- Delivery Method:
- VIA SIGNATURE CONFIRMED DELIVE
Recipient NameDr. Robert C. Blaine
- Blaine Labs Inc
11037 Lockport Place
Santa Fe Springs, CA 90670
- Issuing Office:
- Division of Pharmaceutical Quality Operations IV
May 5, 2020
Dear Dr. Blaine:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Blaine Labs Inc., FEI 3001744192 at 11037 Lockport Place, Santa Fe Springs, from September 25 to 30, 2019.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (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).
Your firm manufactures and distributes “RevitaDERM PSORIASIS Treatment” that is an unapproved new drug in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction or delivery for introduction of such a product into interstate commerce is prohibited under sections 301(d) of the FD&C Act, 21 U.S.C. 331(d). These violations are described in more detail below.
We reviewed your October 11, 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 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).
A. Your investigations into out-of-specification (OOS) test results were inadequate. For example, you did not adequately investigate the failing viscosity test result obtained at bulk stage of Terpenicol AFC 13% topical cream lot BL2534. Although your Quality Unit (QU) was aware of the drug quality failure, no investigation of manufacturing was performed and the lot was approved for release to customers.
Inadequate investigation of viscosity failures was also cited during our November 2015 inspection.
B. Your Tineacide Antifungal Cream 13%, lot BL1684TP failed the (b)(4) long term stability timepoint for appearance and viscosity and failed the (b)(4) long-term stability timepoint for appearance, viscosity, and assay. Notably, this lot also failed the initial viscosity testing. You did not investigate these failures.
C. Your raw material, (b)(4) lot (b)(4), failed the microbial specification for “total yeast count.” You failed to adequately investigate the OOS test result. You used this raw material to manufacture RevitaDerm Wound Care lots BL2696 and BL2697 in (b)(4). These lots were released and distributed to customers.
In your response, you indicated that you will “implement an OOS system” for bulk products and your staff will undergo training to ensure OOS results will be investigated.
Your response is inadequate. You lacked adequate improvements to your investigation program and did not adequately evaluate your manufacturing processes (including raw materials) to ensure that failures are properly remediated. You did not commit to a retrospective review of all your drug products to assess whether you are identifying root causes and implementing adequate corrective actions and preventive actions (CAPA).
In response to this letter, provide the following:
• A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for products currently in the U.S. market and within expiry as of the date of this letter and a report summarizing the findings of the analysis, including the following for each OOS:
o Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.
o For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.
o For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, lot failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.
• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed CAPA plan to remediate this system. Your CAPA plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, quality assurance unit oversight, and written procedures. Also address how your firm will ensure all phases of an investigation are appropriately conducted and the CAPA is are effective.
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, and your firm’s quality control unit did not review and approve those procedures, including any changes (21 CFR 211.100(a)).
Your firm failed to validate your drug product manufacturing processes. For example, your firm lacked process validation for your topical antifungal solution and cream, pain-relieving gel, psoriasis cream, wart removal solution, and wound care gel. Your firm also failed to qualify the equipment used to manufacture your products and failed to qualify the extensive hold times (e.g., multiple months).
The lack of process validation was also cited during our November 2015 inspection.
Further, your firm failed to validate your equipment cleaning processes.
Your response is inadequate because it lacks sufficient details on your approach to perform process and cleaning validation.
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 appropriately and ensure the quality of raw material inputs, in-process materials, and finished drugs. Failure to conduct these studies can result in lack of understanding of process variables, which increases the risk of product quality failures.
Process qualification studies determine whether an initial state of control has been established. Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary 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 http://www.fda.gov/media/71021/download.
In response to this letter, provide the following:
• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
• A timeline for performing process performance qualification (PPQ) for each of your marketed drug products.
• Include your process performance protocols, and written procedures for qualification of equipment and facilities.
• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include, but not be limited to, identification and evaluation of all worst-case:
o Drugs with higher toxicities
o Drugs with higher drug potencies
o Drugs of lower solubility in their cleaning solvents
o Drugs with characteristics that make them difficult to clean
o Swabbing locations for areas that are most difficult to clean
o Maximum hold times before cleaning
In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.
• A summary of updated standard operating procedures (SOPs) that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
• Within five days of receipt of this letter, provide your plan for initiating testing on your reserve samples of all drug product lots within expiry, prioritizing your antifungal and wound care gel products. Test all appropriate quality attributes including, but not limited to, chemical and microbiological quality (total counts and identification of bioburden to detect any objectionable microbes) of each lot. If testing yields an OOS test result, indicate the corrective actions you will take, including notifying customers and initiating recalls. Communicate the results of all testing to the Agency.
3. Your firm failed to conduct microbiological testing before use of each lot of a component with potential for objectionable microbiological contamination in light of its intended use (21 CFR 211.84(d)(6)).
Your firm did not adequately monitor your (b)(4) water to ensure suitability for its intended use. Water from this unvalidated system was used as a component in your drug products and for cleaning your manufacturing equipment. Also, your firm has not established that your (b)(4) water system is adequately designed, controlled, maintained, and monitored to ensure it consistently produced water that meets (b)(4) water standards.
Pharmaceutical water must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes.
In your response, you stated that you would contact the vendor of the water system to establish a (b)(4). You indicated that Quality Assurance is working with the vendor to (b)(4) your (b)(4) water system” and that your firm is establishing a (b)(4) for testing your water system. Your response is inadequate. You did not demonstrate that you have established a remediated system design that will maintain an ongoing state of control.
In response to this letter, provide the following:
• A comprehensive remediation plan for the design, control, and maintenance of the water system. Include a water system validation report of the studies conducted only after system design and control has been fully remediated. Summarize all improvements made to system design and to the program for ongoing control and maintenance.
• A procedure governing your program for ongoing control, maintenance, and routine monitoring that ensures the remediated system consistently produces water suitable for the intended use.
• The chemical and microbiological quality control specifications you use to test and release each incoming lot of component (e.g. ingredients) used in your drug product manufacturing.
4. Your firm failed to establish an adequate quality unit and the responsibilities, and procedures applicable to the quality control unit were not in writing and fully followed (21 CFR 211.22(a)&(d)).
Your QU did not fully exercise its authority and responsibilities. Your QU failed to ensure that you have adequate procedures and oversight of your manufacturing activities. For example, you lacked written or approved procedures describing process validation,
equipment qualification, OOS investigations, stability program, and change control for your manufacturing processes.
Your firm failed to follow proper documentation practices to ensure the accuracy of your CGMP records. For example, you had multiple versions of your bulk material test report template which were not approved by your QU. In addition, your document change control report did not adequately capture all changes made to your bulk material test report template.
Further, your quality control laboratory personnel used loose paper to document raw test data, which was later transcribed onto test reports. The loose paper was not retained or reviewed, and laboratory notebooks or worksheets were not used. Laboratory personnel signed off on their own test reports without secondary verification.
Your response lacked documentation and sufficient detail to support that you are establishing appropriate operational functions, systems, programs, and related procedures to ensure product quality. You also failed to address the potential impact that your lack of quality oversight had on the quality of all drugs that you manufacture.
Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality. See FDA's guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of the CGMP regulations (21 CFR, parts 210 and 211) at https://www.fda.gov/media/71023/download.
In response to this letter, provide the following:
• A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
o A determination of whether procedures used by your firm are robust and appropriate.
o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
o A complete and final review of each batch and its related information before the QU disposition decision.
o A complete assessment of documentation systems used throughout your manufacturing and 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, contemporaneous records throughout your operation.
Unapproved New Drug Charges
“RevitaDERM PSORIASIS Treatment” is a “drug” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because it is intended for the diagnosis, cure, mitigation, treatment, or prevention of disease and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because it is intended to affect the structure or any function of the body. Specifically, this product is intended for use as a combination Over-the-counter (OTC) psoriasis, seborrheic dermatitis, and skin protectant drug product.
Examples of claims observed on your product label “RevitaDERM PSORIASIS Treatment” that provide evidence of the intended uses (as defined in 21 CFR 201.128) of the product include, but may not be limited to, the following:
“PSORIASIS TREATMENT . . . ALSO RELIEVES • ECZEMA • SEBORRHEIC DERMATITIS •
ITCHING . . . Treats Eczema . . .”
OTC drug products intended for psoriasis and seborrheic dermatitis such as “RevitaDERM PSORIASIS Treatment” are subject to the OTC Drug Products for the Control of Dandruff, Seborrheic Dermatitis, and Psoriasis final rule (21 CFR Part 358 Subpart H). Additionally, OTC drug products intended to treat the symptoms of eczema are subject to the final monograph covering skin protectant drug products for over-the-counter (OTC) human use (21 CFR Part 347). However, this product is not labeled or formulated in accordance with these final rules for the reasons explained below.
Neither of the final rules cited above permit the combination of a Dandruff, Seborrheic Dermatitis, and Psoriasis and skin protectant drug product. Furthermore, the product label includes indications such as psoriasis treatment, that is not included under the OTC Drug Products for the Control of Dandruff, Seborrheic Dermatitis, and Psoriasis final rule (21 CFR Part 358 Subpart H) rulemaking, or any rulemaking being considered under the OTC Drug Review. The final rule permits indications for the relief of symptoms associated with psoriasis.
Additionally, the formulation for “RevitaDERM PSORIASIS Treatment” is not consistent with the formulation requirements that describe acceptable active ingredients for skin protectant drug products. Specifically, coal tar is not recognized as an acceptable active ingredient in 21 CFR Part 347. Further, the product label includes indications such as eczema treatment, that is not included under this rulemaking, or any rulemaking being considered under the OTC Drug Review. The skin protectant final rule permits indications for the relief of symptoms associated with eczema.
Furthermore, we are not aware of sufficient evidence to show “RevitaDERM PSORIASIS Treatment” as formulated and labeled, is generally recognized as safe and effective. Therefore, this product is a new drug within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p). As a new drug, “RevitaDERM PSORIASIS Treatment” may not be legally marketed in the United States absent approval of an application filed in accordance with section 505(a) of the FD&C Act, 21 U.S.C. 355(a). “RevitaDERM PSORIASIS Treatment” is not the subject of an FDA-approved application, and therefore, the current marketing of this product violates section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction or delivery for introduction of such a product into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).
CGMP Consultant Recommended
Because you failed to correct repeat violations, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 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.
The violations cited in this letter are not intended to be an all-inclusive statement 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 of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.
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.
Please send your electronic reply to ORAPharm4_responses@FDA.HHS.GOV or mail your reply to:
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food & Drug Administration
Irvine, California 92612-2506
Please identify your response with the unique identifier: CMS 598733.
If you have questions regarding the content of this letter, please contact Maria Kelly-Doggett, Compliance Officer via email at Maria.Kelly-Doggett@fda.hhs.gov or by telephone at 425-302-0427 and reference unique identifier (598733).
CDR Steven E. Porter, Jr.
Director Division of Pharmaceutical Quality Operations IV