Quality of goods for domestic or industrial use has become critical owing to public awareness in all fields of activities and also in view of the changing national scenario. Scientific and technical assessment must have built-in quality assurance and customer protection especially in the field of pharmacy and extraction of active therapeutic compounds from biological origin.
In medical diagnostics, scientific calibration and analytical testing plays a large role in accurate determination of disease condition or therapeutic control or surgery. Hence, a small error of margin due to lack of quality compliance during operations can cause serious consequences on public health. Doses of quality must be administered through routine laboratory analysis to scale-up procedures and transferred during actual production stage.
One of the key challenges of any laboratory settings is tracing of route sources that limit the potential needs of a quality product; and, only routine checks on raw materials, testing procedures, housekeeping procedures, record maintenance and integrating technical and non-technical operations can accomplish this task. Laboratory must perform repetitive calibrations and purity tests of raw material, intermediate metabolites and final products and maintain laboratory data. Lab data affects all aspects of decisions on community health, lifestyle, safety, commerce and environment.
One of the most difficult situations that an analyst may be confronted with is the selection of suitable analytical method for a particular problem. Here we identify key definitions relating quality before moving to our objective of testing and calibration methods in pharmacopeia.
Quality Control: QC keeps a check on anticipated results related to raw materials, calibration procedures. It’s kept in place to correct the defects or alter testing procedures to minimize the margin of error and achieve our target protocol of product or process.
Quality Assurance: QA is oriented towards preventing defects from occurring. “Prevention is better than cure”, QA relates to both technical and non-technical operations, which prevent problems from occurring in first instance. This is accomplishment of proper laboratory records and integration of intra-laboratory or inter-laboratory functions through maintenance and proper selection.
Standardization: It defines the performance of entire system from installation of an instrument or component of calibration to measurement of levels or response of calibrated product or equipment; and, detection of limits of tolerance for application. Standardization relates to validated standards or reference standards of prototype test.
QA protocol depends on selection of referenced raw materials and development of validated testing parameters or process controllers to meet multiple objectives of safety, consumer protection and export promotion. Quality production associates all QA protocols of GLPS along with additional protocols of GMPs like intermediates and finished goods testing, packaging, storage and logistics. Inter–laboratory comparisons, certified reference materials, in house testing as secondary reference, retesting by different methods and establishment of criteria for correlation of results are some QC schemes that must be documented. Participation in staff training to impart technical and non-technical education is step in delivery of quality service and products. The environment in which test is performed shall not invalidate results. Reference to infrastructure in laboratory accommodation, calibration and test areas, energy sources, lighting, heating and ventilation shall facilitate quality performance of laboratory functions. Depending upon the size, laboratory shall have effective monitoring, control and recording of environmental conditions appropriate for biological sterility, dust, electromagnetic interference, humidity, mains voltage, temperature, and sound vibration levels with proper separation of neighboring areas. Inventory management of referenced lab equipment and materials for establishing calibration procedures is essential laboratory record. Maintenance records for equipment, labeling and identification procedures is an integral part of laboratory.
Some general requirements relating QA, QC and Standardization procedure includes:
Legal identity or title: Legal identity is the company or organization located at legal premises as independent functionary. Legal identity of a technical product is Title. Title measures its Identity, Strength, Efficacy and Purity of product for intended application. Legal identity defines the shape and structure of organization with its associated functionary.
In pharmacopeia, Title is associated with monograph that includes brief description on chemical composition, therapeutic category, generic description, nature of dosage and method of application. Similarly, legal identity must associate articles of inclusion, business deed or memorandum.
Organisation and management: The laboratory shall be organized and operated in such a way that its permanent, temporary and mobile facilities meet criteria of country’s accreditation body. The laboratory must document authorities, duties and responsibilities of managerial staff, technical staff, non-technical staff, quality and technical head and director, where applicable. All staff with the authority needs resources to discharge their duties and shall specify the responsibility and interrelation between personnel who manage, perform or verify work affecting calibration and testing. Technical manager must supervise objectives of calibration or test assessment, and analysis of results with overall technical operations.
Similarly, quality manager for quality and maintenance of housekeeping, equipments, products, implementation on established procedures and working standards of the organization. Arrangements must ensure impartiality, confidentiality, independence and integrity of several different departments free of other pressures that may affect their work.
Audit and review: Lab shall establish, maintain a quality manual appropriate to type and range and volume of activities like batch records, testing records, CIP, SIP records, financial records, housekeeping records and regularly update. Quality policy statement should be included with objectives and commitment by top management, procedure of control and maintenance of documents and procedure of amendment of quality systems. Reference manual for technical operation like calibration and verification of testing procedures, reference for measurement values and standards, validation of equipments and reagents should exist. Financial records of procurement and sales and annual audit on taxation must be included. Laboratory shall audit activities at appropriate intervals to verify that its operations continue to comply with the requirements of the quality system. Audits carried out by trained and qualified staff or managers are considered as appropriate, with documentation of findings and corrective actions
Safety and HAZOP: Safety manual of lab explains energy sources used like electricity, thermal units, heating units and safety parameters put in place. Containment of all unit operations, air ventilation of gas emissions is essential for safe working procedure. Nature of hazards like biological, chemical, water waster and air pollution must be identifiable. Method of waste handling, emission rates and disposal documented and practiced. Safety of workers and personnel is of prime importance and staff, should be trained for safety gears and protection equipments. Stress at work place and obligation of workers defines organization philosophy. Impartiality, confidentiality, independence and integrity of personnel from different departments like finance, operation, research and testing maintains a healthy relationship. Organization must have grievance procedure and procedures to boost staff morale.
Quality System Manual (QMS): QMS generally includes all technical and non-technical description that involves laboratory. It includes references and certification of equipment and raw materials, inventory of glassware, chemicals, instruments, specific procurement, test apparatus etc. Standard operating procedures (SOPs) of all tests performed in the laboratory with reference values, clean-in-place (CIP) and sterilization-in-place (SIP) protocols, automated systems can be included in manual. Specific reference for publication of product in relation to application in scientific newspaper and magazines is included in QMS.
Quality is important for each process and service and vital in medicine as it involves life. Unlike ordinary goods, there is no second quality in drugs. Quality control is a concept, which strives to produce perfect products by series of measures designed to prevent and eliminate errors at different stages of production. These become normal obligations arising from the humanism towards the sick humans. Simple analytical procedures in drug testing ensure removal of interfering sample components and selective enrichment of substances. Some selected and specific preparations to produce meaningful analysis and enable application in drug testing and calibration take into consideration the following:
Drug monograph: This includes general description and official standards of compound properties for preliminary evaluation of the integrity of article. Typical measures includes, odor and taste (characterized by FIDOL factors), solubility description as weight of compound (grams) in volume of solute (ml of water), Usual strength for application and nature of dosage, official standards for use in specific application medicine, or nuclear. General expression drugs define % w/w or % v/v and not exceeding 100.5 per cent of total weight or volume of the product; calculated reference standard as solvent-free substance in original form and storage conditions.
Drug monograph describes identity and strength of compound. Efficacy of compound for given strength is indented for specific application and strength can be altered for specific use. Purity of compound gives reference to purity of original source of compound and final purity of compound in formulation for application; impurities indicated in ppm or ppb.
Drug sampling: Sample preparation for testing and calibration is of prime importance.
General procedures in sampling involve proper weight and volumetric measurements; mixing of liquid solution and suspensions to maintain homogeneity; grinding tablets to pass to 40 mesh before preparing solution; use of appropriate incubation and extraction procedures for non-liquid samples; removal of interfering color coatings of tablets and capsules before weighing and sample preparation; using appropriate solvent dissolution characteristics for tablets, lotions, hydrocarbons, shampoos, creams, liniments, anodynes to prevent reaction. Water is solvent for most preparations but for specific assays, strength and type of solvent analysis is important. Certain substances are prone to oxidation like vitamin A, D and phenothiazines, therefore, separation of solvent containing API is extremely important, and reference standards must be obtained from a reliable source. Water–bath means boiling water bath except where temperature indicated.
Drug extraction: All calculations must use a single system of units; SI unit is generally preferred worldwide. Reaction chemistry and stochiometry must explain derivation of actual content of working volumes. UV spectrophotometric measurements and other statistical analysis must accompany working example. Consideration of solubility characteristics of the substance and its partition coefficient is essential. Solvent must not interfere in test results.
Working standards: Working standards of each procedure or unit operation and the complete process calculations must indicate procedure, working conditions and auxiliary requirements.
Drug product: It is finished dosage form such as tablet, capsule, lotion, syrup or any other form with active ingredient and adjuvant. Final product must explain the mechanism of action for intended application and prove therapeutic efficacy for quantity of drug substance indicated. Some general acceptable specifications of drug product is appearance, friability, hardness, color, odor, moisture, strength, disintegration, dissolution, precipitate, cloudiness, pH, phase separation, dissolution and delivery rate. Typical drug products includes tablets, capsules, soft gelating capsules, oral powders, oral solutions and suspensions; small volume parenteral (SVP), large volume parenterals (LVPs), suppositories and metered dose inhalations.
Drug assay: Assay method for drug substance is specific, if possible indicating the stability of material in formulation. Assay can be qualitative or quantitative depending upon the analytical technique employed like microscopy, NMR, and spectrophotometry. Reference standard from a reliable source for comparison of raw material, products, test equipments with working procedures must be established for an assay. Activity assay or any other working procedure like temperature or pressure must establish reliable reference for validated protocol.
Drug assays include secondary drug profiling and mechanism of action, interference to primary drug and interrelation and incompatibility study. Toxicity assay define impurities and limits of usage in application. Biological and microbiological test assays ascertain the purity of material and determine the total activity of the drug in a container. FDA recommends general list of microorganisms for quinolone antibiotics with minimum inoculums level as 0.8 - 1.2 x 106 cells/mL with sampling scheduled every week after initial evaluation. Standards measure Survival levels of bacteria < 0.1% after 2 weeks, vegetative cells < 0.01% after four weeks, yeast and moulds < 10% after two weeks and no increase in number of microorganisms after four weeks. Re challenge 0.1% survival after four weeks.
(The author is MD of VMG Biotech Consultants, New Delhi, a premier biotechnology consultancy and Contract Research Organization)