Out Of Specification Research Articles

Analysis of clinical safety for Shenmai injection based on literature

To analyze the literature about clinical safety of Shenmai injection and know the adverse reaction characteristics of Shenmai injection. Many kinds of information are analyzed. The basic information includes sex, age and disease of patients. The drug information includes dosage and solvent. The time of adverse reaction and symptom is also analyzed. The patients' age between 41 and 50 is the most. The adverse reaction happens more on patients with the disease of tumor and out of specification. All the solvent and dosage can cause adverse reaction. Immediate anaphylactic reaction within 30 minutes is the main type and anaphylactic shock is the most. The occurrence of adverse reaction of Shenmai injection is closely related to production quality of drug, rational drug use in clinical and individual factors of patients. Conclusion is demanded for clinician to ensure the safe medication.

Nonclinical Dose Formulation: Out of Specification Investigations

Nonclinical safety studies are required to follow applicable Good Laboratory Practice (GLP) regulations. Nonclinical dose formulations are required to be analyzed to confirm the analyte concentration, homogeneity, and stability. Analytical samples that fall outside of the acceptance criteria are considered out of specification (OOS), and an investigation should be conducted. The US FDA has issued a guidance document for GMP studies on conducting OOS investigations. However, no regulatory guidance has been issued regarding nonclinical safety study (GLP) OOS investigations, which often vary in regard to content, assessment, and impact statements. There is opportunity to improve the quality of OOS investigations by defining expectations and providing guidance in several areas including root cause assessment, impact statements, and acceptable paths forward. This paper will provide recommendations of best practices for nonclinical dose formulation OOS investigations.

Purity, Potency and Safety: Quality Management Reports (QMR) as the Basis for An Effective Continuous Process Improvement System in An Academic Gene Therapy Program.

Abstract 1417Poster Board I-440Gene-modified cellular products (GMCP) hold great promise for the management of numerous disease indications but are considered high-risk biological agents and are derived through extremely complex design and manufacturing processes. Thus, a robust Quality Management System (QMS) is essential for safe production of GMCP for clinical investigation. Development of a QMS that ensures compliance with current Good Manufacturing Practices (cGMP) and current Good Tissue Practices (cGTP) is particularly challenging in an academic setting where basic researchers, clinical investigators, regulatory, administrative, facilities and manufacturing personnel are all involved in the realization of a single GMCP. Following an ISO9001-based gap analysis of the Cellular Therapeutics program at the City of Hope, we implemented Quality Management Reports (QMR) as a tool for capturing data related to GMCP manufacturing. The QMR system was used to document and facilitate corrective and preventative actions (CAPA) as required following protocol deviation and/or Out of Specification (OOS) analyses. QMR data is captured in real-time and includes a detailed description of the event, impact analysis, root cause investigation, action plan and effectiveness analysis for resulting interventions. QMRs are documented using the Labware® (Wilmington, DE) Laboratory Information Management System (LIMS) that is available in real-time to authorized participants in GMCP production. A key aspect in the development of this on-line system was creation of links between the QMRs, OOS and CAPA documentation and investigation. The investigation database contains a series of templates: CAPA, SOP deviations, OOS and QMR that are designed to fully capture any events that impact or have the potential to impact quality, safety or efficient realization of a GMCP. The QMR process was applied to 2 manufacturing campaigns: a lentiviral vector-transfected CD34 GMCP for autologous transplantation in patients with AIDS lymphoma and a Master Cell Bank that was created for the treatment of patients with recurrent Glioblastoma Multiforme based upon an oligoclonal allogeneic T-cell product that contained both a chimeric antigen T-cell receptor and a zinc finger disrupted glucocorticoid receptor genomic sequence. Between May 2008-June 2009, 22 QMRs were generated related to product/reagent transfer, reagent quality/storage, equipment malfunction/OOS, product/environmental sterility, biological reagent OOS and Quality Control specifications for product release. Seventeen of 22 QMRs were resolved and closed. The average time to closing a QMR was 82 days (range 4-198 days). QMR findings lead to a revision of the program organizational chart, lead to the development and implementation of a new standard operating procedure (SOP) for Root Cause Analysis (RCA) investigations, development of new forms (GMP Equipment Approval Forms, a Quality Systems Project Proposal Form and Quality Assurance Customer Satisfactions Survey Forms), revisions to the SOP for CAPA and retraining of manufacturing staff as part of the resultant CAPA investigations to prevent repeat occurrences. Based upon QMR findings, 2 multidisciplinary RCAs were performed and resulted in revisions to documentation for CD34-cell selection and a major revision to the use of RODI water and manufacturing flow during GMCP production campaigns. Only 1 of 22 QMR-captured events has recurred (failure of an equipment monitoring system) and no events have re-occurred that might have had an impact upon product quality or safety. User satisfaction surveys performed by QA following the completion of a multidisciplinary RCA investigation indicate that the QMR process was viewed as fair, unbiased and transparent by a majority of the users (86% were either “Extremely Satisfied” or “Satisfied” with the experience). The QMR process is a powerful tool for the safe realization of GMCP and allows for real-time capture and multidisciplinary communication of complex events, including OOS that either individually or in aggregate may impact the purity, potency or safety of manufactured GMCP. These are often events that would not be routinely captured either as part of a batch record or merit CAPA. Because effectiveness analysis is included as part of the QMR process, it provides a key mechanism for continuous process improvement. Disclosures:Alvarnas: Novartis: Speakers Bureau.

Validation in pharmaceutical analysis: Part II: central importance of precision to establish acceptance criteria and for verifying and improving the quality of analytical data

Validation of analytical procedures is a vital aspect not just for regulatory purposes, but also for their efficient and reliable long-term application. In order to address the performance of the analytical procedure adequately, the analyst is responsible to identify the relevant parameters, to design the experimental validation studies accordingly and to define appropriate acceptance criteria. Establishing an acceptable analytical variability for the given application is of central importance as many other acceptance criteria can be derived from such a precision. Acceptable precision ranges for types of control tests and/or analytes can be obtained from validation, but also related activities such as transfer, control charts, or extracted from routine applications such as batch release or stability studies (data mining). Apart from compiling a database for general benchmarking, during such an information-building process, the reliability of the analytical variability of the specific procedure is more and more increased. This is important as a reliable target variability facilitates to detect or investigate atypical or out-of specification behaviour of analytical data in a routine application, thus improving the data quality and reliability. According to the life-cycle concept of validation, measures should be taken to maintain and control the validated status of analytical procedures during long-term routine application, such as monitoring relevant performance parameters (system suitability tests), control charts, etc. If the analytical system is demonstrated to be stable, i.e. under statistical control, a major variability contribution in LC originating from the standard preparation and analysis can be reduced. A concept of quantification by pre-determined calibration parameters instead of the classical approach of simultaneous calibration is described.

Outlier Tests and Chemical Assays

In a recent landmark decision resulting from a trial involving the Federal Government and Barr Laboratories, Judge Wolin made many judgments based on his constant probing and the testimony of expert witnesses (1). Remarkably, most of what he had to say was clear, correct and to the point, despite his sparse background in the subject material. Much of the Decision related to testing drug products during their production when failing results (out of specification) were observed. A summary of the Decision is available from the FDA (2). A previous paper by this author (3) presented some alternatives to retesting when a single out of specification result was observed for which no obvious cause was apparent, a situation which is common in my experience. This paper discusses some issues related to the elimination of an out of specification (00s) result with no obvious cause, based on an outlier test. The Judge, in his Decision, stated that tests for outliers which can be used to exclude an aberrant observation are not appropriate for chemical tests. His reasoning was that the USP includes tests for outliers, but presents these tests only in the context of biological assays, which tend to be very variable. This, he suggests, is appropriate because of the large variability of these kinus of procedures. Judge Wolin further suggests in his Decision that such

Synthetic Fabrics as Soil Filters: A Review

The fundamentals of fabric filters, their uses, design, longevity, strength requirements, and testing are reviewed and discussed. For unidirectional laminar flow conditions, particle retention and permeability criteria for fabric filters are well established. All the approaches currently adopted tend to give similar answers and are dependent on the fabric being the `catalyst' in the formation of a `self-induced' filter within the retained soil. When problems occur in practice, it is normally due to clogging of the filter, i.e. the fabric is too fine. Thin fabrics appear most suited for this use. For severe hydrodonamic and reversing flow conditions, the self-induced' filler will not form, and design criteria are not so well established or accepted. Thicker fabrics offer a more tortuous path to the migration of particles and are thus more suited than thin fabrics. However, thin fabrics have successfully been used in conjunction with (out of specification) granular filters.