Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
300 River Place
Detroit, Ml 48207
July 30, 2015
Mr. Ekramul Ameen, President/CEO
American Family Pharmacy, LLC
3250 N. Post Road, Suite 285
Indianapolis, IN 46226
During our June 11, 2014 to July 8, 2014 inspection of your pharmaceutical manufacturing facility, American Family Pharmacy, LLC located at 3250 N. Post Road, Indianapolis, Indiana, aninvestigator from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your drug products to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), [21 U.S.C. 351(a)(2)(B)], in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
Our inspection also revealed that your firm failed to fulfill its registration and listing obligations under section 510 of the Act, which is prohibited under Section 301(p), 21 U.S.C. 360 and 331(p). As a result, your drugs are misbranded under Section 502(o) of the Act, 21 U.S.C. 352(o). These drug products are also misbranded pursuant to section 502(a) of the Act [21 U.S.C. 352(a)] and section 502(f)(2) of the Act [21 U.S.C. 352(f)(2)].
During our inspection, the FDA collected a sample from lot 12084: aspirin tablets, 81 mg (labeled “Aspirin Enteric Safety Coated Tablets”). FDA conducted laboratory analysis per the United States Pharmacopeia (USP) on this sample. Your delayed release product failed to meet compendial specifications for assay, content uniformity, and dissolution. These results cause the product to be adulterated within the meaning of 501(b) of the Act, [21 U.S.C. 351(b)], in that its strength, quality, or purity failed to meet specifications set forth in an official compendium in which the product is represented. This product is also misbranded within the meaning of section 502(a), [21 U.S.C. 352(a)] of the Act because its labeling is false and misleading and 502(f)(2).
You informed the FDA investigator that your firm ceased all operations in May 2014, but you intend to resume operations once you acquire the necessary funds. We wish to be informed if you resume production.
We have reviewed your firm’s one-page response dated July 15, 2014, and note that it lacks sufficient corrective actions.
Our investigator observed specific violations during the inspection, including, but not limited to, the following.
Current Good Manufacturing Practice Violations
1. Your firm failed to follow written procedures applicable to the quality control unit (21 CFR 211.22(d)).
From January to May, 2014, your firm manufactured (b)(4) lots of 81 mg aspirin tablets. You gave all these lots, produced over five months, a single lot number: “12084.” This negated your ability to differentiate between lots. During this time, your firm distributed these “12084” lots with no review from your firm’s quality unit to ensure the identity, strength, quality, and purity of your drug products. This contradicts your “Responsibilities of the Quality and Production Units” SOP.
Furthermore, you followed these same poor practices while manufacturing (b)(4) lots of 500 mg acetaminophen. The (b)(4) lots used common lot numbers “011414B488”, “011414B443”, “011414A357”, and “011414A415,” from January to April, 2014. Your quality unit did not review these lots prior to release for distribution.
2. 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 prior to release (21 CFR 211.165(a)).
For example, you distributed multiple lots of 81 mg aspirin tablets without finished product testing. Your “Lot Release/Reject” SOP defines procedures for lot release before lot distribution including, but not limited to, review of all release data to determine if the products conform to established specifications and then issuance of certificates of analysis.
You did not provide any documentation to demonstrate that you performed the analyses required by your own SOP to determine that these lots were acceptable before you released them for distribution.
Furthermore, when FDA’s laboratory tested dissolution of a sample of 81 mg aspirin tablets from lot 12084, your product failed to meet the USP specifications for assay, content uniformity, and dissolution. In response to your August 27, 2014 request, FDA provided you with these failing laboratory test results. FDA also discussed these results with you during a teleconference on September 10, 2014. On September 15, 2014 you recalled lot 12084 voluntarily.
In addition to the failing results described above, FDA also found that the lot 12084 tablet color was inconsistent. Tablets were different shades of yellow. According to Form FDA 483, Observation 5, your firm received at least four customer complaints about inconsistently colored tablets. You received these complaints from January to May, 2014. You did not investigate them.
3. Your firm failed to establish and follow procedures for the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures (21 CFR 211.80(a)).
For example, your firm did not establish acceptance specifications or procedures requiring that incoming active blends from your suppliers used to manufacture aspirin tablets, 81 mg and acetaminophen tablets, 500 mg, be tested for identity and blend uniformity. Additionally, you did not establish specifications and procedures to evaluate whether active blends, which were used repeatedly over extended periods of time (e.g., 3 months), remained of acceptable quality throughout their extensive use period. Blend segregation problems and moisture uptake are among the problems that can occur during these long use periods and can lead to significant issues with tablet compression (e.g., weight variation, poor content uniformity) as well as stability problems.
4. 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 (21 CFR 211.100(a)).
For example, your firm does not have evidence that your processes for compressing 81 mg aspirin tablets and 500 mg acetaminophen tablets have been validated. Specifically, your procedures for compressing tablets and operating the tablet press do not require in-process sampling for parameters such as tablet weight variation, hardness, and friability.
Your management was unable to provide any validation documentation to demonstrate that your processes for compression are adequately controlled to consistently ensure the potency and uniformity of your drug products. Your firm also lacked sufficient batch instructions to ensure reproducibility.
Your firm’s batch records do not include complete documentation that every significant step in the manufacture, processing, packing, or holding of the batch was accomplished. For example, your “Master Batch Daily Record-Packaging” for “ASPIRIN, 81 mg, YELLOW COATED” does not include:
- weights and measures of components used in manufacturing
- description and lot number for each lot of containers and closures
- labeling and control specimens for each lot of finished, packaged drug products
- in-process or laboratory control test results
- list of production and testing equipment
- reconciliation of actual and theoretical yield values for components, bulk drug product, container closures, and labeling
It is imperative that you record all data and information relating to manufacturing in order to evaluate each batch and monitor the state of control of your pharmaceutical production operation. When batch data and information is lacking for a batch, ongoing adherence to established manufacturing standards and specifications cannot be assessed to assure ongoing control throughout the lifecycle (process validation).
5. Your firm failed to assure that drug products bear an expiration date determined by appropriate stability testing. (21 CFR 211.137).
For example, your firm manufactured (b)(4) batches of aspirin tablets, 81 mg, and (b)(4) batches of acetaminophen tablets, 500 mg, from January to May, 2014. You did not monitor or evaluate the stability of these products. Their expiration dates are not based on any supportive initial or ongoing stability studies.
6. Your firm failed to establish and follow written procedures designed to assure that correct labels, labeling and packaging are used for drug products (21 CFR 211.130).
For example, you did not follow your firm’s SOP, “Lot Number Creation.” From January to May, 2014, your firm used your suppliers’ lot numbers of the active blends in your acetaminophen and aspirin as your own manufacturing numbers. With your single lot number “12084”, it is impossible to distinguish between lots manufactured and packaged over different cycles of manufacturing.
Your “Aspirin Enteric Safety Coated Tablets” are misbranded under section 502 of the Act [21 U.S.C. 352] for several reasons.
The immediate container label does not include the Reye’s Syndrome Warning and Stomach Bleeding Warning, as required under 21 CFR § 201.314 and 21 CFR § 201.326. Only the names of the required warnings are referenced on the immediate container. You tell users to keep the outer carton for the complete warning. This is insufficient.
The Stomach Bleeding Warning on the outer container is also incomplete. It fails to include the word “severe” within the first line of the warning. The “take a blood thinning (anticoagulant) or steroid drug” bullet is missing. Therefore, the product is misbranded under sections 502(f)(2) and 502(a) of the Act [21 U.S.C. 352(f)(2) and 352(a)].
FDA also tested dissolution on a sample of “Aspirin Enteric Safety Coated Tablets.” It failed to meet the USP dissolution specifications for delayed released tablets in accordance with 21 CFR §343.90 (c), which states, “aspirin delayed-release tablets must meet the dissolution standard for … aspirin delayed-release tablets as contained in U.S.P, XXI Supplement 3 at page … 1973.” Therefore, the product is misbranded under section 502(a) of the Act [21 U.S.C. 352(a)]. It is marketed as an enteric coated aspirin tablet without meeting the dissolution testing requirements.
American Family Pharmacy, LLC, manufactured, packaged, and distributed “Aspirin Enteric Safety Coated Tablets” and “Extra Strength Acetaminophen Caplets” and repackaged and distributed “Ibuprofen 200mg Tablets” from January 8 through May 5, 2014. Section 510(j)(1) of the Act [21 U.S.C. 360(j)(1)] requires that all drugs manufactured, prepared, propagated, compounded, or processed for commercial distribution must be listed with the FDA. Currently, no American Family Pharmacy, LLC, products are listed with the FDA. Therefore, these products are misbranded under Section 502(o) of the Act [21 U.S.C. 352(o)].
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 the violations identified above and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements and FDA regulation.
FDA strongly recommends that if you decide to resume production, you undertake a comprehensive assessment of your operations before you restart manufacturing and distributing any drug products. We also strongly recommend that this comprehensive evaluation is conducted by a qualified third party consultant with relevant manufacturing expertise.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Other federal agencies may take this warning letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug applications listing your facility, until the above violations are corrected. A reinspection may be necessary.
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations as well as copies of related documents. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you will no longer manufacture or distribute drug product(s), provide the date(s) and reason(s) you ceased production.
Please send your written response to Tina M. Pawlowski, Ph.D., Compliance Officer, Detroit District Office, Food and Drug Administration, 300 River Place, Suite 5900, Detroit, Michigan, 48207.
If you have any question about the contents of this letter, please contact Dr. Pawlowski at (313) 393-8217.
Art O. Czabanuik
Detroit District Office