Inspections, Compliance, Enforcement, and Criminal Investigations

Product Packaging West, Inc. 11/2/18

 

  

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Division of Pharmaceutical Quality Operations IV
19701 Fairchild Road, Irvine, CA 92612-2506
Telephone: 949-608-2900
Fax: 949-608-4417

WARNING LETTER

VIA SIGNATURE CONFIRMED DELIVERY

November 2, 2018

Mr. Jose M. Arceo
President/Owner
Product Packaging West, Inc.
11921 Vose Street
North Hollywood, CA 91605-5750

Dear Mr. Arceo:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Product Packaging West, Inc. at 11921 Vose Street, North Hollywood, California, from March 7 to 13, 2018.

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 March 30, 2018, response in detail.

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

1. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and (2)).

You failed to test incoming components used in manufacturing your drug products to determine their identity, purity, strength, and quality. Your firm released these components based solely on your suppliers’ certificates of analysis (COA), without establishing the reliability of the suppliers’ analyses through appropriate validation. In addition, your firm does not have a vendor qualification program (e.g., COA validation, vendor audit).

Significantly, your firm failed to perform identification testing for all incoming glycerin lots to verify identity and determine whether diethylene glycol (DEG) or ethylene glycol (EG) was present. Because you did not test each lot and container of glycerin using the USP identification test that detects these hazardous impurities, you failed to ensure the acceptability of component lots used in drug product manufacture. DEG contamination in pharmaceutical products has caused lethal poisoning incidents in humans worldwide.

Your response indicated that you will perform identity tests on active ingredients before use. Your response is inadequate because it is not clear how you will test all incoming components for identity, purity, strength, and quality.

In response to this letter:

• Describe in detail how you plan to test each incoming component lot for conformity with all appropriate written specifications for purity, strength, and quality. If you accept your suppliers’ COA in lieu of testing each component lot for purity, strength, and quality,
describe how you plan to establish the reliability of your suppliers’ test results for these attributes at regular intervals, and include a commitment to test at minimum every incoming component lot (both active and inactive ingredients) for USP identity requirements. Also, provide your revised procedure remediating these deficiencies.

• Provide your revised SOP for testing all incoming lots of glycerin to ensure that they are not contaminated with DEG and EG.

• Provide a detailed risk assessment for drug products that contain glycerin and are within expiry in the U.S. market. As part of your risk assessment, immediately test retained samples of all lots for DEG and EG, and take appropriate market action if the testing yields any aberrant results.

See FDA’s guidance document Testing of Glycerin for Diethylene Glycol for CGMP requirements when manufacturing drugs containing glycerin, at https://www.fda.gov/downloads/Drugs/Guidances/ucm070347.pdf.

2. 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 211.100(a)).

Your firm lacks an ongoing program for monitoring process control to ensure stable manufacturing operations. You have not demonstrated that your manufacturing process is capable of consistently producing drugs of uniform character and quality.

Inadequate Control of Manufacturing Processes

You have not performed process validation studies for your over-the-counter (OTC) drug products (b)(4).

Your response states that you will write a validation plan that will be executed according to information provided by your client. Your response lacks a detailed process performance qualification protocol and an overall program for ensuring maintenance of a validated process throughout the product lifecycle for all your drug products. Your response is also inadequate because you have not provided timelines for your validation plan execution and interim measures to ensure that your processes are under control.

In response to this letter, provide:

• Your validation plans for your manufacturing processes, including your timeline for performing process performance qualification for all your drug products, and a detailed summary of your approach for routinely monitoring (b)(4) and (b)(4) variations on an ongoing basis.

• A risk assessment and retest results (including both microbial and chemical tests) for all distributed drug product batches within expiry that were manufactured using unvalidated processes.

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/guidances/ucm070336.pdf.

Inadequate Control of Water System

You did not follow your procedures to operate a sanitary (b)(4) water system. Further, your procedures to operate your (b)(4) water system were insufficient to ensure a system control. You were unable to provide chemical and microbiological test results that demonstrate your firm can effectively design, maintain, sanitize, monitor, and control your (b)(4) water system to ensure that it consistently produces water that meets the (b)(4) Water, USP monograph specifications and appropriate microbial limits. (b)(4).

Your response stated that you (b)(4) water system and that you will perform system validation. Your response is inadequate because your corrective actions are insufficient. (b)(4) by itself does not ensure that your (b)(4) water system is capable of consistently producing water of acceptable quality. You also did not provide a comprehensive review of system design or a water system validation plan.

In response to this letter, provide:

• A comprehensive evaluation of the water system design, conducted by a qualified consultant, and a thorough Corrective Actions and Preventive Action (CAPA) plan to appropriately modify your water system and validate it.

• Validation outcome for the (b)(4) water system, obtained after all identified design issues have been fully corrected and maintenance repairs have been completed. Include the system validation protocol, the complete test results, and the final validation report.

• An effective written program for validation, ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces water that meets (b)(4) Water, USP monograph specifications and appropriate microbial limits.

• Your total count limit for (b)(4) water. This limit should ensure that water quality is appropriate in view of the intended use of the products produced by your firm.

• A water system monitoring SOP that specifies routine microbial testing of (b)(4) water to ensure its acceptability for use in each batch of drug products produced by your firm.

3. Your firm failed to maintain adequate written records of major equipment maintenance (21 CFR 211.182).

Your firm lacks records of cleaning, sanitizing, and inspecting the (b)(4) water system, (b)(4), (b)(4), and (b)(4) that are used in the manufacture of each batch of your finished drug products. In addition, you stated that there is no documentation identifying the products processed in each piece of equipment.

In your response, you stated that you will create equipment logs for use, cleaning, and maintenance, and that you will write a new standard operating procedure (SOP) that includes provisions for periodic preventive maintenance and repair for each individual piece of equipment. Your response is inadequate because it does not include the SOP or timelines for writing, approval, and implementation of the SOP. You also failed to provide current equipment logs for use, cleaning, and maintenance.

In response to the letter, provide:

• New or revised SOP(s) that establish appropriate manufacturing equipment records.

• Copies of the logs documenting any cleaning, maintenance, and repairs performed on all major manufacturing equipment since the FDA inspection.

4. Your firm failed to establish written responsibilities and procedures applicable to the quality control unit (21 CFR 211.22(d)).

You do not have written procedures for numerous responsibilities of the quality unit, including but not limited to the approval or rejection of labeling, components, in-process materials, and finished drug products; complaint investigations; and various other basic drug manufacturing operations.

In your response, you stated that you will write an SOP outlining the responsibilities of the quality unit. Your response is inadequate because it does not provide the SOP for quality unit responsibilities, and it does not include timelines for the writing, approval, or implementation of the SOP.

In response to this letter, provide:

• A CAPA to ensure that the roles and responsibilities of your quality unit are clearly defined and established, to ensure that the quality unit has the appropriate authority and resources needed to carry out its responsibilities.

• Your SOPs for the quality unit, including the procedures for ensuring that all decisions on manufacturing and quality are appropriate throughout your operations.

Your firm’s quality systems are inadequate. For guidance on establishing and following CGMP compliant quality systems, see FDA’s guidances:

Q8 (R2) Pharmaceutical Development at https://www.fda.gov/downloads/drugs/guidances/ucm073507.pdf; Q9 Quality Risk Management at https://www.fda.gov/downloads/Drugs/Guidances/ucm073511.pdf; and Q10 Pharmaceutical Quality System at https://www.fda.gov/downloads/drugs/guidances/ucm073517.pdf.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, 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 fully resolving all deficiencies and ensuring ongoing CGMP compliance.

Labeling Compliance

According to 21 CFR 201.20, OTC drugs such as your (b)(4) that contain the color additive FD&C Yellow No. 5 (tartrazine) are required to list this ingredient on labels. Specifically, the label for OTC drug products intended for human use administered orally, containing FD&C Yellow No. 5 as a color additive, shall bear a statement such as “Contains FD&C Yellow No. 5 (tartrazine) as a color additive” or “Contains color additives including FD&C Yellow No. 5 (tartrazine).”

However, we note that your product label lists the ingredient as “May Contain Yellow 5 (CI 19140).” We remind you that continued listing of the ingredient in this manner would render your product misbranded.

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 their recurrence, and for preventing 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.

Until these violations are corrected, we may withhold approval of pending drug applications listing your facility. We may re-inspect to verify that you have completed your corrective actions. We may also refuse your requests for export certificates.

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 Kelly.Sheppard@fda.hhs.gov or mail your reply to:

Kelly D. Sheppard
Director (Acting), Division of Pharmaceutical Quality Operations IV
U.S. Food & Drug Administration
19701 Fairchild Road
Irvine, CA 92612

Please identify your response with unique identifier 555705.

Sincerely,
/S/

Kelly D. Sheppard
Director (Acting), Division of Pharmaceutical Quality Operations IV 

Page Last Updated: 11/16/2018
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