Inspections, Compliance, Enforcement, and Criminal Investigations
Global Biotechnologies, Inc. 8/21/12
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|New England District|
One Montvale Avenue
Stoneham, Massachusetts 02180
FAX: (781) 587-7556
VIA United Parcel Service
August 21, 2012
Mr. A Robert Bogosian, PhD.
Global Biotechnologies, Inc.
54 York Street, Suite 1B
Portland, ME 04101
Dear Mr. Bogosian:
The United States Food and Drug Administration (FDA) inspected your dietary supplement manufacturing, packaging, labeling, and distribution facility, located at 54 York Street, Suite 1B, Portland, ME from January 25, 2012 to March 16, 2012. The inspection revealed significant violations of the Current Good Manufacturing Practice (CGMP) in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements, Title 21, Code of Federal Regulations (CFR), Part 111 (21 CFR Part 111). These violations cause your Glucanol and Lactopril dietary supplement products to be adulterated within the meaning of section 402(g)(1) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 342(g)(1)], in that these products have been prepared, packed, or held under conditions that do not meet CGMP requirements for dietary supplements. You may find the Act and FDA regulations through links in FDA's home page at www.fda.gov.
We have reviewed your firm’s response dated March 30, 2012 and note that it lacks sufficient corrective action, as detailed further below.
Your significant violations are as follows:
1. You failed to establish in-process specifications for any point, step, or stage in the Master Manufacturing Record (MMR) where control is necessary to help ensure that specifications are met for the strength and composition of the dietary supplements, as required by 21 CFR 111.70(c)(1). Specifically, our investigator asked you to determine the bulk capsule content weight of (b)(4) capsules of Lactopril to see if it met the labeled weight of (b)(4) mg per capsule. After performing the weight check, it was estimated that the average weight of the contents in each capsule was (b)(4) mg. There is no established specification in your MMR for this examination to be compared with in order to determine if the specification is met. A specification for capsule weight can affect both the strength and composition of the finished product. In addition, without an established specification, you cannot assure that your product meets the established specification for both the strength and composition of the finished product, as required by 21 CFR 111.73.
We have reviewed your response dated March 30, 2012 and determined it to be inadequate. You indicated that you have incorporated an in-process specification for capsule weight to be (b)(4) than the weight declared on the product label, and that you will weigh and record every batch of (b)(4) capsules. Your response is inadequate because your in-process specification for capsule weight should specify the maximum weight for capsule weight to ensure that specifications are met for the strength and composition of the finished product. In addition, you did not provide any MMRs to show that you included this in-process specification.
2. You failed to establish component specifications for each component that you use in the manufacture of your dietary supplements, as required by 21 CFR 111.70(b). Specifically, your raw material specification (RMS) sheet for the gelatin capsule #1 yellow/green only lists an (b)(4) specification for the yellow/green #1 capsule, (b)(4). This specification sheet was associated with your Master Batch Record for your Lactopril 300mg capsule dietary supplement, (b)(4). You used these gelatin capsules (component) to manufacture the Lactopril 300mg product. This component specification for (b)(4) however, is insufficient to determine the identity of these capsules. Further, your RMS sheet does not have component specifications for purity, strength, and composition, or limits on those types of contamination that may adulterate or may lead to adulteration of the finished batch of the dietary supplement. Your supplier’s Certificate of Analysis lists three (b)(4) specifications for the gelatin capsules, and specifications for limits on those types of contamination that may adulterate or may lead to adulteration of the finished batch of the dietary supplement. Your RMS sheet fails to include these specifications. Therefore, without establishing such specifications, you have no means to ensure that you are receiving the correct gelatin capsules.
We have reviewed your response dated March 30, 2012 and determined it to be inadequate because you did not include your RMS sheet for the capsules used in the manufacture of Lactopril demonstrating your corrections.
3. You failed to package and label in a way that ensures that the dietary supplement is packaged and labeled as specified in the MMR, as required by 21 CFR 111.415. Specifically, you confirmed to our investigator that you do not have a written MMR for the Glucanol (b)(4) dietary supplement product that you package and label at your facility.
We have reviewed your response dated March 30, 2012, indicating that you developed a manufacturing record that covers the bottling and labeling aspects of manufacturing. We have determined your response to be inadequate because you did not include a MMR for Glucanol that includes specifications applicable to packaging and labeling for our review. A master manufacturing record for a firm that only packages and labels the dietary supplement must include specifications that are applicable to its operations. [See 72 Fed. Reg. 34752, 34902 (June 25, 2007)].
4. Your batch production records (BPR) failed to include complete information relating to the production and control of each batch, as required by 21 CFR 111.255(b) and 111.260. Specifically, your BPR for your Lactopril 300mg dietary supplement product, (b)(4), did not include the following required information:
a. The date and time of the maintenance, cleaning, and sanitizing of the equipment and processing lines used in producing the batch, or a cross- reference to records, such as individual equipment logs, where this information is retained, as required by 21 CFR 111.260(c).
b. The unique identifier that you assigned to each component, as required by 21 CFR 111.260(d). For example, your BPR lacks a unique identifier for the Bioferrin 1000 component.
c. The weight or measure of each component used, as required by 21 CFR 111.260(e).
d. A statement of the actual yield and percentage of theoretical yield at appropriate phases of processing, as required by 21 CFR 111.260(f). Specifically, the actual and theoretical yields after the encapsulation operation were not listed on the BPR.
e. Documentation that the finished dietary supplement meets specifications established in accordance with 21 CFR 111.70(e) and (g), as required by 21 CFR 111.260(i).
f. Documentation, at the time of performance, of packaging and labeling operations, as required by 21 CFR 111.260(k). Specifically, you failed to include:
i. The unique identifier that you assigned to packaging and labels used, the quantity of the packaging and labels used, and reconciliation of any discrepancies between issuance and use of labels, as required by 21 CFR 111.260(k)(1); and
ii. An actual or representative label, or a cross-reference to the physical location of the actual or representative label specified in the MMR, as required by 21 CFR 111.260(k)(2).
We have reviewed your response dated March 30, 2012, indicating that a BPR has been developed for Lactopril that covers the Bill of Materials, Formulation and Capsule Filling, bottle filling, tamper evident sealing, and labeling including lot number and expiration date. We have determined your proposed corrective action to be inadequate because it does not appear to include all of the information required by 21 CFR 111.260 for your manufacturing, packaging, and labeling operations, and you did not provide a BPR for our review.
5. You failed to establish and follow written procedures for holding and distributing operations, as required by 21 CFR 111.453. Specifically, our review of your procedure entitled Temperature and Humidity Monitoring (GB-BEN-1003) collected during the inspection revealed that your procedure was insufficient to meet the full requirements that apply to your holding and distributing operations. For example, (b)(4) monitoring of temperature and humidity is not frequent enough to determine if products were subjected to temperature that could affect the identity, purity, strength and composition of the products.
We have reviewed your response dated March 30, 2012 and determined it to be inadequate. In your response, you provided copies of your written procedures entitled "GB-GEN-1003, Temperature and Humidity” and “GB-QC-1008, Label Control." However, these documents do not adequately address the following:
a. Holding components and dietary supplements under appropriate conditions of temperature, humidity, and light so that the identity, purity, strength, and composition of the components and dietary supplements are not affected, as required by 21 CFR 111.455(a). Specifically, “GB-GEN-1003, Temperature and Humidity” provides for (b)(4) monitoring of temperature and humidity, which is not sufficient to ensure that 21 CFR 111.455(a) is satisfied;
b. Holding the packaging and labels under appropriate conditions so that the packaging and labels are not adversely affected, as required by 21 CFR 111.455(b);
c. Holding components, dietary supplements, packaging, and labels under conditions that do not lead to the mixup, contamination, or deterioration of components, dietary supplements, packaging, and labels, as required by 21 CFR 111.455(c);
d. Holding reserve samples of dietary supplements in a manner that protects against contamination and deterioration, as required by 21 CFR 111.465(a), including:
i. Holding reserve samples of dietary supplements under conditions consistent with product labels or, if no storage conditions are recommended on the label, under ordinary storage conditions, as required by 21 CFR 111.465(a)(1);
ii. Using the same container-closure system in which the packaged and labeled dietary supplement is distributed, as required by 21 CFR 111.465(a)(2);
e. Retaining reserve samples for 1 year past the shelf life date (if shelf life dating is used), or for 2 years from the date of distribution of the last batch of dietary supplements associated with the reserve samples, for use in appropriate investigations, as required by 21 CFR 111.465(b).
6. You failed to establish and follow written procedures, as required by 21 CFR 111.553, for the review and investigation of product complaints, as required by 21 CFR 111.560, and the maintenance of records, as required by 21 CFR 111.570.
We have reviewed your response dated March 30, 2012 and determined it to be inadequate. In your response, you provided a copy of your written procedures entitled "GB-QC-0021, Customer Complaints and Inquiries." However, your procedure does not address the following:
a. Your procedures do not specify that a qualified person must: (1) review all product complaints to determine whether the product complaint involves a possible failure of a dietary supplement to meet any of its specifications, or any other requirements of 21 CFR 111, including those specifications and other requirements that, if not met, may result in a risk of illness or injury; and (2) investigate any product complaint that involves a possible failure of a dietary supplement to meet any of its specifications, or any other requirements of 21 CFR 111, including those specifications and other requirements that, if not met, may result in a risk of illness or injury (21 CFR 111.560(a));
b. Your procedures do not specify that the review and investigation of the product complaint must extend to all relevant batches and records (21 CFR 111.560(c));
c. Your procedures do not specify what records must be made and kept (21 CFR 111.570). You must make and keep a written record of every product complaint related to good manufacturing practice (21 CFR 111.570(b)(2)). The person who performs the requirements of subpart O of Part 111, Product Complaints, must document, at the time of performance, that the requirement was performed (21 CFR 111.570(b)(2)(i)), and the written record of the product complaint must include the following:
d. The name and description of the dietary suppl ment; the batch, lot, or control number of the dietary supplement, if available; the date the complaint was received and the name, address, or telephone number of the complainant, if available; the nature of the complaint including, if known, how the product was used; the reply to the complainant, if any;and findings of the investigation and follow-up action taken when an investigation is performed (21 CFR 111.570(b)(2)(ii)(A)-(F)).
The above violations are not meant to be an all-inclusive list of violations at your facility or that exist in connection with your products or their labeling. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that all of your products are in compliance with the laws and regulations enforced by FDA. You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in enforcement action without further notice, such as seizure and/or injunction.
We note that the inspection revealed your purchase of various products from your suppliers, such as (b)(4). Because you receive these products from your suppliers for packaging and labeling as dietary supplement products, you have a responsibility to establish specifications to provide sufficient assurance that the product you receive is adequately identified and is consistent with your purchase order, as required by 21 CFR 111.70(f). Further, before you package or label a product that you receive for packaging and labeling as a dietary supplement, you must visually examine the product and have documentation to determine whether the specifications that you established under 21 CFR 111.70(f) are met, as required by 21 CFR 111.75(e).
Please respond to this letter within fifteen (15) working days from your receipt of this letter as to the specific steps that you have taken to correct the current violations cited above and to prevent similar violations in the future. Your response should include any documentation necessary that would assist us in evaluating your corrections. If you cannot complete all corrections within fifteen (15) working days, state the reason for the delay and the time within which you will correct any remaining violations.
Your response should be sent to the U.S. Food and Drug Administration, One Montvale Ave., Stoneham, MA 02180 Attention: Anthony Costello, Compliance Officer. If you have any questions about the content of this letter please contact: Anthony Costello at (781) 587-7492.
Mutahar S. Shamsi
New England District