- Delivery Method:
- VIA EMAIL CONFIRMED DELIVERY
- Issuing Office:
- Division of Pharmaceutical Quality Operations IV
December 9, 2022
Dear Mr. Kravzov and Mr. Gudino:
The U.S. Food and Drug Administration inspected your facility, Premier Nutra Pharma Inc., FEI 3017303868, at 5800 Newton Drive, Carlsbad, CA, from July 5 to July 8, 2022.
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).
We acknowledge receipt of your correspondence dated August 17, 2022. In your correspondence, you indicated your firm never intended, represented to be, or is currently a licensed drug manufacturer. However, documents collected during the inspection indicated that you considered nasal sprays to be over-the-counter (OTC) drug products. Furthermore, you acknowledged that the (b)(4) labels provided by (b)(4) “appeared to have medical claims.”
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 manufactured drug products on behalf of your customer, (b)(4). Your firm failed to perform an investigation into the microbial contamination of (b)(4) Nasal Spray batch (b)(4). Furthermore, there was no evaluation of other drug product batches that may have been similarly contaminated, as you indicated that at least (b)(4), a main ingredient in several drug products you manufactured for (b)(4), were visibly contaminated with insects (bees) and/or yeast yet were still used in production.
The inspection also documented that (b)(4) Nasal Spray drug product batch (b)(4), released to the market, was also contaminated with yeast. Test results provided to you by your customer indicated at least three different samples of this lot having results for yeast greater than 20 CFU/g, with one as high as 70 CFU/g. We acknowledge that your customer voluntarily recalled the affected batch.
2. Your firm failed to establish and follow appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile (21 CFR 211.113(a)).
Your firm failed to establish written, approved procedures to prevent microbial contamination during the manufacturing operations of nasal spray OTC drug products at your facility. Specifically, your firm did not have an environmental monitoring program, did not perform any microbiological testing of facilities or equipment, and did not have established cleaning procedures or records. These conditions and practices increased the risk of contamination of the drug products your firm manufactured.
Furthermore, your firm failed to conduct appropriate laboratory testing of each batch of drug product required to be free of objectionable microorganisms (21 CFR 211.165(b)).
3. Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR 211.188).
Your firm lacked adequate batch production and control records for your manufacturing operations. Your firm indicated that you did not have production records, including batch records, for (b)(4) Nasal Spray batch (b)(4). Although you provided records consisting of emails and initial master batch records, you failed to provide and maintain manufacturing batch records for your formulation, filling, and packaging operations, including equipment used, identification of person performing each step, description of components, complete labeling controls, and actual yield. Without adequate batch records, you cannot assure the uniformity of your drug products from batch to batch.
4. Your firm failed to establish an adequate quality unit and the responsibilities and procedures applicable to the quality control unit are not in writing and fully followed (21 CFR 211.22(a) and 211.22(d)).
Your firm lacked a quality unit (QU) and failed to establish written procedures defining QU responsibilities and controls. For example, your firm failed to establish adequate procedures for reviewing and approving batch records prior to drug product release, annual product reviews, deviations, corrective action and preventive action (CAPA), complaints, maintaining retain samples, and conducting recalls.
It is your responsibility as a drug manufacturer to comply with all CGMP requirements including, but not limited to, ensuring that the roles and responsibilities of QU are understood and fulfilled.
Your firm’s quality systems are inadequate. See the 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 CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations.
In response to this letter, provide:
- A thorough and independent evaluation of your operations to determine if any additional products you released and that remain within expiry, are drugs as defined by the FD&C Act. Include a list of all products released, including examples of labelling.
For all drug products that have been manufactured in your facility, provide the following:
- A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, QU oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
- A comprehensive, independent assessment of the design and control of your firm’s manufacturing operations, with a detailed and thorough review of all microbiological hazards.
- A detailed risk assessment addressing the hazards posed by distributing drug products with potentially objectionable contamination. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.
- Complete investigations into all batches with potential objectionable microbial contamination or an OOS microbiological result (whether or not later invalidated). The investigations should detail your findings regarding the root causes of the contamination.
- Appropriate microbiological batch release specifications (i.e., total counts, identification of bioburden to detect objectionable microbes) for each of your drug products.
- All chemical and microbial test methods used to analyze each of your drug products.
- A summary of results from testing retain samples of all drug product batches within expiry. You should test all appropriate quality attributes including, but not limited to, identity and strength of active ingredients, and microbiological quality (total counts and identification of bioburden to detect any objectionable microbes) of each batch. If testing yields an OOS result, indicate the corrective actions you will take, including notifying customers and initiating recalls.
- A CAPA plan, based on the retrospective assessment of your cleaning and disinfection program, that includes appropriate remediations to your cleaning and disinfection processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning and disinfection. Describe improvements to your cleaning and disinfection program, including enhancements to cleaning effectiveness, improved ongoing verification of proper cleaning and disinfection execution for all products and equipment, and all other needed remediations.
- 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 ensuring you retain attributable, legible, complete, original, accurate, and contemporaneous records throughout your operation.
- A risk assessment of products released to the U.S. market without adequate and approved production and control documentation.
- An independent, comprehensive assessment and remediation plan to ensure your QU is established with 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 and your contract manufacturers’ operations to evaluate adherence to appropriate practices in functions that could affect drug quality.
o A complete and final review of each batch and its related information before the QU disposition decision.
o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all drug products.
Responsibilities as a Contractor
Drugs must be manufactured in conformance with CGMP. The FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. The FDA regards contractors as extensions of the manufacturer.
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 the FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/contract-manufacturing-arrangements-drugs-quality-agreements-guidance-industry.
CGMP Consultant Recommended
Based upon the nature of the violations if your firm intends to resume manufacturing drugs for the U.S. market, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting drug 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.
Drug Production Ceased
We acknowledge your commitment to cease production of drugs at this facility. If you plan to resume manufacturing drugs, notify this office before resuming your operations.
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 any violations and for preventing their recurrence or the occurrence of other violations.
Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure, and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.
Failure to address violations may also cause the FDA to withhold issuance of Export Certificates. The FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to address any violations.
This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
Please identify your response with unique identifier CMS 640210. Electronic responses may be submitted to ORAPHARM4_Responses@fda.hhs.gov with ATTN: CDR Steven E. Porter, Jr. or send your written responses to:
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food and Drug Administration
1907 Fairchild Road
Irvine, CA 92612
If you have questions regarding this letter, please contact LCDR Rumany Penn, compliance officer, at (949) 608-4409, or by email at Rumany.Penn@fda.hhs.gov.
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV SP:rp
cc: Mr. Hector Gudino, Co-CEO
Premier Nutra Pharma Inc.
5800 Newton Drive
Carlsbad, CA 92008