Pharmaceutical Products Manufacture & Analytical Testing Process
When you are sick andyou reach for that box of tablets, how do you know that what you are about totake is safe? All pharmaceuticals are manufactured to rigorous regulatorystandards to ensure that the products reaching patients are safe, effective andof a high quality.
What is GoodManufacturing Practice?
Goodmanufacturing practice (GMP) is just one of the regulatory requirements that ensure quality standards aremaintained and are used to control the suitability of raw materials , manufacturingpremises, equipment , product sampling,specifications, stability testing , determination ofproduct shelf life , testing and the release of products tothe marketplace.
The key objective for any pharmaceutical company is to develop a high-qualitytherapeutic product that fulfils the following criteria:
<!--[if !supportLists]-->§ <!--[endif]-->Therapeutic effect : The drug (the active pharmaceutical ingredient ,API), identified to treat aparticular condition must be proven to be effective at the specified doselevel.
<!--[if !supportLists]-->§ <!--[endif]-->Bioavailability : The manufacturers must ensure that the API isreleased within the body and is available at the site of action. In the case ofa product in tablet form, the tablet must disintegrate and the activeingredient should rapidly dissolve in the stomach and intestine where it isabsorbed.
<!--[if !supportLists]-->§ <!--[endif]-->Manufacturability : The product can be reliably and reproduciblyprepared to the required product specification using pharmaceutical processing equipment.
<!--[if !supportLists]-->§ <!--[endif]-->Stability: The product must have a provenshelf-life (usually 3 to 5 years) with minimal levels of decomposition of theactive ingredient that would reduce the potency or ‘label claim ’ (amount of drug available) or cause theformation of impurities that might be harmful to the patient.
Who developspharmaceutical products?
Developing a suitable product involves a number of different stages within apharmaceutical company: formulation, process development, analyticaldevelopment , regulatory, quality control and clinical .
During the development of the drug, the formulation and process developmentgroups liaise closely with the analytical development group. It is theresponsibility of the analytical development group to develop suitableanalytical methods for the testing of all components used in the manufacture ofa drug product as well as the testing of samples both during and aftermanufacture.
A wide variety of tests is employed to assess the quality of the product ateach stage. chromatographic methods are used toquantify the amount of drug substance in the formulationto ensure that it matches the targeted dosage strength (label claim). Qualitative methods are also used to detect the presence ofany impurities or degradation products.
These methods are used when conducting stability studies to determine the shelf-life of theproduct. The analytical development group in conjunction with the formulation development group determines specifications andtests that demonstrate that a quality product has been prepared.
Once a suitable product is developed, themanufacturing process is transferred to the production group for routinemanufacture and the analytical methods are transferred to Quality Control (QC).
How pharmaceutical products aremanufactured?
Many processes are used to prepare tablets. Below is a process flow diagram fora tablet product prepared by the direct compression route. This is thesimplest way to manufacture a tablet product and involves preparing a mixtureof the drug substance and other materials known as excipients. These excipients are added to improveprocessing, stability and patientcompliance . A coloured coating maybe added to improve identification of the product.
A similar process can be used to manufacture capsules by filling the powderblend into a gelatine capsule shell.
Before manufacturing begins, the API and excipients are tested to ensure theirsuitability for use. A typical tabletting or encapsulation process involvesweighing materials and screening them to remove lumps and to obtain a goodparticle size distribution. The majority of the excipients and drug substancesare mixed together in a blender to form a homogenous powder. The powder is then further mixed with lubricants to ensurethat the tablet machine continues to run effectively. After the compressionstage, full quality testing is carried out and the product is packed for sale.
Drug Substance (API)
Exerts a therapeutic response
Filler or Diluent
Dilutes drug to tablet/capsule of suitable size
Holds tablet together
Promotes disintegration and break-up of tablet in the stomach/intestine
Glidant or Flow-aid
Improves flow and processability of powder during compression
Lubricates machine to ensure effective running.
During manufacture, samples are taken at intervals to ensure that the correctlevel of active ingredient is present and that the process is in control. Thekey assay is carried out using High PerformanceLiquid Chromatography (HPLC) that is specific to the drug substance. Othertests that employ HPLC, such as blend uniformity and tablet content uniformity,are used to ensure that there is a consistent amount of drug in the powderblend and that the finished product corresponds to that of the ‘label claim ’.
HPLC is also a valuable tool for identifyingimpurities and decomposition products and ensures that these remain at minimallevels during product storage.
Dissolution testing is an in-vitro method of mimicking the performance ofpharmaceutical products in the gastrointestinal tract. Dissolution studies areconducted by placing a tablet or capsule in a dissolution apparatus.
This consists of vessels containing a dissolution medium that is maintained ata certain pH and held in a thermostated water bath (37 °C). The contents arestirred at a specified rate (e.g. 50 r.p.m.) and the medium is sampled periodically andtested by HPLC or UV analysis.
A dissolution profile is constructed and the amount of drug dissolved in themedium is determined. A dissolution test indicates a consistent APIrelease. Dissolution profiles are useful quality control methods.
Generallyfor a drug product requiring immediate API release, approximately 75% of thedrug API should dissolve in the dissolution medium within 15 to 30 minutes.
A stability evaluation is required to ensurethat a product is stable within the different climatic zones of the world. InWestern Europe climate variation is relatively limited but in tropical regions,conditions (for example temperatures greater than 40 °C and humidity greaterthan 75%) can be very challenging to the stability of pharmaceuticals.
During development of pharmaceuticals, a stability study is conducted bystoring the product in its packaging under a range of temperature and humidityconditions for specified time periods. Samples are periodically removed andanalysed by HPLC and dissolution testing, and the results compared to theinitial results of the sample.
Changes in purity and differences in dissolution profiles may be indicative ofan unstable product. During development, studies are normally carried out onseveral formulations to assess the best composition for the final product.