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Verifying Raw Materials for Drug Manufacturing and Preventing FDA Warning Letters

May 21, 2020

Analysis of incoming excipients and active pharmaceutical ingredients (APIs) is a crucial aspect of a pharmaceutical QA/QC laboratory.

Identification and/or verification of raw materials used in the manufacturing process forms a central pillar of current good manufacturing guidelines (cGMP). Failure to abide by these regulations can lead to issue of an FDA form 483, demonstrating that certain conditions and practices may constitute violations of compliance standards. If the non-compliance is more significant, or the inspected firm fails to respond appropriately to an FDA form 483, a warning letter is issued.

In 2019 alone, over 770 form 483s were issued, the most in recent history. In addition to this, 81 warning letters were also issued and amongst the most common citations was violation of 21 CFR 211.84, the main FDA regulation relating to testing of components, drug product containers and closures.

As well as the FDA regulation, there is a variety of other compliance documentation issued by multiple governing bodies. The most prevalent regulations include:

  • FDA 21 CFR 211.84 – Testing and approval or rejection of components, drug product containers, and closures.
  • FDA 21 CFR 211.80 – Control of components and drug product containers and closures.
  • GMP Guidance section B of VII7.2 – Receipt and Quarantine of Incoming Materials.
  • ICH – Q7 code, section 6.3 – Records of Raw Materials, Intermediates, API Labelling and Packaging Materials.
  • European Medicines GMP – Chapter 6: Quality Control

Although there may be a slew of different regulations, there are three main themes that are regularly covered:

  • Analysis of materials used during the manufacturing process.
  • Approval or Rejection of materials based on results of analysis.
  • Documentation of collected data in a traceable format.

Infrared Spectroscopy for Pharmaceutical QA/QC

One of the easiest and most rapid ways to analyze samples of pharmaceutical raw materials and packaging is through the utilization of infrared (IR) spectroscopy.

As a technique, IR spectroscopy has become ubiquitous in testing of manufacturing products due to its robust nature and wide selection of sampling accessories. Furthermore, the ability to measure samples and obtain results in less than a minute means that users can test, and therefore reject or accept raw materials thus easily complying with both 21 CFR part 211.84 and 21 CFR part 211.80.

In addition to analysis regulations, analysts must also contend with the FDA 21 CFR part 11 regulation which pertains to the keeping of electronic records and electronic signatures. PerkinElmer’s Spectrum 10 enhanced security (ES) software offers a solution for easy maintenance of audit trails and user electronic signatures. This software, used in conjunction with infrared spectroscopy, allows users to easily fulfil the requirements for the multitude of different regulations surrounding analysis of incoming raw materials.

Two types of infrared spectroscopy are commonly used for quality control of pharmaceutical manufacturing materials, mid-infrared (MIR) spectroscopy and near-infrared (NIR) spectroscopy.

  • MIR spectroscopy is frequently used for analysis of active pharmaceutical ingredients (APIs) and packaging materials. This is because the mid-infrared region of the spectrum generally shows more unique spectral features, commonly referred to as the ‘fingerprint’ region, allowing for easy differentiation between chemically different materials such as APIs or polymer packaging.
  • NIR spectroscopy is more commonly used for analysis of pharmaceutical excipients. In many cases, excipients do not differ in chemical structure, but rather in physical parameters such as moisture content and particle size. NIR spectroscopy is significantly better at differentiating between materials based on these parameters. This feature, along side the ability to use a remote sample accessory (often referred to as a fibre probe), allows for easy analysis of incoming raw materials in a warehouse environment.

Spectrum 3 FT-IR – High Performance Analysis

There are, in fact, three infrared regions – mid, near and far-infrared ranges – all of which have some use in pharmaceutical analysis. In the past, separate instruments would be required to collect data in each range.

Fortunately, our Spectrum 3 tri-range infrared spectrometer allows users to collect high-quality data in the three ranges: mid, near and far-infrared. Spectrum 3, in conjunction with Spectrum 10 ES, provides a complete solution for infrared analysis of pharmaceutical materials.

Want to learn more? Check out our application note on the Analysis of Pharmaceutical Raw Materials Using the Tri-Range Spectrum 3 Infrared Spectrometer

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