ALLURE LABS RECEIVES WARNING LETTER (5/24/11)

ALLURE LABS’ CITED FOR FAILURE TO CALCULATE
MICROBIOLOGICAL DILUTION FACTOR CORRECTLY
WITHIN PRODUCT LEADS TO PRODUCT FAILURE 

We have reviewed your firm’s response dated December 12, 2010, and note that it lacks sufficient corrective actions.

We acknowledge your second written response, dated February 3, 2011, to the Form FDA 483. However, because this response was received more than 15 business days after the Form FDA 483
was issued; this second response has not been considered. We plan to
evaluate this response to the Form FDA 483, along with any other written material provided, as a direct response to this Warning Letter.

Specific violations observed during the inspection include, but are not limited, to the following:

CGMP Violations

1. Your firm has failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products [21 C.F.R. §211.22(a)]. For example,

1. Your Quality Control Unit (QCU) failed to reject a lot of Honeysuckle component (lot (b)(4)) after it failed specifications for yeast, mold, and Aerobic Plate Count. The lot was released and used to manufacture three lots of (b)(4) Moisturizing Face Screen (lots (b)(4)).

COMMENT

Non-sterile components used to manufacture product (see 21 CFR 211.113) that may contain microbial content need to be quarantined and tested.  Organic materials should be tested on an on-going basis and only reduced to skip lot testing when a low bioburden level
is assured.

2. Your QCU failed to detect an employee miscalculating the microbial results for three lots of (b)(4) Moisturizing Face Screen (lots (b)(4)) finished products by not applying a dilution factor of 10^-2. The correct calculation of the results would have shown that these products were Out-of-Specification (OOS). The three lots of (b)(4) Moisturizing
   Face Screen were released and distributed by the QCU based on the erroneous results.

COMMENT 

The use of dilution factors represents a basic element within any Quality Control function and Microbiology Laboratory in particular.  An incorrect dilution calculation, as noted above, led to three lots being Out of Specification (OOS, see also FDA Guidance
for Industry, Out of Specification, July 2006) because of the error.  However, this error was not observed by the Quality Control Unit (QCU) and the product was released.

C. Your QCU failed to detect multiple discrepancies in sample weights and dilution factors between the analyst’s notebook and the Calculation Sheet. As a result, incorrect data was recorded for multiple products and finished products not meeting specifications were released. Specifically, a lot of (b)(4) SPF 30 (lot (b)(4)) was released and distributed even though it did not meet the established specification of (b)(4)% label claim. The correct calculation would have reported a (b)(4)% label claim.

Your QCU did not require a second, independent person to review the raw data, calculations and records before releasing these lots for distribution.

In your response, your firm states that you have removed the employees responsible for the laboratory data errors from employment. However, you have not explained in any detail how you
intend to handle all affected lots or whether you would report these issues to the own-label distributors. Additionally, your response did not propose a timeframe for completing the proposed corrective actions. We acknowledge the results of the retesting for Zinc and Titanium performed by the third party laboratory. However, the response does not include any documentation of the procedure by which your firm qualified the laboratory or demonstrated its
use of a validated methodology. Finally, your response failed to provide a plan to ensure that the QCU will carry out its responsibilities in the future.

COMMENT 

The finding of discrepancies in sample weights and dilution factors led to the release of product with an incorrect label claim.  A review by a second, independent person is a requirement to assure that raw data, calculations and records are reviewed prior to distribution (see 21 CFR 211.194(a) (7, 8)).  A second person should review all data to include calculations and records for each page of a laboratory notebook or independent sheets that pertain to a Batch History Record to assure that no errors are present prior to a product’s release. 

The “firing” of employees responsible for such activities does not assure that additional employees have been adequately trained and will not repeat these errors.  In addition, when lots are released that are OOS, a plan should be in place to manage these lots as well
as manage future lots and any lots remaining in-house.  In addition, if testing is to be performed at a third party laboratory, the third party laboratory must be qualified and demonstrated to be using a validated or verified method.  

2. Your firm has failed to establish appropriate written procedures designed to prevent objectionable microorganisms in products not required to be sterile [21 C.F.R. §211.113(a)].

For example, your firm’s microbial limit specifications for finished product permits a microbial load in your drug product that could allow the presence of objectionable and potentially pathogenic organisms in your topical OTC drug products. In addition, your
firm does not specifically test for Staphylococcus aureus or Pseudomonas aeruginosa that should be absent from topical drug preparations.

In your response, your firm states that you will review all raw material specifications to determine if the current specifications should be changed or whether to add further quality control tests. Your response, however, is inadequate because you do not mention a
similar review for the appropriateness of your current specifications as it is applied to finished products and fails to propose a timeframe for completion.

COMMENT 

“Objectionable” microorganisms, now known as “specified” microorganisms per USP<61> Microbiological Examination of Non-Sterile Products, Microbial Enumeration Tests and USP<62> Microbiological Examination of Non-Sterile Products, Tests
for Specified Microorganisms, indicate that both USP and in-house
microorganisms be considered within both raw materials and finished product. When promises are made to the FDA by a Client, the review should be complete and a time line should be proposed.
Please also visit my Blog re: H & P Industries wherein they found an
in-house bacterium, Bacillus cereus, throughout their facilities and many of their products.

3. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, in-process materials, and drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. §211.160(b)]. For example,

1. Your firm has failed to provide a scientific justification for how the samples of bulk drugs are representative of the lot when they are collected only from the top of the kettle. Also, the samples are taken using a re-usable spatula sprayed with 70% isopropyl alcohol immediately before use. The presence of the alcohol on the spatulas could affect the validity of the test results.

COMMENT 

In-coming components and bulk drug products should be tested throughout the container.  Typically, this occurs in larger containers using a “thief” and samples are obtained from the bottom, middle and top.  In addition, if a re-usable spatula is used and only sprayed with 70% isopropyl alcohol, the alcohol may not kill microorganisms that accompanied other raw materials.  Ideally, the spatulas should be terminally sterilized prior to each use to minimize the possibility of transferring microorganisms from container to container.
Please visit the following FDA document (21 CFR 211.184(c)) to learn
more about correct container sampling.

3. Your firm has failed to validate your Standard Operating Procedure (SOP) (b)(4), “Microbiological Testing of Cosmetics, Raw Materials and Finished Products,” to show the absence of growth inhibition by the tested drug      products.

COMMENT

Growth Promotion testing is a fundamental test within any microbiological program.  Please see USP<61> and USP<62> (above) for additional information.

C. Your firm has failed to verify the assay methods for zinc oxide, titanium dioxide, and salicylic acid under actual conditions of use to determine the amount of active ingredients in your sunscreen products.

We acknowledge your proposed actions to validate all test methods and establish procedures for sampling, cleaning, preventing cross-contamination, and storing intermediate drug materials. However, your response does not specify any timeframes for ompletion.

4. Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess [21 C.F.R. §
211.100(a)]. For example,

A. Your firm’s mixing operations for bulk drugs have not been validated to ensure homogeneity.

B. Your firm has failed to evaluate the holding time and handling (e.g., transfer from mixing kettles to intermediate storage containers) of bulk drugs during and after intermediate storage to ensure the bulk drugs continue to meet established specifications prior to filling. There has been no testing of finished products to verify that
the transfers to intermediate storage containers, and conditions and duration of storage, do not adversely affect the drug products.

We acknowledge your proposed actions to validate the mixing operation and establish holding times for intermediate storage. However, your response does not address the establishment of storage conditions associated with the holding times or specify a timeframe for completion.

5. Your firm has failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform their assigned functions
[21 C.F.R. §211.25(a)].

For example, the employees of your firm, including a member of your quality control staff, admitted to our investigators that they were unaware of and were not trained to follow your SOP for handling deviations. There were at least two instances in which an OOS
investigation was not conducted.

While your response proposes to provide training to all employees, it does not provide documentation that you have initiated the training and does not specify a timeframe for completion. In addition, your response fails to specifically address how the proposed training will ensure that all employees will be trained in SOPs that are relevant to their job functions.

COMMENT 

Education and training are two areas where the FDA continues to focus.  Even when a Client’s response proposes training to all employees, a date of initiation and a timeframe for completion
should be provided in any response to the FDA. Further, documentation of training should include testing following the
training which may take the form of True/False, multiple “guess” and short answers.  If manufacturing or laboratory SOPs are involved, actual demonstrations of proficiency should be provided –
ideally three times.