WARNING LETTER
Aspen Pharmacare Holdings Limited
MARCS-CMS 701671 —
February 24, 2025
Delivery Method:
VIA EMAIL WITH READ RECEIPT
Reference #:
320-25-46
Product:
Drugs
Recipient:
Recipient Name
Mr. Stephen Saad
Recipient Title
Group Chief Executive
Aspen Pharmacare Holdings Limited
9 Rydall Vale Park
Douglas Saunders Drive, La Lucia Ridge
Durban
KwaZulu-Natal
4051
South Africa
SSaad@aspenpharma
Issuing Office:
Center for Drug Evaluation and Research (CDER)
United States
Warning Letter
320-25-46
February 24, 2025
Dear Mr. Saad:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Aspen SA Sterile Operations (Pty) Ltd. (an Aspen Pharmacare Holdings Limited subsidiary), FEI 3007490529, at 8B Gibaud Road, Kortsen, Gqeberha, South Africa 6020, from September 9 to 17, 2024.
This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (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).
We reviewed your October 8, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigators observed specific violations including, but not limited to, the following.
1. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).
Your firm did not establish appropriate specifications or test your sterile over-the-counter (OTC)
(b)(4)
drug products to monitor impurities at release and throughout expiry. For example:
You did not perform impurity testing prior to release and during stability for
(b)(4)
.
You did not establish scientifically justified specifications to monitor impurities during stability testing of drug products containing Naphazoline Hydrochloride or Tetrahydrozoline Hydrochloride active pharmaceutical ingredient (API).
In your response, you state that the impurity limits were established based on your customer’s requirements and that no limits were included for release testing. You provide your customer’s health hazard evaluation (HHE) which concluded that the presence of Impurity
(b)(4)
at stability levels of up to
(b)(4)
% of the labeled
(b)(4)
content would not pose any safety risk for those that use the products according to directions. The Agency disagrees with the HHE assessment and concludes that the presence of impurity levels at
(b)(4)
% may pose a risk to patient safety at the recommended dosage. It is your responsibility to ensure that appropriate specifications are established to monitor impurities throughout the expiry period.
Your response is inadequate. You lack adequate scientific rationale for the current impurity specifications of your drug products. A similar deficiency for the lack of impurity specifications for release and stability testing for
(b)(4)
API containing products was also identified during the 2016 inspection. However, this deficiency has not been fully addressed to date. Additionally, your risk assessment does not include an evaluation of reserve samples of potentially impacted product batches distributed to the United States.
Drug product batches must be tested for identity, strength, quality, and purity prior to release. Insufficient release and stability testing to appropriately detect impurities in your drug products could potentially impact product quality and patient safety.
In response to this letter, provide:
A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
Degradation study protocols and reports for your drug products, which should include impurities that will be monitored throughout the product life cycle as well as your scientific justification for the acceptance criteria and study design.
A list of current and revised specifications for release and stability testing, including test methods, used to analyze each batch of your drug products before a batch disposition decision.
o An action plan and timelines for conducting full chemical testing of reserve samples to determine the quality of all batches of drug product distributed to the United States that are within expiry as of the date of this letter.
o A summary of all results obtained from testing reserve samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.
2. Your firm failed to 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)).
Poor Aseptic Practices
During the inspection of your facility, we observed poor practices and behaviors in ISO 5 areas during the manufacturing of sterile
(b)(4)
drug products. These poor practices included, but were not limited to:
Operators blocked first air by placing their gloved hands directly over open sterilized bottles without clearing them from the aseptic filling line.
Operators used their gloved hands instead of using appropriate sterile tools to remove jammed bottles.
Operator movements in the critical areas were not always slow and deliberate.
Operators used goggles that had numerous open holes and therefore had exposed skin during line set-up and aseptic processing.
In 2022, your firm identified contamination in two media fill batches one on the “
(b)(4)
” aseptic filling line and another on the “
(b)(4)
” aseptic filling line. You identified the root cause as poor aseptic behavior. These contamination events along with the poor aseptic practices observed during our inspection indicate your aseptic manufacturing operations may lack adequate control. Your firm did not perform a sufficiently comprehensive evaluation of aseptic behavior of operators as part of this recurrent trend.
We also note that open door interventions required a large door to be opened. On numerous occasions, the door remained opened for extended periods of time while the line was still in-operation. When opened, the door was exposed to the ISO 7 area, and when being closed, there was a significant risk of the lower quality room air sweeping into the ISO 5 aseptic processing area. Empty sterile containers were located extremely close to the door. In addition, operators did not adequately disinfect the open door. While spraying disinfectant on the
(b)(4)
, operators failed to consider open sterilized bottles on the line, exposing them to potential contamination.
Inadequate Smoke Studies and Cleanroom Design
Your smoke studies did not adequately demonstrate unidirectional air flow in the ISO 5 classified areas used for the aseptic filling of ophthalmic drug products on the “
(b)(4)
” and “
(b)(4)
” aseptic filling lines. For example:
Your smoke studies lacked simulation of aseptic line set-up, dynamic operations, and interventions that occur during aseptic manufacturing operations.
Generation of smoke was not sufficient to demonstrate unidirectional air flow.
We also note that there were multiple aspects of your cleanroom and aseptic processing line design which represented fundamental contamination risks:
There was no physical barrier between the operator and the open
(b)(4)
-sterilized bottles on the conveyor. Your production operator remained inside the ISO 5 aseptic processing area, sitting or standing next to the conveyor line where open, exposed bottles pass.
There were extensive manual interactions with the aseptic processing line and its exposed sterile drug product and containers/closures.
Operators performed multiple manual interventions during filling by
(b)(4)
or
(b)(4)
due to
(b)(4)
not being installed on these
(b)(4)
. These interventions may pose inherent risks to your aseptic processes.
The ISO 5 area is critical because sterile product is exposed and therefore vulnerable to contamination. Your aseptic filling process should be designed, and operations executed, to prevent contamination hazards to your sterile product. The flawed design of the filling line and execution of the aseptic operations promote influx of contamination into the critical filling areas.
In your response, you indicate that you temporarily suspended manufacturing on the “
(b)(4)
” aseptic filling line. You acknowledge that the design of your aseptic filling lines is not optimal and indicate that an independent review of your design and remediation plans for both “
(b)(4)
” and “
(b)(4)
” aseptic filling lines will be performed. You also commit to perform new smoke studies under static and dynamic conditions and evaluate associated risks. You indicate that you have engaged a third-party consultant to assist in improving aseptic practices.
Your response is inadequate because it does not sufficiently address the lack of oversight of aseptic behavior of operators. Further, you do not adequately investigate poor aseptic practices to determine the impact on sterile drug products manufactured and aseptic processing areas. You also do not clearly specify how you will improve your smoke studies, including what interventions will be included, and how you will address potential deficiencies.
For 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 https://www.fda.gov/media/71026/download.
In response to this letter, provide:
Your plan to ensure appropriate aseptic practices and cleanroom behavior during production. Include steps to ensure routine and effective supervisory oversight for all production batches. Also describe the frequency of quality unit (QU) oversight (e.g., audit) during aseptic processing and its support operations.
A thorough retrospective review and risk assessment that evaluates how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs.
Comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:
o All human interactions within the ISO 5 area
o Equipment placement and suitability, including ergonomics for each human interaction.
o Air quality in the ISO 5 area, and surrounding room including, but not limited to, air volume, air flow, and microbial/particulate levels
o Reduction or elimination of aseptic manipulations and connections (e.g., replacing post-filtration aseptic connections with sterilize-in-place system)
o Facility layout
o Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations)
A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.
Smoke studies under dynamic conditions, with thorough and complete evaluations of aseptic interventions and operator positioning within the critical filling areas. After you remediate your aseptic operation, provide smoke studies that visualize airflow and critically evaluate unidirectional airflow. Include a video of your dynamic smoke studies.
3. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).
Your Production and QU did not review electronic raw data and audit trails to ensure data integrity prior to batch release. Your operators obtained and printed a passing result after multiple production filter integrity tests failed. Your operators did not record or print the failing results. For example:
On August 8, 2024, two operators performed four post-use sterilizing filter integrity tests for
(b)(4)
batch
(b)(4)
. The four tests included three failing results and the final passing result. Your operators only reported the passing result.
On July 25, 2024, two operators performed nine filter integrity tests associated with
(b)(4)
, bulk batch
(b)(4)
. The nine tests included five failing results, three aborted tests, and the final passing result. Your operators only reported the passing result.
In your response, you acknowledge the deficiency and commit to perform a full audit trail review of your production equipment. You also indicate that you are completing the investigations into anomalous filter integrity tests.
Your response is inadequate as you do not provide details of the investigation outcome or explain whether effective corrective actions and preventive actions (CAPAs) have been implemented. Further, you do not provide the scope and time period of the retrospective review to ensure all batches potentially affected are part of the assessment.
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/media/97005/download.
We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide:
A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.
o 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.
o A management strategy for your firm that includes the details of your global CAPA plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including manufacturing records.
A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
o A determination of whether procedures used by your firm are robust and appropriate.
o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
o A complete and final review of each batch and its related information before the QU disposition decision.
o Ensure that appropriate procedures are in place regarding the review of all critical electronic data (e.g., filter integrity testing).
o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.
4. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
You did not establish an adequate system for monitoring environmental conditions on the “
(b)(4)
’ aseptic filling line. For example:
You did not conduct viable monitoring of the air and surfaces in ISO 5 areas where an operator was continuously present removing fallen bottles.
You did not place the non-viable particle monitoring (NVPM) probes in representative ISO 5 areas where the product and primary components were exposed. Our investigators noted the following:
o The NVPM probe closest to the
(b)(4)
was located approximately
(b)(4)
above the level of the
(b)(4)
.
o The NVPM probe nearest to the sterile cap
(b)(4)
was located approximately
(b)(4)
above the level of the
(b)(4)
.
Your operators routinely placed mobile NVPM devices in locations different from those specified in your procedures to monitor the ISO 5 areas. As such, NVPM data may not accurately represent the critical areas in operation.
In your response, you commit to upgrade your “
(b)(4)
” aseptic filling line and perform a Quality Risk Assessment for NVPM in Suite
(b)(4)
.
Your response is inadequate. While you commit to conducting a Quality Risk Assessment for NVPM to identify, assess, and mitigate all gaps, you have not provided any updates on the status of risk assessment. Vigilant and responsive environmental monitoring programs should be designed to provide meaningful information on the state of control of your aseptic processing environment. Operations that include highly manually intensive aseptic activities warrant a more extensive environmental and personnel monitoring program, including but not limited to, heightened emphasis on well-timed sampling to appropriately monitor batch manufacturing conditions.
In response to this letter, provide:
A thorough, independent assessment, and CAPA for your environmental monitoring program. Include a comprehensive evaluation of monitoring, recording, alarm documentation, deviation investigation, data retention, and overall environmental control in your assessment.
Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
An independent, retrospective evaluation of all ISO 5 NVPM deviations, root causes, and a relevant CAPA plan.
Responsibilities as a Contractor
Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors, such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.
You are responsible for the quality of drugs you produce as a contract facility regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA’s guidance document
Contract Manufacturing Arrangements for Drugs: Quality Agreements
at https://www.fda.gov/media/86193/download.
CGMP Consultant Recommended
We acknowledge you engaged a consultant to assist your firm in meeting CGMP requirements. You are responsible for ensuring consultants you use are qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements and to correct repeat violations. 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.
Drug Production Suspended
We acknowledge your commitment to suspend production of all drugs for the U.S. market.
If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. You are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all CAPAs.
Conclusion
The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.
FDA placed products offered for import into the United States from your firm on Import Alert (IA) 66-40 on February 10, 2025.
Correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.
Failure to address any violations may also result in the FDA continuing to refuse admission of articles manufactured at Aspen SA Sterile Operations (Pty) Ltd., 8B Gibaud Road, Kortsen, Gqeberha, South Africa 6020 into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused 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).
This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days
1
. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion. We request you email CDER-OC-OMQ-Communications@fda.hhs.gov, within 5 days of receipt of this letter to schedule a regulatory meeting.
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3007490529 and ATTN: Anita Narula, Ph.D.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
____________________
1
Under program enhancements for the Generic Drug User Fee Amendments (GDUFA) reauthorization for fiscal years (FYs) 2023-2027, also known as the GDUFA III Commitment Letter, your facility may be eligible for a Post-Warning Letter Meeting to obtain preliminary feedback from FDA on the adequacy and completeness of your corrective action plans.
Content current as of:
03/18/2025
Regulated Product(s)
Drugs