- Delivery Method:
- VIA UPS
Recipient NameMr. Jagrat N. Dave
Recipient TitleChief Executive Officer
- Contacare Ophthalmics & Diagnostics
Block Number 310B, Dabhasa, Padra Taluka
Dist. Vadodara 391440
- Issuing Office:
- Center for Drug Evaluation and Research
10903 New Hampshire Avenue
Silver Spring, MD 20993
Warning Letter #320-19-19
April 23, 2019
Dear Mr. Dave:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Contacare Ophthalmics & Diagnostics at Block Number 310B, Dabhasa, Padra Taluka, Dist. Vadodara, Gujarat from October 25 to November 1, 2018.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
According to your products’ labeling, your firm introduces or delivers for introduction into interstate commerce unapproved new drugs, in violation of Sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d). Furthermore, these unapproved new drugs are misbranded under Section 502(f)(1) of the FD&C Act, 21 U.S.C. 352(f)(1), and by introducing or delivering these products for introduction into interstate commerce, you are in violation of Section 301(a) of the FD&C Act, 21 U.S.C. 331(a).
We reviewed your November 26, 2018, response in detail.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas (21 CFR 211.42(c)(10)).
The (b)(4) used to separate the ISO 5 (Class 100) area from the ISO 7 (Class 10,000) area in your “(b)(4)” aseptic filling room had substantial gaps and provided insufficient barrier protection. Additionally, your firm did not perform any smoke studies under static or dynamic conditions of the aseptic processing line to determine if airflow is unidirectional.
The “(b)(4)” filling room was used to manufacture multiple batches of an (b)(4) drug product ((b)(4) solution, USP (b)(4)%) for the U.S. market. During the inspection you stated to our investigator that this product was (b)(4). However, upon review of inspectional documents and information your firm provided to our office after the conclusion of the inspection, we discovered that this product was in fact aseptically filled.
Based on the deficiencies identified during our inspection, your filling room and processing line are not properly designed to support the manufacture of aseptically filled drug products. In addition to poor processing line protection, we observed factors such as excessive personnel engaged in aseptic manufacturing, poor line design, and improper aseptic technique, which further establish your deficient capability to manufacture sterile drug products. Manual or mechanical manipulations of the sterilized drug, components, containers, or closures before or during aseptic assembly pose the risk of contamination and require strict control.
Your response failed to address the deficiencies identified in your “(b)(4)” filling room. Additionally, the smoke studies you provided lacked a substantive assessment of the ISO 5 airflow. This included, but was not limited to, failure to thoroughly visualize the smoke at work surfaces during both static and dynamic conditions, the presence of smoke turbulence at the (b)(4), and the impact of multiple people at or near the aseptic filling line (where four people were observed during our inspection). You also failed to meaningfully simulate representative aseptic operations and manipulations. While the studies you provided were limited, we note that they indicate a flawed process.
Your response also lacked a commitment to perform an independent, retrospective risk assessment of all drug products, within expiry, produced in the “(b)(4)” filling room that were shipped to the United States to determine potential patient hazard.
In response to this letter, provide the following:
- Smoke studies conducted under static and dynamic conditions to fully evaluate air flow patterns on the aseptic processing line.
- A summary of results from testing retain samples of all drug products, within expiry, produced in the “(b)(4)” filling room that were shipped to the United States for attributes including, but not limited to, sterility.
- Comprehensive identification of all contamination hazards with respect to your aseptic processes, equipment, and facilities. Provide an independent risk assessment that includes, but is not limited to:
- All human interactions with the ISO 5 (Class 100) area
- Equipment placement and ergonomics
- Air quality in the ISO 5 (Class 100) area and surrounding room
- Facility layout
- Personnel flow
- Material flow
- Classified room design and construction
- A detailed corrective action and preventive action (CAPA) plan with timelines to address the deficiencies identified by the contamination hazards risk assessment. Describe how you will comprehensively improve your aseptic processing operations.
- If your risk assessment determines any marketed lot may pose a potential patient hazard or yields an out-of-specification (OOS) result, indicate the corrective actions you will take including notifying customers and initiating recalls.
2. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).
During our inspection we observed that your firm’s media fills are inadequate because they failed to fully simulate the various manual interventions in your (b)(4) process and ensure each person involved in aseptic operations performs sufficiently rigorous simulations.
In your response, you stated that you are retraining personnel and updating your media fill procedure. However, you did not adequately address how the deficient simulations adversely impact the accuracy of past media fill results and confidence in ongoing aseptic production capability. You also did not commit to immediately perform additional media fills to address this lack of assurance. Additionally, you did not commit to performing a retrospective assessment of impact on aseptically processed drug products.
In response to this letter, provide the following:
- A retrospective assessment of all media fills conducted since November 2015. List all media fills conducted, fill date, number of units runs, number of vials rejected, number of units incubated, number of positive units, and identity of microbial isolates. Identify all staff who participated in each media fill and the number and type of interventions they performed. Also describe the circumstances under which any integral media fill vials were removed from each media fill batch. Explain in detail why they were rejected.
- A three-year history of all sterility positives, regardless of whether it was later invalidated by your firm. Include data for products shipped to both the United States and the rest of the world.
3. Your firm failed to establish an adequate system for maintaining equipment used to control the aseptic conditions (21 CFR 211.42(c)(10)(vi)).
The filling machine and high efficiency particulate air (HEPA) filters located directly above the filling machine in your “(b)(4)” filling room were significantly discolored with an unknown (b)(4) substance. Also, your firm reused “laundered” wipes in your aseptic processing rooms. You lacked supporting studies indicating that these wipes can be reused without causing a particle contamination hazard.
In your response, you stated that the discoloration on the HEPA filters and filling machine was because of fumigation agents used by your firm ((b)(4)). However, you did not provide any evidence or justification demonstrating the source of the staining.
Additionally, in your response you stated that the “discolored HEPA filter is recolored.” However, it is unacceptable to “recolor” HEPA filters. Furthermore, you did not provide an assessment of the impact of the residues on HEPA filter performance or the contamination hazard to the drug products exposed to these filters. Your response also states that you have updated your procedure for washing, inspection, folding, and sterilization of your aseptic wipes and garments to include a visual inspection of these supplies after they are washed. However, you failed to provide your updated procedure.
In response to this letter, provide the following:
- Evidence and justification of the source of the discoloration observed on your HEPA filters, HEPA filter framework, and filling machine.
- Detailed description of how your firm “recolored” your discolored HEPA filters and whether they are still in use.
- A thorough qualification of cleaning and sterilization procedures for your wipes and garments to determine appropriate cleaning, reuse practices, and a maximum number of uses before discarding.
- Your revised procedure for washing, inspection, folding, and sterilization of your aseptic wipes and garments and your newly developed inspection log sheet.
- An independent, retrospective review of all products within expiry produced in the “(b)(4)” filling room that were shipped to the United States to determine if the (b)(4) residue on your HEPA filters affected drug product quality. Also, perform a retrospective review of all products within expiry that were shipped to the United States, to determine if deteriorating wipes affected drug product quality. Include a review of all viable and non-viable particle monitoring.
4. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
Your firm lacked meaningful and timely investigations of non-sterility test results. For example:
(b)(4) Solution, lot (b)(4)
You experienced a sterility failure on or about October 24, 2018. You discarded the failing sample, did not identify the microbial isolate, and failed to initiate a timely investigation for this drug product. In addition, your firm provided two different versions of the test report for this sterility sample to our investigator. Your documentation practices raise questions regarding the integrity of data generated by your firm.
(b)(4) Solution USP (b)(4)% - (b)(4)mL, lot (b)(4)
Your quality unit (QU) failed to perform an investigation when personnel monitoring for operators engaged in the manufacture of this drug product exceeded your firms action limits identifying the presence of gram-positive rods. Your firm approved the personnel monitoring report as “complies.” Subsequently, this lot was released by your QU and distributed to the U.S. market. Furthermore, FDA tested this drug product upon entry into the United States and confirmed that this sterile (b)(4) drug product was contaminated with multiple microorganisms (gram-positive coccobacillus: Globicatella sulfidifaciens, gram-positive spore-forming rods: Bacillus pumillus, gram-positive cocci: Staphyloccus lentus, and gram-negative rods: Sphingomonas paucimobilis).
In your response, your retrospective sterility failure investigation indicates that the positive sample for (b)(4) Solution, lot (b)(4) was because of a power failure. However, you provided no supporting documentation to substantiate this claim or any indication that any other analyses or manufacturing processes were affected by the stated power failure. In your firm’s response to the observation you indicate that satisfactory retain sample testing suffices to invalidate the original positive result.
You have not provided any thorough investigation into the conditions that led to the sterility failure or determine potential root causes to ensure effective CAPAs are promptly implemented. Whenever an OOS test result is obtained, it is essential that you conduct a thorough investigation to determine potential causes and implement effective CAPAs.
Also, in your response, you stated that no investigation was conducted regarding the sterility failure for (b)(4) Solution USP (b)(4)% - (b)(4)mL, lot (b)(4) because no additional lots of this particular drug product were manufactured after this lot. This response is unacceptable. A sterility failure signals severe hazards in your operation and is indicative of the overall capability of your aseptic processes. Investigations must be conducted for any sterility failures even if no additional lots of that specific drug product are manufactured. It is imperative that investigations identify deficiencies in your aseptic processes that may have affected other drug products produced by your firm.
In response to this letter, provide the following:
- Documentation of any power outages that occurred on the referenced date and their direct effects on the failing test results and on other batches manufactured during that time. Additionally, list all analyses performed and batches processed during power outages since November 2015. Describe the duration of the power failure and areas of the plant that were affected. Describe criteria used by your firm to decide if power failures affected the adequacy of your analyses and/or processing conditions. Also, provide the related investigation reports and an assessment of suitability of any batch or analysis that may have been impacted by a power outage.
- All deviation and maintenance records relating to the power failure for lot (b)(4), all areas of the plant affected, and all other details on its extent and impact.
- Describe in detail the uninterrupted power source coverage in your facility. Provide any standard operating procedures describing what actions are taken in the event of a power failure during manufacturing and laboratory analysis. Provide an explanation of why your firm did not abort the sterility test when a power failure occurred and what measures are being put in place to prevent recurrence in the future. Any disruption in power supply, however momentary, that could affect drug product quality is considered a manufacturing deviation.
- A comprehensive, independent assessment of your system for investigating deviations, atypical events, complaints, OOS results, and failures. Your CAPA plan should include, but not be limited to, improvements in investigations, root cause analysis, written procedures, and QU oversight. Also include your process for evaluating CAPA plan effectiveness.
- Complete investigations into all lots with sterility positive results, regardless of whether the result was later invalidated by your firm. The investigations should detail your findings regarding the root causes of the contamination.
- A thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, raw materials, process capability, deviation history, and batch failure history) for any OOS results with inconclusive or no root cause identified.
- A review and remediation of your system for investigating OOS results. Provide a CAPA plan to improve OOS handling. Your CAPA plan should ensure that your revised OOS investigations procedure includes:
- Enhanced QU oversight of laboratory investigations
- Identification of adverse laboratory control trends
- Resolution of causes of laboratory variation
- Investigations of potential manufacturing causes when a laboratory cause cannot be conclusively identified
Unapproved New Drug Violations
Inspection of your firm revealed that your firm caused the introduction or delivery for introduction into interstate commerce of Bio-Glo (fluorescein sodium ophthalmic strips USP) and Green-Glo (lissamine ophthalmic strips) in violation of sections 505(a) and 301(d) of the FD&C Act, 21 U.S.C. 355(a) and 331(d). Your Bio-Glo (fluorescein sodium ophthalmic strips USP) and Green-Glo (lissamine ophthalmic strips) are “drugs” within the meaning of section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1) because they are articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals and/or an article (other than food) intended to affect the structure or any function of the body of man or other animals. Labeling statements documenting the intended uses of your products include, but are not limited, to the following:
Bio-Glo (fluorescein sodium ophthalmic strips USP), labeled with statement of intended use:
- Intended for use when fitting contact lenses.
Green-Glo (lissamine ophthalmic strips), labeled with statement of intended use:
- For use as a diagnostic agent when superficial corneal or conjunctival tissue change is suspected.
Further, these drugs are “new drugs” within the meaning of section 201(p) of the FD&C Act, 21 U.S.C. 321(p) because they are not generally recognized as safe and effective for use under the conditions prescribed, recommended, or suggested in their labeling.
Under section 505(a) of the FD&C Act, 21 U.S.C. 355(a), new drugs may not be introduced or delivered for introduction into interstate commerce unless applications approved by FDA under either section 505(b) or (j) of the FD&C Act, 21 U.S.C. 355(b) or (j) are effective with respect to such drugs. There are no FDA-approved applications in effect for your products listed above. The introduction or delivery for introduction (or the causing thereof) into interstate commerce of new drugs in violation of section 505 is prohibited under 301(d) of the FD&C Act, 21 U.S.C. 331(d). Consequently, your marketing and distribution of these products without approved applications violate provisions of the FD&C Act.
Misbranded Drugs Violations
According to section 502(f)(1) of the FD&C Act, 21 U.S.C. 352(f)(1), a drug is misbranded if, among other things, it fails to bear adequate directions for its intended use(s). “Adequate directions for use” means directions under which a layman can use a drug safely and for the purposes for which it is intended (21 CFR 201.5).
Bio-Glo (fluorescein sodium ophthalmic strips USP) and Green-Glo (lissamine ophthalmic strips) are intended for conditions that are not amendable to self-diagnosis and treatment by individuals who are not medical practitioners and are prescription drugs. Prescription drugs, as defined in Section 503(b)(1) of the FD&C Act, 21 U.S.C. 353(b)(1), are drugs, “because of its toxicity or potential for harmful effect, or the method of its use, or the collateral measures necessary to its use, is not safe for use except under the supervision of a practitioner licensed by law to administer such drugs.” Accordingly, adequate directions for use cannot be written for prescription drugs so that a layman can use them safely for their intended uses.
In sum, adequate directions for use cannot be written for Bio-Glo (fluorescein sodium ophthalmic strips USP) and Green-Glo (lissamine ophthalmic strips). Moreover, Bio-Glo (fluorescein sodium ophthalmic strips USP) and Green-Glo (lissamine ophthalmic strips) are not exempt from the requirement that the labeling bear adequate directions for use because there are no FDA-approved applications in effect for either Bio-Glo (fluorescein sodium ophthalmic strips USP) or Green-Glo (lissamine ophthalmic strips) nor is there an effective IND for either product. (See, 21 CFR 201.100(c)(2) and 201.115). As such, Bio-Glo (fluorescein sodium ophthalmic strips USP) and Green-Glo (lissamine ophthalmic strips) are each misbranded under section 502(f)(1) of the FD&C Act, 21 U.S.C. 352(f)(1). The introduction or delivery for introduction into interstate commerce of this misbranded product violates section 301(a) of the FD&C Act, 21 U.S.C. 331(a).
Repeat Violations at Facility
In previous inspections, dated April 2013 and April 2017, FDA cited similar CGMP observations You proposed specific remediation for these observations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
CGMP Consultant Recommended
If your firm intends to resume manufacturing drugs for the U.S. market, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA.
Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.
Additional Guidance on Aseptic Processing
See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at .
Data Integrity Remediation
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM495891.pdf.
We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide the following:
- A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:
- A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
- Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
- An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.
- A comprehensive retrospective evaluation of the nature of the data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.
- A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.
- A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:
- A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA.
- A comprehensive description of the root causes of your data integrity lapses including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
- Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
- Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.
- A status report for any of the above activities already underway or completed.
Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations.
FDA placed your firm on Import Alert 55-05 on August 23, 2017 and Import Alert 66-40 on February 20, 2019.
Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.
Failure to correct these violations may also result in FDA continuing to refuse admission of articles manufactured at Contacare Ophthalmics & Diagnostics at Block Number 310B, Dabhasa, Padra Taluka, Dist. Vadodara, Gujarat into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
Send your electronic reply to or mail your reply to:
CDR Frank Verni, R.Ph., MPH
U.S. Food and Drug Administration
White Oak Building 51, Room 4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
Please identify your response with FEI 3006217304.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research