This response from the Quality Assurance Manager addresses concerns raised in a warning letter from the FDA regarding three observations: (1) lack of adequate qualified personnel, (2) failure to establish time limits for production phases, and (3) lack of strict control over labeling. For each observation, the response provides corrective actions taken, preventative actions implemented, and an expected completion date of two months from the warning letter date. The overall tone is one of commitment to addressing the issues and ensuring compliance with regulations to protect patient safety.

1. Public Health Service
Food and Drug Administration
Center for Biologics Evaluation and Research HFM-600
1401 Rockville Pike, Suite 200N
Rockville, Maryland 20852-1448
Dear Ms. Mary A. Malarkey:
We are in receipt of your communication dated 16 on April 2014. We take your communication very seriously and commit ourselves to address your concerns adequately and expeditiously. We would take all the necessary measures to ensure our customers’ well-being and safety. I've been reached out to consult on the issued observations on the behalf of Mr. Antonio Lopez de Silanes Perez the President/CEO of the company. The warning letter has been brought to my attention late. Therefore, I apologize for the late response. Enclosed please find an attachment that addresses your concerns on an individual and on a systematic basis. This documentation includes the following:
7. You failed to assure that there are an adequate number of qualified personnel to perform and
supervise the manufacture, processing, packing, or holding of each drug product [21 CFR 211.25(c)].
Specifically, during an interview, the Quality manager stated that investigations are often not conducted due to a lack of personnel. The actions identified by the inspector in this observation resulted in the production of the drug product being stopped. An extensive review of number, qualifications and experience of the personnel in all departments directly or indirectly affecting quality of the drug product including manufacture, processing, packing and holding departments was performed by Quality Assurance and senior management. In addition, the manufacturing, processing, packing and holding process and procedures were reviewed by Quality Assurance and senior management. Moreover, an investigation was conducted by third party inspection company to determine batches of the drug product affected by lack of adequate number of personnel in departments previously mentioned. To ensure compliance, the corrective actions were introduced such as affected drug products that met the requirements would be released. GMP retraining would been carried out for all staff by Quality Assurance. Several qualified personnel with several years of experience would recruited for multiple operator and supervisor positions and trained according to GMP. The SOP regarding personnel in the company would been updated to incorporate inspecting the number and qualifications of personnel. The Quality manager in question is no longer with the company. Preventative actions would include a weekly follow-up would be conducted by Quality Assurance to ensure the competency of the personnel. The manufacturing, processing, packing and holding processes would be reviewed by Quality Assurance to detect any non conformance. Number of investigations conducted per month would be assessed and reviewed by Quality Assurance to ensure its compliance to GMP requirements. Status of the proposed corrective and preventative actions is ongoing and the expected date would be two months from the issue date of the warning letter (16 June 2014).

2. 9. You failed to establish time limits for the completion of each phase of production to assure the quality of the drug product [21 CFR 211.111]. Specifically, you have not established time limits for Anascorp® sterile filtration and aseptic filling. This observation has led to stopping the production of the drug product in question. Affected drug products were held in quarantine for further testing by third party inspection. Procedures and personnel related to production of the affected drug product were extensively investigated and reviewed by Quality Assurance. This investigation included procedures for sterile filtration and aseptic filling of Anascorp and was specifically assessed by Quality Assurance. Corrections actions would include the release of affected drug products including Anascorp in case the requirements were met. Time limits for completion of each phase of production would be developed by Research and Development and later validated. Validation protocol and procedures for the time limits would be developed. SOPs for the established time limits would be developed and personnel would be trained on this SOP to ensure compliance. Preventative actions would include a third party inspection conducted on daily basis on the drug intermediates after each phase of production to ensure the quality of the drug product. Time limits for completion of each phase of production including time limits for sterile filtration and aseptic filling would be regularly assessed daily by third party inspection. The competency of the personnel in the production area would be reviewed weekly by Quality Assurance. Status of the proposed corrective and preventative actions is ongoing and the expected date would be two months from the issue date of the warning letter (16 June 2014).
11. You failed to assure strict control is exercised over labeling issued for use in drug product labeling
operations [21 CFR 211.125(a)]. Specifically, during the inspection the packaging components
warehouse door was unlocked and therefore access to the room was not limited to authorized personnel. The observation of lack of strict control over labeling prompt an investigation for this labeling issue. Drug products affected by this issue were recalled and their labels were further assessed by Quality Assurance. The supervisor of the Packaging department and personnel in the packaging and warehouse department as well as every personnel authorized to unlock the door in question were investigated as a result of not complying to GMP requirements. Corrective actions includes that the affected drug products would be released if the labels met the requirements. Quality Assurance would conduct a GMP retraining of all staff including personnel in packaging department. Retraining would emphasize the importance of adhering to regulations regarding strict control of areas (i.e. packaging and labeling area) limited to authorized personnel. Quality Assurance would update the current SOP regarding strict control of GMP areas. A log book developed by Quality Assurance would be situated at these areas as authorized personnel would have to sign before unlocking the door and entering the room. The Facility Planning and Designing department would assess all doors in GMP areas for their ability to provide strict control over these areas. Preventative actions include a daily inspection of all GMP areas conducted by Quality Assurance. A follow-up including inspecting the doors to provide strict control would be conducted by Quality Assurance and the Facility Planning and Designing departments. Log books presented at the locked doors would be reviewed daily by Quality Assurance. Status of the proposed

3. corrective and preventative actions is ongoing and the expected date would be two months from the issue date of the warning letter (16 June 2014). I hope the above responses represent a clear portrayal of actions taken and of the new policies that have been implemented to comply with regulations and prevent such occurrences in the future. We would not limit our corrective and preventative actions to the above observation. We plan to continuously monitor our quality system for defects and correct them immediately. We remain committed to patient safety by ensuring GMP compliance. Sincerely, Muna Ali Manager, Quality Assurance Department
Instituto Bioclon S.A. de C.V

4. Observation Number
Observation
Response
Corrective Action
Preventative Action
Status
Expected or Completed Date
7
You failed to assure that there are an adequate number of qualified personnel to perform and
supervise the manufacture, processing, packing, or holding of each drug product [21 CFR 211.25(c)].
Specifically, during an interview, the Quality manager stated that investigations are often not conducted
due to a lack of personnel.
The actions identified by the inspector in this observation resulted in the production of the drug product being stopped. Also, an extensive review of number, qualifications and experience of the personnel in all departments directly or indirectly affecting quality of the drug product including manufacture, processing, packing and holding departments was performed by Quality Assurance and senior management. In addition, the manufacturing, processing, packing and holding process and procedures were reviewed by Quality
Affected drug products that met the requirements would be released. GMP retraining would been carried out for all staff by Quality Assurance. Several qualified personnel with several years of experience would recruited for multiple operator and supervisor positions and trained according to cGMP. The SOP regarding personnel in the company would been updated to incorporate inspecting the number and qualifications, of personnel. The Quality manager in question is no longer with the company.
A weekly follow-up would be conducted by Quality Assurance to ensure the competency of the personnel. The manufacturing, processing, packing and holding processes would be reviewed by Quality Assurance to detect any non conformance. Number of investigations conducted per month would be assessed and reviewed by Quality Assurance to ensure its compliance to GMP requirements.
Ongoing
16 June 2014

5. Assurance and senior management. Moreover, an investigation was conducted by third party inspection company to determine batches of the drug product affected by lack of adequate number of personnel in departments previously mentioned. Affected drug products were held in quarantine and only released if it met specifications through analytical testing performed by third party inspection company.
9
You failed to establish time limits for the completion of each phase of production to assure the
quality of the drug product [21 CFR 211.111].
This observation has led to stopping of production of the drug product in question. Affected drug products were held in quarantine for further testing
Affected drug products including Anascorp would be released in case the requirements were met. Time limits for completion of each phase of
A third party inspection would be conducted on daily basis on the drug intermediates after each phase of production to ensure the quality of the drug product.
Ongoing
16 June 2014

6. Specifically, you have not established time limits for Anascorp® sterile filtration and aseptic filling.
by third party inspection. Procedures and personnel related to production of the affected drug product were extensively investigated and reviewed by Quality Assurance. This investigation included procedures for sterile filtration and aseptic filling of Anascorp and was specifically assessed by Quality Assurance.
production would be developed by Research and Development and later validated. Validation protocol and procedures for the time limits would be developed. SOPs for the established time limits would be developed and personnel would be trained on this SOP to ensure compliance.
Time limits for completion of each phase of production including time limits for sterile filtration and aseptic filling would be regularly assessed daily by third party inspection. The competency of the personnel in the production area would be reviewed weekly by Quality Assurance.
11
You failed to assure strict control is exercised over labeling issued for use in drug product labeling
operations [21 CFR 211.125(a)]. Specifically, during the inspection the packaging components
warehouse door was unlocked and
The observation of lack of strict control over labeling prompt an investigation for this labeling issue. Drug products affected by this issue were recalled and their labels were further assessed by Quality Assurance. The supervisor of the Packaging department
The affected drug products would be released if the labels met the requirements. Quality Assurance would conduct a GMP retraining of all staff including personnel in packaging department. Retraining would emphasize
Quality Assurance would conduct a daily inspection of all GMP areas. A follow-up including inspecting the doors to provide strict control would be conducted by Quality Assurance and the Facility Planning and Designing departments. Log books presented at
Ongoing
16 June 2014

7. therefore access to the room was not limited to authorized
personnel.
and personnel in the packaging and warehouse department as well as every personnel authorized to unlock the door in question were investigated as a result of not complying to GMP requirements.
the importance of adhering to regulations regarding strict control of areas (i.e. packaging and labeling area) limited to authorized personnel. Quality Assurance would update the current SOP regarding strict control of GMP areas. A log book developed by Quality Assurance would be situated at these areas as authorized personnel would have to sign before unlocking the door and entering the room. The Facility Planning and Designing department would assess all doors in GMP areas for their ability to provide strict control over these areas.
the locked doors would be reviewed daily by Quality Assurance.