Root Cause Analysis: What can be found in FDA Warning Letters?

corrective action and preventive action (CAPA) according to your procedure until after FDA cited your firm.

Bell International Laboratories, USA (February 2024)

"Your quality unit (QU) lacked adequate control over your over-the-counter (OTC) drug manufacturing operations and failed to ensure that you had adequate procedures. For example, your QU failed to ensure:

- Adequate investigations into non-conformances (21 CFR 211.192).

- Adequate investigations into complaints (21 CFR 211.198(a))."

"Your response is inadequate because you did not address how you will ensure that investigations contain adequate root cause determinations, corrective action and preventive action (CAPA), and effectiveness checks".

Sichuan Deebio Pharmaceutical, China (February 2024)

"Your firm's quality unit (QU) failed to (...) extend product quality complaint investigations to other batches or APIs potentially associated with the root cause, failure, or deviation".

Cosmetic Specialty Labs, USA (February 2024)

"For example, your QU failed to ensure: (...) Thorough investigations into out-of-specifications (OOS) results, deviations, and other discrepant results are performed per an adequate written and approved procedure".

Antaria Pty. Ltd., Australia (March 2024)

"The root causes were not clearly defined nor adequately documented"

"you failed to describe a holistic review of all investigations, root cause analyses and corrective actions for adequacy"

"ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation".

Cohere Beauty, USA (April 2024)

"Your investigation only focused on reviewing formulation and customer complaints but did not adequately investigate the root cause".

Natco Pharma, India (April 2024)

"Your firm's investigations into unexplained discrepancies were inadequate. Your quality unit (QU) failed to thoroughly investigate all finished product batches and components associated with unexplained discrepancies."

"You concluded your investigations without a root cause determination supported by evidence or initiating CAPA."

USP Chapter 621 Chromatography Intent to Revise

The USP has issued a Notice of Intent to Revise General Chapter <621> Chromatography. Based on stakeholder feedback, updates will be made to the sections on System Sensitivity and Peak Symmetry to improve clarity and applicability.

The Notice, dated September 25, 2024, states: "Chemical Analysis Expert Committee is canceling the PF 49(6) proposal and will publish an amended proposal in PF 51(2) with a targeted official date of June 1, 2026, to address comments received on the following sections. This upcoming revision will further clarify the use and applicability of the two sections."

For more details  

Lab Data Integrity issues by US FDA

The significant violations of CGMP regulations for finished products, which are mentioned in the Warning Letter, are listed as follows:

"Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a))."

"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 firm failed to establish the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e))."

Especially, the second observation mentioned in the Warning Letter is related to the lack of Laboratory Data Integrity. It is listed as an example that the firm failed to have "appropriate controls to assure the integrity of electronic test data, such as an audit trail and defined user access levels".

The observed findings resulted in a long list of Data Integrity remediation activities and CAPA measurements requested.

Coming to the final conclusion mentioned in the Warning Letter, the U.S. FDA placed the company on import alert. Additionally, the U.S. FDA may refuse new applications or supplements listing the company as manufacturer until the site has addressed all observations and fully complies with CGMP requirements, which might be checked by a further inspection.

Management circumvents Quality Department in Deviation Classification - FDA Warning Letter

From 6 February to 15 March 2024, the FDA inspected the pharmaceutical manufacturing facility of Wittman Pharma, Inc. in Brooksville and found violations of Current Good Manufacturing Practices (CGMP) for finished drug products, which led to a number of quality risks for the manufactured products. The subsequent 483 letter from the FDA was inadequately responded to, so that the FDA now published the following Warning Letter.

Number of deficiencies

In summary, the following deficiencies were listed in the FDA's Warning Letter :

1. Failures in quality control (in accordance with 21 CFR 211.22)

Quality assurance/quality control (QU) did not ensure that the products met the required identity, strength, quality and purity standards. Drug batches were released without proper product testing and, for example, in the case of colour-changed tablets, management bypassed QU responsibilities and downgraded deviation classifications to ‘minor’ without adequate investigation to eliminate the need for root cause analysis, resulting in non-compliance with CGMP regulations.

2. Inadequate written procedures for production (21 CFR 211.100(a))

The water system used for drug production was not properly qualified, resulting in the presence of harmful microorganisms (Objectionable Microorganisms) such as Burkholderia cepacia. Exceedances of the TAMC (Total Aerobic Microbial Counts) were also not tracked accordingly. Despite these problems, medicines continued to be manufactured and distributed. Their justification that preservatives offset these risks is insufficient, as the use of preservatives does not render proper manufacturing practices obsolete. 

3. Lack of proper testing of components used (21 CFR 211.84(d)(1))

Your company failed to conduct identity testing for propylene glycol, a component at high risk for contamination with diethylene glycol (DEG) or ethylene glycol (EG), substances known to cause fatal poisoning incidents. Their response that comprehensive testing is not required is inadequate because proper identification testing is required under CGMP, e.g., FDA's Guidance on Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol.

The FDA also emphasises at this point that the argument that there is generally no mandatory requirement for routine testing of raw materials is incorrect, as this is required in 21 CFR 211.84. There it says under (d)(1) ‘At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used.’

Equipment Qualification and Process Validation by US FDA

In a recent Warning Letter, the FDA has criticised inadequate equipment qualification and deficiencies in process validation. What does the FDA require?

The deficiencies at the inspected company also occurred during past FDA inspections in 2014 and 2016. The company responded to the 483 deficiency report by stating that they will validate the processes used to manufacture all future medicinal products. They also said they were discussing internally revisions to calibration and preventive maintenance practices.

This was not enough for the FDA, in particular a retrospective assessment of the potential impact was requested. Furthermore, the FDA still expects:

• Corrective actions to better ensure ongoing management oversight throughout the manufacturing cycle of all medicinal products.
• A data-driven and science-based programme that identifies causes of process variability and ensures that manufacturing (including packaging) meets appropriate parameters and quality standards. This includes - but is not limited to - assessing the suitability of equipment for the intended purpose, ensuring the quality of raw materials, determining the capability and reliability of individual manufacturing steps and their controls, as well as ongoing monitoring of process performance and product quality.
• A detailed summary of the validation programme with associated procedures
• Timelines for conducting the PPQ, including PPQ schedules
• A programme for the qualification of premises and equipment and the associated work instructions
• A programme describing the monitoring of intra- and interbatch variability to demonstrate the state of control

Conclusion: The FDA requires a data-based and scientifically sound programme for process validation. Although it is not described in great detail in the FDA guidance on process validation, the FDA also prioritises the qualification of equipment and premises.

Does Purified Water have to be tested for Endotoxins?

When planning new purified water (PW) systems, the question arises as part of the risk analysis or later, when drawing up the qualification and sampling plans as to whether endotoxins should be tested for.

According to the specifications of the pharmacopoeias (e.g. USP or Ph.Eur.), endotoxin testing is not required for Purified Water. The endotoxin content is not a test parameter in the valid pharmacopoeia monographs for purified water.

However, if purified water is used as feed water for distillation plants and pure steam generators for the production of WFI (water for injection) or pure steam, it may be useful to test for endotoxins as part of the qualification process. This is due to the fact that distillation systems and pure steam generators - depending on the technology and manufacturer - can only achieve a reduction of 3 to 6 log levels of endotoxins.

For the validation of the water system, the performance of the purification process must be proven. This applies to all quality parameters, including the endotoxin content in the WFI. However, such validation is only possible if the initial concentration of a contaminant is known.

Many operations with PW and WFI systems do not measure endotoxins in PW as part of routine sampling. Instead, endotoxins are measured in the WFI, where there are usually values below the detection limit (<0.06 IU/ml). However, some companies consider these random sample measurements in the WFI to be insufficient. If endotoxin values above the detection limit (0.06 IU/ml) but below the pharmacopoeia limit for WFI (0.25 IU/ml) are occasionally found, it is necessary to analyse the cause as part of the trend evaluation. For this reason, some sites have included the measurement of endotoxins in their sampling plans for PW for information purposes.

PW systems with membrane technology generally have endotoxin levels below the pharmacopoeia limit for WFI (0.25 IU/ml). However, PW systems without membrane technology, especially older, poorly flowing deionized water systems (with anion and cation exchangers), can have values significantly above the pharmacopoeia limit.

There are also applications of purified water in the biotechnology sector in which endotoxins can play a role, for example in the fermentation process or during purification. In such cases, purified water should also be tested for endotoxins.

A 'mini-risk analysis' is recommended here to clarify two questions:

What is the purified water used for? 

In which cases could endotoxins be problematic?

Based on these answers, the necessity of testing for endotoxins can then be concluded and, if necessary, alarm and limit values as well as specifications for the test interval can be defined

Swissmedic introduced it's own GMDP Database

Swiss medic took new step towards its own database to post GMP/CDP certificate 

The Swiss health authority Swissmedic launched the SwissGMDP Database, similar to the European Medicine Agency's (EMA) EudraGMDP database. It lists the GMP and GDP certificates of all companies in Switzerland with a valid establishment licence issued by Swissmedic. The certificates in the SwissGMDP database include all authorised activities, i.e. unlike EudraGMDP, the GDP activities and Switzerland-specific GMP activities of Swiss companies will also be listed in the certificates. All companies, authorities and individuals can easily view a company's GMP/GDP status using the SwissGMDP database.

Furthermore, SwissGMDP enables a query of all establishment licence holders with a valid establishment license including their sites and licenced operations and will replace the previous table of establishment licence holders.

The SwissGMDP database offers:

Public access for all users;

Free-of-charge access to electronic GMP/GDP certificates;

Access to GDP certificates of companies whose licence covers only GDP activities;

Inclusion of Switzerland-specific activities;

Creation of Excel lists based on specific search criteria or for all sites;

Improvement of the exchange of information between regulatory authorities, industry and the public;

Support in protecting the medicinal product and active substance distribution chain by making it easier to check legitimate players.

Host Cell Proteins - FDA seeks Comments on Immunogenicity Assessment

Additional substantive information

I. Background

The FDA uses the term ‘peptide’ in this notice to refer to alpha-amino acid polymers consisting of 40 or fewer amino acids. Peptides can be isolated from natural sources or produced synthetically or by recombinant expression in a host cell. Peptides isolated from recombinant sources (i.e., genetically modified) prokaryotic or eukaryotic host cells by cell culture/fermentation processes are referred to as recombinant peptides (rPeptides). The FDA describes at this point:

HCPs are process-derived impurities from the host cell that copurify with the recombinant peptide of interest and may be present in the final drug product. HCPs are characterised and routinely well controlled during the manufacture of the peptide product. The types and amounts of HCPs in a product depend on many parameters, including differences in the substrate of the expression cells, culture conditions, purification procedure and between different facilities. Therefore, for a proposed rPeptide follow-on product, differences in HCP profiles between the follow-on product and the listed drug product are to be expected, and these differences may impact the safety and/or efficacy of the follow-on product by increasing the immunogenicity risk of that product. Advances in technology may support the use of IVISIA methods to assess comparative immunogenicity risk. Comments submitted by 23 September will be considered. This cannot be guaranteed for comments submitted later.

II. Request for comments

Interested parties are invited to submit detailed information (including supporting data) and comments on appropriate methods for the detection, identification and quantification of HCPs and the minimum residual levels of HCPs that can be achieved in commercial batches of rPeptide products. To assess the potential impact of HCP differences, the FDA is particularly interested in answers to the following questions:

1. What is the lowest and routinely achievable total HCP content in your well-controlled rPeptide manufacturing processes, and how is it calculated/determined?

2. What are the challenges in reducing HCP levels?

3. What analytical methods are currently used to detect, identify and quantify HCPs in a rPeptide product? Do you perform comparative assessments of HCPs during production development, e.g. ELISA (enzyme-linked immunosorbent assay) versus LC/MS/MS (liquid chromatography tandem mass spectrometry)? How sensitive are these methods for the detection of HCPs and what are their quantification limits? Do you use a combination of orthogonal analytical methods (e.g. ELISA + LC/MS/MS) for HCP control during process development and manufacturing?

4. What is the generally achievable percentage coverage of the HCP spectrum for your HCP quantification test? What considerations (e.g., percentage coverage of HCPs, other coverage characteristics, etc.) are important when selecting methods for evaluating HCPs?

5. Are there qualitative or quantitative characteristics of HCPs that are associated with a higher likelihood of adverse clinical outcomes?

6. What tools (in silico, in vitro or in vivo studies) do you currently use or plan to use to compare the potential immunogenicity risk of two products with different HCP profiles? What is your approach to risk assessment of HCPs based on such data?

FDA Issues Warning Letter for Repeated CGMP Violations and Quality Control Failures

The U.S. Food and Drug Administration (FDA) issued a Warning Letter dated 03 September 2024 to a Canadian over-the-counter (OTC) product manufacturer. The letter follows an inspection conducted in April 2024, discovering multiple violations of Current Good Manufacturing Practices (CGMP).

Key Findings

Key findings of the FDA include: 

Failure to Perform Identity Testing on Components: The company did not adequately perform identity testing for all incoming components used in drug manufacturing. The firm's failure to conduct these tests raises concerns about the potential for contamination or mislabeling of their products. The company also relied on certificates of analysis (COA) from suppliers without verifying the identity of the components themselves, which further compounded the issue.

Inadequate Validation of Manufacturing Processes: Another significant issue identified by the FDA was the company's failure to adequately validate its manufacturing processes. The inspection revealed that the firm did not establish and document the effectiveness of their manufacturing procedures through appropriate validation studies.

Lack of Proper Oversight by the Quality Control Unit: The inspection further highlighted deficiencies in the quality unit (QU), which failed to ensure the consistent quality of drug products. The FDA noted that the QU did not have sufficient oversight to review and approve materials used in production, the manufacturing processes themselves, and the final product testing.

Repeat Violations

The letter emphasized that many of the current violations were previously identified in earlier inspections of the facility. In fact, the FDA had already issued a warning about similar problems in the past, yet the company had failed to implement sufficient corrective actions. This repeated non-compliance indicates a systemic failure to maintain proper manufacturing standards over time, and the FDA expressed serious concerns about the company's commitment to adhering to CGMP regulations.

Conclusion

In light of these significant violations, the FDA strongly recommended to hire an external consultant to assist in bringing their operations back into compliance. The FDA expects a detailed action plan to address the specific issues identified in the inspection report. If the company does not take adequate corrective measures, it may face further regulatory actions, including the seizure of products or legal injunctions. The company was already placed on Import Alert 66-40 ("Detention Without Physical Examination of Drugs From Firms Which Have Not Met Drug GMPs").

FDA Observation Not using Statistical Process Control (SPC) in Validation

With the introduction of the updated FDA guidance on process validation, a process validation life cycle was introduced in 2011. One of the stages in the cycle is the so-called Continued Process Verification stage 3, which shows whether the process remains permanently in a validated state. Many companies use statistical process control (SPC) to show the 'state of control' in this stage 3.  

In a recent Warning Letter, the FDA criticised a drug manufacturer's statistical process control. What was criticised?

No control charts created

The methods used in the 'Continued Process Verification' to show the 'state of control' are not specified. One possibility mentioned in the Process Validation Guidance is statistical process control. This is what the company inspected by the FDA had planned.

Was it intended that way? Yes, that is how it was intended. Citing section 21 CFR 210/211, the FDA criticises the lack of activities that show that the process is permanently 'under control'. They are referring to the manufacturing and engineering departments, which have not created control charts to monitor and control the manufacturing process. This is exactly what the company had specified in its internal procedures. This was rectified during the inspection, with the result that four previously undetected trends were discovered. The usefulness of an SPC was thus demonstrated directly during the inspection.

The inspected company also recognised this and responded to the inspection report by stating that it was committed to complying with its internal procedures on SPC in future. This was not enough for the FDA. It also expects an investigation into how it was possible that the control charts were not created in the first place.

Scientific approaches in the context of process validation

One of the innovations in the update of the FDA Process Validation Guidance was the introduction of a more scientific approach to process validation. This is also clearly reflected in this Warning Letter. The FDA criticises an unscientific approach to a validation run. The mixing uniformity was criticised as insufficient in terms of sample locations and sampling (number, sample size, sample preparation).

Conclusion: Statistical process control is not a mandatory requirement in the context of process validation. However, if it is required by internal company specifications, then it must also be implemented. And in this case, the advantage of an SPC was demonstrated very impressively, which was then followed up. Four previously undiscovered trends were identified. Furthermore, a scientific approach to process validation is required.