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OOS Results in FDA Warning Letters

How to Perform Appropriate Investigation, and a Touch of CAPA plus Case Studies

Abbass Kamalizad, Ph.D.President, ACPC Group

[email protected]

Presented to SCPDG, Nov. 8, 2012

OutlineIntroduction to OOSDefinitionU.S.A. vs. Barr Labs, Inc.Regulatory CGMP’s 21CFR 210, 211 FDA GuidanceWarning LettersCase Studies

IntroductionBarr Decision, Feb. 1993US FDA Draft Guidance, 10 Sept 1998USFDA Final Guidance, 12 October 2006 in the Federal Register21 CFR 210 & 211, Federal Food, Drug, and Cosmetic Act (the Act) (section 501(a)(2)(B)EMA, MHRA, WHO, Health CANADA, TGA,

DefinitionA specification (often abbreviated as spec) is an explicit set of requirements to be satisfied by a material, product, or service. Should a material, product or service fail to meet one or more of the applicable specifications, it may be referred to as being out of specification; the abbreviation OOS is generally used.

Where OOS is found

..All test results that fall outside the specifications or acceptance criteria established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications.”Drug Products, Drug substances, Excipients, Validation, Qualification, Water, Stability

Barr Decision The US vs. Barr, Inc.

Cannot average OOS results with in-Spec to get a Passing Result.Cannot conduct multiple retest with no defined end point.Cannot use outlier test to reject results. Should have a retest policy and procedure.Over 3400 pages of testimony and 500 exhibits. FDA’s OOS Investigation Draft Issued in Sept 1998 was based on this rulings.

Barr Decision“Testing lies at the heart of a drug manufacturer’s successful operation. Through testing companies validate their processes and ensure the quality of batches for release.” Judge Wolin

OOS Issues in Barr CourtOut of specification resultsProduct “failure”Informal and formal investigationsTesting and retestingSampling and resamplingAveragingOutliers

CFR 211.192“Any unexplained discrepancy of the failure of a batch or any of its contents to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed.”

21 CFR 211.192“The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy.A written record of the investigation shall be made and shall include the conclusions and follow-up.”

Guidance for Industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production

U.S. Department of Health and Human Services Food and Drug Administration

Center for Drug Evaluation and Research (CDER) October 2006

Pharmaceutical CGMPs

ApplicabilityChemistry-based lab testing of drugs regulated by CDER.Tests are performed on API, excipients and other components, in-process materials, and finished drug products.Products purchased outside but tested in house.Contract firms performing testig on such products.As long as CGMP regulations (21 CFR 210 and 211 and the FD&C Act Section 501(a)(2)(B) apply.

Guidance for IndustryOOS Investigation

FDA requires that:

Finished Pharmaceuticals (DP) and Active Pharmaceutical Ingredients (APIs)

to be manufactured in accordance with current good manufacturing practice under section 501(a)(2)(B) of the Act.


Current good manufacturing practice for APIs includes the performance of scientifically sound

Raw material testing, In-process monitoring, Release and stability testing, Process validation, and adequate investigations of any OOS result obtained from such testing.


The responsibility of a contract testing laboratory in meeting these requirements is equivalent to that of a manufacturing firm.


FDA regulations require investigation for any OOS.The source of OOS is either

1. Aberration of measurement process or2. Aberration of manufacturing process

The purpose of investigation is to find the cause of OOS.

PHASE I: LABORATORY INVESTIGATION

• The first phase includes

Assessment of the Accuracy of the laboratory’s Data

The investigation should be thorough, timely, unbiased, well-documented, and scientifically sound. .

PHASE I: LABORATORY INVESTIGATION

Test preparations (including the composite or the homogenous source of the aliquot tested)are not to be discarded as they are necessary for investigationFor contract laboratories, the laboratory should convey its data, findings, and supporting documentation to the manufacturing firm’s Quality Control Unit (QA), who should then initiate the full-scale OOS investigation.

PHASE I: LABORATORY INVESTIGATIONThe Analyst’s Responsibilities

“The first responsibility for achieving accurate laboratory results lies with the analysts who is performing the test.”“The analysts should be aware of potential problems that could occur …”


Check all steps of preparationCheck all equipment (21CFR 211.160 (b)(4)System Suitability and bracketing standard

If there is indication of system problem, the data from the suspect time period should not be used. However, investigation is needed.

“Analysts should check the data for compliance with test specifications before discarding test preparations or standard preparations.”An assessment of the accuracy of the results should be started immediately


For obvious errors, analyst should document everything.Analyst should not continue analysis until a decision is madeAnalyst should inform the supervisor immediately

PHASE I: LABORATORY INVESTIGATIONThe Supervisor’s Responsibilities

Supervisors assessment should be:– Objective– Timely– No preconceived assumptions– Prompt assessment of data– Laboratory or manufacturing?

PHASE I: LABORATORY INVESTIGATIONThe Supervisor’s Responsibilities

1. Discuss the method with analysts2. Examine raw data3. Verify calculations4. Confirm performance of instruments.5. Confirm reference standards, reagents6. Evaluate performance of method7. Document (most important)8. Must prove your hypothesis

INVESTIGATING OOS TEST RESULTS —PHASE II: FULL-SCALE OOS INVESTIGATION

In summary, when clear evidence of laboratory error exists, laboratory testing results should be invalidated.When evidence of laboratory error remains unclear, a full-scale OOS investigation should be conducted by the manufacturing firm to determine what caused the unexpected results.


This investigation may consist of a

Production Process Review and/or Additional Laboratory Work

The objective of such an investigation should be to identify the root cause of the OOS result and take appropriate corrective and preventative action.


Quality Control Unit (QA) conducts the investigation.Other pertinent departments participate:

1. Manufacturing2. Process Development3. Maintenance4. Engineering5. QC, Metrology, etc.


The key to unlock the OOS problem:

Complete review of all manufacturing and process development documents with a written record of the review.


A written record of the review includes:1. A clear statement of the reason2. Summary of manufacturing process aspects that

could cause the problem3. Results of documentation review with probable

cause.4. Results of previous reviews5. Description of corrective actions to be taken.


Additional Testingfull-scale OOS investigation may include additional laboratory testing. A number of practices are used during the laboratory phase of an investigation. These include (1)Retesting (a portion of the original sample)(2)Resampling.

Additional TestingRetesting is performed for:

Finding problems with testing instrument (malfunctions)

to identify a possible sample handling problem (e.g. a dilution error)

A critical task, because it could determine the root cause of the OOS.

RetesingFDA wants a second qualified analysts do the retest.Don’t “test into compliance.”Specify the number of retests (must be in SOP).Prepare a protocol before retesting.If the error is clearly identified, the retest substitutes the OOS results.

Resampling“Resampling involves analyzing a specimen from any additional units collected as part of the original sampling procedure or from a new sample collected from the batch.“In some situations, however, it may be appropriate to collect a new sample from the batch. Control mechanisms for examination of additional specimens should be in accordance with predetermined procedures and sampling strategies see § 211.165(c).

ResamplingResampling should be a rare event.Investigation might conclude sampling error (widely varied results).For inherently inadequate sampling method, a new accurate sampling method must be created with all the controls. See §§ 211.160 and 211.165(c).

Reporting Test ResutsAveraging

appropriateinappropriate

Outlier Test"The USP expressly allows firms to apply thistest to biological and antibiotic assays, ..., butis silent on its use with chemical tests.""In the Court's view the silence of the USPwith respect to chemical testing and outliers isprohibitory."

CONCLUDING THE INVESTIGATION

If a cause is found, invalidate the initial result and use the retest value(s) in its place.If the OOS is confirmed the batch is rejected.If the OOS is inconclusive and the retests are within specification, then QA may be able to justify releasing the batch.

Field Alert“For product that are subject of approved full or abbreviated new drug applications, regulation require submitting within 3 working days a field alert report of information concerning any failure of a distributed batch to meet any of the specifications ….”

June 3, 2011Dr. Reddy's Laboratories Limited

3. Your firm's out-of-specification (OOS) investigations did not include analysis of all available data.For example, the inspection revealed that your firm rejected three consecutive lots of (b)(4) (an intermediate used in the manufacture of an API for the product "(b)(4)") on February 26, 2010, for appearance problems. The deviation investigation into the cause of the failure did not include an analysis of all available data including batches manufactured prior to the failures.

June 3, 2011Dr. Reddy's Laboratories Limited

The inspection also found many deficiencies regarding handling OOS investigations. These include the timeliness of closing investigations, notification of the quality unit (including four to eight-month delays for reporting failing stability batches), and failure to follow written procedures. Although some of your proposed corrections to these individual items appear to be adequate, we remain concerned that a thorough evaluation of your investigation approach has not been conducted. Please include in your response a corrective and preventive action plan regarding handling investigations.

Oct. 31, 2008Deltex Pharmaceuticals Inc.

Also, your SOP QC-01 0-1 "Procedure for out of spec Inspection" is inadequate in that it lacks a defined protocol for the number of retests allowed, and has no requirement for expansion of an OOS investigation to manufacturing processes and procedures or any provision for expansion on an investigation to other lots potentially impacted.

Oct. 31, 2008Deltex Pharmaceuticals Inc.

We acknowledge your correspondence of September 2, 2008, in response to the FDA-483 in which you outline corrective action on the calibrations of the spectrometer and balance. The response is incomplete because it does not include the promised revised SOP addressing the deficiencies in your written procedures for handling OOS test results. Additionally, the response fails to provide any documentation of the corrective actions related to the balance and spectrometer.

May 5, 2011Alpha Laboratories, Inc

1. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].For example, (b)(4) samples and (b)(4) and (b)(4) failed to meet the assay specifications. However, no investigation was conducted. The inspection also found that your analyst did not record these out-of specification results in the OOS logbook as required by your SOP.Please include in your response the specific corrective actions taken to improve your program for handling OOS results, including ensuring that both analysts and management are properly trained on how to document and conduct investigations.

May 5, 2011Alpha Laboratories, Inc

The inspection also documented that your Quality Control Unit reviews and approves Certificate of Analysis containing OOS results, but without conducting any investigation.Your response states that a plan to investigate all OOS results, obtained as of November 1, 2010, has been implemented. However, there is no commitment to conduct a retrospective review of all lots tested and found OOS. Please provide a list of all OOS results obtained during the last 3 years. Include the name of the raw material or finished product, the lot number, date tested, and customer. Please indicate if all your customers were notified of these failures and date of notification.

.May 5, 2011

Alpha Laboratories, Inc

2. Your quality control laboratory has not followed written procedures for testing and laboratory controls designed to assure that the drug products you tested have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.160(a)(b)(3)(4)].For example,a. The inspection revealed that your procedure for Out-Of-specification results (SOP-GEN-0008 Rev 4) is not followed.The OOS procedure requires that as part of Phase (b)(4) a re-test be performed if no assignable cause has been found. The inspection found that no re-test was performed for OOS samples #542, #545, #546, #521. Your firm failed to document the reason(s) for not conducting a Phase (b)(4) investigation for an OOS results and for not documenting that your clients were notified as in your procedure.

Jue 20, 2012Ercros S.A.

4. Inadequate or lack of any investigation of critical deviations or a failure of a batch to meet its specifications or quality standards. For example, the IR spectra of (b)(4) API lots (b)(4), and (b)(4) did not match the IR spectrum of the standard. The quality unit released these lots. The quality unit failed to document and investigate the presence of bands in the IR spectra that did not match the spectrum of the standard.In your response, you indicate that the quality unit did not investigate because it believed the additional peaks in the IR spectra were due to ambient (b)(4). Your response failed to explain why ambient (b)(4) bands appear to only affect the spectra for the above-mentioned lots but not the reference standard spectrum. Your response also did not address under what conditions analysts could potentially perform background corrections to remove the (b)(4)bands.

Jue 20, 2012Ercros S.A.

In your response your firm promised to revise the procedures for each of these issues. Your response lacks specific corrective and preventive actions to ensure that future out of specification results (OOS) and deviations are thoroughly investigated and documented. In your response, please describe how this concern will be addressed for all laboratory and quality oversight procedures.

Feb. 22, 2012APP Pharmaceuticals, LLC

c. Your firm failed to identify an assignable cause for a failing assay result for Heparin Lock Flush (OOS# (b)(4)) and failed to extend your investigation into other batches of Heparin Lock Flush.In your response, you state investigation (b)(4) was completed to identify the root cause of the out of specification (OOS) results. We cannot evaluate your response since investigation (b)(4) was not included in your response. We are also concerned about a potentially related trend of OOS assay results for other batches of heparin active pharmaceutical ingredient (API) and Lock Flush.

Feb. 22, 2012APP Pharmaceuticals, LLC

Please provide the following information or data: 1) A copy of investigation (b)(4) including root cause analysis and corrective actions implemented for this batch; 2) Whether other associated lots may be affected by this issue; 3) Whether you have implemented, for commercial production and release, the new filter and tubing that was being used when you produced the failing exhibit batch; and 4) A three-year history of heparin API and Heparin Lock Flush batches that have had OOS results, the testing results obtained, the root cause, and the investigation conclusion.

Sept. 1, 2011Deibel Laboratories of Illinois, Inc.

4. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications, whether or not the batch has already been distributed [21 C.F.R. § 211.192]. For example:a. Your firm failed to conduct an investigation when you were made aware on March 15, 2011, that a lot of Butterfield Phosphate Buffer (Lot (b)(4) was Out-of-Specification (OOS) for pH.


Your firm continued to use this buffer until March 30, 2011, to test approximately (b)(4) drug products.Your response is not adequate because you did not provide copies of the investigation or the pH test results.Your response also minimizes and attempts to justify the failure to initiate an investigation by indicating that the buffer's pH was within 5% of the target value. In accordance with 21 C.F.R. § 211.192, any deviations from the specification are considered to be discrepancies and must be investigated.


b. Your firm has failed to conduct an investigation for numerous OOS results (e.g., for colony forming units, conductivity, assay, etc.). Many of these OOS results were not reported to your client.In your response, your firm indicates that you will revise your procedure for nonconformances to state that investigations for raw materials, water, swabs, and stability samples will only be initiated upon client request. As discussed above, when your laboratory obtains out-of-specification results, it is imperative that you promptly initiate an investigation to determine whether your laboratory's practices led to the failure (analysts error, equipment failure, etc.) or the results are valid. Your firm is responsible for fully meeting CGMP for operations that you conduct. Accordingly, your firm is responsible for investigating all non-conformances associated with your laboratory and testing.Please see FDA's Guidance for Industry entitled, "Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production" (October 2006).

Summary of FDA Warning Letter 2011-2012

Failure to investigate and document out-of-specification results obtained for … . Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed, and you failed to extend the investigation to other batches of the same drug product that may have been associated with the specific failure or discrepancy.


Your QCU approved and released a batch of … despite an initial OOS bulk assay result. These results were later confirmed through repeat testing, but further testing of additional samples produced passing results. Your QCU released the batch even though the investigation did not identify a discernable cause.Your QCU did not require a second, independent

person to review the raw data, calculations and records before releasing these lots for distribution.


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 … was released and distributed even though it did not meet the established specification of … % label claim. The correct calculation would have reported a … % label claim.


The inspection also found that your analyst did not record these out-of specification results in the OOS logbook as required by your SOP. Your investigation failed to follow your procedures when your firm … initiated Phase 2 sample testing prior to completing Phase 1 of the investigation, and … only analyzed two samples as opposed to the required three samples


Your firm's out-of-specification (OOS) investigations did not include analysis of all available data. Inadequate or lack of an investigation of critical deviations or a failure of a batch to meet its specifications or quality standards. Your firm has failed to conduct an investigation for numerous OOS results (e.g., for colony forming units, conductivity, assay, etc.). Many of these OOS results were not reported to your client.

Case Study IMislabelling

In the morning of March 9, we received a call from our client regarding a mislabeled antibiotic shipment of their reference standard to their PR plant. Based on this call

An immediate investigation was initiatedDetermined where else, if any, the reference was shippedRecalled all the vials for inspection and investigationDevelop a CAPA plan


We opened all vials and compared the content with the retained ref. std. in our site. We found 7 vials contained the same mateial but different label.We reviewed dispatch of more than 15 lots sent to 5 different labs throughout the world and found no problem.The likelihood of mislabeling was possible shortage of the label so the chemist continued using labels available to him and not realizing the proper lable had been depleted.


We found we did not have proper control on the number of labels needed and printed.We changed SOP to reflect that based on the number of vials to be dispatched (requested by the and client approved by QA), exact number plus 2 is printed in one “lot” (no mixing of labels on the same sheet).Created log book and trained all the personnel

Case Study IIABC (Coated) Caplet

Out of Specification (OOS) results were obtained for a number of ABC samples. The samples were tested for Calcium by ICP per an approved and validated test procedure


Investigation of the record of analysis showed that:

Correct reagent and solvents were used for the sample and standard preparation.ICP instrument was set up correctly The instrument passed calibration and system suitability requirements before sample analysis.Sample and standard solution were executed correctly.Standard checks throughout the run were consistent and passed the requirements.Review of the sample preparation and interview with the chemists showed that during the initial charring of the samples on the hot plate, the samples may not have been charred completely.


Lot # First Test mg/Caplet Reanalysis, mg/Caplet

30058275124 123120 125122 124

30058051129 137112 132120 135

30058252100 134118 134100 134

3005825397 124103 132100 128

30058254120 139115 132117 136

3005826399 11995 11588 114

30058264120 142121 135121 139

Case Study IIINanopure® Water

During the course of routine analysis of water from our NanoPure® systems, two units, one located in the QC Labs, ID # 0075-00 and the second unit located in the R & D Department, ID # 0792-00, generated out of specifications results for a period from Sept 2, until Oct. 13. Water samples were taken once every week and tested for conductivity, total organic carbon (TOC) and microbial plate. During the stated period, specifically, the results of TOC for the water samples were out of specification.


Report of Analysis of the QC Labs

Similar Results were obtained for the R&D Labs

Date Sampled Date Tested

Plate Count, Heterotrophic, Water Organic Carbon, Total Conductivity

09/02/03 10/17/03 1CFU/mL 0.43 ppm 0.70µmho/cm

09/08/03 10/22/03 1CFU/mL 0.11 ppm 0.80µmho/cm

09/15/03 10/24/03 1CFU/mL 0.14 ppm 0.70µmho/cm

09/22/03 10/22/03 1CFU/mL 0.29 ppm 0.80µmho/cm

09/29/03 10/22/03 <1CFU/mL 0.16 ppm 1.16µmho/cm

10/06/03 10/22/03 <1CFU/mL 0.06ppm 0.78µmho/cm

10/13/03 10/23/03 1CFU/mL 0.18 ppm 1.50 µmho/cm


HPLC analysis of Feed Water, and water samples from QC and R& D Labs using an aminoacid derivitizing agent and an internal standard revealed indication of contamination consistant with TOC analysis.

DI Water NanoPure Room 115 (ID # 0075-00)

NanoPure Room 225 (ID # 0972-00)

tR min. Area tR min. Area tR min. Area

Ammonia 30.1 265572 30.2 1463368 30.3 1862470AABA 34.7 1339912 34.8 1192145 34.8 1479593

Chromatographic Data From Analysis of Water


Chromatogram of NanoPure® Water (Fed from DI Water)


The samples were not run in a timely manner and this was mainly due to capacity and resource in the sense that samples from clients were run first and therefore, our water samples were all tested late.The function of the NanoPure® systems was questionable, possibly due to the “bad” filter and/or beds in the systems


CAPA

We changed all the filters and beds of the two NanoPure® systems and revalidated the two systems based on a newly revised and approved protocol. Changed SOP to reflect weekly water samples would be tested within 24 hours of sampling for TOC to avoid possible OOS due to late testing. Assigned appropriate responsibilities and controls and performed training.

Thank You

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