A new FDA revised guidance targeted towards drug manufacturers submitting quality metrics data to the Agency aims to improve the data collection and management process in the pharmaceutical industry. Amongst the requirements is a condition related to stability testing which states that invalidated Out Of Specification (OOS) rates should be included in the quality metrics submission for finished drug products and APIs, as well as long-term stability test results. This includes stability test results that indicate OOS, even if the OOS source was an anomaly in the measurement process. Stability testing is a vital component in drug manufacturing and LIMS are commonly used to record and report stability data. However, there is a niche market for stability testing LIMS, which can help streamline the stability testing process and help labs save time and reduce costs, while still conforming to FDA guidelines. Companies such as Autoscribe Informatics and LabVantage offer stability test solutions that improve the efficiency of stability test projects and comply with the revised FDA draft guidelines.

In January, the FDA released an updated revised draft guidance based on the feedback received about the previous November 2016 guidance. The guidance, which is for finished drugs and the manufacturing of APIs, entails a voluntary rollout of metrics submissions related to manufacturing, compounding or processing a finished drug or an API used in a finished drug, starting January 2018. Though submission of quality metrics is not mandatory, the FDA encouraged all drug manufacturers to submit data to improve the industry and quality of drugs, as well as to create a more streamlined, reliable process in which data can be easily accessed and examined.

The problem of drug companies falsifying and mishandling data is a worldwide issue that can directly affect the revenues and reputation of the company involved.

In April 2013, the FDA had implemented the Quality Metrics Initiative, which encouraged pharmaceutical companies to record and report data based on manufacturing quality. Quality metrics are defined by the FDA as data that are “used throughout the drugs and biologics industry to monitor quality control systems and processes and drive continuous improvement efforts in drug manufacturing.” The FDA published a revised draft guidance in July 2015 for “Submission of Quality Metrics Data,” in which drug manufacturing companies could voluntarily submit quality metrics data to the FDA to help the Agency improve its quality metrics reporting program. Drug manufacturers were able to submit comments to increase the efficacy of the quality metrics reporting, which led to the FDA’s further revised draft guidance in November 2016.

The problem of drug companies falsifying and mishandling data is a worldwide issue that can directly affect the revenues and reputation of the company involved. Just earlier this month, the FDA sent warning letters to two pharmaceutical companies in Asia, USV in Daman, India, and Jinan Jinda in Zhangqiu City, China, regarding violations related to data integrity and manufacturing that were unearthed thanks to FDA inspections in 2016. Also this month, in the US, Illinois-based Morton Grove Pharmaceuticals was warned about data integrity violations and issues with quality control.

The Importance of Stability Testing

With the FDA cracking down on mishandled quality metrics at pharmaceutical companies, it is important for drug manufacturers to have a system in place that ensures the proper collection and submission of quality data. An important component of assessing drug quality is stability testing, for which the FDA revised the cGMP for Finished Pharmaceuticals in April 2016. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) also has a guideline, emphasizing stability testing as a vital part of quality drug manufacturing.

Stability testing is important for determining the stability of a finished drug, which is done through testing numerous samples in varying environments. This test helps manufacturers assess the shelf-life and expiration date of the product. The FDA requires stability data pertaining to storage conditions of the samples, listing the specific test methods used, testing the product in the same container it is to be marketed in, and ensuring that if a manufacturer used accelerated studies instead of long-term studies to determine a tentative expiration date, the product must be tested for stability at various intervals to prove the provisional expiration date is valid.

For each stability study, products are defined into batches or lots. As Tim Daniels, marketing manager at Autoscribe Informatics, explained to IBO, “By testing each batch or lot, manufacturers determine the initial quality of the product and the shelf-life (deterioration over time) of the product.” He continued, “Typically, enough sample product for each lot is put into storage to cover expected needs during testing.”

While stability testing data can be entered manually into a LIMS, using a LIMS made specifically for the pharmaceutical industry and stability testing in particular can greatly help labs ensure accuracy of data and compliance with FDA guidelines.

Purpose-built LIMS for Pharma

A LIMS is a valuable tool in recording and managing data for quality metrics, but a purpose-built pharmaceutical LIMS provides an easier and more streamlined approach that makes quality tests such as stability testing more efficient and accurate. When pharmaceutical companies perform analyses for drug quality through methods such as stability testing, all information about the compound, such as its chemical properties and formulations, must be stored in the LIMS. Although this information can be entered manually, preconfigured LIMS save time, money and ensure the least amount of human error. Moreover, typical LIMS organize data based on the sample the data is for, but in the pharmaceutical industry, data is usually organized by study, batches and lots, making a pharmaceutical-geared LIMS a more efficient choice for organizing quality metrics for drug manufacturing.

The Matrix Gemini Stability LIMS by Autoscribe Informatics is a system that is built for stability testing in various industries, including drug manufacturing.  The system is able to create stability protocols and can monitor pull points. “A pull schedule specifies the time intervals for removing samples of the product from storage in order for testing to be conducted,” Mr. Daniels said. Unless a weight test is performed, samples are not returned to storage. This test helps measure fluctuations of sample weight during the stability study. Matrix Gemini has a template capability that ensures that conditions and pull points do not have to keep being recreated. “For each combination of condition and pull point, samples are removed for testing in the analytical laboratory,” said Mr. Daniels. “In Matrix Gemini, the tests can be specified for each individual combination of pull-point and condition if required.” The tests performed depend on the nature of the product that is being tested.

Matrix Gemini is also used for contract stability tests and R&D labs, and can create quotes and reports regarding the capacity of storage chambers. “Matrix Gemini Stability manages this process and provides a reliable, audited management framework to record and report batch pass/fail rates against defined test limits,” said Mr. Daniels. “In the event of failure, a quality cycle is typically started to understand the failure mechanisms and eliminate them.” The system also complies with the FDA-revised draft guidance regarding OOS. As Mr. Daniels explained, the pass/fail results of the lots being tested are combined into a “Lot Acceptance Rate” and an “Invalidated OOS Rate,” eliminating the need for manual entry.

“In Matrix Gemini, the tests can be specified for each individual combination of pull-point and condition if required.”

Various instruments are used for stability testing, with HPLC and UV being most common. “Instruments may be connected to the Matrix Gemini Stability system either via an API, or via a file interface, to automatically gather the test results,” said Mr. Daniels. “This avoids transcription errors and speeds up recording of the various test results.”

LabVantage also offers a purpose-built LIMS for the pharmaceutical industry with LabVantage Pharma, which is the only system in the industry that comes preconfigured for QA and quality control (QC) labs based on FDA cGMPs and guidelines, according to the company. It comes complete with validation documentation that is needed by regulated labs. “As batch and stability testing is performed and results are automatically compared to manufacturing specifications, OOS and Out Of Trend (OOT) conditions are flagged and investigations performed,” noted Robert Voelkner, director of North American sales at LabVantage. “When testing is completed and released, QA can review the batch and provide a final disposition.” As Mr. Voelkner explained, LabVantage Pharma provides the quality metrics requested by the FDA in real-time through formatted reports and XML exports.

LabVantage Pharma helps accelerate the collection and management of chromatography data through its informatics capabilities. “LabVantage Pharma can interface directly with a wide variety of Chromatography Data Systems (CDS), complex computer-controlled instruments and simple benchtop devices, such as pH [meters] and balances,” explained Mr. Voelkner.

Being prevalidated helps users of LabVantage Pharma streamline their time and costs. “It acts as a project accelerator, saving time and money compared to a more traditional ‘ground up’ LIMS project,” said Mr. Voelkner. “This means going live and realizing the benefits of automating stability studies and QA/QC testing sooner, and reducing overall project risk.”

“[LabVantage Pharma] acts as a project accelerator, saving time and money compared to a more traditional ‘ground up’ LIMS project.”

To avoid the mishandling of stability testing data, LabVantage Pharma provides the automation of data, including location, inventory management of study samples and sample pull data. If a sample pull was missed, the system flags the missed pulls and prompts an investigation. Although the test results can be entered manually into the system, LabVantage Pharma has the capability to capture data directly from the lab instrument. “As results are captured, they are fully audited and subject to electronic signature and a formalized approval process,” said Mr. Voelkner. “When using LabVantage Pharma, stability testing data is fully secure and audited compared to paper-based processes or using Excel.”

Matrix Gemini has similar capabilities. “Data held within the Matrix Gemini Stability database is version controlled and provides defendable data that records the history of each lot in the stability study program,” noted Mr. Daniels. “Any changes to the records in the database keep a history of past results, along with an audit trail of who changed the record, the date they changed it and why.” He added, “Automation like this is a key reason to move towards stability management solutions and away from pen and paper or Excel spreadsheet approaches.” Matrix Gemini also generates management reports that provide insight into understated trends in shelf life before lot failures occur, which can save drug manufacturers from losses of revenue and warnings from the FDA.

The ability to customize the system to whatever is required by its users is a key differentiating feature of Matrix Gemini, according to Mr. Daniels. “Graphical configuration tools provide a means of changing any aspect of the workflow without the need for software programming skills,” he said. “This approach to LIMS configuration allows faster implementation and a longer system life, as changing business needs can be easily accommodated.” This is due to the fact that graphical configuration can lower costs of ownership, he explained.

The Future of Stability Testing LIMS

Both Matrix Gemini and LabVantage Pharma provide purpose-built pharmaceutical LIMS that comply with FDA guidelines and enable users to submit accurate and streamlined data for the purposes of quality metrics submissions. Though the market for stability testing LIMS is a niche, it is still of key importance when it comes to QA in the industry, and challenges pertaining to the configurability of these LIMS systems remains a concept that companies continue to work to improve. As Mr. Daniels stated, “The challenge for solution providers is to provide a stability management solution flexible enough to meet the needs of industry and flexible enough to keep up to date with fast pace of change within drug development, production and IT technology.”

LabVantage is also working on giving its pharmaceutical LIMS even more functionality than it already has for QA/QC and stability labs. “The pre-configured, pre-validated scope of LabVantage Pharma will continue to expand to include more of this native functionality,” said Mr. Voelkner. “Examples would be expanding to use our new Laboratory Execution System and our CAPA module for lab investigations.”