An Evaluation Of The Stability Of A Pharmaceutical Biotechnology Product For Licensing Purposes Essay Sample

Type of paper: Essay

Topic: Drugs, Products, Business, Stability, Medicine, Degradation, Aliens, Manufacture

Pages: 7

Words: 1925

Published: 2023/02/22


A biological substance, in the European Union is a material madefrom a biological source.It needs for its labelling and qualitydeterminationa collection of physical, biological and chemical tests. The production process and its regulation are also scrutinized for quality determination.Biotechnological drug products have unique, identifying characteristicsthathave tobe taken into consideration in any precise testing program meant to prove their stability in the course of the planned storage period.
For the products having proteins and polypeptides as their active components, the preservation of their molecular structure andbiological actionis heavily dependent on covalent and non-covalent forces. These products are easily affected by the slightest environmental changessuch as light, temperature differences, oxidation, ion amount, and shear. For one to ascertain the preservation of biological activity and not bring about degradation, rigorous storage conditions are necessary (Gandhi & Rajput 2009, p. 438).

Selection of Batches

In cases where bulk material is to be kept in storage after manufacture but before preparation and manufacturing, it is important that stability data for at least three batches be provided for which production and storage represent the entire manufacturing scale of production. In cases where storage periods exceed six months, at least six months’ worth of stability data has to be submitted (Patel &Chaudhari 2012, p. 27). For biotechnological drugs with storage durations not exceeding six months, then the least amount of stability data in the first submission has to be defined in a case-by-case setting. Information from pilot-plant scale consignments of biotechnological drug substances made at a compact scale of fermentation and refinement may be delivered when the record is submitted to the regulatory bodies. Submission of this information occurs with a pledge to place the initial three manufacturing scale consignments into the long-term stability program following approval(Shah et al. 2012, p. 2978).

Drug Product

The quality of the consignments of biotechnology drug substances used in the stability program should represent the quality of the materials usedin both pre-clinical and clinical trials. It should also demonstrate the quality of the drugs that will be made during the actual drug manufacturing (Shah et al. 2012, p. 2978).Furthermore, the bulk material of the drug substance synthesized during the pilot-plant scale has to be made via a processsimilar to that to be used in the actual manufacturing. The bulk material also has to be kept under conditions similar to that made use of in the actual manufacturing.
The bulk material used in the stability program has to be kept in containers that correctly identify and represent the real containers that will be used during manufacture. Smaller-sized containers may be satisfactory for biotechnological drug substance stability testing provided they are made using one material, and use an identical form of container-closure mechanism that is to be usedduring manufacture (Kshitija & Mrinalini 2015, p. 116).

Degradation of proteins by reactive oxygen species

The environment in which proteins are found tends to contain plenty of oxygen. The reactive oxygen species (ROS) in such environments reacts with nucleic acids and proteins. With proteins, the ROS lead to racemization, dimidiation, and isomerization. The proteins modified by oxidation cannot be repaired; they have to be removed. When the ROS reacts with a protein, it leads to the introduction of carbonyl functional groups into the protein structure. This ends in breaking down of the protein to form products with lower molecular weights. It also leads to the cross-linking of proteins to form products with higher molecular weights.

Sample selection

In a case where one biotechnological drug product is to be distributed in batches that differ in fill volume (for instance 1 ml, 2 ml, 5 ml), unit (for instance 10 units, 20 units, or 40 units), mass (for instance 1 mg, 2 mg, or 10 mg) the samples to be used in the stability program can be chosen using the bracketing and or the matrixing system (Kelber et al. 2014, p. 1124).
Matrixingdeals with the statistical component of the stability evaluation phase, in which diverse sample fractions are tested at varying sampling points. It is only used when when suitable documentation is offered. The documentation ascertains that the stability of the samples verifiedrepresents the stability of all the samples (Kelber et al. 2014, p. 1124).Any variations in the samples for the similar drug product have to be identified as, for instance, covering different consignments, varying strengths, different container-closure mechanisms (Kelber et al. 2014, p. 1124).
Matrixing should not be used with samples that have differences that can affect stability, like differentstrengths and differingcontainer-closure mechanisms, in which case it will not be possible to ascertain that the products react in the same manner under storage conditions (Kelber et al. 2014, p. 1124).
In the case where identical strength and similar container-closure mechanisms are used for three or more fill contents, the drug manufacturer may choose to enter only the biggest and smallest container sizesinto the stability program. Such a procedure is called bracketing. Coming up with the design of a protocol that includes bracketing calls forassuming that the stability of the drug intermediate samplesis characterized by those samples that are at the limits. In some cases, information can be requested to help establish that all samples are correctly represented by information collected for the limits (Kelberet al. 2014, p. 1124).

Stability-indicating profile

Overall, there is no one definite stability-identifying parameter or assay that profiles the stability features of a biotechnological drug. Consequently, the drug manufacturer has to recommend a stability-identifying profile that offers assurance that varies in the identity, purity, and potency of the biotechnological drug product that will be detected (Gandhi & Rajput 2009, p. 438).
During submission, applicants should haveverified the authenticity of the procedures that include the stability-identifying profile. Such information has to be made available for review. Determinations of those tests which have to be included are specific to the biotechnological product being tested (Patel &Chaudhari 2012, p. 27).


The dossier that accompanies the application for theauthorization to market a particular drughas to include a comprehensive protocol for the stability assessment of the drug substances and drug products in support of the recommended storage settings and durations of the expiry periods(Shah et al. 2012, p. 2978). The protocol has to include all the required information which proves the stability of the biotechnological drug product during the proposeddating of expiry durations,including, for example, specifictest intervals and specifications (Collen 2012, p. 13).


When the planned use of a biotechnological drug product is related to measurable and quantifiable biological activity, the potency testing has to be included in the stability studies (Mullard 2008, p. 1320). In the stability testing of the biotechnological products, potency is the capacity of a drug product to accomplish its intended effects. It is dependent on the quantification of various attributes of the drug product. It is determined by an appropriate and suitable quantitative procedure (Van Arnum 2011, p 35).
Generally, the potencies of a biotechnological drug determined by various laboratories can be compared in an expressive manner only if it measured in relation to that of a proper reference material (Kshitija & Mrinalini 2015, p. 116). For this purpose, the reference material incorporated into the assay has to be calibrated indirectly or directly against the equivalent national (or international) reference material (Kimberet al. 2001, p. 198).
Potency studies have to be done at appropriate breaks as stated in the stability protocol. The results have to be reported in terms of the calibrated units of biological activity, and wherever possible, against the nationally (or internationally) recognized standards(Basketter et al. 2013, p. 269). In cases where there are no nationallyor internationally recognized reference standards, then the results of the assay results can be reported in terms of the in-house units obtained through the use of a characterized reference material (Annisa & Abdulah 2012, p. 96).
In some biotechnological drug products, the potency depends on the conjugation of the active ingredients to a second moiety. Breaking down of the active ingredients from the carrier used in conjugates has to be analyzed in real-time, while taking real-time temperaturemeasurements (including the environmental conditions encountered in the shipment) (Hiľovská et al. 2015, p. 3).

Purity and molecular characterization

During tests to determine the stability of the biotechnological drug products, it is of paramount importance to discuss purity. Because of the effects of deamidation, and glycosylation, the total purity of a biotechnological drug product is hard to determine (Robinson 2002, p. 5283). Therefore, the purity of a biotechnological drug product has to be determinedusing at least two methods. The purity value obtainedis dependent on the method used to measure the purity. For stability testing, the purity tests should focus on the methods that determine degradation products (Gibbons et al. 2007, p. 1191).
The level of purity, together with the individual and overall levels of degradation products of the drug product used in the stability studies, has to be reported and recorded if possible (Pleuvry 2009, p. 348). The limits of acceptable degradation are obtained from the analytical profiles of consignments of the drug substances and drug products used in preclinical and clinical trials (Stareket al. 2009, p. 351).
The use of suitablephysical, chemical, immunochemical, and biochemical analytical procedures should allow for a thorough representation of the biotechnological drug product. Properties such as hydrophobicity, molecular size, and charge have to be determined,together with the precise determination of degradation products that can be as a result of oxidation, deamidation, aggregation, sulfoxidation, or fragmentation throughout the storage period (Galli 2007, p. 2557).The methods that may be used in this determination include electrophoresis (methods including immunoelectrophoresis, isoelectrofocusing, and Western blot), high-resolution chromatography (affinity chromatography, gel filtration, reversed-phase chromatography, and ion-exchange), and peptide mapping (Theviset al. 2008, p. 35).
When important quantitative and qualitative changes that reveal information about the formation of degradation product are identified during long-term stress stability studies, together with accelerated studies, then extra thought should be given to the likely hazards that might be encountered, and to the necessity for determination of characteristics and quantification of the number of degradation products in the lasting stability program. Satisfactory limits should be proposed and justified, while taking into account the quantities observed in the material used in preclinical and clinical trials.

Other product properties

These product properties, though not precisely related to biotechnological drug products, have to be scrutinized and reported: the visual appearance of the drug product (opacity and colour of solutions and suspensions; the texture, colour, and the time of dissolution time for drugs in powder form).The presence of any visible particles in drug solutionsor suspensions, or following the re-formation of lyophilised cakes, powders, and pH, the moisture content of powders and lyophilised products also have to be checked (Leu-Fen &Bunnell 2012, p. 96). Testing the sterility of various containers and the container-closure mechanism should be done at a minimum at first, and at the end of the suggested shelf-life.


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