This week, the FDA released a Form 483 noting observations made when inspecting Celltrion’s manufacturing facility in May and June 2017.
The heavily redacted form notes 12 observations:
- Failure to review unexplained discrepancies. Since the fourth quarter of 2015, the FDA has received 140 complaints related to vial stoppers. Celltrion has not implemented adequate corrective and preventative actions to address the issue, nor has it ensured that the affected vials are removed prior to the release of batches. Furthermore, investigations into foreign matter detected in drug products and drug substances were not conducted in a timely manner. Batches of a drug that contained particles were released for packing and labeling, and some samples contained particles “too numerous to count.” Unexpended trends in environmental monitoring data were not investigated thoroughly, and current practices do not ensure that changes in microbial flora are detected and evaluated.
- Procedures to prevent microbiological contamination are not established or followed. The report notes such practices as operators reaching over exposed sterile surfaces with hands and arms, as well as a lack of oversight of aseptic production operations during some work processes.
- Procedures designed to prevent microbiological contamination do not include adequate validation of the sterilization process. No effective system to identify which personnel have entered the filling room is in place, there exists no documentation of personnel who participate in reading media fill units, nor are there qualifications or procedures for reading media fill units. No dynamic airflow studies have been performed to determine risk to product sterility.
- Aseptic processing areas are deficient in environmental monitoring. Active volumetric air sampling is not included in the monitoring program for aseptic filling areas, the locations for surface monitoring are not described in procedures, and production personnel perform both environmental and personnel monitoring.
- Aseptic processing areas are deficient in terms of cleaning and disinfecting. The disinfectant used failed acceptable criteria for all surfaces, mold was identified on the walls, disinfectant efficacy studies did not include surfaces such as those used for filling machine format parts, and dust buildup was visible on air-intake vents.
- Equipment used in manufacturing is not of an appropriate design. Identification numbers for parts were found taped onto equipment surfaces.
- Failure to demonstrate that manufacturing processes can reproducibly manufacture drug substances meeting predetermined quality attributes. Process validation for a drug substance did not establish sound sampling plans to evaluate variability among batches. The report notes that this observation was also made in a March 2015 Form 483.
- Laboratory records do not include complete data. Failing test results are not reported, though such reports are mandated by procedure. After failures, tests are repeated without documentation of failing results or actions taken.
- Appropriate controls are not exercised over systems. Operation personnel share a common login to some systems, allowing the possibility that data could be deleted. Audit trails are not reviewed.
- Procedures for master production and control records are not followed. No system to track issuance and use of laboratory raw data forms is in place. The report also notes that the quality control department had a document shredder that filled with destroyed documents during the inspection.
- Data are not documented contemporaneously. General times are recorded to represent collection of multiple environmental monitoring samples from more than 1 area.
- Batch production records are incomplete. Production personnel create unofficial records of activities, and comments on these documents are not always reflected on official batch records.
Some analysts have suggested that the FDA’s observations could explain the slow uptake of Celltrion and Pfizer’s infliximab biosimilar, Inflectra, in the United States. Speaking with the Regulatory Affairs Professionals Society, biotechnology analyst Ronny Gal said that problems noted in the form could be why Pfizer “did not push Inflectra more broadly. Now with competitor [Samsung Bioepis and Merck] launching [Renflexis], the latter has an advantage.”
Celltrion and Pfizer’s Inflectra, which launched at a 15% discount to the list price of the reference Remicade, has only gained a 2% market share for infliximab. Pfizer has recently adjusted its average sales price for the drug in an effort to be more competitive with the originator product.