All of us who work in pharmaceuticals in Europe and the US recognize the need for our manufacturing operations to meet compliance requirements. Quality levels that meet or exceed the expectations of our regulators are a given for our operations. In fact, we all understand that next to cGMP compliance, other important business considerations such as speed to market and cost of production are in a distant second place. If we are not in compliance, we have a problem, a very serious problem.
If we are not in compliance, then we cannot sell our products, no matter how quickly we develop them nor how inexpensively we can make them. Compliance is a fundamental requirement for product sales in our industry.
Why then do so many companies have difficulty with compliance?
Between December of 2010 and January of 2013, over a period of 26 months, the FDA issued over 1,600 warning letters. Granted, these cover all areas of FDA supervision, but nonetheless, a sampling of 100 warning letters issued to human healthcare fi rms shows a surprising consistency in the types of issues highlighted by the inspectors.
Let us briefl y review the inspector’s role. (Though we will focus on the FDA inspection in this discussion, the same general principles apply to inspections by other agencies, whether EMA, MHLW, TGA, PEI, MHRA, HC-SC, SFDA, WHO, or whichever is your favorite.)
An inspection is very much like QC sampling: one does not try to test every container, but rather one seeks to take samples here and there to confi rm compliance with specifi cations. Every manufacturing and quality assurance manager knows his or her plant has problems. The inspector knows this also. The real question is not whether there are problems, but whether they are serious enough to warrant an observation or a warning letter. So if we get to the point of a warning letter, we have serious problems and should promptly remediate them.
Over our time period, the FDA issued multiple warning letters to pharmaceutical manufacturers outside of the US who failed to register their manufacturing plants with the FDA. The result of this failure is that products made by these companies and sold in the United States are considered “misbranded”. The US Federal Food Drug and Cosmetic Act requires “each foreign establishment you own or operate that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug that is imported or off ered for import into the United States” submit registration information annually [1]. Remediation of this issue is straightforward.
Another common issue is lack of adequate control over raw materials and suppliers. For example, several fi rms failed “to adequately control, process, analyze, and approve or reject raw materials and finished APIs.”
This issue includes the following blatant failure to document incoming materials. The warning letter reads as follows:
“For example, [deleted] batches of [deleted] USP were released for distribution from April 2010 through March 2011 without adequate sampling of starting materials. It was observed within the in-house analysis records and through discussion with a firm employee that starting material [deleted], internal lot [deleted] had come from an unknown supplier via a distributor without product label or manufacturer information. According to the in-house records, it was tested by GC, KF and MP, but no raw data could be found to support the testing, nor records of instrument use logs.
Additionally, there is no traceability of the finished APIs as the completed batches were not properly identified and were then commingled, allowing for commercial lots to contain an unknown blend of manufactured batches.”
Another example reads as follows:
“Failure to perform at least one identity test of each batch of incoming material.
For example, the starting material [deleted] lot [deleted], used for the production of [deleted] USP, API lot [deleted] was not tested for identity.”
And yet another violation is described here:
“Failure of your quality unit to evaluate raw materials prior to release and use in drug production operations. The inspection revealed that your firm recovers [deleted] from the purification processes and reuses the recovered solvent without performing any test to ensure the purity and quality of the recovered solvent.”
And again:
“Failure to have a system in place to evaluate suppliers, and failure to adequately test each batch of incoming materials intended to be used in drug production. For example, the inspection found that you have not evaluated the suppliers of [deleted], [deleted], and [deleted], all used in the manufacturing process of [deleted]. Your firm currently accepts certificates of analysis (COA) from unevaluated suppliers in lieu of testing each batch of an incoming component to ensure conformity with the established specifications.”
Along these same lines are issues with control of testing. Here is an example of inadequate procedures.
“Failure of your quality unit to conduct review of completed batch production and laboratory control records before release for distribution. For example, your firm lacks raw data to demonstrate that the [deleted] test for the lots of [deleted] shipped to the United States met the acceptance criteria. Your firm sends samples of [deleted], produced by your firm, to your contract laboratory [deleted] for [deleted] testing. The material is released without adequate review of laboratory control records. Instead the results used for release are summary results accepted via text messaging, e-mail, or phone. In addition, your contract testing laboratory [deleted] for proton-nuclear magnetic resonance (HNMR) only provides you with a partial spectra zoomed in on the range for [deleted] and [deleted]. It is important for your firm to review the entire spectrum for other potential impurities or contaminants. All documents related to the testing of your [deleted] should be reviewed and approved by your quality unit according to established procedures. Contract laboratories are an extension of your operations and, as such, your quality unit is responsible for all data acquired at the contract laboratories you choose to use.”
Another firm received the following notice:
“Failure of your quality unit to ensure that materials are appropriately tested and the results are reported. For example, your Quality Control Unit (QCU) approved the release of four [deleted] USP batches [deleted] without data to support that the test for organic volatile impurities (OVI) met release specifications.
While your Certificates of Analysis state that OVI levels conformed to specifications, the inspection found that no testing was done. It is essential that your firm only report results to customers when you have actually performed the analysis. This serious CGMP deviation raises concerns regarding the reliability and integrity of other data generated by your firm. While we acknowledge the commitment in your November 19, 2010 response to improve the QCU, we remain concerned that your investigation is not comprehensive enough to determine the extent and impact of the problem. A review of the [deleted] OVI records of batches that were not previously tested is not sufficient. In your response, provide a complete corrective action plan that includes a retrospective review of the analytical data and batch records for all products manufactured at your facility that remain within expiration. In addition, provide the actions taken to prevent recurrence of the problem. Your investigation should be expanded to all other products manufactured at this site and include the establishment of a comprehensive training program for analysts and QC personnel.”
Likewise, refusing to share data with the inspector is a problem.
“Component test records specifically associated with batches of drug product manufactured at your facility were not readily available for an authorized inspection during their retention period. [21 C.F.R. § 211.180(c)]
a. Your firm refused to provide the test records of [deleted], an active pharmaceutical ingredient (API) used to manufacture the drug products, [deleted] Skin Protectant and [deleted] Skin Protectant. Your firm refused to provide the results of tests performed on [deleted] and instead redacted the test methods and acceptance criteria in your [deleted] raw material specification sheet prior to providing a copy of this document to the investigator.
b. Your firm also refused to provide the test records for [deleted], an API used in your [deleted] Skin Protectant Cream, by redacting this data before providing a copy of [deleted] raw material specification sheet to the investigator.
These documents are component test records that must be retained and are subject to review and photocopy during an inspection. The above examples constitute unreasonable denials in permitting FDA to assess the manufacturing conditions at your facility. In your response to this letter, please provide your testing requirements and results for the [deleted] and [deleted] APIs used in your drug products. Specifically, include information regarding the drug products shipped to the US and that remain within expiration.”
Another often cited problem area is environmental monitoring. Here are a few examples:
“On January 21, 2011, the FDA investigator observed the microbiological plates, MA 5 and MA 6, from air sampling locations in the Class 100/Grade A laminar air flow cabinet in the Microbiology Lab. Each microbiological plate contained one (1) CFU/m3. Your microbiologists reported these microbiological plates as “nil” on your form FM/QC/252-9. However, the action limit for these sample locations is [deleted] CFU/m3 which requires an investigation per your procedure SOP/QC/049 entitled Environment Monitoring of Aseptic Area.”
“Our investigators found that gowns worn by operators working in the aseptic processing areas are only monitored [deleted] per week. Additionally, gloves are only monitored at the [deleted] the shift. We are concerned with the fact that operators performing critical operations may not be adequately monitored. Therefore, there is no assurance that your environmental monitoring program is capable of detecting all microbiological contaminants.”
“The technician performing the air sampling held the probe close to the HEPA filter face rather than [deleted] as specified in section 4.5 of your written procedure SOP/QC/049.”
“On December 17, 2010, the investigator noted that many microbial plates containing environmental monitoring and personnel samples, collected on December 12, 2010 during production, were missing from the incubator. Your response confirmed that 33 of 150 (22%) of the personnel monitoring samples were missing and that in one instance, 9 of 10 samples were missing for a single operator. Your response indicates that no missing plates were reported for the period of January 2009 through November 2010. We have determined that this conclusion is not reliable because neither reconciliation procedures nor data regarding the number of microbial plates used for environmental monitoring and microbiology laboratory samples were available at the time.”
“Your firm has not established or followed appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 C.F.R. § 211.113(b)]. For example, during the December 2010 inspection, the investigators found that your SOPs related to your environmental programs failed to adequately identify (e.g., diagrams) the locations where active and passive environmental monitoring samples are to be collected from. The inspection also found that your procedure for environmental sampling does not require that employees be sampled [deleted] time they exit the Class [deleted] clean rooms. This deficiency increases our concern regarding the reliability of the data generated and your ability to identify the source of your microbial contamination.”
The examples presented here require little commentary to explain why they are failures and how they should be corrected. However, they provide a sobering look at the challenges faced by some of our colleagues and lessons for paying attention and being ever vigilant.
Compliance is an important part of what we do in the pharmaceutical industry. We follow cGMP regulations to ensure the safety of our patients, to control the quality of our products, and to demonstrate to clients, investors, and employees that we are responsible and in control of our operations. We maintain our quality standards because it is good business practice to do so. After all, without compliance we cannot sell our product.
Acknowledgement
The assistance of Angela Xu in the preparation of this article is gratefully acknowledged.
References
- Guidance for Industry, Providing Regulatory Submissions in Electronic Format – Drug Establishment Registration and Drug Listing, U.S. Department of Health and Human Services Food and Drug Administration Office of the Commissioner May 2009 Electronic Submission http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ ucm072339.pdf
Note
All quotes in this article are taken directly from warning letters available from the FDA website.
Author Biography
Scott M. Wheelwright, Ph.D., is one of the founders and served as Chief Operating Officer of Innovent Biologics, a biopharmaceutical firm in China developing products for the China market with a largescale full cGMP manufacturing capability (total cell culture capacity is expected to exceed 70,000 L). Dr. Wheelwright is also founder of Strategic Manufacturing Worldwide, Inc., a consulting firm focused on manufacturing compliance and outsourcing, and is a founder of Complya-Asia, a Chinese consulting firm focused on Quality Assurance and cGMP compliance for pharmaceuticals. Dr. Wheelwright has over twenty-five years’ experience in bringing novel products to market with work experience that encompasses both large and small pharmaceutical, biotech and other life science companies. Dr. Wheelwright received his Ph.D. in chemical engineering from the University of California at Berkeley and performed post-doctoral studies at the Max Planck Institute for Biophysics in Frankfurt, Germany. He is the author of a book on protein purification and has published numerous articles on manufacturing, process development, and bringing products to market. Dr. Wheelwright resides in Suzhou China.