Key Considerations When Manufacturing APIs for Injectables

Four Best Practices to Ensure Sterility

Posted: January 13, 2020

API Manufacturing and Pharmaceutical Manufacturing

When synthesizing Active Pharmaceutical Ingredients (APIs) for finished drug products – whether for use in injectables or opthalmics, a critical concern is ensuring the sterility of the drug and the elimination of residual toxins. When it comes to drugs delivered via vials and that enter directly into the bloodstream – as is the case with injectables – this concern goes into overdrive. Products that are injected are more likely to cause an infection if they are contaminated than products in other dosage forms.

To understand the consequences of tainted injectables we don’t need to look much further than the widely publicized case of the Framingham compounding pharmacy that sent out tainted drugs that killed more than 100 patients and harmed 793 in a national outbreak of fungal meningitis, after receiving injections of the tainted drug.

The key question asked with such a tragedy is how it could possibly have happened given the strict oversight the FDA has over drug manufacturers. As discussed by Drug Administration Commissioner, Scott Gottlieb, when he released his 2018 Compounding Policy Priorities Plan, many facilities have avoided FDA scrutiny by operating with a pharmacy license, which falls under the jurisdiction of state pharmacy boards, and many states do not do routine inspections at these compounding facilities. For this reason, many legislators are pushing for better classification of compounding centers as outsourcing facilities, so that they can be better regulated by the FDA.

While the New England Compounding Center case represents extreme negligence, including allegations that expiration dates on drugs were falsified and other dishonest behavior,  it underscores what can happen when residual toxins exist without proper cleaning of GMP suites, equipment and staff.


To avoid these deadly problems, most Contract Development & Manufacturing Operations (CDMOs) take extreme precautions when it comes to manufacturing injectables. Consider the following four best practices to ensure sterility:

  1. Utilize GMP suites. GMP suites, also known as cleanrooms, maintain extremely low levels of particulates, such as dust, airborne organisms or vaporized particles. The cleanliness is rated by the number of particles per cubic meter at a predetermined molecule measure. Our suites at Seqens NA CDMO have been validated to class 100,000. However, our annual recertification tests have shown our suites to be between 12,000-14,000 on an ongoing  basis.
  2. Conduct repeat testing. After an API is produced for an injectable, samples are sent out for microbiological testing where endotoxin tests are performed to make sure they don’t contain bacteria, such as salmonella, fungi or other residual bacteria. These tests are conducted by heating the samples in a petri dish to see if anything grows (since in organic chemistry those types of microbes cannot survive in organic media, they need water and oxygen and warm conditions). Outside microbiological testing can be expensive a but it’s worth the cost to get validated result
  3. Follow safe protocols for cleaning of equipment. A prerequisite for GMP manufacturing is the cleaning of equipment to meet a predetermined specification. This is established by assessing the toxicity and potency of the existing residues on potential human consumers of the next product to be manufactured by the same equipment. Cleaning procedures are based on the nature of the residues, the equipment design and the expected effectiveness of the procedure. These procedures can employ rinsing, soaking, or spraying equipment surfaces with a liquid-medium. It can also include boiling a solvent inside the enclosed space of a piece of equipment, and manual scrubbing or wiping of equipment surfaces.
  4. Ensure proper gowning of staff. Everyone working on an injectable API project should be gowned from head to toe (in that order), wearing masks at all times.  Each person should wash and dry exposed body parts, such as face and hands, before putting on gloves and garments. In addition, all staff working in or near the GMP suite or handling the materials in any way should have a flu shot and be free of any illness before coming to work.

Patients, providers and drug manufacturers are concerned with contamination of injectable drug products, and rightly so. When entered directly into a patient’s blood-stream, the chances of contaminated particles causing serious harm are magnified. With sound business practices and a hyper focus on cleanliness, however, CDMOs can prevent these problems before they cause serious damage to patients.

For more insights, check out: Whose Manufacturing Your Prized API?, How to Stem the Flow of Tainted Generic Drugs, or Coming Clean on Cleanroom Operations in GMP Manufacturing.

About the Author

Ed Price CEO of PCI Synthesis
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.