Yusef Manufacturing, Clearfield, UT was audited by the FDA from May 23 – 26, 2016. Subsequent to the audit the firm received a total of five citations relating to 21 CFR 211.22(d) (1)(2); 84(d) (1), (2); 100 (a); 192; 165(a), (b). Because of an on-going history of a failure to correct similar citations, the FDA issued the enclosed Warning Letter.
In previous inspections, dated September 2007 and February 2011, the FDA cited similar CGMP deficiencies. While the Company proposed specific remediations for the violations noted above, they were very similar to commitments following previous FDA inspections. These repeated failures demonstrate that Yusef Manufacturing facility’s oversight and control over the manufacture of drugs is inadequate.
Examples of these citations include:
3. Your firm does not 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 and freedom from objectionable microorganisms, prior to release (21 CFR 211.165(a), (b)).
You failed to test any of your finished drug products for chemical attributes, including identity and strength, prior to release. FDA collected and tested samples from different batches of your reserve samples of SPF 15 sunscreen lip balm products. FDA laboratory analysis found in all samples that the active ingredients octinoxate and oxybenzone were sub-potent. Both ingredients were found to have an average potency of 66%.
In addition, you failed to test each batch of your YMLabs Aloe Gel Sanitizer (62% ethyl alcohol) drug products for total count and objectionable microorganisms prior to release.
The FDA found the response to be inadequate. Yusef Manufacturing did not provide sufficient detail or evidence of corrective actions. The FDA is seeking the following additional information to include:
“a list of the current quality control criteria and test methods you currently use to test each drug product batch prior to release.
a thorough assessment to determine insufficiencies in chemical, physical, and microbiological specifications and analytical methods established for each of your drug products. Include a full remediation plan with appropriate specifications and analytical methods to be used for testing each batch of drug product.
an action plan and timelines for testing all in-date drug products for identity and strength of active ingredients, and all other appropriate chemical and microbiological quality attributes (e.g., total count, objectionable microorganisms). Regarding drug products found to be of substandard quality, including YMLabs Aloe Gel Sanitizers (62% ethyl alcohol) and SPF 15 sunscreen lip balm products, specify the actions that you will take, such as notifying customers and product recalls.”
4. Your firm failed to test samples of each component for conformity with all appropriate written specifications for identity, purity, strength, and quality (21 CFR 211.84(d)(1), (2)).
You do not test incoming active pharmaceutical ingredients and other components used in manufacturing your SPF 15 sunscreen lip balm products for adherence to all appropriate quality attributes. Your procedures only required routine incoming component testing for color, odor, and appearance.
Your response is inadequate. You did not sufficiently address your program for testing incoming components.
In your response to this letter, provide a summary of test results obtained from full testing (e.g., strength, identity, purity) of all of your incoming components. Also provide your current incoming raw material batch release specifications for each component. Describe which tests are done for each batch and which are generally accepted based on a validated Certificate of Analysis (COA). Specify whether all incoming component batches are analyzed using at least one specific identity test. Also provide a procedure describing your supplier qualification program.
ICH Q7 and ICH Q11 should be reviewed prior to Yusef Manufacturing developing a Supplier Qualification Program and rationalizing which tests should be performed for each raw material and which may be accepted on a validated COA.
5. Your firm failed to establish and to follow 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)).
Poor Control of Manufacturing Processes
Your manufacturing processes lack an adequate state of control. Manufacturing processes must be designed and controlled to assure that in-process materials and finished products reliably and reproducibly meet predetermined parameters, manufacturing standards, and quality requirements.
FDA analyzed beginning, middle, and end samples of your SPF 15 sunscreen lip balm batch W12072. Our laboratory found that the batch was not of uniform character and quality. These analyses showed active ingredient results that widely varied in strength across the batch, with assay values ranging from 26% to 93% of label claim. It is essential that your firm’s manufacturing processes, including mixing, provide for robust and homogenous distribution of active ingredients.
Inadequate Control of Water System
You also have not validated your “(b)(4)” water system. You must design your water system to reproducibly yield suitable water for use in production operations. Your firm had not demonstrated that you can effectively control, maintain, sanitize, and monitor the system so it consistently produces pharmaceutical grade water that, at a minimum, meets the USP monograph for purified water. The water from this unvalidated system is used as a component in your drugs.
You lacked testing of the water produced by this system. It is imperative that you routinely test water for chemical (e.g., total organic carbon, conductivity) and microbiological attributes.
In your response to this letter, provide an action plan:
• to ensure appropriate design, control, maintenance, and monitoring of your manufacturing processes and water system
• for validating your water system and your drug product manufacturing processes
• with detailed timelines for accomplishing each of these corrective actions
Without the knowledge of the identity, strength, quality, and purity, it becomes impossible to assure that the in-process intermediates and the final product will meet the product’s specifications.
In addition, without the validation of the water system, it is impossible to assure that pharmaceutical grade water meets USP monograph requirements on an on-going basis. Microbiological specifications for purified water include a requirement for <100 CFU/mL. In an uncontrolled Purified Water system, it becomes very difficult to assure this number on an on-going basis
The complete Warning Letter may be viewed at (Click Here).