Triad Group Hartland, WI Form FDA-483 Inspection Dates 11/29/2010 – 1/7/2011
Enclosed are comments from a total of seven observations representing various Systems to include Laboratory Control, Production, and Material obtained as a subset from the forty six observations within Triad Group’s recent FDA 483 which resulted in a recall of their alcohol prep pads, swabs, and swabsticks.
Laboratory Control System
Each batch of drug product purporting to be sterile is not laboratory tested to determine conformance to such requirements.
Specifically, there is no finished product sterility testing or laboratory (b)(4) testing for sterile alcohol prep pads or sterile alcohol swabsticks.
§211.167(a) states “for each batch of drug product purporting to be sterile and or pyrogen-free, there shall be appropriate laboratory testing to determine conformance to such requirements.” SOPs should exist at each site to manage the sterility testing, USP<71> Sterility Tests, of product sold as “sterile”. In addition, SOPs should exist that cover such areas as Growth Promotion, (see USP<61> Enumeration of Microorganisms) , as well as the management of all of the equipment to include ISO 5 Sterility Test Hoods, refrigerators and incubators.
Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process.
Specifically, the validation for sterile alcohol pads only collected samples for bioburden determination from one production line. There are (b)(4) production lines for alcohol. Additionally, the recovered bioburden was not identified.
The microbial bioburden must be collected from representative production lines on a randomized basis to assure a complete examination of microflora. The identification of this bioburden assists in assuring that the most radiation resistant microorganisms are included as part of the Dose Setting Protocol (see AAMI).
The master production and control records for each batch size of drug product are not prepared, dated, and signed by one person with a full handwritten signature and independently checked, dated, and signed by a second person.
Specifically, the electronic batch record files for every product manufactured at this facility are kept on a shared network drive that is accessible to at least (b)(4) people. The Label Clerk responsible for issuing batch records demonstrated her ability
to change any part of the batch record prior to issuance (including in process and finished product specifications), these fields can be changed by anyone with access to the shared drive. In addition, the Label Clerk said she routinely changes the batch
size based upon the production schedule to ensure that enough product is manufactured to meet demand. Batch records generated for production are not checked against the master batch record for accuracy. Master batch records are not signed.
Only a limited number of personnel should have access to electronically modifying the Master Production and Control Records (see 21 CFR Part 11). They also should be independently verified by a second individual prior to being issued to the “manufacturing floor”.
Written production and process control procedures are not documented at the time of performance.
a) On November 29, 2010 the production of Adult Glycerin Suppository lot #OL268 was observed. The operators were observed weighing the bulk totes and placing them in the appropriate area. Review of the batch record revealed that the weights had not been recorded for the first 25 totes of suppositories. Further discussion with the operator revealed that only one of the three could read and write English. As a result he is the only operator that can record information on the batch record and was not able to keep up with production and recording the information.
Weights need to be recorded as the event occurs. With the recent changes to 21 CFR 211, if an electronic recording system is in place, a second individual is not required for verification purposes. In addition, personnel should be capable of performing the task to which they are assigned. The inability to read English would disqualify the other two operators unless the document also existed in the language in which they are proficient.
b) An interview with an operator on December 2, 20 I 0 revealed that the operator documented in the batch record that he had added the active ingredient Phenylephrine to a batch of (b)(4) Children’s Multi-Symptom Very Berry, lot #OK227B, when in fact it had not been added. In addition, the batch record has the addition of the active ingredient to the batch documented as “verified” by a second individual.
Falsification of data is a very serious issue. The FDA recently encountered this with Ranbaxy Laboratories, an Indian firm which manufactures various regulated products (see their various Warning Letters).
The batch records do not record the distinctive identification number to identify major equipment to show the specific equipment used in the manufacture of a batch of a drug product.
Specifically, tanks used for batching the oral products are not specifically identified at the steps in which they are used in the execution of the batch record. The only place specific tanks are identified is in the “Process Equipment Cleaning and Sanitization” section of the batch record which demonstrates the tanks were cleaned prior to use.
Batch records should show distinctive identification of the major equipment used during manufacturing. §211.105 Equipment Identification states a) all compounding and storage containers, processing lines, and major equipment used during the production of a batch of a drug product shall be properly identified at all times to indicate their contents, and, when necessary the phase of processing of the batch.
Reports of analysis from component suppliers are accepted in lieu of testing each component for conformity with all appropriate written specifications, without establishing the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals.
When a vendor is initially qualified, the vendor should be audited. This will either take the form of an on-site audit or a written request to respond to a series of questions. While the latter is not as desirable, it often is used for component suppliers where the material is not deemed “Critical”. While a Certificate of Acceptance is acceptable with periodic testing, the initial testing should be obtained on each incoming lot. If very few lots are received during the course of a year, then each lot should be tested. Establishing AQLs are quite helpful to determine the reliability of the supplier’s analyses.
Each lot of a component, drug product container, and closure that is liable to microbiological contamination that is objectionable in view of its intended use is not subjected to microbiological tests before use.
a) The prep pad material, isopropyl alcohol, and packaging foil used in the packaging of sterile and non-sterile alcohol prep pads are not tested prior to use to determine if microbiological contamination is present.
b) The hot melt adhesive, cotton coil, polystyrene sticks, and packaging foil used to manufacture the swabsticks and package the sterile and non-sterile swabstick products are not tested prior to use to determine if microbiological contamination is present.
Primary materials that are objectionable include the gauze that is received from the Client’s vendor. Without prior gamma irradiation of the gauze, there exists a strong likelihood that the incoming gauze will be contaminated with Bacillus sp. and in this situation, Bacillus cereus, in particular. While the isopropyl alcohol may contain contamination, and Bacillus sp., in particular, most isopropyl alcohol will not be contaminated with either Gram positive or Gram negative cocci or non-spore forming rods. In addition, the method of manufacturing packaging foil should minimize the number of microorganisms present unless the packaging foil is not maintained within dust covers.
Within (b) above, the cotton coils probably provide the most microorganisms, especially if the cotton coil has not been treated with gamma irradiation prior to assembly of the swabsticks.