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Quality Control During Drug Development

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Pharmaceutical products are controlled by quality regulations that ensure the finished drug product has the required identity and purity characteristics. If a pharmaceutical product does not meet established quality standards, it may lack the desired therapeutic effect, lead to toxic and adverse reactions and be a tremendous waste of financial resources.

The quality control department thus holds special importance in pharmaceutical production. The quality of the drug product may be affected by the initial raw materials, the manufacturing process, packaging, transportation and storage conditions. Melissa Rodriguez, senior director of quality control at Kiromic Biopharma, explains, “Quality control in pharmaceutical supply systems ensures that raw materials introduced into the facility and/or process meet the quality standards for human use and that all materials are accounted for throughout each step of the process.” This ensures that each product reaching the market is safe, effective and of acceptable quality.

Quality control in drug development is performed at different phases of production

Quality control in drug development involves testing the drugs at different phases of their production. It may include evaluating the quality aspects of raw materials, finished products, packages, closures, storage conditions and labeling. The quality control department also tests the manufacturing process to ensure confirmation of specifications and limits. It also determines the acceptability of each batch before release.

Some vital characteristics that need to be tested in a pharmaceutical product are identity, purity, strength, potency, uniformity, bioavailability and stability.

The identity test is used to confirm the existence of the active pharmaceutical ingredient (API) indicated on the label. Apart from the API, the excipients in the drug products should be free from potentially harmful contaminants or microorganisms. Cross-contamination from other products should also be avoided.

Strength, or potency, is another important characteristic. The finished product should contain the cited amount of API. Harmful drug degradation products should be absent or should be below defined limits.

Uniformity is an important quality measure of the finished product. Non-uniformity can indicate issues with the strength, potency, identity and purity of the product which can reflect a lack of good manufacturing practices. Uniformity can be defined by assessing the color, shape, consistency and size of the finished product. These uniformity parameters should not vary from one dose to the next.

Testing bioavailability is a key criterion of clinical effectiveness and an important quality parameter. Two drug products can be said to be bioequivalent if both are released into the bloodstream at the same rate and to the same extent. The bioavailability of a drug product may depend on the excipients and even the manufacturing processes. Checking bioavailability is critical with generic products which are introduced from multiple sources within health care systems. Though generics are helpful in improving accessibility to medicines, the widespread distribution of counterfeit or substandard products is a concern. By checking the bioavailability, the therapeutic equivalence of such medicinal products can be assured.

Checking the storage conditions is also critical as the finished drug product must retain its properties in the prescribed storage conditions. Inappropriate storage conditions may lead to physical and chemical decomposition of the finished product which can lead to decreased potency and even the production of toxic substances. The stability of the drug product may depend on the active ingredient, which in turn depends on the formulation and the packaging.

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Analytical techniques in pharmaceutical analysis

Quality control testing of pharmaceuticals should follow strict guidelines and can involve the use of several analytical techniques, including:

  • High-performance liquid chromatography (HPLC)
  • Thin layer chromatography (TLC)
  • High-performance thin-layer chromatography (HPTLC)
  • Gas chromatography–mass spectrometry (GC-MS)
  • Mass spectrometry (MS) – including liquid chromatography–mass spectrometry (LC-MS), liquid chromatography with tandem mass spectrometry (LC-MS/MS) and time-of-flight mass spectrometry (TOFMS)
  • Nuclear magnetic resonance spectroscopy
  • Fluorimetry and phosphorimetry
  • Ultraviolet–visible spectroscopy
  • Fourier transform infrared spectroscopy (FTIR)

HPLC analysis can help confirm the drug identity and provide quantitative results. One advantage of HPLC is the application of the liquid mobile phase with the possibility of modification of mobilized polarity during chromatography. The mobile phase can also be transformed based on the characteristics of the substance being tested.

In TLC, the substances are separated from one another based on their relative affinities for a polar solid stationary phase and a nonpolar mobile liquid phase. HPTLC is a variation of TLC that is a simple, rapid and efficient tool for the quantitative analysis of substances. HPTLC is based on TLC but comes with improvements that increase the resolution of the compounds to be separated, lower the limit of detection and enable its quantitative analysis. Enhancements may include the use of higher-quality TLC plates for better resolution.

GC-MS is mainly utilized to identify impurities in active pharmaceutical ingredients.

FTIR spectrometry is a rapid technique for the analysis of solid, liquid and gaseous samples. Originally, FTIR was used to identify the functional groups of chemical constituents, but now it is widely used for the identification, quality control and manufacturing process supervision of pharmaceutical drugs.

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Improving analysis of antibody-drug conjugates

An emerging class of therapeutics, antibody-drug conjugates (ADCs) are comprised of a small molecule drug linked to a monoclonal antibody (mAb). They are an attractive treatment option for several types of cancer since the antibody enables the cytotoxic effects of the drug to be targeted to a subset of cells, sparing other healthy cells from harm. Despite the potential of ADCs, their analysis can be challenging and there is a need for improved quality control methods to ensure safety and efficiency.

“Two key challenges to the analysis of ADCs are the molecular complexity and size of ADCs. Any antibody-based therapeutic must assess the myriad of factors known to effect pharmacokinetics, binding efficacy and stability. These include primary sequence variants, C-terminal lysine clipping, deamidation, glycosylation variants, oxidation and many others,” Eli J. Larson from the Ge lab at the University of Wisconsin-Madison previously told Technology Networks. In addition, “The drug conjugation process adds complexity resulting from varied drug-to-antibody ratios (DAR), drug positional isomers due to stochastic drug conjugation, and possible conjugation in unintended regions of the mAb such as the complimentary determining region,” Larson added.

Larson is lead author of a research study published in Analytical Chemistry showcasing a novel MS-based method that enables high-throughput multi-attribute analysis of ADCs. Bottom-up LC-MS/MS and middle-down LC-MS/MS are two of the most common methods to assess the quality attributes of ADCs but are associated with several limitations. Bottom-up analysis can be time-consuming, and quantitation of global molecular features can be difficult to achieve. Middle-down LC-MS/MS can offer a more global perspective, but sample preparation time and LC-MS/MS analysis is still relatively long.

In the study, the team developed a rapid method using top-down MS, with vastly reduced sample preparation steps and an improved signal-to-noise ratio. The use of trapped ion mobility spectrometry (TIMS) enabled the collision cross section (CCS) of the analytes to be measured as well as providing a boost in sensitivity. “TIMS combined with a three-tiered MS approach provides greater breadth of information than traditional methods, specifically through collection of intact ADC mass and determination of CCS values for the ADC,” Larson said.

The approach can be used for the characterization of ADCs in pre- and post-clinical quality control to rapidly monitor batch-to-batch variability. “The results generated from this method provide a roadmap of therapeutic attributes which shows practitioners whether further molecular detail is needed,” Larson added.

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Implementing a quality management system

In addition to improved methods of analysis, Rodriguez discusses how education is also one of the key aspects that ensures the pharmaceutical quality control supply chain process goes smoothly. “Not everyone understands the importance of ensuring the quality of materials for human clinical trials and often thinks any material in the market will do. There is often lots of pushback in the implementation of quality control standards due to the same reason,” Rodriguez explains.

The quality control laboratory needs to implement a quality management system to achieve the quality policies and objectives of the organization. The system should be established after assessing the organization’s scope of activities such as the type, range, volume of testing and/or calibration, validation and verification.

The staff involved in the quality operations should be well-versed in all documentation of the quality management system. Each component of the quality management system can be collated in a quality manual. Appropriate training and effective communication of the key aspects is necessary. The management should assure that the quality systems, policies and processes are described in the documentation appropriately, assuring the quality of the results produced.

Once the quality management system is established in an organization, it should be audited at regular intervals in a systematic manner. The audits should include assessments by both internal and external auditors. During audits, all activities of the quality department should be checked for compliance with the quality management system and if required, appropriate corrective and preventive actions should be taken.