Stability Articles

Forced Degradation Studies: Regulatory Considerations and Implementation

The current regulatory guidances governing forced degradation studies of biological pharmaceuticals are extremely general. They itemize broad principles and approaches with few practical instructions. There is no single document that comprehensively addresses issues related to stress studies such as objectives, timing, selection of stress conditions, and extent of degradation. We will attempt to fill that gap by summarizing regulatory guidance for stress studies of biological products and present some examples of their practical applications.

Journal: 
BioPharm International, July 2005

Photosensitivity of Internal Standard Valerophenone Used in USP Ibuprofen Bulk Drug and Tablet Assay

In the ibuprofen (IBP) bulk drug (1) and tablet (2) assay methods (high-performance liquid chromatography [HPLC]) of the United States Pharmacopeia (USP), valerophenone (ISTD) is used in standard solutions for system-suitability determination and as an internal standard for the quantitation of ibuprofen in bulk drug and tablets. ISTD is prepared in a solution of 1% chloroacetic acid (pH 3.0  0.05):acetonitrile (40:60). This ISTD solution is used as an extraction solvent for IBP tablets (tablet assay preparation) and for IBP bulk drug substances (bulk drug assay preparation) as well as for the preparation of system-suitability standard solutions. The HPLC mobile phase for this method is 1% chloroacetic acid (pH 3.0 0.05):acetonitrile (40:60). The peak response ratios of IBP and 4-isobutylacetophenone (4-IBAP) to ISTD are factored in the quantitation of IBP and 4-IBAP in bulk drug and tablet assay samples.

Journal: 
Pharmaceutical Technology AUGUST 2004.

A Stability Program for the Distribution of Drug Products

Stability is defined as the capacity of a drug substance or drug product to remain within established specifications to maintain its identity, strength, quality, and purity throughout the retest or expiration dating periods (1). Physical, chemical, and microbiological data are  generated as a function of time and storage conditions (e.g., temperature and relative humidity [RH]). Stability testing provides evidence that the quality of a drug substance or drug product under the influence of various environmental factors changes with time (2). Although the storage conditions are relatively constant, the distribution environment can vary greatly, especially when a drug product is shipped between various climatic zones (1). Seasonal changes, mode of transportation, and the number of drop-off points are also variables that should be considered within the pharmaceutical supply chain.

Journal: 
Pharmaceutical Technology JULY 2004.

The Effect of Buffers on Protein Conformational Stability

Buffers used to formulate proteins should not serve as substrates or inhibitors. They should exhibit little or no change in pH with temperature, show insignificant penetration through biological membranes, and have maximum buffer capacity at a pH where the protein exhibits optimal stability. In conformity with the proposition that “Nature designs the optimum molecules,” buffers should mimic the antidenaturant properties of nature exhibited by osmolytes (1–5) that are independent of the evolutionary history of the proteins (6, 7). Such properties may include preferential exclusion from the protein domain (8–11) and stabilization without changing the denaturation Gibbs energy (Gd) (12).

View Full Article

Journal: 
Pharmaceutical Technology MARCH 2004.

The Square Root of N Plus One Sampling Rule

In the pharmaceutical industry, bulk product characteristics are routinely tested to determine whether the product meets in-house quality assurance specifications. Raw or processed materials are frequently stored in drums or containers. In these instances, one must know how to choose a representative sample that exhibits characteristics similar to those processed by the population as a whole. The common method in statistical practices is choosing a simple random sample from the population.

Journal: 
Pharmaceutical Technology MAY 2003

Identification of Out-of-Trend Stability Results

Out-of-specification (OOS) regulatory issues have been well documented in the literature (1). Out-of-trend (OOT) stability data identification and investigation is rapidly gaining regulatory interest. An OOT result is a stability result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study. The result is not necessarily OOS but does not look like a typical data point. This article discusses the regulatory and business basis, possible statistical approaches, and implementation challenges to the identification of OOT stability data. Representatives from PhRMA member companies met to consider these topics, review current practices, and summarize various approaches to potentially address this issue. It is noted that the identification of OOT results is a complicated issue and that further research and discussion is needed.

Journal: 
Pharmaceutical Technology APRIL 2003.

Implementing Successful Stability Testing Operations

Once a candidate drug reaches use in humans, all stability storage and testing must be
conducted according to current good manufacturing practices  (CGMPs). The regulatory mandate for stability testing in the United States is contained in 21 CFR Part 211 Section 166, which states that There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include…. Although 21 CFR addresses stability data treatment and reporting for expiration dating, it says almost nothing about how to ensure control within the stability storage operation or how to design stability protocols. There are many ways to run a stability operation in a GMPcompliant manner, but the bottom line is to have written procedures and protocols with documented evidence that they are followed.

Journal: 
Pharmaceutical Technology Analytical Chemistry & Testing 2003.

Microbial Bioburden on Oral Solid Dosage Forms

Life first appeared on Earth in the form of bacteria-like organisms. Cellular fossils, recovered from rocks that have been dated to 3.5 billion years old, have been identified as prokaryotic cells (bacteria and cyanophytes) and stromatolites (mats of sediment trapped and glued together by prokaryotic cells in shallow marine waters) (1,2). For billions of years, bacterial life has remained the most common and most successful form of life on Earth.

Journal: 
Pharmaceutical Technology.FEBRUARY 2002

Available Guidance and Best Practices for Conducting Forced Degradation Studies

Forced degradation or stress testing is undertaken to demonstrate specificity when developing stability-indicating methods, particularly when little information is available about potential degradation products. These studies also provide information about the degradation pathways and degradation products that could form during storage. Forced degradation studies may help facilitate pharmaceutical development as well in areas such as formulation development, manufacturing, and packaging, in which knowledge of chemical behavior can be used to improve a drug product.

View Full Article

Journal: 
pharmaseutical technology.

Effects of Water Vapor Absorption on the Physical and Chemical Stability of Amorphous Sodium Indomet

This
study reports on the effects that water absorbed into amorphous sodium
indomethacin (NaIMC) can have on simultaneous tendencies to crystallize
to its trihydrate form and to undergo base-catalyzed hydrolysis because
of the plasticizing effects of water on molecular mobility. Measurement
of water vapor absorption at 30°C and powder x-ray diffraction patterns
as a function of relative humidity (RH) reveal that upon exposure to
21% RH, NaIMC does not crystallize over a 2-month period. Measurements
of the glass transition temperature as a function of such exposure
reveals a change in Tg from 121°C, dry, to 53°C at 21% RH, such that Tg
at 21% RH is ~13°C above the highest storage temperature of 40°C used
in the study. At 56% RH and higher, however, crystallization to the
trihydrate occurs rapidly; although over the 2-month period,
crystallization was never complete. Assessment of chemical degradation

Journal: 
AAPS PharmSciTech .2004; 5(2):article 26.

Preparation and Stability of Poly(Ethylene Glycol) (PEG)ylated Octreotide for Application to Microsp

The purpose of this study was to prepare poly(ethylene glycol) (PEG)ylated octreotide and investigate the stability against acylation by polyester polymers such as poly(lactic acid) and poly(lactic-co-glycolic acid). Octreotide was modified by reaction with monomethoxy PEG-propionaldehyde (molecular weight 5,000) in the presence of sodium cyanoborohydride. The mono-PEGylated fraction was isolated by reversed-phase high-performance liquid chromatography (HPLC) and characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Circular dichroism demonstrated no significant secondary structural differences between mono-PEGylated octreotide (mono-PEG-octreotide) and intact octreotide. As a test system for the stability study against acylation reaction, lactic acid (LA) solutions with various concentrations and pH values were prepared with water dilution and subsequent accelerated equilibration at 90°C for 24 hours.

Journal: 
AAPS PharmSciTech.2003; 4(4):article 72.

Effect of Hydroxypropyl Beta Cyclodextrin Complexation on Aqueous Solubility, Stability, and Corneal

The
purpose of the study was to investigate the effect of hydroxypropyl
beta cyclodextrin (HPβCD) on aqueous solubility, stability, and in
vitro corneal permeation of acyl ester prodrugs of ganciclovir (GCV).
Aqueous solubility and stability of acyl ester prodrugs of Ganciclovir
(GCV) were evaluated in pH 7.4 isotonic phosphate buffer solution
(IPBS) in the presence and absence of HPβCD. Butyryl
cholinesterase-mediated enzymatic hydrolysis of the GCV prodrugs was
studied using various percentage w/v HPβCD. In vitro corneal permeation
of GCV and its prodrugs (with and without 5% HPβCD) across isolated
rabbit cornea was studied using side-by-side diffusion cells.
HPβCD-prodrug complexation was of the AL type with values for
complexation constants ranging between 12 and 108 M-1. Considerable
improvement in chemical and enzymatic stability of the GCV prodrugs was
observed in the presence of HPβCD. The stabilizing effect of HPβCD was

Journal: 
AAPS PharmSciTech 2003; 4.

Optimization & Stability Study of an EUDRAGIT E100® Based Transdermal Therapeutic System of Nitrendi

ABSTRACT Nitrendipine, a potent antihypertensive molecule undergoes extensive first-pass metabolism with oral bioavailability in the range from 10% to 20%. The objective of present research investigations was to fabricate an Eudragit E100® pressure sensitive adhesive (PSA)-based stable transdermal therapeutic system (TTS) of nitrendipine, which could deliver drug at a maximum input rate through a transdermal route. Monolithic TTS of nitrendipine was fabricated in Eudragit E100® PSA-based pressure sensitive adhesive. To enhance flux, d-limonene was investigated as a permeation enhancer, and effect of concentration of d-limonene on permeation kinetics of nitrendipine through guinea pig skin was examined. Optimized TTS was evaluated for in-vitro flux though human skin (volar arm) to determine patch size needed to deliver drug through the transdermal route. The optimized TTS was kept for stability study for a period of 1 year at refrigeration, 25?

Journal: 
Drug Delivery Technology ,,Vol 2 No 3 · May ,2002.

Photodegradation and Photostability Studies of Bendroflumethiazide in Pharmaceutical Formulations

A simple HPLC procedure is described for the determination of bendroflumethiazide (BFMT) in pharmaceutical formulations and urine samples. No interferences from common additives or other drugs frequently administered with BFMT or from endogenous compounds in urine samples were found. The lack of an organic solvent in the mobile phase reduces the risk of environmental contamination and human toxicity.

Bendroflumethiazide (BFMT: (RS)-3-phenylmethyl-3,4- dihydro-6-trifluoromethyl-2H-1,2,4-benzothiadiazine-7- sulphonamide-1,1-dioxide) is a potent diuretic drug extensively used for the treatment of hypertension and oedema that belongs to the thiazide family.1 BMFT is well absorbed from the gastrointestinal tract after oral administration and the absorption is not affected by food. It lowers blood pressure and removes extra salt and water from the body by acting on the kidneys. BFMT is usually prescribed as tablets and frequently in combination with -blockers.

Journal: 
LCGC Europe, Jan 1, 2005.

Stability Indicating Assays

How do you prove everything is separated?

During the past couple of months, I’ve had several readers write with questions about stability-indicating assays for pharmaceutical products, so I’d like to focus on that topic in this instalment of “LC Troubleshooting.” Stability-indicating assays are some of the most difficult types of liquid chromatography (LC) separations to develop, because chromatographers can’t be sure how many components are present and need to be separated. Let’s look at what these separations are all about and how to develop high-quality assays.
 
Stability Indication If you look at the label on your favourite prescription or over-the-counter pharmaceutical product, you’ll see a use before date. Before this date, the product should remain fully effective under normal storage conditions.

Journal: 
LCGC Europe, May 1, 2002.

Implications of Photostability on the Manufacturing, Packaging, Storage, and Testing of Formulated P

Allen C. Templeton, PhD, et al
Pharmaceutical Technology, Mar 2, 2005
The authors evaluate the implications of product photosensitivity and how it influences various aspects of product development.They discuss a product photosensitivity classification system and present a photosensitive pharmaceutical product case study. Photostability testing in the pharmaceutical industry has evolved rapidly, particularly since the May 1997 publication of the ICH Q1B guidance “Photostability Testing of New Drug Substances and Products” in the Code of Federal Regulations (hereafter referred to in this article as Q1B) (1).Although some notable criticisms have been leveled against the document for its perceived shortcomings (2–4), Q1B has provided much-needed input to pharmaceutical applicants about regulatory requirements for photostability testing.

Journal: 
Pharmaceutical Technology, Mar 2, 2005.