API outsourcing is increasingly predictable. Many companies provide a range of services and technology types for pharmaceutical clients who may need to outsource one API1, or they may need to outsource many APIs over a long period2. Herein I describe criteria to select API manufacturing companies, and methods to maintain those relationships.
All successful partnerships start at the end-in-mind. For small molecule API supply, chemistry types many times describe an API providers’ business. Suppliers of synthetic peptides and oligonucleotides, for example, may provide that service exclusively. Most API supply companies can provide exclusive synthesis across a broad array of chemistries and API types. Regardless of your needs companies exist to provide you with a long service relationship. Further, many companies offer process design capabilities in the event you do not have a synthetic route chosen. Given this range of needs, these are criteria to use for identification of a good supplier:
Manufacturing and Containment
- Facilities: Tour the supplier’s facilities and evaluate age, material of construction, scale, and cleanliness, including signs of corrosion. Review their maintenance records and deviations for a history of facility and equipment failures.
- Production Processes: Review the material flow from receiving, to warehousing, dispensing and charging, then to drying, milling and packaging. Review the airflow in these areas. Look for sources of potential contamination and include a review of such deviations.
- Review the cleaning methodology and ensure it meets current GMPs. Inquire about cleaning verification for connecting equipment, including hoses, piping, vent risers, condensers, and material inlets; these are unanticipated sources of contamination.
- Documentation: Review the documentation history for the process and methods for each product, including the transfer to production, batch records and release.
- Personnel: What are the qualifications and experience of the personnel performing all of the above tasks? Companies that employ personnel with advanced degrees will be more reliable and more likely to succeed.
- API Physical Characteristics
a. Look for various drying and milling capabilities to match your needs.
b. Dry processing areas are notorious for extraneous material contamination. Review the material of construction of mills, and the air qualification of the dry end, including its maintenance records.
c. Companies must have the capability to measure particle size, surface area and other important factors. Verify that their analytical labs include such capability3. - cGMP: Most suppliers today use the same equipment and processes for cGMP and non-GMP, differing by the level of investigation of process deviations, validation of analytical methodology, and release testing. This may save project time and money if the material is not required for human clinical studies.
- Scale: While your objective may be a 25 kg API supply, a company that can provide that scale and scales 10x - 100x larger will be a better choice in the end.
- Safety , Health and Environmental (SHE):
a. When possible, this evaluation should be performed by an SHE expert or process engineer.
b. Review HSE staff and qualifications, facility containment capabilities and IH monitoring.
c. Verify the supplier has criteria to identify which employees require industrial health surveillance for evidence of exposure.
d. Verify that the firm has a process to reject projects for which their facility is not qualified
e. Review the fate of hazardous and API wastes (including wastewater), fire protection systems and the overview of general safety programs
f. Verify that employees always follow SHE procedures.
g. Review the supplier’s SHE compliance history.
Quality and Regulatory
- Quality Organization and Capabilities – a thorough review is required
- Quality Systems
a. Confirm that the supplier meets the regulatory requirements for your API.
b. Review the audit history; review any 483s for serious departures.
c. Confirm that employees in cGMP areas follow procedures.
Process and Analytical Development Staff and Technical Services
- The staff should include experienced PhDs in organic chemistry, analytical chemistry and chemical engineering with experience in route design and selection, process and methods design and validation.
- Review the lab-to-production tech transfer process.
- Evaluate analytical instrumentation and equipment, including the use of any contract laboratories.
Business Methods
Documented business methods for customer service are essential for successful suppliers. Suppliers typically govern project selection, project management and performance metrics. Ask to review:
- On-time delivery performance, complaints and failed batch frequency history.
- Leadership methods, including:
a. Governing bodies and processes,
b. Technology transfer,
c. Selection process for key personnel,
d. Business continuity processes,
e. Employee exiting criteria. - For selection of a supplier for a commercial product, evaluate:
a. Manufacturing Science methods
i. Process conformance monitoring
(control charting),
ii. Annual reporting of process and product conformance for validated processes,
iii. Examples of deviation investigations by technical staff.
d. General financial situation,
e. Does the supplier’s strategy match your value proposition?
f. Sourcing methodology4.
Evaluation Planning and Execution
Client companies must visit potential suppliers before selecting a company to supply an API. Using the outline given above, appropriately trained and educated personnel should meet together and determine specific questions and themes to cover during the site visit. In most cases, this will involve additional details and criteria depending on process and analysis types. For each area of diligence, determine the success criteria prior to the visit. The visiting team should include an analytical chemist, process engineer, organic chemist, QA professional and a responsible scientist or manager.
During the visit, keep a list of questions, criteria and key observations with you. Focus on making visual observations and listening to the supplier’s descriptions and answers to questions in lieu of writing notes. Once the review of each area is complete, your group should meet briefly separate from the host to compare impressions of the area and note critical findings. Once the visit is completed, your group should meet immediately to fully document essential observations and findings, and score the supplier.
Scoring a Supplier: During and After the Tour
A successful supplier must meet your performance criteria. Developing criteria prior to a site visit will inform your scoring method for the supplier’s selection and future continuance. Consider these factors in scoring:
Score each criterion as 0, 1 or 25 to provide a total score diagnostic of your supplier’s performance. During initial evaluation of the supplier, be sure to make observations of the supplier’s predicted performance for each criterion to allow an informed final selection. For each criterion with a “0” rating, the supplier must agree to corrective actions to ensure reliability.
Continuance
Many pharmaceutical companies qualify a variety of suppliers for their API needs, and maintain these suppliers over time6. This allows quotations from 2-4 suppliers for competitive selection based on price or other factors. Clients should meet periodically with suppliers to review performance, and changes to critical factors from the original selection process. Changes in management and technical personnel are a key consideration, for example. Major modifications require a new site visit for due diligence. Finally, using these techniques, client companies should repeat their physical diligence every 2-4 years.
References
- Levy SG. Effective Outsourcing of Small Molecule Chemistry R&D and API Manufacturing for Emerging Pharmaceutical Companies: A Stepwise Approach to Risk Management. Pharmaceutical Outsourcing. 2014; 15(1). Posted February 3, 2014: https://www.pharmoutsourcing.com/Featured-Articles/153810-Effective-Outsourcing-of-Small-Molecule-Chemistry-R-D-and-API-Manufacturing-for-Emerging-Pharmaceutical-Companies-A-Stepwise-Approach-to-Risk-Management/
- Lepore J, Seibert KD, Watson T, Wollowitz S. Performance Expectations for Suppliers in the QbD Era: Leveraging Suppliers to Support an Enhanced Submission for an API. Pharmaceutical Outsourcing. Posted September 30, 2013: http://www.pharmoutsourcing. com/Featured-Articles/147058-Performance-Expectations-for-Suppliers-in-the-QbD-Era- Leveraging-Suppliers-to-Support-an-Enhanced-Submission-for-an-API/
- In-line physical property analysis during manufacturing is an advantage. Be sure to evaluate the comparability of the plant technology to the release lab measurements for these characteristics.
- Selection of a supplier with a competitive sourcing process will help ensure long-term cost benefits.
- Impact ratings: 0 = deficient; 1 = expected; 2 = advantage. With the criteria exemplified above, the overall expected score would be 10 points, where 11 – 20 would be quite good, and scores of 0 - 10 requires a supplier’s agreement to correct deficiencies, or consideration of other options.
- Eckrich TM. Building a Sustainable API Supply Chain. Pharmaceutical Outsourcing. 2013; 14(1). Posted January 29, 2013: http://pharmoutsourcing.com/Featured-Articles/129469-Building-a-Sustainable-API-Supply-Chain-1/.
Author Disclaimer: I am an advocate for Active Ingredient Suppliers. I understand and vigorously endorse the importance of creating the most productive relationship possible between client and supplier, which produces API of the highest quality and maintains relationships of the highest standards.
Thomas M. Eckrich, PhD., is Founder and Principal of Eckrich Consulting Services, LLC. Tom provides expertise to the chemical and pharmaceutical industries in chemical process development and manufacturing, with a focus on synthetic organic chemistry. Tom is an expert in outsourcing of active ingredient manufacturing, including creation, qualification and management of partnerships. Tom earned a doctorate in chemistry from Harvard University in 1984, studying with Professor E. J. Corey. Tom worked for Eli Lilly and Company until 2014, working in a variety of laboratory and management positions in chemical development and manufacturing.