Avoid These 29 API Manufacturing Deficiencies

By Norbert Waldöfner, Ph.D., blue inspection body GmbH

During audits and inspections of active substance manufacturers, GMP deficiencies are found at every stage of the production process. The application of quality management instruments, including deviation and risk management, often remains superficial and thus misses the actual point.

Deficiencies are also frequently found in the areas of documentation and electronic data management. GMP deficiencies can also be found in materials management and production and laboratory controls, as well as in other quality-relevant areas.

This summary presents typical GMP deficiencies that are frequently encountered by manufacturers of active substances, based on my audit experience and publicly available information including FDA warning letters. It’s based on excerpts from Chapter 20.F of the GMP Compliance Adviser, a publication of GMP Publishing in Schopfheim, Germany.

The following list makes no claim to completeness, nor does it provide a rating/classification of the individual deficiencies. It also is not intended to give the impression that active substance manufacturing generally takes place at a low level of quality, as most manufacturers are constantly working on  improving their processes.

The following list provides an overview of the GMP deficiencies that, in my experience, are frequently encountered during audits of active substance manufacturers.

At A Glance: The Most Common GMP Deficiencies At Active Substance Manufacturers

Deviations

• Insufficient documentation of deviations
• Inadequate root cause analyses
• Lack of risk assessment with regard to further potentially impacted batches
• Insufficient qualification/training of the employees

Quality Risk Management

• No systematic approach
• Superficial risk assessments
• Insufficient follow-up of actions from risk analyses

Product Quality Review

• No in-depth assessment of the available data
• Lack of evaluation of the effectiveness of corrective actions
• Insufficient evaluation of returns
• PQRs are prepared too late

Personnel

• Insufficient compliance with hygiene regulations
• Inadequate training of external service providers

Water

• Insufficient monitoring
• Lack of rationale for setting warning and action limits
• Insufficient actions taken when limits are exceeded

Documentation and Protocols

• Violations of ALCOA rules and data integrity requirements for electronic systems

Materials Management

• Inadequate pest control measures
• Insufficient sampling conditions
• Insufficient qualification of suppliers of raw materials, active substance starting materials, and intermediates

Production

• Inconsistent measures to prevent contamination at different stages of production
• Lack of definition of the maximum campaign length
• Lack of definition of holding times of uncleaned or cleaned equipment

Packaging and Labeling

• Insufficient controls before starting the packaging process

Laboratory Controls

• Shortcomings in the examination of OOS results
• Stability samples not stored in containers that mimic market containers

Cleaning validation

• Insufficient consideration of possible microbiological or endotoxin contamination
• Insufficient care in the identification of worst-case products and the selection of sampling points

Returns

• Inadequate procedures for handling returns

Key Takeaways From The Most Common API Manufacturing GMP Shortcomings

Thematically, there is thus a striking overlap here with the deficiencies found during GMP inspections of medicinal product manufacturers (see Chapter 21.C Frequent deficiencies in GMP inspections, their recurring pitfalls, and how to avoid them).

From my point of view, the production of active substances generally takes place at a high level; regarding the fulfillment of the respective GMP requirements, active substance manufacturers are not necessarily in a worse position than medicinal product manufacturers.

Due to the increasing use of electronic systems, I expect that deficiencies in documentation or, for example, the handling of deviations and out-of-specification results, will be identified and avoided more quickly in the future. However, this evolution will also introduce new sources of errors and requirements, especially with regard to the validation of electronic systems and the maintenance of data integrity.

In my opinion, the focus of audits at active ingredient manufacturers will certainly continue to shift in the direction of checking these requirements.

This article is an excerpt from GMP knowledge contained in the online portal GMP Compliance Adviser, which provides in-depth information about GMP best practices and regulations with a focus on Europe, but also referring to the U.S., Japan, and international organizations PIC/S, ICH, WHO, etc.

About the Author:

Norbert Waldöfner has been working for blue inspection body GmbH, an ISO 17020 type A accredited service provider for GMP audits, since 2011. Since then, he has audited more than 200 companies worldwide, including manufacturers of starting materials and active ingredients for pharmaceutical products, as well as other suppliers and service providers. Previously, he worked in the development and production of sterile injection solutions for tumor therapy. He studied chemistry at the University of Duisburg and earned his Ph.D. at the Max Planck Institute for Coal Research. He began his professional career at Magfore AG in Berlin producing nanoparticles for medical applications as head of the laboratory unit. At blue inspection body GmbH, he is responsible for the quality of all audits.