Updated GDP Guide for Excipients

In October 2024, the IPEC (International Pharmaceutical Excipients Council Europe (IPEC Europe) asbl) announced on its website the new version 3 of its GDP guide 'Good Distribution Practices Guide for Pharmaceutical Excipients'. The document is currently only available in the IPEC member area. The updated guide is to be published after a period of three months (probably at the beginning of 2025). It can be assumed that this will be available as usual under the 'Resources' section in the 'Guidelines' area of the IPEC website. You can currently view a summary and table of contents of the revised guide.

The table of contents of the new version is as follows:

1 INTRODUCTION
   1.1 Purpose
   1.2 Scope 
   1.3 Principles Adopted
2 PHARMACEUTICAL GRADE EXCIPIENTS
3 GOOD DISTRIBUTION ACTIVIES FOR PHARMACEUTICAL EXCIPIENTS
Table 1 Matrix of Applicability
Table 2 Applicability for Supply Chain Activities 
   1. Quality Management
   2. Organisation and personnel
   3. Premises
   4. Procurement, warehousing and storage
   5. Equipment
   6. Documentation
   7. Repackaging and relabelling
   8. Complaints
   9. Recalls
  10. Returned Goods
  11. Handling of non-conforming materials
  12. Dispatch and Transport
  13. Contract activities
4 REFERENCES

This largely corresponds to the table of content of the previous version from 2017, although subsections 1.1-1.3 have been added.

Batch Production and Control Record discarded Unexo Lifesciences, India.

Torn batch production records were found in plastic bags on the rooftop. These included missing batch production records, which allegedly could not be found during an FDA inspection. Furthermore, duplicate, incomplete batch records with the same batch numbers and issuance dates as the batch records presented during the inspection were found among the torn records. Batch records were "retrospectively prepared" in order to present them to the inspectors.

Unfortunately, it happens again and again that pharmaceutical companies do not archive their documentation but discard it, a violation of basic GMP requirements. Occasionally this is discovered during inspections. The number of unreported cases is certainly higher. Now Unexo Lifesciences, an Indian manufacturer, has been caught by the FDA.

Access here US FDA WL

Pest Activity, Water Leaks, and Misuse of QC Laboratory in U.S. Drug Manufacturing Facility

On 29 October 2024, the U.S. Food and Drug Administration (FDA) has published a Warning Letter dated 21 October 2024. The document goes back to an inspection performed earlier this year at a manufacturer of over-the-counter (OTC) topical drug products in North Carolina.

The Warning Letter summarizes a couple of significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals

Condition of the Laboratory

The initial observation already says a lot about the condition of the buildings and facilities, especially the laboratory. The authority writes: "Our investigator observed pest activity in your raw material storage area, and evidence of water leaks and missing ceiling tiles in your drug manufacturing area. In addition, our investigator observed that your quality control (QC) laboratory was used by employees for meal preparation, dishwashing, and storage of soiled employee garments."

This misuse of the laboratory environment poses a high risk of contamination and compromises the reliability of product testing and quality control procedures. As the company failed to maintain clean and sanitary conditions in their manufacturing areas and was unable to provide sufficient measures to improve the condition in its response to the inspection report, the FDA is now demanding a series of measures, including:

A detailled corrective action and preventive action (CAPA) plan

Creation of detailed procedures

A risk assessment for all drug products distributed to the U.S. market

Laboratory Testing and Stability Testing Program

The company did not conduct appropriate laboratory tests for each batch of drug product to ensure conformance to specifications, including the identity and strength of active ingredients and microbial contamination. This oversight meant that products were released into the U.S. market without sufficient proof of their safety and effectiveness.

Furthermore, the firm failed to establish and maintain an ongoing stability testing program to support the labeled expiry of the distributed drug products. The FDA concludes: "There is no assurance that [the] drug products will remain acceptable throughout their labeled expiry period without an ongoing stability program."

Unapproved New Drug Violations and Misbranded Drug Violations

Another focus of the FDA's Warning Letter was the violation concerning the marketing of unapproved new drugs. Some of the company's products were found to be unapproved new drugs, violating various sections of the Federal Food, Drug, and Cosmetic Act. The Warning Letter also addressed issues related to misbranding under section 502 of the FD&C Act. The FDA explains in detail why the products did not meet the “generally recognized as safe and effective” (GRASE) standard required for OTC drugs

Conclusion 

The FDA warned that failure to promptly address these issues could result in severe regulatory actions, including product seizures, injunctions, and restrictions on new application approvals. The letter emphasized that the company's executive management must oversee and ensure compliance with CGMP requirements.

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FDA announces Experiential Learning Site Visit Program

The U.S. Food and Drug Administration (FDA) is announcing the Fiscal Year 2025 CDER Office of Pharmaceutical Quality (OPQ) Experiential Learning Site Visit Program (ELSVP). ELSVP is an educational initiative aimed at enhancing FDA staff's understanding of pharmaceutical manufacturing processes, innovations, and industry challenges. The program provides FDA staff with the opportunity to engage directly with pharmaceutical industry sites, gaining hands-on experience and insights into contemporary manufacturing and quality practices.

Background

The OPQ is responsible for ensuring the quality of medicines produced for the U.S. market. To better align regulatory oversight with the current industry practices and innovations, the FDA established the ELSVP as a mechanism for improving staff knowledge of pharmaceutical processes. This initiative supports FDA's mission to apply a science- and risk-based approach to pharmaceutical regulation.

How it works

The ELSVP is a site-based learning initiative where FDA staff visit pharmaceutical manufacturing facilities. These visits provide FDA reviewers, inspectors, and scientists with the opportunity to observe real-world manufacturing technologies and quality control systems. Key areas of focus include continuous manufacturing, advanced analytical tools, and comprehensive quality management systems. The program relies on voluntary participation from pharmaceutical manufacturers who apply to host FDA staff at their facilities. Participants from the FDA are then matched with the appropriate facilities for immersive, practical learning experiences.

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