PRESS INFORMATION No. 04/2014 August 2014

Transcription

1 PRESS INFORMATION No. 04/2014 August 2014 Atris Information Systems GmbH. Kartaeuserstr. 49. D Freiburg Experience with System-supported Continued Process Verification by Peter Trochim Since January 2011 FDA demands in its recent guidance Continued Process Verification (CPV) for stage 3 (continuous routine process) of the life cycle. For FDA it takes over Traditional Process Validation (TPV) in three batches together with stage 2 Process Performance Qualification (PPQ). EMA still offers in its guideline on Process validation (February 27th 2014) besides Continuous Process Verification the opportunity for the three-batches-approach, which is to be repeated according to risk assessment. A combination between both approaches is according to EMA as well admitted (Hybrid Approach). The implementation of the Continued Process Verification represents an enormous challenge for pharmaceutical industry. Yet no standards for implementation and structuring are set. What is the data to be evaluated, and how do we obtain it in an appropriate manner? What statistics do we use for the different tasks of process validation? How might solutions look like? Can a database-supported system with statistical functions be such a solution? Is experience in implementation and use of database-supported systems consisting? Prospects for Process Validation Depending on the target-markets of drugs in future (i.e. in 3-5 years) either Performance Process Qualification / Continued Process Verification or Continuous Press Information No. 01/2015 Atris Information Systems Page 1/8

2 Process Verification / Traditional Process Verification / Hybrid Approach is expected. For bigger and globally established pharmaceutical companies the question is raised, whether FDA s CPV-Approach is generally to be approved, which is on a mediumand long term-basis the more efficient method of supporting continuous processimprovement. In the following CPV will be mentioned according to FDA s approach. Once data integration and tools involved are mastered, this method supports the organizational processes, effectiveness and cost reduction. In this way, for example, the elaborate quality and release controls can be reduced in scope. The process risk can be significantly reduced by continuous monitoring with statistical analyzes such as control charts by CPV. The role of Risk Analysis in Process Validation The decision about the method to choose in stage 3 is to be supported in any case by a risk-analysis in connection with already existing and documented processknowledge. This applies also to reflect the kind of statistical process evaluations appropriate and what the key CQA (Critical Quality Attributes) and CPP (Critical Process Parameters) are. It is ideally worked out already in phase 1 of the Process Validation (Process Design) by DoE (Design of Experiment). To isolate these attributes and parameters in the resulting data analysis and machine process data and to undergo a specific study is carried out in stage 2 (Introduction and qualification of productive processes) or stage 3. How are implemented the requirements of the CPV? The implementation of the CPV calls for the processing of the CQA and CPP in periodic data analysis. Depending on the amount of data this can be the traditional Annual Product Review or monitoring reports at shorter intervals (e.g. on a monthly or quarterly basis). Where ever possible Statistical analysis methods such as trending, control charts or CPK calculations should be used in data analyses. The data aggregation, as often used in practice, can be realized manually and consuming from LIMS systems and process data systems such as EBR (Electronic Batch Records) or PDA (Production Data Acquisition) product-wise and for temporary periods and summarized in Excel Sheets. The required evaluations could be generated with a standard program for statistical analysis based on the Excel data with great effort. Press Information No. 01/2015 Atris Information Systems Page 2/8

3 H4 PIT Trending: ASSAY HCTZ MW T _LOSGROESSE: 920 Gleitendes Mittel für N = 5 BAT CH No.: ASSAY HYDROCHLOROT HIAZID Mittel: ASSAY HYDROCHLOROT HIAZID letzte 15 T age(l) ABCD trochimp USL UCL NOM LCL LSL Machine Process Data Coater data Weighings Capsule filling machines etc. GECCO GEneriC COmmunicator Configurable web interfaces for supplemental batch entry SAP/R3 Order data Batch data API and raw material data Pharma-LIMS Systems SAP/QM QDIS/QM LabWare PANDA Process ANalysis DAtabase BDE- / OSI PI- Data Monitoring Error messages Alarms EBR Batch Records Production and process data collecting heterogeneous data output of structured information with detailed access management Batch Tree Complete batch tree in graphical interface Analysis results for CPP and CQA included control chart Defined Statistical Analyses, Trendings and Quality Reports on demand line plot histogram indices chi-squared table of values process capability box plot ASSAY [%] Data Mining Open Interfaces for Spotfire RapidMiner SPSS Modeler Oracle SQL Tools Figure 1: Data-integration, treatment and process analysis by means of database Requirements for a Database-supported System for CPV Based on years of experience with database-driven data analysis, the following requirements for such a system arose: Structured import, processing and provision of CQA and CPP Clear and unambiguous attribution (mapping) of the relevant data for later analysis (e.g. by means of a GUI for a product manager with the appropriate know-how) Formation of product groups for material comprehensive evaluations Definition of trend-types (parameters for statistical evaluation) Selection of appropriate charts and statistics by means of GUI Definition of reports and selection of report-templates by means of GUI Selection of evaluation variants (e.g. for different statistical perspectives) Direct generation of statistics and reports Combination of defined evaluations and reports Providing the selected and attributed data in appropriate grids (control of data, further analysis of the data, use for data mining, etc.) Protection of data between the product groups, departments, or locations Press Information No. 01/2015 Atris Information Systems Page 3/8

4 Cyclic and monitored data update of all information (e.g. on a daily basis) Validation of the system (e.g. according to GAMP 5) Application of a Computerized System for CPV The scope for a database-supported data analysis tool goes far beyond the creation of reports. Once the data is available in a structured and electronically processable form, it can be used for complex purposes. Besides in stage 3 (CPV), the system can also provide comprehensive services in stage 1 and 2, if data is already included in the source systems (LIMS and process data). Beyond that the system can support the implementation of processes and process qualification (stage 2). Least in this stage, the attributes (CQA), Parameters (CPP) and trend types with the respective evaluation methods (charts, statistics) should be defined. Figure 2: Screenshot and statistical evaluation Press Information No. 01/2015 Atris Information Systems Page 4/8

5 Is a global deployment of a system solution useful? CQA are generally obtained from the LIMS systems, whereas CPP are present in MES systems, in EBR or PDA. Despite the diverse and heterogeneous landscapes of systems used for data acquisition, the criteria to the data analyses, as experience shows, are almost identical. These are e.g. the following for the processing of data quality and obtaining the CQA from LIMS systems: Evaluation of analytical data of routine and stability tests. For the stability analysis, packaging information and storage conditions are to be taken into account Merging the same test points for evaluatable attributes with different information in the descriptive key- or data fields. Descriptions of test points vary frequently over time and across the lab boundaries (e.g. versions of the testing properties, etc.) Trending and evaluation of a drug over various final products (materials), which are different in packaging, quantity or target market. This makes sense, since these are mainly the same processes that produce the final products. As a result, the case number is increased for the statistics in favor of greater significance, which is realizable through the formation of product groups. Merging the analysis data from different LIMS systems for certain product groups. This is suitable for replacement of a LIMS system with the goal of seamless and clean evaluations for an APR (Annual Product Review) or production of a drug at different locations (data entered in different LIMS systems) Consideration and different processing (aggregation) of Multi Values (multiple readings per batch) and Single values (one value per batch) It is possible to solve these challenges systemically and at the same time benefit from the solution idea and experience at other locations. Also applies to CPP, that repetitive tasks can be automated: Extraction of data from machine-oriented systems Compression and aggregation of large amounts of data at defined time intervals and using appropriate methods Clear definition of the parameters to enable material and batch-related evaluations By a systemic and modular approach to build a system enormous resources saving can therefore be achieved in the implementation of the CPV. Press Information No. 01/2015 Atris Information Systems Page 5/8

6 How does the review process become a continuous routine process? Is a system for CPV available, that offers import, cleanup and aggregation of different source data of the different locations which allows integrating necessary process know-how through data mapping and determination of the CQA and CPP and allows configuration of the table views and statistics and reports, then transition from determination of first specifications for products or processes in stage 1 to CPV in stage 3 does not require great efforts any more. Data, parameters, as well as charts and reports are automatically made available after a systemically supported configuration. New programming and therefore additional costs for creating new evaluations for new products are no longer necessary. An exception is the integration of the data of new production machines or new source systems. What to do in order to introduce a system for CPV? The experience of the last few years teaches, that there are comprehensive turnkey solutions for a system for CPV. These solutions are with their opportunities for individual configurations by the user in terms of parameters, their evaluations and reports very well usable in pharmaceutical companies. After introduction with adjustments for new interfaces and requirements, the modular and scalable design of such systems allows flexible use. Press Information No. 01/2015 Atris Information Systems Page 6/8

7 Abbreviations: ICH International Conference on Harmonization CPV Continued Process Verification (FDA) or Continuous Process Verification (EMA) TPV Traditional Process Verification (3 Batches Method) APR Annual Product Review CQA Critical Quality Attributes CPP Critical Process Parameter Cp Process Capability Cpk Process Capability Index GUI Graphical User Interface (intuitive usability) PI Plant Information with Process and Production Data EBR Electronic Batch Records MES Manufacturing Execution Systems PDA Production Data Acquisition Press Information No. 01/2015 Atris Information Systems Page 7/8

8 Sources: Guidance for Industry, Process Validation: General Principles and Practices, FDA, January 2011 Guideline on process validation for finished products information and data to be in regulatory submissions, EMA, February 27 th 2014 Author: Peter Trochim Atris Information Systems Freiburg im Breisgau, GERMANY Press Information No. 01/2015 Atris Information Systems Page 8/8