WARNING LETTER
Orean Personal Care Ltd.
MARCS-CMS 682813 —
August 29, 2024
Delivery Method:
Via Email
Product:
Drugs
Recipient:
Recipient Name
Mr. Daniel Williams
Recipient Title
CEO
Orean Personal Care Ltd.
Unit E1, Stubs Beck Lane
West 26 Ind. Estate
Cleckheaton, West Yorkshire
BD19 4TT
United Kingdom
dan.williams@orean.co.uk
Issuing Office:
Center for Drug Evaluation and Research (CDER)
United States
Warning Letter
320-24-57
August 29, 2024
Dear Mr. Williams:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Orean Personal Care Ltd., FEI 3010999645, at Unit E1, Stubs Beck Lane, West 26 Ind. Estate, Cleckheaton, from March 11 to 15, 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 April 4, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2))
You failed to perform adequate identity testing for each component lot including your active pharmaceutical ingredient (API),
(b)(4)
, used in the production of your over-the-counter (OTC) drug products.
Additionally, you did not test
(b)(4)
for the presence of
(b)(4)
. You relied on the certificates of analysis (COAs) from your suppliers and failed to establish the reliability of each of your suppliers’ COA for component specifications and characteristics.
Component testing is fundamental to quality. Without adequate testing, you do not have scientific evidence that your incoming components conform to appropriate specifications before use in the manufacture of drug products.
In your response you provide a copy of an updated procedure for approving new raw materials, sampling raw materials, and testing them. You also commit to create and fill a position for analytical testing of raw materials, to purchase equipment, and to train staff.
Your response is inadequate. It lacks specificity regarding your plans to ensure sampling and testing of each shipment of each lot of
(b)(4)
before use in the manufacturing of drug products. Additionally, you do not commit to conduct a retrospective risk assessment for products in the market that are within expiry and for which adequate component identity testing was not performed.
This is a repeat finding from your 2017 inspection. You failed to fulfill the commitment in your 2017 response and implement comprehensive corrective actions and preventive actions (CAPAs).
(b)(4)
In response to this letter, provide:
A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of
(b)(4)
, and certain additional high-risk components we note that this includes the performance of parts A, B, and C of the United States Pharmacopeia (USP) monograph and testing should include each container of each lot.
A commitment to provide
(b)(4)
test results, no later than 30 calendar days from the date of this letter, from testing reserve samples of all lots of high-risk drug components used in the manufacture of your drug products. Alternatively, if a reserve sample of a component lot is unavailable, perform retain sample testing of all implicated finished drug product batches for the presence of
(b)(4)
.
A full risk assessment for drug products that are within expiry which contain any ingredient at risk for
(b)(4)
contamination (including, but not limited to,
(b)(4)
). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain
(b)(4)
, including customer notifications and product recalls for any contaminated lots. Identify additional appropriate CAPAs that secure supply chains in the future, including, but not limited to, ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.
The chemical quality control specifications you use to test each incoming lot of high-risk drug components to determine acceptability for use in manufacturing.
A comprehensive review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
2. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess. Your firm also failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.100(a) and 211.67(b)).
Lack of Process Validation
You did not adequately demonstrate that your manufacturing processes are reproducible and controlled to consistently yield drugs of uniform character and quality. You failed to adequately validate your manufacturing process for
(b)(4)
, for example:
After obtaining out-of-specification (OOS) results for viscosity, adjustments were made to the amount of components added to batches in order to obtain passing results. Your “Inspection and Testing – In-Process” procedure stated in part, “
(b)(4)
.”
Remaining portions of previously manufactured bulk batches were
(b)(4)
with in-process batches to create new bulk batches. Notably, the new bulk batches were not placed on stability.
We also noted that your batch record for
(b)(4)
lacked complete manufacturing and control instructions such as
(b)(4)
to ensure that processes are under control.
In your response you state you created procedures for validation of drug products and will no longer
(b)(4)
any previous batches with new batches.
Your response is inadequate because you do not provide supportive documentation or timelines for your drug process validation, and your interim production plans are unclear. You also do not consider a retrospective impact assessment.
This is a repeat finding from your 2017 inspection. You failed to fulfill the commitment in your 2017 response and implement comprehensive CAPAs to encompass all drug products.
You are responsible for assuring your manufacturing processes will consistently result in drug products meeting predefined quality attributes.
Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies includes intensive monitoring and testing of throughout each significant process stage to characterize intra-batch variation and evaluates batches to determine whether an initial state of control has been established.
Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.
See FDA’s guidance document,
Process Validation: General Principles and Practices
for general principles and approaches that FDA considers appropriate elements of process validation, at https://www.fda.gov/media/71021/download.
Cleaning Validation
You have not validated your cleaning process for your non-dedicated manufacturing equipment, which is used to manufacture
(b)(4)
and OTC drug products such as
(b)(4)
.
Inadequate removal of residues from manufacturing equipment during cleaning can lead to contamination of drug products subsequently manufactured on the non-dedicated equipment.
In your response you state you will create a procedure for cleaning validation and review and update your cleaning sanitization procedure.
Your response is inadequate. You fail to assess the impact of your unvalidated cleaning processes on drug product that is currently on the market and within expiry. You also do not provide your cleaning validation protocol indicating the relevant sources of risk, predetermined acceptance criteria, acceptable amount of time for storing dirty equipment, and other considerations relevant to your equipment cleaning program.
In response to this letter, provide the following:
A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
A timeline for performing appropriate process performance qualification (PPQ) for each of your marketed drug products. Also include an explanation how you will ensure proper satisfactory PPQ studies are performed prior to future distribution of any drug products.
Process performance protocol(s), and written procedures for qualification of equipment and facilities.
A detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.
An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes, and will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.
A CAPA plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.
A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product.
Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:
o Drugs with higher toxicities
o Drugs with higher drug potencies
o Drugs of lower solubility in their cleaning solvents
o Drugs with characteristics that make them difficult to clean
o Swabbing locations for areas that are most difficult to clean
o Maximum hold times before cleaning
In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.
A summary of updated standard operating procedures (SOPs) that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
3. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).
Your quality unit (QU) lacked adequate control over your OTC drug product manufacturing operations and failed to ensure that you had adequate procedures. For example, your QU failed to ensure:
Adequate investigations into non-conformances are performed (21 CFR 211.192).
Adequate systems for document control and retention are established and followed (e.g., missing, or incomplete batch records, missing testing records and out-of-specification (OOS) investigations) (21 CFR 211.188).
Establishment of an adequate ongoing stability program (21 CFR 211.166(a)).
Annual product quality reviews are conducted (21 CFR 211.180(e)).
In your response, you state that you are in the process of implementing procedures to ensure quality control over your processes. You also state you will perform training for employees.
Your response is inadequate. You do not describe how you intend to verify that the procedural updates and employee training are effective. You also do not include the interim measures that you have implemented as part of your remediation to prevent continuing release of products that do not meet CGMP.
Your firm’s quality system is inadequate. Your inspectional history indicates that your QU is not able to fully exercise its authority and responsibilities. Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality. See FDA’s guidance document
Quality Systems Approach to Pharmaceutical CGMP Regulations
for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download.
In response to this letter, provide:
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 Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products
A comprehensive, independent assessment of:
o Your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, QU oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
o Your documentation systems used throughout manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
o A CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
 Stability indicating methods
 Stability studies for each drug product in its marketed container-closure system before distribution is permitted
 An ongoing program in which representative batches of each product are added each year to the program to determine if the self-life claim remains valid
 All procedures that describe these and other elements of your remediated stability program
A timeline for performing annual product quality review (APQR) for each of your marketed drug products.
A plan to ensure that you will complete, and document adequately, product quality reviews at least annually for all drug products; and procedures for investigating, responding to, and correcting any deviations from product quality and safety standards identified as a part of your product quality review findings and risk assessments.
CGMP Consultant Recommended
Because you failed to correct repeat violations you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements.
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.
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.
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 refusing admission of articles manufactured at Orean Personal Care Ltd at Unit E1, Stubs Beck Lane, West 26 Ind. Estate, Cleckheaton, West Yorkshire, BD19 4TT United Kingdom 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 or misbranded 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. 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.
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3010999645 and ATTN: Yasamin Ameri.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
Content current as of:
09/10/2024
Regulated Product(s)
Drugs