Past Projects

After receiving an FDA Warning Letter, a well-known pharmaceutical company requested from Synergy to get involved in the remediation of their warning letter. Part of the warning letter remediation efforts was related to several thousands of product manufacturing Batch Records reviews. We started the work by verifying the calibration records, NCRs/Deviations, OOS investigations, and the in-process data. Based on our review process, we presented our conclusions and recommendations to the executive management. Our recommendations were instrumental in highlighting the need to establish a mechanism to separate between their R&D and the QC laboratory activities and building a new and separate R&D laboratory, as this lied at the heart of the root cause behind the warning letter. Our success in this project was a factor in having the management extend the scope of the project for Synergy.

In the second phase of the project, Synergy team of chemists, scientists, and a regulatory compliance specialist performed Analytical Method Transfer Gap Assessment for 137 analytical methods. The outcome of the gap assessment was a determination that the methods were not properly validated according to approved protocols or compendial specifications. So, Synergy embarked on a collaborative effort to optimize these test methods using chromatographic and spectrometric techniques, by writing and executing the validation protocols for those methods that don’t have a proof of validation documentation. These analytical methods included HPLC, LC-MS/MS, GC, GC-MS, ICP-MS, TOC, among many others. Writing the validation protocols, Work Instructions, executing the validation and transferring these test methods to the QC laboratories took 3 years.

A CRO/CMO pharmaceutical start up requested from Synergy to help with the set up and initial operation of their chemistry laboratory to support in the development and manufacturing of generic drug products. We started our collaboration effort by commissioning and qualifying the needed analytical instruments (HPLC, GC, TOC, etc.) and their related LIM System Software (Agilent OpenLab Software) as well as providing training and mentoring to the technical staff. Then, we worked on establishing the development strategy for the first three generic drug products the company wanted to start with. After that, we worked on developing the formulation study for the first drug product. During the formulation development, a dissolution variation problem caused by a complex relationship between process variables and raw material properties presented itself. Using the concept of Design of Experiment (DOE), we were able to identify key interactions between raw materials and process variables. This effort helped us identify the need to tighten raw material specifications to establish a bio equivalency between the generic formulation and the brand name drug product formulation.

In parallel with these activities, our scientists worked with the client’s technical team on developing and validating analytical methods for the drug products, establishing their Stability Indicating Studies, performing dissolution studies, as well as identified and quantified degradation components and profiling any residual solvents of the drug substances. Then, we developed and validated an analytical method for identifying and quantifying class III residual solvents and calculated the DPE limits for each solvent. The work for the first drug product was completed successfully and on time and was approved by the FDA. The client still has an ongoing relationship with Synergy, and we are still involved in drug development activities for them.

As part of their cGMP facility operation readiness, a client of ours requested that we develop and validate a cleaning validation program to support their development and manufacturing activities of drug products that are in their late development stages. Using the Design of Experiment (DOE), we started by developing a master validation plan for sterilized processes (aseptic processing). After that, we developed the cleaning validation process map, the characterization of the residuals of drug products. Then, we performed the recovery studies and authored the cleaning process SOP and the validation protocols, followed by providing training to the client’s technical staff on how to ensure successful completion of the protocols. Then, we monitored their performance while executing the protocols to ensure compliance with the established procedures.

Using Synergy’s in-house state of the art analytical capabilities, we performed the TOC analysis of the collected samples, analyzed and tabulated the results of rinse and swab sampling, and then wrote the summary report of the cleaning validation study, so it can be included in the CMC section of the drug filing applications. From start to finish, the project took only 4 months. This is a record time to complete a project of this nature in such a short amount of time. It is also a clear testimony that relying on professionals who have the expertise and the technical know-how can save you time and money and protect your business from regulatory noncompliance risk.

A biopharmaceutical company requested from Synergy to work with their engineering department and help in the optimization and revalidation of their manufacturing process of a therapeutic protein drug product. To integrate the upstream process with the downstream one, we did a re-validation of the downstream process of a monoclonal antibody and performed chromatographic HPLC analysis for samples from different phases such as biomass product separation, product purification, concentration, crystallization, drying and fill-finish among other activities. Along with this effort, there were concurrent effort for optimizing and re-validating the chromatographic testing methods for identification and quantitation of the therapeutic protein molecule in biological samples. After revalidating these methods, they proved to be specific, accurate, and precise and were used throughout the entire processing program. In addition, we got involved in the development and validation of a therapeutic protein lyophilization (freeze-dry) study for another product, by establishing and optimizing the lyophilization parameters (shelf temperature, chamber pressure, drying times, and end point). This study served as a precursor of process development and validation for the commercial processing.

Concurrent with this effort, Synergy’s team was involved in the optimization of the Quality Management System (QMS), providing GMP training, compiling the Biologic License Application which included sections for Establishment Description, Safety/Purity/Potency, Chemistry (CMC), Summary Report, and preparing the facility for FDA Pre-Approval Inspection. Along the line with these activities, our team of consultants were involved in the assessment and remediation of a manufacturing processes and its related quality system, as per 21 CFR 211 and 21 CFR 610 regulations, of a biopharmaceutical company manufacturing drug product. We were also able to provide practical solutions to mitigate and optimize the following processes: Producess and Production Controls for aseptic manufacturing, which included Packaging and Labeling Controls, Master production record, Validation protocols/reports, manufacturing equipment qualifications (IQ/OQ/PQ), and manufacturing process validation. The team’s efforts helped in the reduction of manufacturing related deviations, OOS, and CAPAs, which led to the improvement of the process outcome from about the 3 Sigma level to the needed 6 Sigma level. Also, we were able to reduce the time required for the required biannual verification of the manufacturing process validation from over 4700 hours to less than 2500 hours. The company passed the FDA inspection with no audit findings and shipped the first shipment valued at over $68M.

A medical device company, developer and manufacturer of implantable class III medical devices, hired us to help in one of their cGMP facilities transfer. The project scope included the transfer of the manufacturing equipment and their related processes such as real-time control/manufacturing automation systems. Our team started the qualification process of newly designed ISO Class 7 cleanroom suite by performing the validation studies for the cleanroom (as built, at rest, and operational) as well as their related utilities, and rewriting and implementing the equipment re-qualification protocols (IQ/OQ/PQ) for equipment/processes as well as re-writing SOPs for three lines of manufacturing (37 pieces of equipment) and completing the technical summary reports.

As part of the project execution, there were numerous software platforms that required validation and testing as part of developing and executing system life cycle deliverables (URS, SRS, FRS, DDS, RTM, Unit Integration, User Acceptance testing, Delta V, FAT, SAT, Validation Planning, IQ, OQ, PQ, Final Validation Summary Report) as per 21 CFR Part 11 and provided training and mentoring to the technical staff. Getting this project done on time was not only critical for the client to bring the entire transfer project back on schedule but to bring the product inventory level to a safe one as well.

A well-known biotechnology company requested from Synergy to review and improve their Supplier Quality Management system. The review process led to recommendations for the need to implement significant number of improvements and the need to revalidate their Supplier Quality software (Master Control). Then, we were asked to develop and execute a plan to perform audits to their large and diversified network of suppliers. A total of 53 supplier audits for their supply chain were performed in less than a year. The outcome of these audits resulted in numerous audit observations, some of them were critical. To close the audit reports, these observations required to be addressed first but some of the suppliers were resisting any changes. Our effort resulted in successfully persuading these suppliers to address these compliance issues which were overlooked during previous audits. Initially, the suppliers were reluctant to address them because they were supplying other companies and their clients never raised any issue with their products.

A well know medical devices company was under Consent Decree and in desperate need of special expertise to help them get out of it sooner so they can resume their business. So, they contacted Synergy and we dispatched 22 of our consultants to expedite their remediation effort. Several of their business processes had compliance issues and we were asked to start with the Corrective Action/Preventive Action (CAPA) process. The initial review showed the need to overhaul the entire CAPA process, build a new one, and provide extensive training to the entire organization as part of organization cultural change, which we were successful in doing. Then, we started clearing of a very large backlog of open CAPA records, some of them were as old as 3 years back. As part of this effort, we had to validate the EtQ software platform and mentor the CAPA investigators on how to properly investigate for identifying and confirming root causes, using the quality risk management as the basis for their investigation. Furthermore, optimizing the CAPA process and clearing the backlog exposed other processes that needed our immediate attention as well, such as product complaint handling and manufacturing process nonconformance investigations. To ensure sustainable compliance of the company’s quality system, we had to improve the internal audit program of the organization and mentor the company’s internal auditors while performing their internal audits. Then, we moved to prepare the company for the next FDA recertification inspection. Our effort helped the company get out of their consent decree after only 19 months from our involvement date.