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The master Production and control record
1. The master production and control records are deficient in that they do not include complete manufacturing, instructions, and procedures. Specifically, your firm’s master batch records to not contain the parameters to set the automated (redacted) filler for each count configuration of (redacted) products packed in bottles.
Failure Investigations
2. There is a failure to thoroughly review the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed. Specifically, SOP ## entitled “Failure Investigations” documents, in part, that an investigation will be conducted whenever an in-process material, bulk product, or finished product fails to meet specifications. Review of the batch production records for (product, lot #) revealed that the firm rejected a total of ## buckets of compressed tablets which failed to meet specifications for friability. An investigation was not performed as required per SOP ##.
GMP training
3. GMP training is not conducted on a continuing basis to assure that employees remain familiar with cGMP requirements applicable to them. Specifically, there is no documentation for continuous cGMP training for management including the Director of Quality Assurance who has the authority to accept or reject final product, the Plant Manager who supervises employees in the manufacturing area, or the Technology Manager who is responsible for calibration, validation, and higher end quality functions.
Storage area for labels and labeling materials
4. Access to the storage area for labels and labeling materials is not limited to authorized personnel. Specifically, a tour of the warehouse area found labeling material, including prescription drug package “outserts” stored on shelves in the same vicinity as other manufacturing components. These labeling materials are not appropriately segregated or secured to ensure access by only authorized personnel.
Postmarketing adverse drug experiences
5. Written procedures have not been developed for the surveillance, receipt, evaluation, and reporting to FDA of postmarketing adverse drug experiences. Specifically, the firm has not established a written procedure describing the processing and evaluation of adverse drug events and the reporting requirements of adverse drug events to the agency.
Component testing
6. Component testing is deficient in that each component is not tested for conformitywith all appropriate written specifications for purity, strength, and quality.
Inspection of automatic and mechanical equipment
7. Routine inspection of automatic and mechanical equipment is not performed according to a written program designed to assure proper performance. Specifically, the firm’s equipment qualification activities failed to confirm the capability of the facility to provide adequate supply resources to sufficiently operate production equipment.
Cleaning and maintenance of equipment
8. Procedures for the cleaning and maintenance of equipment are deficient regarding inspection of the equipment for cleanliness immediately before use. Specifically, the firm has not established clean equipment hold times for the 800L manufacturing tanks used in the production of (product). There are no equipment start-up procedures outlined regarding additional cleaning and/or purified water rinses immediately before use of the tanks.
Aseptic processing areas
9. Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions. Specifically, HEPA filter performance is not evaluated or monitored for uniformity of velocity across the filter face and relative to adjacent filters within APA 1079 (outside of the RAB) or in APA 1077/1077B to facilitate detection of adverse airflow patterns and the need for maintenance or replacement of the filters.
Cleaning and Sanitization of equipment and utensils
10.Equipment and utensils are not cleaned and sanitized at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product. Specifically, there is no data to support the monthly clean out of place (COP) cleaning frequency for non-product contact belts and filler parts in the ISO Class 5 and 6 areas. Cleaning validation and verification studies are not performed for non-product contact parts.
Buildings and Facilities
11.Buildings used in the holding of a drug product are not maintained in a good state of repair. Specifically, the following conditions were noted during a walkthrough of the facility: (a) On 1/28/10, a leak in the reverse osmosis water system was noted at the reject valve leading to the second pass of the RO. A bucket was placed under the leaking valve with a plastic type wrapper placed on top of the leak to prevent water spray. The initial leak was noted during a routine equipment check in 1/22/10. (b) On 1/25/10, a roof leak was noted in the 542 warehouse aisle (redacted). A review of work orders found two additional leaks in the roof above the aisle in warehouse 542 had occurred previously dated July 14, 2008 and August p25, 2008.
Laboratory controls
12.Laboratory controls do not include the establishment of scientifically sound and appropriate sampling plans and test procedures designed to assure that drugs products conform to appropriate standards of identity, strength, quality, and purity.
Written records of investigations
13.Written records of investigations into unexplained discrepancies and the failure of a batch or any of its components to meet specifications do not always include the conclusions and follow-up. Specifically: Investigation (redacted) was initiated on 3/15/2010 to document the recall decision for (product) after conclusion of investigations (redacted). The investigation concluded that no definitive root cause was determined for the atypical behavior of the dissolution failures. However, your firm’s investigation did not include documented evidence that the characteristics of the container/closure system (e.g. permeability) were thoroughly assessed as part of the investigation.
Rejection criteria
14.Drug products failing to meet established quality control criteria are not rejected. Specifically, there is no assurance that the established material controls are adequate to prevent the approval of finished product, in-process materials, and raw materials in “quarantine” (“hold/block”) or “rejected” status.
Stability program for drug products
15.The written stability program for drug products does not include sample size based on statistical criteria for each attribute examined to assure valid estimates of stability. Specifically, our review of (product) manufacturing process found a trend of out-of-specifications (OOS) and out-of-trend (OOT) results for low assay of Calcium Carbonate in the production of 2009 and 2010. Your firm identified variability issues in the (redacted). Although corrective actions were implemented in June 2010, (redacted) was initiated on July 15, 2010 due to OOS results in theCalcium Carbonate test of batch (redacted). This investigation was still open at the start of the current inspection and a root cause has not been identified.
