WARNING LETTER

Delta Laboratories Pty Ltd MARCS-CMS 537641 — December 19, 2017

Recipient:: Recipient Name

Mr. Gary Leach; Delta Laboratories Pty Ltd; 8 Warringah CL
Somersby, New South Wales 2250
Australia

Issuing Office:: Center for Drug Evaluation and Research; United States

10903 New Hampshire Avenue
Silver Spring, MD 20993

Via UPS Warning Letter 320-18-21

Return Receipt Requested

December 19, 2017

Mr. Gary Leach

Managing Director

Delta Laboratories Pty. Ltd.

8 Warringah CL

Somersby, New South Wales, 2250

Australia

Dear Mr. Leach:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Delta Laboratories Pty. Ltd. at 8 Warringah CL, Somersby, from March 27–31, 2017.

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

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products 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 April 13, 2017 response in detail.

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

1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

You failed to thoroughly investigate release and stability testing failures concerning two batches of your (b)(4) drug products. These product failures included viscosity and appearance. During stability testing, you also identified packaging defects. You did not initiate investigations for each of these drug quality issues. When you did investigate, you failed to adequately evaluate the manufacturing process and associated records, identify root causes, and implement effective corrective actions and preventive actions (CAPA).

For example, you found tubes swelling at the 3-month stability time point. You did not investigate this significant defect, which can be indicative of microbial growth and spoilage. Notably, your packaging stability specification requires “no change in packaging.”

In response to our findings, your customer recalled the remaining in-date batch of this product on November 28, 2017.

For more information about handling failing, out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070287.pdf.

2. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

The processes used to manufacture your (b)(4) drug products have not been shown to be consistent and reliable, and consequently batches of your drug products are likely to significantly vary in strength, quality, and purity.

For example, you lacked adequate process validation studies. Your validation report summarized a retrospective analysis of a single process qualification batch, (b)(4). You manufactured and released this batch in 2015.Notably, testing of this batch found stability failures of multiple quality attributes, including appearance and viscosity. Your validation report was approved on March 17, 2017, shortly before we inspected your facility. You lack evidence of process validation because you have not addressed all potential sources of variation that must be controlled to consistently yield drugs of uniform character and quality, and have not demonstrated that the process is reproducible.

Senior management stated that your firm has struggled with manufacturing this drug product, and that you were still conducting research to gain better product and process understanding. Although you acknowledged a lack of understanding to assure consistent quality, you still commercially distributed (b)(4) drug products to consumers.

Each significant stage of a manufacturing process must be designed to assure that raw material inputs, in-process materials, and finished drugs meet their quality attributes and specifications. Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Process qualification studies provide a determination whether an initial state of control has been established. Successful process qualification studies are required prior to commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is essential to ensure you maintain a stable manufacturing operation throughout the product lifecycle.

See FDA’s guidance document, Process Validation: General Principles and Practices, for general principles and approaches that FDA considers appropriate elements of process validation, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf.

3. Your firm failed to follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).

You did not have adequate stability data to demonstrate that the chemical and physical properties of your (b)(4) drug products remain acceptable throughout the labeled (b)(4) expiry period. Two lots reviewed during our inspection failed on stability at various tests and time points. You distributed these two lots of (b)(4) drug products to the U.S.

Batch (b)(4) failed for viscosity at multiple time points, and you terminated the stability study for batch (b)(4) after you identified phase separation in all samples at the 9-month time point.

At the time of the inspection, you had not taken appropriate action on these batches, such as notifying your customer or recalling products from the market.

Inadequate Response

Your April 13, 2017, response to FDA’s inspectional observations was inadequate. You did not provide sufficient evidence that you are taking corrective actions to bring your operations into full compliance with CGMP. In response to this letter, provide the following:

A summary of the actions you have taken to comprehensively remediate your investigation process, and an improved procedure.
Your investigations, using your revised procedures, for all drug quality related failures. A detailed summary of your review of all test results, root causes of specification failures, affected batches distributed to the U.S. market, and related CAPA.
A data-driven and scientifically sound process validation program that appropriately identifies sources of variability, and ensures oversight of intra-batch and inter-batch variation on an ongoing basis throughout the product lifecycle.
Timelines for performing prospective process qualification for your drug products.
A procedure describing your stability program.
Data for (b)(4) batches successfully manufactured as part of prospective qualification studies, to demonstrate that these batches are stable over the shelf life.
The disposition of (b)(4) batch (b)(4), including whether you plan to distribute it in the U.S.
Data to demonstrate that your (b)(4)Test–BP methodused to test drug products marketed in the U.S.is equivalent to, or better than, the current USP (b)(4)Test.
A thorough assessment of your adherence to CGMP requirements, and a CAPA plan to assure full remediation.

You should comprehensively address each of these items in your written response.

Quality Unit Authority

Significant findings in this letter indicate that your quality unit is not fully exercising its authority and/or responsibilities. Your firm must provide the quality unit with appropriate authority, sufficient resources, and staff to carry out its responsibilities and consistently ensure drug quality.

Responsibilities as a contractor

Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors, such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.

You and your customer, (b)(4), have a quality agreement for the manufacture of (b)(4) drug products. You are responsible for the quality of drugs you produce as a contract facility, regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA’s guidance document, Contract Manufacturing Arrangements for Drugs: Quality Agreements, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM353925.pdf.

CGMP consultant recommended

Based upon the nature of the violations identified at your firm, you should undertake a comprehensive and global assessment to ensure that your systems and processes, and ultimately, the drug products you manufacture, conform to FDA requirements. We strongly recommend engaging a consultant, qualified as set forth in 21 CFR 211.34, to assist your firm in meeting CGMP requirements.

We request that the qualified consultant provide FDA with a detailed written report describing their efforts to assist with comprehensive remediation of your facilities, methods, controls, and quality systems to ensure they are in compliance with 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 fully resolving all deficiencies and ensuring ongoing CGMP compliance.

Conclusion

Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing the recurrence, and for preventing other violations.

FDA placed your firm on Import Alert 66-40 on September 28, 2017.

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

Failure to correct these violations may also result in FDA continuing to refuse admission of articles manufactured at Delta Laboratories Pty. Ltd., 8 Warringah CL, Somersby, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

After you receive this letter, respond to this office in writing within 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 CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:

Bill Fowler

Consumer Safety Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Please identify your response with FEI 3004085558.

Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research