Archives: Case Studies

Remediation & Resulting Sustainable Compliance

Background

A recently registered 503B sterile outsourcing facility was facing significant FDA enforcement action following two critical FDA Form 483 observations. The FDA requested an immediate cessation of compounding activities and a full recall of all sterile compounded preparations due to a lack of sterility assurance. Regulatory Compliance Associates® Inc. (RCA) was engaged as an independent third-party cGMP expert to support the facility in navigating these regulatory challenges and restoring compliance.

RCA Approach

RCA’s team of experts guided client personnel in developing a comprehensive and effective response to the FDA Form 483 observations. A thorough baseline cGMP audit was conducted under the draft 503B regulations, followed by RCA’s support in managing subsequent FDA communications. Six months later, RCA led a certification audit to assess the facility’s progress. While additional observations were noted, RCA determined that no outstanding sterility assurance concerns remained.

RCA also prepared and trained facility staff for the follow-up FDA inspection. Despite the FDA deploying three specialized drug investigators, the facility received only minor, easily correctable Form 483 observations—all of which were fully addressed in the response, marking a significant regulatory turnaround for the client.

Results

Following a comprehensive review by the FDA’s Dallas District Office and the Center for Drug Evaluation and Research (CDER), the Agency formally issued a letter stating it had no objection to the firm resuming sterile drug compounding operations. With this clearance, Unique Pharmaceuticals became one of the first outsourcing facilities to successfully remediate FDA’s sterility assurance concerns related to pharmaceutical compounding. The facility also demonstrated full compliance with the new regulatory framework established under Section 503B of the Federal Food, Drug, and Cosmetic Act, setting a precedent for the industry.

Biologics Manufacturing: Design & Build Out

Background

A biological drug development company based in Europe came to RCA as their facility expansion was under construction. A team of RCA experts engaged in guiding this company through the entirety of its planning, qualification, engineering and management stages. RCA was challenged with bringing this facility to effective operation while meeting all US, EU and other international compliance requirements, within project timeline.

RCA Approach

RCA experts collaborated with the client engineers to support and assist in a customized design and build out of a microbiology and physical chemistry laboratory, in which its up-and down-steam fermentation processes were used. RCA reviewed conceptual designs for the following areas including Facilities and utilities, Environmental Monitoring, Building Management System, and Extension of Clean Media Automation System.

RCA ensured all design specifications and qualifications for Technical Systems and USP processes were in place to support this design of the facility.

RCA provided the client with a design review and documented findings, with a list of compliance statuses and risks. All items were addressed with the client, action plan developed and executed including recommendations for:

  • Segregation of manufacturing activities, including pre- and post-viral inactivation sections.
  • GMP Water systems supporting each stage of the manufacturing process.
  • GMP Clean Steam systems supporting each stage of the manufacturing and sanitation processes.
  • Steam In Place system.
  • Site Validation Master Plan.

RCA provided the guidance and technical management roles, to support the Quality Management System requirements for FAT/SAT/IQ/OQ/PQ.

Results

RCA assisted in leading this client through a very enduring design and build of a Biologics Facility. With QA, cGMP and Validation expertise provided by RCA this client was able to navigate through all compliance and regulatory challenges. Aligning strategy, leadership and proven industry experts to address FDA, global regulatory and operational related issues, RCA provided a customized plan of action with experienced resources to meet our client’s specific requirements and goals.

 

 

Biosimilar Drug Development

Client Challenge

A European based company engaged in biosimilar drug development requested RCA to develop a regulatory strategy for seeking approval for their drug in the US and EU. The challenge was that the client wanted to utilize the data from a recently completed Phase III clinical trial conducted entirely outside the US and not under an IND. RCAs regulatory affairs team confirmed that CDERs Office of Biotechnology would have jurisdiction and proposed that the client request an initial advisory meeting as their first contact with FDA.

RCA Approach

Originally, the client did not intend to seek FDA approval making the first step verification that the clients clinical data met cGCP and cGMP, as well as the regulations and guidance documents for the Use of Foreign Clinical Data. RCA supported the client as they retrieved the proper records and documents which were sorted to conform to EMAs similar but different requirements. When reconstructed, this documentation essentially met FDAs requirements for cGCP.

Step two was to document a briefing package on behalf of the client to support an Initial Advisory Meeting request with the FDA. As the client was in the process of preparing a Biological License Application in Europe at the time, substantial Safety, Efficacy, Pharmacology and Bioanalytical data was available. The client had substantial bioanalytical data comparing their biosimilar to the European marketed reference listed drug “RLD”. Generation of comparative bioanalytical data that could be used to build a bridge, to the US RLD drug, was still on-going.

RCA submitted the briefing package to the FDA on behalf of the client and the FDA rejected the meeting request based on insufficient bioanalytical comparison data between the clients biosimilar and the US RLD. Over a four- month time period the client was able to generate additional bioanalytical comparison data to the US RLD.

RCA updated the original briefing package to include the additional data and resubmitted another meeting request. This time the meeting request was granted. However, due to the extensiveness of the supporting data presented in the briefing package, FDA offered the option to the client to convert the advisory meeting into a BPD type II meeting request. As a result, the client saved a significant amount of time towards their goal of filing a BLA in the US.

Results

The outcome of the meeting request with FDA is being withheld at this time to maintain confidentiality for our client.

 

 

EU MDR Compliance and Regulatory Submission

Background

A global medical device manufacture needed to meet the May 26, 2021 EU MDR compliance deadline. Collecting the reference documentation from suppliers was a challenge due to their geographic location. Based on the new CE mark requirements, the client moved from a self-submission filing status, to a Class 1 medical device.

RCA Approach

RCA collaborated with the client’s leadership team to create a cohesive strategy based on the new EU MDR regulatory environment. Training sessions were conducted to educate their team on the changes from MDD to MDR.

RCA performed an assessment to understand the current state and identified all gaps that existed in relation to the new EU MDR. This included a review and assessment of the existing Design History Files (DHF) and the Quality Management Systems (QMS). It was identified that the documentation was in several locations and lacked the efficiency of a culture of quality.

A Project Plan was developed that outlined the creation or revision of 12 Standard Operating Procedures (SOP), along with the development of complete design history files for 3 current/legacy product families. Clinical Evaluation Reports were created for 3 product families to help the client determine their new MDR classification.

RCA increased the efficiency of the documentation process so a single hub of information was available for future assessments or audits. Change control processes were implemented to improve how revisions of SOP’s and quality records were documented.

Results

RCA successfully delivered submission files for the 3 product families on time. This enabled the client to continue their business under normal operating conditions in each global market.

Packaging validation was also optimized based on improved procedures that met the new MDR regulatory guidelines. Supply chain partners and suppliers were educated on the client’s new requirements for optimized validation protocols.

Finally, RCA helped the client identify additional opportunities to optimize their QMS and product portfolio based on the new regulatory environment. This led to the potential for expansion opportunities based on the current certification approval.

Client Takeaways

  • Technical files for EU MDR submission were optimized including generation or updates for every element of the file.
  • The Client successfully transitioned to ISO certification.
  • One of the client’s suppliers was impressed which led to additional assessment projects with vendors in the client’s model.

Outsourced QA Leadership Benefits Emerging Device Maker

Client Challenge

The client’s team had developed a strong business plan, secured a solid intellectual property (IP) platform, and established a clear manufacturing strategy. However, they lacked a defined regulatory affairs (RA) and quality pathway. Operating in a bootstrapped environment, they initially implemented off-the-shelf quality management system (QMS) software, only to later discover that this approach was insufficient to meet their regulatory and quality compliance needs.

RCA Approach

Regulatory Compliance Associates® Inc. (RCA) was engaged to perform a gap analysis, identifying discrepancies between the company’s existing systems and the regulatory affairs (RA) and quality management system (QMS) requirements. RCA initiated a structured remediation effort, providing targeted support where needed—such as aligning standard operating procedures (SOPs) with the company’s unique business needs and refining the product development process to meet evolving QMS expectations. To support the development of a compliant and robust QMS, RCA deployed experts in quality systems and quality engineering, including specialists in electronics.

As the new product launch approached, RCA further supported the implementation of a Corrective and Preventive Action (CAPA) system, a complaint management process, and an internal audit plan—ensuring a sustainable and inspection-ready quality infrastructure.

Results

Through the combination of RCA’s outsourced quality and regulatory expertise and the client’s internal team, the company successfully launched its product, achieved full regulatory compliance, passed audits, and implemented a robust Quality Management System—all without the need to hire costly full-time executives. By addressing compliance gaps and optimizing the use of existing QMS software, RCA helped the company preserve its prior investment and avoid unnecessary system replacement costs.

Additionally, RCA structured a flexible payment plan with fixed monthly fees, enabling the client to manage cash flow effectively during a critical growth phase. Following RCA’s initial engagement, the product achieved commercial success. As the company scaled, RCA was retained for ongoing support as the outsourced QA/RA manager, providing strategic guidance while keeping operational expenses manageable.

This successful partnership and the company’s continued growth ultimately attracted investor interest, culminating in an acquisition by one of the top 100 global medical technology companies.

Pharmaceutical Shipping Validation Study

Background

A pharmaceutical start-up, located in the USA, approached RCA to design their shipping validation study given the complexity of their supply chain, manufacturing, and distribution process.

The challenge is to design a study that proves the SQuIPP of the drug product is maintained throughout the multi-national manufacturing and distribution process given the multiple modes of transportation and multiple hand offs between four different companies. The company has two API manufacturers, located in different parts of Europe, that they need qualified using both air and sea transportation between Europe and Canada. The finished drug product is to be manufactured in Canada and then shipped to the USA by air or ground transportation for distribution.

RCA Approach

Based on the request of the client, multiple shipping studies were required. Each API manufacturer needs to be qualified for each route using different modes of transportation, and each route needs to be challenged by “anticipated extremes”. There were a multitude of shipping configurations (# of drums, drum sizes, drum weights, # of pallets per container, types of containers, etc.) that differed by manufacturer, but in some cases also changed within the same manufacturer, that added complexity to this project. Additionally, any possible new challenges associated with international shipping practices had to be identified (languages, time zones, holidays, etc.).

RCA was able to generate multiple shipping study protocols. These protocols included representative transportation load configurations, defined packaging configurations, and calibrated temperature monitor positioning. Given the delicate nature of the API, lot samples were pulled and sent with each shipment to undergo chemical testing following shipment. The testing results were used to illustrate that the SQuIPP of the API material was not impacted by the shipment. Since the client couldn’t be present at each CSP site, the protocol included clear, multilingual instructions and diagrams to ensure correct temperature monitor placement and pallet configuration.

Multiple different companies were involved in manufacturing and distributing the finished product, therefore, the hand offs had to be effectively managed. Each company was required to provide documentation to RCA illustrating the protocol had been followed. Given that the product is temperature-sensitive, a delayed or missed hand off puts the product at risk. It was RCA’s job to analyze the shipment documentation and temperature data to determine whether the validation passes and generate the final reports.

Results

The company was able to provide sufficient data proving the drug product and it’s materials was maintained within the established temperature range throughout the cold chain distribution by all modes of transport during both winter and summer seasons. The data also illustrated the SQuIPP of the product was not impacted during the shipments. The thorough design of the study, combined with data tracking and analysis from RCA, enabled the company to prove this consistency over time.