Is that part of GMP concerned with: Quality Control Is that part of GMP concerned with: sampling, specification & testing, documentation & release procedures which ensure that the necessary & relevant tests are performed & the product is released for use only after assuring it’s quality

Quality control of raw materials In-process control Sources of Quality Variation The diversity of drugs and dosage forms produced the size and complexity of the operation and varying processes and equipments employed differ from company to company

Due to involvement of series of successive operation during manufacture of pharmaceutical products and each of the operations affects the quality of finished products.

The risk of error increases as the number of materials involved in a formulation becomes greater, the process becomes more complex and the operation becomes larger.

To minimize and eliminate these sources of variation which can cause product quality variation approaches such as material control, good manufacturing practice (GMP), in-process quality control (IPQC) and many other techniques, such as packaging control, automation and statistical sampling are employed.

Certain quality control measures should be taken which can be categorized in the following manner: Material control (drug substances, excipients, packaging materials, and printed supplies)

In-process quality control IPQC: In general in-process control procedures are usually rapid and simple tests or inspections that are performed when the manufacturing of a product batch is in progress. They are used to detect variations from tolerance limits of the product so that prompt and corrective action can be taken. The in-process control procedures and tests should be openly discussed, experimentally justified, written in detail, properly explained, and in particular, rigidly enforced once they are established .

Quality control of raw materials In-process control---Continued Drug substance control: Drug substances must meet the specifications previously established for it. The materials used in the manufacture and processing of drugs shall be identified, stored, examined, tested, handled and otherwise controlled. Drugs generally are not absolutely pure, since they may contain substances that are by-products of the synthesis of products.

The in-process checking during manufacturing plays an important role in the auditing of the quality of the product at various stages of production. Duties of the auditor or the control inspector consist of checking, enforcing, and reviewing procedures and suggesting the change for upgrading the procedures when necessary. The primary objective of an IPQC system is to monitor all the features of a product that may affect its quality and to prevent errors during processing.

Drug substance control---continued Appropriate records should be maintained as to their origin, receipt, testing, and disposition and as to the assurance of their conformance to the appropriate standards of identity, purity, quality, strength, potency, and freedom of contaminants at time of use. The quality control inspector performs appropriate visual examination of the incoming materials and then follows a prescribed sampling procedure to provide test material for laboratory evaluation.

Drug substance control---continued The testing results submitted by the suppliers are compared and reviewed with those acquired by the quality control department of the drug manufacture. Control of raw materials whether active or inactive and of packaging and printed materials actually begins before purchase and is maintained by careful handling procedures throughout the manufacture of the packaged dosage form.

Excipients control: Excipients are components of the finished dosage form other than the therapeutic ingredient. Although they are inert, they may influence the quality of a product owing to interaction with the drug substance affecting the physical properties of the dosage form or influencing the production process. To prevent such effects:

Excipients control continued------- Excipients should be examined carefully and critically for compliance with established standards. They must be supplied in clean and properly sealed containers. They should be inspected prior to laboratory testing. Labeling should be correct. The material should be packaged in the correct container. No obvious damage of the container in transit.

Quality control is of crucial importance to the pharmaceutical industry, and for this reason numerous checks are made at every stage of production to ensure that quality is not compromised and that the code of good manufacturing process is adhered. Quality control is not only a laboratory procedure, but also the procedures through which a raw material is transformed to a drug and the finished product till it is used by the patient. One of the important function of quality control department is to establish specifications for raw materials, packing materials, intermediates and finished products to ensure the quality.

Quality control procedures Sampling of raw materials: All incoming raw materials are initially quarantined and samples are taken and tested to ensure that the material meets strict purity guidelines. Testing of raw materials includes both microbiological and chemical testing, as is laid out in the relevant pharmacopeia (a reference book on the preparation of pharmaceuticals three are published British, United States and European).

Quality control procedures continue--- In-process checks The manufacturing staff carry out checks on such things as tablet weight and size at frequent intervals. At hourly intervals the quality control staff takes samples to check for contamination and to ensure that composition is as expected.

Quality control procedures continue--- Final product checking Checking similar parameters to those measured during production. Monitoring cleaning When a batch of a certain drugs has been made, all equipment that has been used must be cleaned. When the next pharmaceutical to be made on that line is going to be different, this cleaning must be particularly through to prevent contamination. In this instance, after cleaning the QC staff takes swabs off each piece of equipment and test them to see if they can detect the presence of the active previously used.

Quality control procedures continue--- The results of all these tests are recorded on the batch records for the pharmaceutical, as well as the name and batch number of the pharmaceutical made immediately prior on the same production line. Raw material standardization is the only way for all the drug manufactures to produce the drugs in same quality and to maintain the uniformity.

Quality control procedures continue--- Raw materials: Medicinal Minerals Herbs and animals etc. Microbes, pathological products, healthy tissues, drugs 2. Non medicinal (Vehicles) Alcohol, lactose, sugar, white petroleum jelly, maize starch, coconut oil,wax

Quality control can be defined as: Day-to-day control of the quality of---- Raw materials (active or inactive) Containers & packaging materials Semi finished & finished drug products Also carry out IPC tests during manufacture & assessment of results & making necessary measures. Adequate and proper documentation (GDP)

Quality assurance can be defined as: Responsibility of an organization to determine that: Systems & facilities and standard operation procedures (SOPs) of production & analysis are adequate and strictly followed to assure that the drug product will meet the quality specifications.

The ultimate goals of QC/QA programs are to assure that: The drug product contains the labeled amount (s) of the active ingredient (s), within the accepted tolerance limits. The ingredients (active or inactive) were of the acceptable Pharmaceutical Purity according to quality specifications as cited by drug compendia. The variation of drug levels between dosage units is minimized. The finished dosage forms should be of the highest possible purity i.e. no contamination.

The ingredients in the finished dosage form are stable within specified time (shelf-time). The finished dosage form is therapeutically efficacious i.e. bioavailability studies or bioequivalency studies have been carried out properly in the research and development (R&D) phase. The manufacturer physically inspects and assigns lot numbers to all raw materials received and quarantines them untill they are approved for use.

Each raw material is sampled according to standard sampling procedures and is sent to the quality control laboratory for testing according to the written procedures. If acceptable, it is moved to the release storage area, after being properly stickered to indicate the item number, name of material, lot number, date of release, reassay date and signature of the quality assurance inspector.

Approved materials should be rotated so that the oldest stock is used first. Any raw material not meeting specifications must be isolated from the acceptable materials, stickered as a rejection, and returned to the supplier or disposed of promptly.

Quality control of raw materials, and in-process control (Cont.) In general, raw materials may be classified into two groups (1) active or therapeutic and (2) inactive or inert Active or therapeutic materials for example antibiotics: Testing of antibiotics is usually performed either chemically, microbiologically, biologically, or by all three methods. Caution must be exercised in testing antibiotic raw material to assure that it is not altered during the sampling procedure.

Quality control of raw materials, and in-process control (Cont.) The sample must be taken in a relatively dry atmosphere, relatively free from dust, and free of both chemical and microbial airborne contamination, and exposure must be reduced to minimal time of sampling. Special attention should be given to assay for potency of antibiotic raw materials. It is recommended that at least two separate weighing of such antibiotic raw material powder be assayed on each of three different days (six different assays using six different weighing).

Quality control of raw materials, and in-process control (Cont.) Other active materials: USP and NF contain monographs of most therapeutically active materials used in manufacturing. In general, a typical raw material currently found in a compendium has a purity requirement of at least 97%. Drug compendia state limits for the presence of impurities which would be safe, compatible with excipients and also compatible with assay method.

Quality control of raw materials, and in-process control (Cont.) The selection must then result in the highest purity practical for each raw material, consistent with safety and efficacy of the final dosage form. Raw materials specifications normally include solubility, identification, - melting range, loss on drying, residue on ignition, special metal testing, specific impurities that are pertinent to the method of synthesis of each individual raw material and assay. The methods of assay are usually chemical in nature.

Quality control of raw materials, and in-process control (Cont.) The setting of limits for impurities in bulk drug substances is a complex process that considers a number of factors: The toxicology of a drug substance containing typical levels of impurity relative to a drug substance. The route of administration e.g. oral, topical, or parental. The daily dose i.e. frequency and amount.

Quality control of raw materials, and in-process control (Cont.) The target population (age and disease state) e.g. neonates, children or senior. The source of the drug substance e.g. natural or synthetic. The capability of the manufacturer to produce high quality material at a reasonable cost to the consumers.

Quality control of raw materials, and in-process control (Cont.) Other evaluation techniques: Raw materials cannot be adequately evaluated and controlled without special instrumentation such as electrochemical methods (potentiometry), chromatography methods (thin layer TLC, gas GC, and high pressure liquid chromatography HPLC), and miscellaneous methods (mass spectrometry, x-ray diffraction, spectrophotofluorimetry, colorimetry).

For highly purified and well characterized raw materials: Particle Size Crystal Shape Crystalline vs Amorphous forms

Inactive or inert materials: They usually make up the major portion of the final dosage form. Therefore, their physical characteristics, such as colour, odour, and foreign matter are as important as their chemical purity. Among other important specifications of inactive or inert materials are particle size, heavy metal content, arsenic, water content, microbial limit, foreign matter, residue on ignition and PH.

The FDA determines and approves colorants for use in food and drugs with recommendation of limits, if any. A typical analysis of a color contains identity tests tests of total volatile matter, heavy metals, water-insoluble matter, synthesis impurities, arsenic, lead and total color.

Sweetening agents are usually tested for water content, heavy metals, residue on ignition, arsenic and special tests such as melting range, selenium.

In-process quality control for some dosage forms Parenteral products: Checking the bulk solution before filling for drug content, pH, colour and clarity for solution. Checking the filled volume of liquids or the filled weight of sterile powder. Physical examination of the product (appearance, clarity and particulate contamination). Examining sterility and other biological tests to establish the safety and other parameters of the product.

solid dosage forms (Tablets, Capsules): Determining the drug content of the formulation. Checking the weight variation for tablets and capsules in predetermined intervals during manufacturing. Checking the disintegration and/or dissolution time, hardness and friability of the tablets at least during the beginning, middle and end of production or at prescribed intervals during manufacturing. Testing soluble tablets for compliance with solution time requirements.

Packaging control: Specifications for packaging and packaging operations. Checking for cleanliness of containers. Checking labels for printings, lot and control numbers. Testing for leakage of the final product.

For semisolid preparations: Checking for uniformity and homogeneity of drug content, prior to filling operation. Determining the particle size of the preparation. Appearance, specific gravity and viscosity. Testing the filling weight during the filling operation. Testing for leakage on the finished jars or tubes.