Regulatory Considerations for Forced Degradation Studies to Assess the Stability of Drugs

M V Narendra Kumar Talluri,  Asst. Professor, Department of Pharmaceutical Education and Research, India

Quality, safety and effectiveness are the most important attributes of drugs and pharmaceuticals. The ICH issued the guidelines on pharmaceuticals stability. The present article focuses main regulatory considerations for the stability of drugs including typical acceptance criteria for HPLC based SIMs and WHO pre-formulation stress testing protocols and QbD etc.

Quality, safety and effectiveness are the most important attributes of drugs and pharmaceuticals. Because of its key role in public health, the pharmaceutical industry has always been a comparatively highly regulated industry. Until the end of 2nd World War, the quality of pharmaceutical products was determined mainly by assaying the content of their active ingredients. Since then, analytical instrumentation has undergone an extraordinary revolution, successively enabling the resolution of increasingly complex samples and the detection of minor amounts of any kind of analyte contained therein. This revolution facilitated the setting of an analytical chemistry-based regulatory framework to govern the development of pharmaceuticals. This paradigm has been continually evolving, especially in those aspects that define their standards of quality. Since the early 1970s, it has become a concern that unstable Drug Products (DPs) may not be able to maintain their quality attributes after being stored over a period of time, so, in 1975, the United States Pharmacopeia (USP) included a clause regarding the drug-expiration-dating period.

The regulatory timeline

  • 1975 -  USP included –Drug expiration period
  • 1984 - The US Food and Drug Administration (FDA) issued the first stability guideline
  • 1987 -  Publication on specific requirements on statistical design and analysis of stability studies for human drugs and biologics with the aim of establishing expiration dates
  • 1987 -  FDA - Guidelines on  stability data for applications to the Investigational New Drugs (INDs) and  New Drug Applications (NDAs)
  • 1993 - The International Conference on Harmonization (ICH) issued the Q1A guideline on stability.

In 1993, the International Conference on Harmonization (ICH) issued the guidelines on stability (Table 1). The regulatory bodies of Japan, USA, the European Union, Canada, Australia and other countries have adopted and now have the law in force.

In general, pharmaceutical items intended for the global pharmaceutical market are currently tested for stability under normal storage conditions for as long as 36 months, though, typically, regulatory agencies would initially assign only a 24-month conformance period, thereby providing an extra stability reserve. Thus, a satisfactory 3-month accelerated data submission may also permit granting a 24-month tentative expiry date, provided the room temperature data also meet specifications. Hence, Stability-Indicating Methods (SIMs) play a key role in current pharmaceutical regulation.

However, despite the official requirement to use SIMs, as emphasised in the British Pharmacopoeia, the USP and several ICH regulatory guidelines, none of these documents provide the definition of a SIM. Moreover, the stability-indicating requirement is absent from several well-recognised Pharmacopoeias (the Japanese Pharmacopoeia,15th Edition). From the FDA perspective, a SIM must ‘accurately measure the active ingredients, without interference from degradation products, process impurities, excipients, or other potential impurities’. Furthermore, available official guidance concerning scope, timing and best practices for degradation studies, required for developing SIMs, is still very general. SIMs are required for stability studies, and stability information is needed for regulatory submissions, such as INDs and NDAs, and to set expiration dates for APIs and Drug Products. SIMs are also required for complying with other regulated events, such as API and DP release, toxicology dosing solutions, excipient-compatibility evaluation, pre-formulation and packaging studies, and line extension. They are also powerful tools for routine quality control and for investigating out-of-specification and out-of-trend results.

Bakshi and Singh distinguished the terms ‘specific stability-indicating method’ (specific SIM) and ‘selective stability-indicating method’ (selective SIM).

A specific SIM is an analytical method suitable for unequivocally measuring the API in the presence of all of its degradation products, as well as excipients and additives, expected to be present in the formulation.

However, a selective SIM is a method capable of unambiguously measuring the API and all of its degradation products in the presence of excipients and additives, expected to be present in the formulation.

They considered that the development of a SIM likely to meet regulatory requirements is a seven step process that entails:

  1. Critical study of the drug structure to assess the likely decomposition routes
  2. Collection of physicochemical properties information
  3. Conducting stress studies
  4. Preliminary separation studies on stressed samples
  5. Final method development and optimisation
  6. Identification and characterisation of degradation products and preparation of standards and
  7. Validation

The ability of a SIM to monitor changes in the chemical properties of the drug over time, according to the regulatory guidance, is that they provide valuable information, including the determination of the degradation pathways of Drug substances and Drug Products, revealing the intrinsic stability of the API in the solid state and in solution and its susceptibility to hydrolytic, oxidative, thermolytic, and photolytic degradation. Moreover, the resulting structural elucidation of the degradation products enables the discernment of compounds in formulations related to the drug substances from those arising from the excipients.

Stress tests also fulfil the purpose of providing meaningful amounts of degradation products, which can be isolated and purified for complete characterisation and acquisition of impurity standards before carrying out the method development and validation studies. Alternatively, by resorting to the high sensitivity and excellent separation capability of hyphenated techniques, such as UPLC with Mass Spectrometry (MS) detection (UPLC-MS), which also provide structural information, In this case, no purified impurity standards are generated by the approach. Monitoring of degradation reactions is also helpful for better understanding of some important characteristics of the drugs (polarity, stability etc.) and to decode which degradation product is really relevant and which is not. WHO suggested pre-formulation stress testing protocol for the development of Fixed-Dose Combination (FDC) - Finished Pharmaceutical Product (FPP). (Table 2). In addition, Table 3 depicts typical acceptance criteria for an HPLC-based SIMs. The current WHO guideline is modelled on ICH Q1A(R2).

ICH Q1A is now two decades old. Also, there is wide adoption of the ICH CTD format for dossier submission, so ICH requirements that were meant for new drugs/products have been extended to generic drugs/products, including limits of degradation products, as evident in the WHO stability-testing 2009 guideline. So, there is a clear trend towards aligning global, regional and country requirements for stress testing to ICH CTD. While ICH guidelines require stress testing results as a part of registration dossier, US-FDA emphasizes stress testing requirement in IND phases 2 and 3. Similarly, EMA seeks stress testing details in application for permission on investigational medicinal and biological products in clinical trials.

USFDA and EMA include stress testing in their guidelines on individual product categories, such as metered dose-inhalation aerosols, nasal sprays, liposomal products, biological and protein products, vaccines, coronary drug eluting stents, transdermal patches and botanical drug products. Stress conditions that can cause incremental product degradation over a defined time period are also mentioned. While USFDA insists on stress testing of herbal drugs and products to establish an analytical method capable of detecting degradation products, the same is not a clear requirement under EMA guidelines, where omission is allowed, if justified. Stress testing of radioactive substances is not considered feasible, so simulated testing is recommended in certain cases on the non-radioactive chemical form, and on radiopharmaceutical kits

Accordingly, any regulatory agency would appreciate the presence of an elaborate study as a part of the dossier for a new or generic drug or attachment with dossier application of an intensive study, if available in the literature for an existing molecule. It is in the interest of the manufacturer to assess that in-house or the literature study has been conducted systematically and would prove so as a right-first-time data package.

Moreover, the major emphasis of regulatory agencies in the current times, as projected well through the requirements laid down in ICH quality guidelines Q1–Q11, is that new drug substances and products should be designed and produced to optimal quality, batch after batch, in line with the stringent limits contained in the guidelines. Incidentally, stringent thresholds have been prescribed under ICH guidelines Q3A and Q3B for degradation products/impurities in the new drug substances and products, respectively. The general reporting, identification and qualification thresholds are 0.05 per cent, 0.1 per cent and 0.15 per cent, respectively. Higher limits are allowed for specific degradation products if they prove to have a better safety profile, while the confines are much more stringent for genotoxic degradation impurities. As the same ICH thresholds now even apply to existing and generic pharmacopoeial products, in that respect, all kinds of drug substances and products need to be designed and manufactured so that degradation products/impurities are under control through their total life cycle, starting from manufacture to consumption by the patient. The importance of drug degradation can be gauged from the fact that plenty of recalls ordered from the market by USFDA in recent times, involving huge quantities of drug products, have been due to degradation in them surpassing the approved limits.

Quality by Design (QbD) initiative was introduced by the FDA in 2002 and is being promoted within the pharmaceutical industry with the aim of increasing regulatory flexibility and creating an easier path for the manufacturers to introduce process/product improvements. The QbD concept is also being implemented for analytical method development. Application of statistical design of experiments is currently encouraged by the regulatory agencies, sometimes together with the use of chromatographic modelling and optimisation software (DryLab, LC Simulator, Fusion AE and Design Expert). This allows systematic assessment of the critical parameters of the SIM, since method sensitivity, specificity and robustness are properties especially addressed by QbD approach with a few experiments and relatively little laboratory efforts.


M V Narendra Kumar Talluri is an Asst.Professor & In Charge LC-MS at NIPER-H. Previous positions held by him include Associate Scientific Manager at Biocon. He received PhD from IICT, Hyd. The Indian Drug Manufacturer’s Association conferred prestigious ‘Young Pharmaceutical Analyst Award 2011’ for his outstanding research contribution in the field of Pharmaceutical Analysis. Science direct declared 4 times one of his article published in journal of pharmaceutical and biomedical analysis was among Top 25 hottest articles.

-- Issue 22 --

Author Bio

M V Narendra Kumar Talluri