FDA ENFORCEMENT IN 2010: TRENDS & ANALYSIS

MADHU RAJU SAGHEE Gland Pharma, India Madhu@glandpharma.com

Introduction
The year 2010 was a harsh year in terms of enforcement actions by the US Food and Drug Administration (FDA). The Agency ramped up its enforcement mandate. This trend is clearly perceptible and vivid if one simply glances at the Division of Drug Marketing, Advertising, and Communications (DDMAC) enforcement trends. (Figure: 1). DDMAC issued 11 more letters in 2010 than it did in 2009 (52 letters versus 41 letters). The past year also saw a significant uptick in the number of 483s, warnings letters and further escalations to severe enforcement actions such as seizures and permanent injuctions to firms across the globe. A comparative summary of FDA enforcement statistics between 2009 and 2010 is shown in Table: 1. Table 1: Overall FDA Enforcement Statistics in 2009 & 2010 Enforcement Actions FDA 483s Issued Warning Letters Seizures Injunctions Recall Events 2009 9,666 474 6 11 2,781 2010 9,910 673 10 17 3,799

Figure 1: Trends in DDMAC Warning and untitled letters (Source: Eye on FDA blog http://www.eyeonfda.com/)

Numbers tell the tales

Apart from the increase in the numbers of 483s, a comparison of the enforcement statistics of 2009 with 2010 reveals that those trends which commenced in 2009 - increased enforcement activity, stricter settlement terms, and tougher penalties - became entrenched in 2010. This aggressive enforcement can be attributed to several factors but primarily due to new enforcement polices initiated by the commissioner (Dr. Hamburg) in 2009. FDA's streamlined legal review process has resulted in 673 warning letters for 2010, a 30% increase over the 474 warning letters in the year 2009. In addition, Dr. Hamburg has publically emphasized a more vigorous enforcement role. She initiated the new FDA enforcement campaign saying, The FDA must be vigilant, the FDA must be strategic, the FDA must be quick, and the FDA must be visible. FDA had an active 2010, resolving investigations against several companies by consent decree and other mechanisms. FDAs actions in 2010 corroborate that consent decrees debarment proceedings are on the rise. Firms encountered a tougher and more aggressive stance from the FDA, and many of the firms only realized too late that the repercussions of noncompliance are devastating. Examples of this era of enforcement can be seen by looking at a 2010 list of companies entering into consent decrees and paying hefty penalties (Table: 2). Table 2: FDA enforcement actions (Consent Decrees and Penalties) in 2010 (Source: Memorandum by Skadden LLP) Company (Month) Product(s) Outcome Consent decree (no producing or distributing products until in compliance with quality standards; independent expert to inspect operations and certify corrections) Consent decree (transition plan and rebate program for customers to transition to legal alternatives; destruction of used product) Allegations Claims for devices not in FDA clearances and/or major changes in intended Marketing unapproved system

Sybaritic Inc. (Jan.)

Various devices

STERIS Corp. (Apr.)

Medical device sterilization system

Company (Month) Beehive Botanicals, Inc. (May)

Product(s) Bee-derived products marketed as drugs Cerezyme, Fabrazyme, Myozyme, Thyrogen

Outcome

Allegations

Misbranding; false Consent decree (no manufacturing or medical claims; selling new drugs unless in accord marketing with U.S. law; independent expert to unapproved drugs inspect labeling and certify claims) Consent decree ($175M in disgorgement, timetable to bring plant into compliance, independent expert to inspect plant and issue recommendations) Fined (per 2003 consent decree) $9.8M for violations related to mismanagement of certain blood products and $6.4M for GMP violations Consent decree (no selling unapproved new drugs with unauthorized health claims, independent expert to review future claims, certification that all violative claims have been omitted)

Genzyme Corp. (May)

GMP violations

American Red Cross (Jun.) Risingsun Health, The Center for Complimentary and Alternative Health (Oct.)

Blood products

Mismanagement of blood products; GMP violations

Black Salve, Cancema, and Can-Support

Selling unapproved Drugs

The total number of 483s issued by the FDA in 2010 was around 10,000. This is a significant increase from previous years, notably during 2005-2008 when the agency averaged only 7,000. The FDA issued 9,910 483s in 2010, at least a 10-year high based on available data. Trends in Warning Letters A total of 673 warning letters were issued to noncompliant firms in 2010 (Figure: 2), a clear upswing showing the marked intensity of FDA enforcement in the issuance of WLs. Among the six centers, CDRH issued the most warning letters (Figure: 3). A detailed analysis of important FDA Warning Letters issued in 2010 is provided in the Appendix.

Drugs Warning Letters issued in 2010 in the Human Drug area: 88 Warning Letters issued regarding drug violations 15 related to unapproved new drug/misbranded 15 related to unauthorized products to treat H1N1 flu 27 related to GMP deficiencies in finished pharmaceuticals and APIs 30 related to promotional claims/false & misleading/misbranding

1 related to ADE Reporting Of these, the top 10 Drug Citations in 2010 were: 1. Quality Unit: 21 CFR 211.22(d) - The responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed]. 2. Production Controls / Written Procedures: 21 CFR 211.100(b) -Written production and process control procedures are not [followed in the execution of production and process control functions] [documented at the time of performance]. 3. Process Validation: 21 CFR 211.110(a) - Control procedures are not established which [monitor the output] [validate the performance] of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. 4. Laboratory Controls: 21 CFR 211.160(b) - Laboratory controls do not include the establishment of scientifically sound and appropriate [specifications] [standards] [sampling plans] [test procedures] designed to assure that [components] [drug product containers] [closures] [in-process materials] [labeling] [drug products] conform to appropriate standards of identity, strength, quality and purity. 5. Deviation Investigations: 21 CFR 211.192 - There is a failure to thoroughly review [any unexplained discrepancy] [the failure of a batch or any of its components to meet any of its specifications] whether or not the batch has been already distributed. 6. Production Controls /Procedures associated with IPCs: 21 CFR 211.100(a) - There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. 7. Batch Release: 21 CFR 211.165(a) - Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the [final specifications] [identity and strength of each active ingredient] prior to release. 8. Training: 21 CFR 211.25(a) -Employees are not given training in [the particular operations they perform as part of their function] [current good manufacturing practices] [written procedures required by current good manufacturing practice regulations]. 9. Production Controls / BPRs: 21 CFR 211.188 -Batch production and control records [are not prepared for each batch of drug product produced] [do not include complete information relating to the production and control of each batch]. 10. Cleaning and Maintenance: 21 CFR 211.67(b) - Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product. These warning letters have been issued by different FDA inspectorate centres, as figures 3 and 4 show below. Figure 2: FDA Warning letters 2004 to 2010

Figure 3: Warning letters by FDA Center in 2010

Devices
A total of 196 warning letters were issued to device firms in 2010 compared to the 136 warning letters in 2009 (Figure:5). The data shows that the number of overall device-related warning letters rose 40 percent between 2009 and 2010. But the total number of quality-related warning letters was only 93 in 2010, only one more than in 2009. The Top 20 device observations used in Turbo EIR for FY 2010 are shown in Figure: 6. Corrective and Preventative Action (CAPA) requirements and Medical Device Reporting (MDR) tied as the most frequently cited violations last year, next to the list Complaint Handling, Design Controls, Process Validation, Management Responsibility, Purchasing Controls, Acceptance Activities, Quality Audit and Device History Record were the most common cited observations during 2010. These trends are summarized in figures 4 and 5 below. Figure 4: Warning letters issued for medical device firms by FDA in 2010

Figure 5: Top 20 device observations used in Turbo EIR for the year 2010

Foreign Inspections
FDA now has a greater outreach, having a footprint in foreign soils due its newly established offices in India, Brazil, China and Mexico. FDA is continuing to develop a more quantitative risk model to help predict where FDAs inspections are most likely to achieve the greatest public health impact. Due to complexity in the supply chain and the increased risk posed from the active ingredients sourced from emerging markets, FDA has increased its scrutiny of supplier controls and intensified its international inspectional activities. FDA clearly believes that inspections are the frontline defense to identify sub-par companies and restrict the ingress of adulterated drugs into US market. The common cGMP deficiencies cited in international inspections and in countries like Europe, India and China are presented in the following figures (6 to 9 below). Figure 6: cGMP deficiencies cited during international inspections in 2010

Figure 7: cGMP deficiencies cited during inspections in Europe, 2010

Figure 8: cGMP deficiencies cited during inspections in India, 2010

Figure 9: cGMP deficiencies cited during inspections in China, 2010

Conclusion

In summary, some of the key focus areas which were high priorities for FDA inspectors in 2010 are listed below. Failure to conduct comprehensive and timely investigation to find the root cause of the problem found with customer complaints, adverse events, deviations and out of specification results. Failure to extend the investigation to the other lots which might be affected by these systemic issues. OOS results are disregarded or negated without a documented investigation. Consistent patterns of non compliance and repeated observations noted in past inspections Analytical methods used are inadequate. Failure to follow your stability programme. Processes not validated, or cleaning sufficiently validated for multi-product equipment, leading to manufacturing processes that dont reproduce consistently and may lead to cross contamination. Inadequate process validation studies and in-process sampling plan without statistical confidence Failure to submit Field Alert Reports within three working days after receiving complaints of quality critical in nature Failure to select appropriate supply chain and Lack of vendor oversight and control, or failure to qualify vendors Failure to follow scientifically sound and appropriate sampling plans. Unapproved and Misbranded Prescription Drugs Violations Processes improperly validated leading to manufacturing processes that dont reproduce product quality consistently and may lead to cross-contamination. Failure to assure data integrity in both written paper records and electronic records Looking ahead, we can expect more inspections due to hundreds of new inspectors hired by the agency, current GMP revisions, and growing public concerns over the safety of medicines. Internal FDA goals call for a target of 750 inspections in 2011, an increase by 50 inspections over 2010. Undoubtedly, this will lead to recall actions receiving greater scrutiny and oversight and increased prosecutions of individuals.

Appendix

Learning from the mistakes of others

The following list provides a detailed analysis of important FDA Warning Letters issued in 2010. About 30 drug, biologic and API warning letters issued by FDA during 2010 that address GMP concerns are analyzed. The company receiving the warning letter, the letter date, the date of the inspection generating the letter and a brief description of the main areas of concern cited. The warning letters are categorized by the types of products covered during the relevant inspection: Drugs (23) Biologics (3) API (4)

Drugs (23)
S. No Company Name, the letter date & dates of inspections Brief description of the main areas of concern cited

Centaur, Inc. Inspection Dates: June 17-26, 2009 1 Letter date: Jan 8, 2010

QC unit OOS investigations, No written records of investigations into unexplained discrepancies. No documentation records for training, Failure to include the initials or signature of a second person Failure to follow written procedures (SOPs) No control of rejected in-process materials under a quarantine system No adequate equipment for the control of humidity and temperature Consistent patterns of non compliance and repeated observations noted in past inspections The 483 response lacked specific documentation to support their reply Misbranded drugs Manufacturing prescription drugs without approved applications No established laboratory control mechanisms Ex: Out-of-specification (OOS) humidity levels for the controlled room temperature stability chamber were noted on January 27, March 17, and April 5 and 6, 2009. Investigations and corrective actions were not conducted at the time to address these out-of-specification results. During the inspection, however, the Quality Unit presented backdated service requests to investigators as evidence of proper

Sunrise Pharmaceutical, Inc. New Jersey 2 Inspection Dates: June 19-July 17, 2009 Letter date: Jan 14, 2010

OOS result handling when in fact no actual service requests were initiated. No adequate written procedures for production and process control Ex: Specifically, one of your three validation lots, failed the blend uniformity test specifications. This same lot was blended for an additional 10 minutes without the review and approval of the Quality Unit. In addition, the validation protocol was not approved until April 2008, which is four months after the validation lot was manufactured. No master production and control records that justify variation in the amount of components necessary for the preparation of the dosage form No appropriate controls over computer or related systems The 483 response lacked sufficient corrective actions. Consistent patterns of non compliance and repeated observations noted in past inspections There were several patterns of non compliance related to the uncharacteristic odor" on Tylenol Arthritis Relief caplets. The initial investigation was unjustifiably delayed and terminated prematurely. o The firm failed to conduct comprehensive and timely investigation to find the root cause of the problem. The delayed investigation revealed the root cause ascribing 2, 4, 6 Tribromoanisole (TBA) contamination in the product and/or bottles from TBP treated wooden pallets. TBP is a pesticide and flame retardant used to treat wooden pallets for transporting packaging materials and finished product. o The same investigation was not extended to the other products manufactured in the facility to evaluate its impact. At the same time FDA was not informed about the investigation findings until the initiation of inspection. Warning letter says that the quality management of the company should have ensured the start of chemical testing far earlier. Failure to do so prolonged identification and resolution of the problem, resulted in continued consumer exposure. Agency emphasizes that Quality problems must be thoroughly investigated, root cause determined, and appropriate corrective and preventive actions implemented as quickly as possible to limit exposure of the public to substandard drugs. The firm has failed to submit Field Alert Reports within three working days after receiving complaints of quality critical in nature as per 21 CFR 318.81.

McNeil Consumer Healthcare Inspection Dates: June 19-July 17, 2009 Letter date: Jan 14, 2010

Kirk Pharmaceuticals Inspection dates: June 17- July 2, 2009 Warning letter: February 4, 2010

The firm didnt reject a lot of the finished product which had an OOS, and the lot was distributed with the OOS written in CoA and was overlooked by the Quality unit. The investigation was only initiated after 6 months after distribution of the lot and the root cause was attributed as analyst error without adequate justification. Failure to thoroughly investigate the batch failures and the initiated investigations were not timely. Repeated observations In-process specifications are not consistent with drug product final specifications. The responsibilities and procedures applicable to the quality control unit are not followed Ex: The firm's QCD failed to follow SOP on "Change Control System." Firm failed to conduct annual product reviews Failure to reject a lot of material that does not meet appropriate written specifications. The firm did not reject the Active Pharmaceutical Ingredient (API), when it failed to meet established specifications for the potency assay. These results were subsequently invalidated by QCD even though the investigation was unable to confirm a laboratory error as the root cause of the failure. The firm selectively used passing results from a different analysis to approve the lot without providing justification for invalidating the original results and utilizing retest results to approve product. Purified water samples were tested six days after the samples were obtained without written justification for the adequacy of bacterial recovery when holding and retesting water samples. Failure to follow written procedures The firm has not cleaned and maintained equipment at appropriate intervals to prevent contamination. The firm has not provided any evidence to support dirty hold time for equipment (e.g., mixing tanks) used in Production and maximum clean equipment hold time. Unapproved and Misbranded Prescription Drugs Violations Repeated observations Failure to thoroughly investigate unexplained discrepancies mainly with yield OOL values, in-process fill weight OOL results and non viable particulate excursions Procedure for the visual inspections of filled vials is inadequate Process validation didnt consistently producing acceptable quality products, and with numerous OOL results The firm didnt follow written procedures with respect to the SOP for visual inspections. The time frame in the batch record is not matching the cumulative elapsed time required for visual inspections.

Tri-Med Laboratories, Inc. 5 Inspection Dates: September 9-25, 2009 Letter date: February 23, 2010

Aquitaine Pharm International Inspection Dates: September 1 to 8, 2009 Letter date: March 26, 2010

Apotex Inc. 7 Inspection Dates: July 27- August 14, 2009 Letter date: March 29, 2010

Capricorn Pharma, Inc. Inspection Dates: September 15 through October 13, 2009 Letter date: April 20, 2010

Hospira, Inc. Inspection Dates: January 12 - 19 and January 26 - February 23, 2010 Letter date: April 12, 2010

L. Perrigo Company 10 Inspection Dates: November 17, 2009 to January 14, 2010

Consistent patterns of non compliance Quality control unit failed to follow the responsibilities and procedures applicable to release of the drug product Using contamination raw materials for manufacturing finished products quality control unit failed to follow the responsibilities and procedures applicable to release of the drug product Releasing different lots of product manufactured from defective components Process validation issues inadequate investigations and the scope of the investigation did not extend to other batches that may have been associated with the failure or discrepancy Inadequate equipment cleaning and maintenance procedure to prevent contamination. Inadequate preventive maintenance and failure to conduct a timely investigation into all equipment and products potentially affected by the deviations Field alert reporting violations Distribution of products before the completion of the stability study Process validation issues: Your response states that the specification for hardness is an average of individual results. However, your Process Validation protocol does not specify that this specification be applied to an average of all samples." It is unacceptable to establish process validation acceptance criteria and then dismiss such criteria as insignificant when the results do not conform. Repeated violations Cleaning validation studies hasnt been thoroughly conducted to demonstrate the adequacy of the study Unapproved Over-the-Counter Drug Product Violations Failure to retain and store the retention samples No appropriate controls over computer or related systems Failure to assure adequate process design and control: Persistent problems of particulate contamination due to stainless steel which resulted in recalls of several lots of products were not resolved Failure to follow written procedures to assure prompt investigation, determine root cause, and implement appropriate corrective action No established scientifically sound and appropriate sampling plans No scientific rationale for employing a matrix approach for the validation of solution tank mixing process The firm failed to reject a lot of product contaminated with metal shavings Inadequate investigations regarding contaminated product lots Quality control unit (QCD) failed to follow its own written procedures

Letter date: April 29, 2010

Failure to adequately inspect the packaging and labeling facilities immediately before use to assure that all drug products have been removed from previous operations Repeated violations

Braintree Laboratories, Inc, 11 Inspection Dates: December 3, 2009 through January 22, 2010 Letter date: May 10, 2010 Presence of foreign materials in finished products (e.g., insects, insect parts, and spiders) No thorough investigation to trace the root cause of the issue. Inadequate investigation of failing stability testing results Firm failed to conduct an adequate investigation of OOS Media fill failures: Failure to document the evaluation of media fill units after 14 days of incubation, and to identify the organisms in contaminated media fill units. Proper aseptic techniques were not followed by the operators performing aseptic operations during the filling. Inadequate environmental program in detecting environmental contaminants. Investigations were not adequately conducted for OOS obtained and initial OOS results are invalidated without justification No assessment of the cross-contamination risks posed by the manufacture of several potentially hazardous compounds (e.g., beta lactam antibiotic and steroid products) No smoke studies were conducted at critical areas to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. No procedure or documentation for monitoring differential pressure within the aseptic processing areas. The products were released and distributed even though they failed stability testing. Firm failed to review the Certificate of Analysis (COA) for products prior to release and distribution Unapproved and Misbranded Prescription Drug violations Failed to review, investigate and approve Complaints received A lot was manufactured and released in between two failed media fills. Firm has not conducted a thorough investigation regarding the media fill failures

Laboratorios L.O., Inspection Dates: February 22 26 and March 1 2, 2010 Letter date: May 12, 2010

12

River's Edge Pharmaceuticals, LLC Inspection Dates: July 13 thru August 12, 2009 Letter date: May 20, 2010

13

K.C. Pharmaceuticals Inc. Inspection Dates: December 14 - 30, 2009 Letter date: May 21, 2010

14

Dead legs were observed in the piping system used for water distribution.
Inadequate environmental program in detecting environmental contaminants.

Ribbon Pharmaceutical and Chemical Products Inspection Dates: December 8 15,2009 Letter date: May 27, 2010

15

Media fills failed to include simulation of the routine interventions performed in a typical campaign. No Dynamic smoke studies were conducted to demonstrate that the personnel activities during aseptic filling do not compromise the sterile API. Firm failed to clean and maintain equipment at appropriate intervals to prevent contamination. Firm has not thoroughly investigated any unexplained discrepancy or the failure of a batch, Product was released and distributed without investigating and resolving the OOS generated with the product. Drug product that was manufactured using expired components. Firm failed to follow procedures for the handling of complaints Firm failed to reject any lot of components that did not meet the appropriate written specifications Firm has not established written procedures for cleaning and maintenance of equipment Firm did not conduct a formal risk assessment of the particulate contamination found in the drug product and its possible impact on product quality. Poor aseptic technique was observed by manufacturing and quality control microbiology personnel working inside the aseptic fill suite and core. Deficiencies in the environmental and personal monitoring program No documentation or procedure to demonstrate that tools used in the aseptic filling suites and cores are autoclaved prior to use.

BENEV Company, Inc. Inspection Dates: September 21 - 30, 2009, and February 2 - 4, 2010 Letter date: May 18, 2010

16

Albany Molecular Research, Inc. Inspection Dates: March 2, 2010 to April 1, 2010 17 Letter date: August 17, 2010

IriSys, Inc. Inspection Dates: March 16 through April 01, 2010 Letter date: August 23, 2010 Changes were made to equipment and process modifications without adequate change control. No documentation to demonstrate that your firm's water system can produce purified water of adequate quality. Unapproved and Misbranded Prescription Drugs violations.

18

Qualiphar n.v. Inspection Dates: May 3 7, 2010 19 Letter date: September 30, 2010

Process validation for the manufacturing of the product was deficient No documentation of equipment qualification Release of batch without conducting an OOS resulted from testing of in-process material No adequate laboratory controls and sampling plans Records do not include the disposition of rejected filled drug product containers Failure to have written procedures for the preparation of

annual review of your products. Discrepancies in Annual product reviews No adequate cleaning validation No adequate justification to Deviations. The firm manufactured a small batch due to insufficient raw materials with a deviation form using process parameters of the large batch without proper justification Adding of overages without justification No specific identity test was conducted on incoming materials to establish the reliability of the supplier's analyses Firm does not have adequate stability data to support the labeled expiry Unapproved and Misbranded Prescription Drugs violations Manufacturing and distribution of the batch prior to requalifications of the room for aseptic processing No adequate environmental monitoring program in the aseptic filling areas Inadequate HEPA Filter integrity testing Proper aseptic technique were not followed Inadequate investigations

NexgenPharma, Inc. Inspection Dates: March 1 to April 2, 2010 Letter date: September 27, 2010

20

Gilead Sciences, Inc. Inspection Dates: January 25, 2010 to February 12, 2010 Letter date: September 21, 2010

21

Bristol-Myers Squibb Company Inspection Dates: March 17-31, 2010 22 Letter date: August 30, 2010 Operators at the facility have failed to comply with procedures for aseptic operations. Routine Interventions were not covered in the media fill protocol Inadequate investigation of excursion in environmental monitoring Firm does not have adequate written procedures for production and process controls Suppliers are not adequately qualified Inadequate investigations of OOS and customer complaints QCU failed to adequately review production and control records to ensure no errors occurred Failure to follow written procedures Firm didnt adequately inspect the packaging and labeling facilities immediately before use to assure that all drug products have been removed from the previous operations Failed to submit NDA Field Alert Reports

Sun Pharmaceutical Industries, Inc. Inspection Dates: February 25 - April 28, 2010 Letter date: August 25, 2010

23

Biologics Baxter Healthcare Corporation 24 Inspection Dates: October 12 and October 19, 2009 Letter date: Jan 15 2010 No adequate investigations, Investigations related to recurrent clogging of filters is incomplete. Failure to follow written procedure There are no extractable/leachable studies for the used filters. Studies performed by the filter manufacturer used material that was not representative of the actual process. Failure to inform FDA about each change in the production

process established in the approved license application. Fertility and Reproductive Medicine Center for Women Inspection Dates: November 4 through November 12, 2009 Letter date: January 26, 2010 Failure to determine whether a donor is eligible based upon the results of donor screening in accordance with 1271.75 Failure to screen an anonymous or directed reproductive donor of cells or tissue by reviewing the donor's relevant medical records for risk Failure to ensure that establishments who by contract, agreement or other arrangement, perform any manufacturing steps for you were in compliance with applicable CGTP requirements factors

25

DBA IVF Phoenix 26 Inspection Dates: February 1, 2010 to February 5, 2010 Letter date: March 29, 2010 API Manufacturers

Failure to determine as ineligible, a donor whose specimen tests reactive on a screening test for a communicable disease agent [21 CFR 1271.80(d)(1)]. Failure to follow established procedures for determining donor eligibility [21 CFR 1271.47(a)].

27

XiAn Libang Pharmaceutical Co., Ltd.Inspection Dates: July 27-30, 2009 Letter date: January 28, 2010

Failure of the quality unit to ensure that materials are appropriately tested and the results are reported. The firm tested only a single lot and released the remaining two lots without conducting atleast one identity testing. It is essential that at least one test be conducted to verify the identity of each lot of incoming material. Falsified and Altered laboratory documents: The firm has failed to detect that IR spectra being substituted by a laboratory employee and therefore, misrepresenting the actual results of the tested incoming material. Lack of integrity and security of raw analytical data, manipulation of test results

Eli Lilly & Company 28 Inspection Dates: July 08 - 31, 2009 Letter date: February 5, 2010

The firm has used a test method which was not validated for its intended use. The firm released several lots of API which were under investigation without sound rational. The agency states that the firm's response to 483 lacks sufficient corrective actions.

AMPAC Fine Chemicals, LLC 29 Inspection Dates: February 9-19, 2010 Letter date: June 25, 2010

The firm lacked proper cleaning procedures to prevent contamination. Dirt, blistering paint, rust, and oil droplets were found to be in close proximity to manufacturing equipment in several building The firm failed to ensure documentation of cleaning of major equipment after each batch is processed; and failure to clean non-dedicated equipment between the production of

different APIs to prevent cross-contamination. Failure to identify and quarantine returned APls. It imperative to all of us to ensure that returned APIs are properly identified and quarantined separately from material approved for distribution and to have sound procedures governing this system. The firm failed to properly investigate and find the root cause of the OOS obtained. The firm has attributed laboratory error as the root cause of the OOS without proper rationale. A retesting was authorized without identifying a possible root cause. Instead, a new sample preparation was used to retest the product, which was found within specification. The passing retest results were used to invalidate the original OOS results, with no laboratory error attributed in obtaining the original result lacking scientific justification. Test methods employed do not include system suitability test requirements. Sampling plan for incoming raw materials is not appropriate and scientifically sound. Failure to ensure your analytical methods used to evaluate the stability of your APIs are validated to be stability indicating. No control system for the issuance of laboratory records to ensure the integrity and reliability of laboratory raw data. (repeated violation) No cleaning validation for components used for manufacturing process

Kyowa Hakko Kogyo Co., Ltd. Inspection Dates: Kyowa Hakko Kogyo Co., Ltd. 30 Letter date: September 29, 2010 (Read this letter in entirety to understand what FDA expects in your sampling procedure for incoming raw materials)

Acknowledgments I would like to thank my friend T. Rajesh for his valuable inputs & directions in preparation of this report and to John Avellanet, a promise made to him which propelled me to finish this report and last but not the least Douglas A. Campbell, Consumer Safety Officer, FDA, Larry Spears, FDA and Jeff Yuen whose presentations were the basis in compilation of this report. About the Author Madhu Raju Saghee is working in corporate quality and sterility assurance department at Gland Pharma Limited, a producer of small volume parenterals located in Hyderabad, India. In this position, he is responsible for implementing a robust quality system and well versed with GMP Quality Assurance & Regulatory Compliance, 483s and Warning Letter Assistance, Due Diligence, Assessments & Audits and involved in qualification and validation of sterile and aseptic manufacture. He has written many articles pertaining to regulatory compliance, quality assurance, quality risk management, cleanroom contamination control and microbiology. He is the co-editor of the book Microbiology and Sterility Assurance in Pharmaceuticals and Medical Devices. Raju has a Master of Science in Microbiology from Andhra University and Master of Science in Chemistry from Nagarjuna University. He can be reached at madhuraju.sagi@gmail.com