Mr. Chi Fai Ching
April 5, 2018
Warning Letter 320-18-43
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Ming Fai Industrial, Shenzhen Co., Ltd. at Bainikeng, Pinhu Longgang, Shenzhen, Guangdong Province, from August 7 to 11, 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 product is 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 August 30, 2017, response in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).
You released over-the-counter (OTC) (b)(4) drug products without data to support their conformance to specifications, including identity and strength. For example, during the inspection, you acknowledged that you do not test your (b)(4) Gel product for active ingredient content. While your label claims that it contains (b)(4)% (b)(4), you have no data to support the label claim.
Also, your certificate of analysis (COA) did not include the active ingredient content for (b)(4). Your staff stated that the final concentration of (b)(4) was based on the calculation of the material added during the (b)(4) step. Testing for active ingredient concentration is essential to ensuring the each lot of drug product you manufacture meets its label claim.
In your response, you committed to developing a method to determine the content of the (b)(4) active ingredient in your final product and to include the results in your COA.
Your response was inadequate because you did not commit to developing an analytical method to perform identity testing for (b)(4) in the final product. You also failed to provide your interim plan while you are developing your analytical method. You continue to lack assurance that product lots will be released to the U.S. market only if they meet all specifications, including but not limited to identity and strength.
In your response to this letter, provide timelines for the development and validation of the analytical method to test the strength and identity of (b)(4) in your final product. Also provide an action plan and timelines for promptly testing retain samples to determine the identity and strength of active ingredients in all drug products distributed to the United States that are within expiry. If the testing reveals any product lots that do not meet specifications, provide your corrective actions, including notification of customers and recall.
2. Your firm failed to establish and 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 perform appropriate stability testing, such as chemical and microbiological tests, to determine the expiration date for your (b)(4) drug product. You established a (b)(4)-year shelf life based on the stability of one batch stored for up to 12 weeks. You monitored the stored stability samples only for changes in texture, color, fragrance, and packaging.
In your response, provide your plan with timelines for the development and implementation of a complete drug stability program, including chemical and microbiological (i.e., total count, objectionable organisms, efficacy) tests.
3. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).
During the inspection, you could not provide written procedures describing the roles and responsibilities of the quality unit nor could you provide a standard operating procedure (SOP) for deviation investigations. Also, our investigator noted that you do not perform annual product reviews.
Furthermore, your quality unit failed to approve certain CGMP documents and SOPs. During the inspection, our investigator found several blank documents, such as filling batch records, cleaning logsheets, and microbiology testing sheets, that were not issued and controlled by your quality unit. Our investigator also found that your quality unit did not approve your SOPs for gas chromatography and fourier-transform infrared spectroscopy testing.
Our investigator also found that batch records approved by your quality unit contained numerous documentation errors such as missing information and unexplained crossouts and changes.
In your response, you provided draft SOPs including drafts for document control, records control, labeling control, and traceability.
Your response is inadequate because you failed to indicate a timeline for implementing these draft SOPs. You also did not indicate what steps you will take in the interim to properly control documents and records for the manufacture and release of drug products while the procedures are being implemented.
In response to this letter, provide your corrective and preventive action (CAPA) plan for establishing an effective quality control unit with the appropriate responsibility and authority to review batch production records and test results, and to establish and implement adequate procedures to ensure drug quality. Also provide a CAPA that comprehensively and systemically remediates documentation practices used throughout your operations.
See FDA’s guidance document, Quality Systems Approach to Pharmaceutical CGMP Regulations, for help in implementing modern quality systems and risk management approaches to meet the requirements of CGMP regulations (21 CFR, parts 210 and 211) at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryinformation/Guidances/UCM070337.pdf.
4. Your firm failed to establish 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.l00(a)).
During the inspection, you acknowledged that you have not validated the processes used to manufacture your OTC drug products. You also lack an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.
Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed to assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies provide a determination of whether an initial state of control has been established. Successful process qualification studies are necessary prior to commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is essential to maintain manufacturing operations in a state of control throughout the product lifecycle.
In your response, you stated that you will establish a process validation SOP. Your response is inadequate because you failed to indicate your interim controls for the manufacture and release of drug products prior to the implementation and completion of your process validation activities. The response also lacks a commitment to establish whether the active ingredient is consistently and uniformally distributed in your gel products by extensively testing final units produced throughout processing. You also failed to conduct a risk assessment for your drugs already distributed to the U.S. market.
In response to this letter, provide the following:
• A detailed plan for designing, validating, maintaining, controlling, and monitoring your manufacturing processes and your approach for routinely monitoring intra-batch and inter-batch variation to ensure an ongoing state of control. Your plan should include but not be limited to provisions for extensively testing finished units to ensure uniform distribution of the active ingredient throughout the filling process.
• A comprehensive validation program that, in addition to assuring stable processes, includes validation of analytical methods as well as qualification of your equipment and facility.
• Updated master batch records that include improved specificity and require detailed entries in order to fully document each significant manufacturing step.
We acknowledge that you engaged a consultant to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve you firm’s obligation to comply with CGMP. The third party should comprehensively audit your entire operation for CGMP compliance. Your corrective and preventive actions should be evaluated by the third party to help ensure systemic remediation before you pursue resolution of your firm’s compliance status.
Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance. ·
Quality Unit Authority
Significant findings in our inspection indicate that your quality unit is not able to fully exercise its authority and responsibilities. Your firm must provide the quality unit with the appropriate authority and sufficient resources to carry out its responsibilities that are-essential to drug quality assurance.
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 their recurrence, and for preventing other violations.
FDA placed your firm on Import Alert 66-40 on December 21, 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 Ming Fai Industrial (Shenzhen) Co., Ltd. at Bainikeng, Pinhu Longgang, Shenzhen, Guangdong Province, 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 maybe subject to refusal admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 50l (a)(2)(B) of 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 [email protected] or mail your reply to:
Cesar E. Matto M.S.
Senior Policy Advisor
U.S. Food and Drug Administration
White Oak Building 51, Room 4235
10903 New Hampshire A venue
Silver Spring, MD 20993
Please identify your response with FEI 3003340745.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research