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  1. Warning Letters


Grace Analytical Lab Inc MARCS-CMS 586510 —


Recipient Name
Grace H. Kim
Recipient Title
President and CEO
Grace Analytical Lab Inc

5300 McDermott Drive, Suite A/B
Berkeley, IL 60163
United States

Issuing Office:
Division of Pharmaceutical Quality Operations III

United States

November 19, 2019

Case # 586510

Dear Ms. Kim:

The U.S. Food and Drug Administration (FDA) inspected your contract testing laboratory, Grace Analytical Laboratory Inc., FEI 3007291509, at 5300 McDermott Drive, Suite A/B,
Berkeley, Illinois, from May 8 to 30, 2019.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, 21 CFR parts 210 and 211.

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drugs are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
We reviewed your June 20, 2019, response to our Form FDA 483 in detail. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.

During our inspection, our investigator observed specific violations including, but not limited to, the following.

1. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).

Your laboratory records do not include complete testing data. For example, we observed microbiological laboratory records that lacked incubation dates, times, and growth promotion test results for media prepared in-house, as well as humidity readings for a stability chamber.

This is a repeat observation from our January 30, 2017, inspection. Following our regulatory meeting with your firm in June 2017, you sent a written response and claimed that employees received training in document control. However, based on our recent 2019 inspection, it does not appear this corrective action was effective.

In your June 20, 2019, response, you stated the technician had informally recorded the media test data elsewhere with an intent to subsequently transfer the data to an appropriate document. You did not investigate why the technician recorded raw data outside the official logbook, or evaluate the extent and impact of this practice. Regarding the missing stability chamber data, you stated the cause was a malfunctioning temperature sensor which had been replaced. However, you failed to document, investigate, and implement changes to prevent recurrence.

In response to this letter, provide your investigation into the missing entries of media test data and stability chamber humidity records. Include an impact assessment evaluating the effects this missing information had on the reliability of microbiological testing and stability study results. Provide your investigation into why personnel were recording raw data outside the official logbook. Include your evaluation of the extent of this practice throughout your facility, along with your corrective action and preventive action (CAPA) plan to prevent recurrence of this event.

2. Your firm’s quality control unit failed to approve or reject all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product (21 CFR 211.22(d)).

Your Quality Unit failed to establish an adequate system of issuance, use, and reconciliation of laboratory test records. In addition, there were inadequate controls over forms generated by the Quality Unit for change controls, out-of-specification (OOS) investigations, and laboratory deviations.

In your June 20, 2019, response, you stated that standard operating procedures (SOPs) will be updated to include instructions for the issuance, use, and reconciliation of Laboratory Test forms and Quality Data forms. However, you did not provide copies of the updated SOPs, specify what changes will be made, or state when the revised changes will be implemented. You also failed to assess the impact of inadequate document control on the test data reported to your customers.

In response to this letter, provide:

• Updated copies of your procedures requiring the issuance, use, and reconciliation of all forms used to support CGMP operations, including OOS investigations.
• A complete assessment of how your lack of controls may have impacted the data generated and released to your customers.
• A complete assessment of the documentation systems used throughout your laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, and contemporaneous records throughout your operation.

3. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

Your firm does not adequately control access to your high-performance liquid chromatography (HPLC) system, such as using employee-specific logins, and has not enabled the audit trail feature for the chromatographic data management system. You utilize these systems to provide CGMP test results to your customers.

This is a repeat observation from our January 30, 2017, inspection. In your July 20, 2017, response, you committed to having Quality Assurance verify documents in real time with time stamps and signatures until you installed compliant software. However, based on our 2019 inspection, it appears that you have not made appropriate corrective actions to ensure the integrity of laboratory data.

In your June 20, 2019, response, you stated that the audit trail feature will be enabled, and a “lack of attention was the cause of this deviation.” Your response is inadequate because it lacked details on how you will prevent recurrence of this issue.

In response to this letter provide:

• Your action plan, with timelines, describing your interim controls and when audit trails will be enabled for all applicable electronic laboratory data systems, as well as when procedures will be implemented for the review of audit trails.
• Your investigation into the failure to enable the audit trail functionality in your electronic laboratory data systems and the impact this recurring failure could have on generated data.
• Documentation verifying that employee-specific logins and passwords are in place for all applicable electronic laboratory equipment.
• Configuration changes made to your systems to ensure restricted access with established rights and privileges, and to prevent disabling the audit trail feature.
• A detailed summary of employee training to ensure no recurrence of these issues.

4. Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).

Your SOP for determining the concentration of propylene glycol by (b)(4) is neither a USP method nor been shown to be equivalent or better to the USP method.

This is a repeat observation from our January 30, 2017, inspection. In your February 2017 response, you committed to revising your analytical method validation procedure to include a comparability method qualification when there are deviations from a USP method. However, based on our 2019 inspection, it appears that you have not made appropriate corrective actions.

In your June 20, 2019, response, you stated that the client for whom your firm performed the propylene glycol analysis was aware of and preferred your method for testing their samples. You reported that you do not possess a (b)(4) outfitted with (b)(4) that is needed to demonstrate comparability with the USP method. We acknowledge that your firm is not currently performing this analysis and your commitment to perform comparability testing prior to performing any future analyses.

In response to this letter, provide your assessment of each analytical method used to test a compendial material to ensure it follows the compendial test procedure. For each analytical method found to differ from the compendial method, provide your detailed plan to demonstrate the method is equivalent or better to the compendial method and the date by which this activity will be completed.

5. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

Drug product formulation changes made in the pH of (b)(4) ointment by your client did not result in any documented assessment of the continued suitability of your associated test method. Knowledge of this drug product change did not result in initiation of any change control or evaluation of the continuing suitability of associated test methods for microbiological analysis.

In your June 20, 2019, response, you stated that the change controls are documented per SOP, and employees are undergoing retraining. Your response is inadequate because you did not provide data to support your method is suitable to test the new drug product formulation.

In response to this letter, provide:

• Your analysis of method suitability for all test methods used for (b)(4) drug product.
• Your investigation into why your employees failed to follow the change control procedure.
• Your detailed plan to ensure all employees receive training with sufficient frequency to assure they remain familiar with the procedures.

Responsibilities of a Contract Testing Lab

FDA considers contractors as extensions of the manufacturer’s own facility. Your failure to comply with CGMP may affect the quality, safety, and efficacy of the drugs you test for your clients. It is essential that you understand your responsibility to operate in full compliance with CGMP, and that you inform all your customers of any out-of-specification results or significant problems encountered during the testing of these drugs.

Repeat Observations at Facility

In a previous inspection, dated October 24, 2016, to January 30, 2017, FDA cited similar CGMP observations. You proposed specific remediation for these observations in your response.

Repeated failures demonstrate that executive management oversight and control over the testing of drugs is inadequate.

CGMP Consultant Recommended

Because you failed to correct repeat violations, we strongly recommend engaging a consultant to assist your firm in meeting CGMP requirements.

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Data Integrity Remediation

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you test for your customers. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/downloads/drugs/guidances/ucm495891.pdf.


The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of other violations.

Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.

FDA may also withhold approval pending new drug applications or supplements listing your facility until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.

Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm.

After you receive this letter, respond to this office in writing within fifteen (15) working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Send your electronic reply to ORAPHARM3_RESPONSES@fda.hhs.gov.

Attn: Russell K. Riley
Compliance Officer
U.S. Food and Drug Administration
Division of Pharmaceutical Quality Operations III

Please refer to the unique identification number (Case 586510) when replying. If you have questions regarding the contents of this letter, please contact Mr. Riley by phone at (630) 323-2763 x. 101.


Art O. Czabaniuk
Program Division Director
Division of Pharmaceutical Quality Operations III

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