Troubleshooting in pharmaceutical manufacturing processes – Root cause analysis of quality defects

Pharmaceuticals are an important part of medical care. This is clearly demonstrated by the current discussions on drug shortages and the demand for greater transparency in supply chains, which put a spotlight on the pharmaceutical industry long before the COVID-19 pandemic.

The reasons for supply challenges are complex. They happen, for example, because there are temporarily not enough raw materials available for production. They are also the result of production facilities being relocated to a small number of sites. Often, production downtimes due to quality problems also affect the global market - these are unpredictable and hardly avoidable in their entirety.

Pharmaceutical companies have interest to maximize their supply security. However, if supply shortage occur, efforts are made to overcome them as quickly as possible to prevent supply problems at the patients.

In this blog post, we would like to present how unexpected quality problems in the pharmaceutical manufacture can be investigated, which requirements need to be applied, and what challenges might arise - for a reliable root cause analysis, a quality and safety assessment, and the definition of subsequent preventive measures to avoid such incidents.

Quality is the most important criterion – The requirements

Special guidelines and laws apply to the distribution and manufacture of medicinal products: Medicinal Products Act (AMG) and Ordinance for the Manufacture of Medicinal Products and Active Pharmaceutical Ingredients (AMWHV), as well as the EU GMP Guideline, in particular also the guidelines of the "International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use" (ICH).

These guidelines ensure that medicinal products are not only consistently of good quality but are also assessed with regard to their efficacy and safety as part of the approval process. Implementation requires not only validated manufacturing and quality control procedures (raw materials, excipients, finished products, packaging) but also suitable premises, qualified equipment and trained personnel - in short, a quality management system - to ensure good manufacturing practice.

Deviations in the process must be documented and subsequently evaluated. In-process controls (IPCs) at critical steps in the manufacturing process enable the detection of potential quality defects at an early stage and thus, if necessary, the production process to be stopped in good time.

In general, when deviations and quality defects are detected in the manufacturing process: a root cause analysis must be initiated to prevent future defects.

Root Cause Analysis - The challenges

Contaminated raw materials, malfunctions at the production equipment or cross-contaminations due to non-compliance with hygiene procedures affect the quality of pharmaceuticals and pose a safety risk to patients. Incidents which must be handled at highest priority. On the one hand, because in most cases the production of further batches is stopped until the troubleshooting has been successfully completed and evaluated. On the other hand, batches already on the market may have to be evaluated retrospectively and recalls may be initiated.

A major logistical hurdle in root cause analysis is the availability of the appropriate analytical methods and techniques to identify the impurities/contaminants which forms the basis for quality and safety assessment.

At manufacturing plants often only standard quality control techniques are available at all. However, the identification of unknown contaminants requires much more specialized analytical equipment that is generally not available at manufacturing plants. Moreover, there is a need for free resources on the equipment as well as trained and qualified personnel to plan and perform the tests.

What needs to be done?

Solution approaches - A look behind the scenes

Since the incidents happen at the manufacturing plant, but often no suitable analytical equipment exists there to solve the problem, all relevant information must be transmitted as completely as possible to the analytical "task force".

• 1. What happened (= description of the problem)
• 2. When did the incident happen (= time frame)
• 3. Who was involved (= people, materials, raw materials, equipment)

The analytical team collects all relevant data and ideas for possible root causes to design a solution strategy on the basis of empirical values, incorporating different analytical procedures which should run in parallel due to the tight time frame.

The solution approaches are evaluated with regard to their results, so that the quality problem can be assigned as follows:

• 4. Where did the incident happen (localization of the affected manufacturing step)
• 5. How did it happen (what circumstances led to it)
• 6. Why did the incident occur (which risks occurred that were not obvious in advance)

The use of the right analytical methods permits the chemical identification of the contamination, which can be assigned to a specific step in the manufacturing process. From this, it can be deduced which circumstances led to the incident and which preventive measures need to be defined.

The complexity increases when there is a combination of several causes that lead to different problems, e.g. an introduced contamination that cannot be detected visually at first, but which, as a consequence, leads to a reduction in the effectiveness of the product.

There are many examples and despite the strictest regulations and requirements, quality problems are not rarely present. This is particularly critical when quality defects are noticed after the drug has been placed on the market and, as a consequence, product batches have to be recalled for patient safety.

Analytical approach – best practices

The analytical troubleshooting is used to quickly characterize the manufacturing defect, which usually occurs spontaneously, with minimal downtime of the production. To fulfill this goal, the analytical strategy must include various analytical routes and the combination of their results provides a clear, coherent picture of the incident.

Let’s take the case study of a particle contamination:

The use of physical methods at the beginning of the investigations offer a fast, cost-effective and basically non-destructive approach. Especially if the contamination comprises only a few individual particles, valuable results can be obtained here in a first step.

For example, scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX) can be used for chemical identification of inorganic compounds but also for surface topography and determination of particle size distribution.

This method is especially applicable for metallic contaminations, e.g. abrasion of steel alloys from production equipment, defects of material containers of auxiliary materials (metal drums), also the determination of rust formation is possible. Moreover, non-metallic materials such as filters, seals, funnels, ports, membranes or other single-use equipment can be comparatively identified with this technique.

Using Raman spectroscopy, organic particles can be analyzed non-destructively and identified by comparison with databases and reference materials. X-ray microtomography (XMT) can also be used as an imaging technique for non-destructive analysis. However, all these methods are fast and inexpensive, but require specialized equipment and experienced personnel. Often, the data obtained is already sufficient to complete a troubleshooting study.

In cases where further analytical information is required, chemical approaches are started in a second step. The particles are cleaned from residual matrix or product in a purification step. Qualitative solubility tests in various media provide information on the polarity and nature of the contamination.

If the particles are soluble, classical structure elucidation methods, such as mass spectrometric and high-resolution mass spectrometric methods (MS, MS/MS, HRMS) or nuclear magnetic resonance (NMR) can provide important information. These techniques are particularly powerful when coupled with a liquid (LC) or gas chromatographic (GC) method for the separation of individual components (LC-HRMS, GC-MS). Often, a particle does not always consist of one single compound.

To identify and isolate the individual components, the LC-UV-SPE method is a good choice – it’s an automated trapping method that uses solid-phase extraction (SPE) after chromatographic separation with UV (or MS) detection to characterize isolated impurities by HRMS and/or NMR.

Given the solubility of the contaminants, these methods can be used to detect almost all pharmaceutical excipients and active ingredients as well as their degradation products in comparison with the corresponding reference standards. Furthermore, reaction products initiated by contaminants can be detected and identified. These methods are significantly more complex and do not work non-destructively due to the required solubility of the contaminants, but they are a powerful tool in structure elucidation and purity testing.

These are only some of the possible analysis techniques that can be applied in a production troubleshooting. Not one single method alone, but the clever combination of suitable methods embedded in the overall analytical strategy developed on the basis of the information transmitted from the manufacturing plant, provide the key to a successful root cause analysis of quality problems in the production of pharmaceuticals.

Conclusion and vision

Pharmaceutical products require special care to avoid contamination and cross-contamination by materials.

Legislative measures and regulatory reforms require that product manufacturing be safe, predictable, and at a high level of quality. Despite the highly regulated environment, quality defects in drug product manufacturing are not uncommon, although they can lead to product recalls, drug shortages and, most importantly, harm to patients.

For the required troubleshooting from the regulatory perspective, the manufacturing plant often lacks the appropriate analytical equipment, qualified personnel and the relevant experience to generate the necessary data in a short time. Nevertheless, the time and cost pressure on the pharmaceutical company is high.

As an innovative partner of the pharmaceutical, biotech and medtech industry, HWI offers an extensive pool of analytical instruments and supports troubleshooting in pharmaceutical production with a team of experts and a distinctive scientific network. Tight collaborations with our partners, a smart targeted analytical strategy and a fast and open exchange help our customers to meet the requirements of successful root cause analysis in regulated GMP environments.