Incomplete Documentation Can Make or Break Projects in API Manufacturing

A Contract Development & Manufacturing Organization (CDMO) could have the most robust methods, purest synthesis and consistent Standard Operating Procedures (SOPs) when working on a critical API project, but if they’re not properly documented it doesn’t matter. A key roadblock to FDA approval often comes from incomplete or improper documentation each step of the way.

Inadequate documentation not only can significantly delay a project, adding additional costs and headaches, but it can prevent critical treatments and therapies from getting to people who need them the most. As an example,  just this summer, Eli Lilly’s COVID-19 antibody trials were stopped by the FDA because of its manufacturing controls at a New Jersey site producing the antibody.  It cited one of its manufacturing facilities on two counts of inadequate control of computer systems, including deleted data and failed quality control over audit paper trails.

Why is documentation so important?

Aside from the fact that documentation is the only way to preserve critical project data, record steps, track findings and results, it’s also been a source of dangerous misrepresentation. Data can be manipulated and falsified, which can lead to projects being perceived to be in spec, when in fact they may not be.

Inaccurate data has been a key reason for drug recalls, such as Zantac’s link to a possible carcinogen, which caused “thousands of people across the U.S. to develop cancer.” In another case, “four deaths and 350 adverse events” led to a recall of the blood-clot -treating drug, Heparin. Articles have cited that a big reason for these catastrophes is the falsification and manipulation of data often by overseas manufacturing facilities. 

Documentation Central to cGMP Guidance

cGMP guidance recommends that a CDMO maintain proper documentation and records, in order to record what was done in the past on a specific project and what is being done now, to provide a basis for planning how to proceed in the future.

Documentation is the key to cGMP compliance, enabling traceability of all development, and manufacturing activities. Typically the head of each manufacturing department or project is the one responsible for developing, distributing, maintaining, controlling and archiving all documentation for his/her respective projects, but it ultimately lies with the Quality Assurance (QA) and Quality Control (QC) managers.

CDMOs and other manufacturers are responsible for ensuring that all cGMP activities are performed according to the company’s clearly defined and documented Standard Operating Procedures (SOP). Any time those SOPs change, they must be reported to management for documentation.  And when a document has been revised, systems must be in place to ensure proper version control.

Records are kept at each stage of the manufacturing process so that all activities within preclinical studies, clinical trials, and the manufacture and control of products are traceable.

The Types of Documentation

Complex documentation is required at each step of the API manufacturing process, as well as during all clinical trials. Six of the key areas requiring formal documentation include the following:

1. Quality Assurance. These documents outline the company’s practices for ensuring quality at each step of the process. They’re continuously updated as new levels of quality assurance are added.
2. SOP Documentation. Provides step-by-step instructions for performing each stage in the manufacturing process.
3. Batch records. Outline production-related tasks and activities.
4. Test methods documents. Provide step-by-step instructions for testing supplies, materials and the corresponding tasks and activities. 
5. Specifications listing. Outlines what is required of a product before it can be commercialized.
6. Logbooks. Document all core activities, such as the operation, maintenance, and calibration of equipment; or the quality of clean rooms, solution preparation, etc.

Ensuring proper documentation, constantly updating it and maintaining it electronically is a time-consuming yet critical process. Key considerations that can ensure data integrity and more efficient data collection, include the following.

1. Follow written procedures. Document preparation, processing, distribution and obsolescence practices should be developed and governed by carefully defined written procedures that are understood and unwavering between different staff members.
2. Ensure data back-up. CDMOs should use multiple databases to control, track and cross-reference material and manufacturing records, company SOPs, employee training records, preventative maintenance, equipment calibration, deviation and quality investigations  and other data. 
3. Review and reconcile documentation. When batch manufacturing is complete, the QA team should review and reconcile all issued documentation to ensure the information is complete, before securely archiving it.
4. Scan documentation.  As an added measure, and to allow for rapid retrieval of information, all original data and documentation should be scanned into a digital format. There are a number of off-the-shelf tools available to help CDMOs do this.
5. Conduct ongoing training. It’s important to conduct ongoing training of staff to ensure that everyone is up to speed on proper documentation practices.
6. Store it in the cloud.  Here at Seqens CDMO NA, we create electronic vaults where all documentation is safely stored in the cloud. This ensures easy access to documentation without requiring onsite computing resources.

Documentation provides the perpetual record of each step of each project a CDMO undertakes, and can set quality CDMOs apart from others. It not only can make or break successful commercialization of a critical API, but it also ensures adherence to quality which results in safe and effective drugs.

For additional insights and observations, please check out: API Manufacturing Technology Transfer; Shattering 5 Myths About CDMOS; or Best Ways to Keep GMP Polymer Projects on Schedule.

About the Author

Ed is President & CEO of SEQENS North America (formerly PCI Synthesis). He serves as a co-chair of the New England CRO/CMO Council and sits on the Industrial Advisory Board for the Department of Chemical Engineering at UMass, Amherst. Ed is also a long standing member of the American Chemical Society and advises the Bulk Pharmaceutical Task Force of the Society of Chemical Manufacturer’s and Affiliates (SOCMA)...

Do you have questions? Talk to Ed.