus its inspections efforts to the points which present the highest danger for patient safety. One should thus not be surprised – also in view of the past incidents – that these efforts will particularly address the securing of sterility. Decidedly, the following topics are addressed:
One interesting thing is that the FDA itself isn’t quite sure about certain aspects, whether its requirements will be suitable for compounders. In the chapters “Components” and “Laboratory Controls”, an “Alternative Approach for Comment” is respectively presented in the Guidance to both topics “Reducing the Need for Laboratory Testing of Incoming Components” and “Minimize Need for Facilities to Have an In-House Laboratory”.
All in all, this is an interesting development, and most of all has been a necessary evolution in the regulation of compounders which comes a few years too late.
◆ Review of GMP deficiency data from January 2013 – December 2013 (15-Oct-14 MHRA)
MHRA published inspection trend data from 2013. The report includes longer term trends in ‘top 10 deficiencies’, and highlights areas for continued focus.
GMP Inspection Deficiencies 2013 says “Of 630 GMP inspections carried out in 2013, 216 (34%) resulted in Major or Critical Deficiencies.”
There are Example of Top 5 Defect Area Findings and the first example “Investigation of Anomalies” says there was no scope to define when or how planned deviations may be
used. This allowed such deviations to be used indefinitely.
◆ What are the EU GMP Requirements for the Validation of Excel Spreadsheets? (05-Nov-14 ECA)
Everyone uses Excel Spreadsheets. Also in pharmaceutical companies, Excel Spreadsheets are used in different departments. The easy to use calculations allow making calculations in a very convenient way. Yet, this can also represent a huge risk. In a pharmaceutical environment, computerized systems need to be validated. Spreadsheets also need to comply with a number of requirements. However, controls are quite often inadequate and this may result in a compliance risk.
When it comes to spreadsheets, what should be validated? A Q&A issued by EMA provides the following answer: “Validation according to paragraph 4 of annex 11 is required at least for spreadsheets that contain custom code (e.g. Visual Basic for applications). Formulas or other types of algorithm should be verified for correctness.” Therefore, appropriate controls for templates of spreadsheets must be in place. Erroneous calculations due to data remaining from previous calculations must be avoided. The templates should also be suitably checked for accuracy and reliability (annex 11 p7.1) and should be stored in a manner which ensures appropriate version control (chapter 4 p4.1).
When it comes to accuracy checks (as required in Annex 11 p 6), data integrity is an important issue. The Q&A document explains that both the files and the calculations should be secured in such a way that formulations are not accidentally overwritten. Accidental input of an inappropriate data type should be prevented or result in an error message.
◆ Mutual reliance between the United States Food and Drug Administration and the European Union on good-manufacturing-practice inspections (14-Nov-14 EMA)
On 14 and 17 November 2014, representatives of the United States Food and Drug Administration (FDA) are meeting with a cross-agency team from the European Medicines Agency (EMA), the European Commission and good-manufacturing-practice (GMP) experts from European Union (EU) Member States in order to make progress on mutual reliance between the FDA and EU on GMP inspections. Initiatives have been ongoing in this field for several years but there is now renewed momentum on this issue. Representatives of both teams have met several times in recent months, answered questions and exchanged information. This meeting is the first face-to-face meeting of both complete teams specifically organised on this topic. It is intended to clarify and align aspirations and goals, detailed scope and timelines as well as to continue the exchange of information, clarification and discussion on respective systems for supervision of manufacturers.
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