1. Quality control of raw materials and in-process control (Cont.)

2.  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.  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. Since the potency value in terms of micrograms per milligram obtained for this material is used in calculating the number of grams or kilograms required for the working formula procedures. 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).

3. Other active materials: - The current editions of the USP and NF contain monographs of most therapeutically active materials used in manufacturing. - Since there is such a wide variance in the nature of the active ingredients used in manufacturing, it is impossible to summarize briefly the testing of those raw materials. - It is common to find an appreciable variation in the degree of purity between samples of the same raw material purchased from different commercial sources. - The selection must then result in the highest purity practical for each raw material, consistent with safety and efficacy of the final dosage form. - 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.

4. - 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. - Chemical purity of a drug means its freedom of foreign matters. Absolute purity is unattainable, as approaching it would be highly expensive. - The origin of chemical impurities may be (the source, method of manufacture, and method of sterilization). - Limits are set for impurity level as one of the steps in ensuring the identity, strength, quality and chemical purity of drug substances. The ultimate goal is to produce a final drug product of high quality at a reasonable cost, that it is safe and efficacious and remains so through its shelf-life.

5. The setting of limits for impurities in bulk drug substances is a complex process that considers a number of factors: (1) The toxicology of a drug substance containing typical levels of impurity relative to a drug substance. (2) The route of administration e.g. oral, topical, or parental. (3) The daily dose i.e. frequency and amount. (4) The target population (age and disease state) e.g. neonates, children or senior. (5) The source of the drug substance e.g. natural or synthetic. (6) The duration of therapy i.e. administration over a long period (chronic disease) versus administration intended for short duration. (7) The capability of the manufacturer to produce high quality material at a reasonable cost to the consumers.

6.  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 certain products, even when highly purified and well characterized raw materials are involved, specifications should include additional critical tests, such as particle size, crystal shape, and crystalline versus amorphous forms. Any of these characteristics could affect the safety of effectiveness of the final dosage form.  It is a CGMP requirement that all raw materials, active or inactive, be assigned a meaningful reassay date that ensures the purity and potency of the raw material at time of use. This confirms the continued stability of each raw material.

7. 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 and tests of total volatile matter, heavy metals, water-insoluble matter, synthesis impurities, arsenic, lead and total color.  If a flavored oral dosage form is desired, flavors or volatile oils may be used. Flavors or volatile oils are usually tested for refractive index, specific gravity, solubility and alcohol content, if any. A GLC chromatogram can be used as a "fingerprint“ for each specific flavor to help in assuring the supplier‘s continuous compliance to specifications.

8.  The most popular sweetening agents used are sucrose, glucose, mannitol, lactose, crystalline and liquid sorbitol and such artificial sweetening agents as saccharin and aspartame.  Testing for unwanted impurities resulting from synthesis side reaction in the manufacturing procedure is essential in the analysis of sweetening agents, for example reducing sugar in mannitol.  Sweetening agents are usually tested for water content, heavy metals, residue on ignition, arsenic and special tests such as melting range, selenium.

9. In-process items control:
 To ensure that products have the intended characteristics of identity, strength, quality and purity, the in-process quality control (IPQC) procedures should be rigidly followed as instructed in the master formula record.
 IPQC is a system to identify the materials, equipments, processes and operations, to enforce the flow of manufacturing and packaging operations according to the established rules and practices. To minimize human error, or to detect the error if and when it does occur, as well as to pinpoint the responsibility to the personnel involved in each unit operation of the entire process.

10. 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.  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.

11. Examples of in-process quality control for some dosage forms:
 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.
Examples of 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.
- Testing the leakage of flame-sealed ampoules.
- 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.

12. The in-process quality control for solid dosage forms are: - 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. - Examining products by line inspection or other equally suitable means and removing the defective units prior to packaging.

13. 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.
Packaging control
Packaging materials and containers are controlled by:
- 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.

14. ● At the end of manufacturing process as well as in-process stages, actual yields are checked against theoretic value, and the representative samples are withdrawn for laboratory testing by the control inspector according to the predetermined sampling plan. ● The operators actively performing the process, their supervisors, and the control inspector must all verify that the entire operation was accomplished in the prescribed manner. ● The batch production records and other needed documents are then delivered to the quality control office, together with the withdrawn samples of the product. ● These records and test results are reviewed for conformance to specifications and CGMP. ●The bulk finished products are held in quarantine until they are released for packaging by quality control personnel.

15. The importance of in-process control:  The final dosage forms are frequently produced in hundreds or thousands or even millions of units. The numbers of units assayed ate the end of the process is not likely to be representative of more than a small fraction of the actual production.  The FDA-CGMP regulations emphasize environmental factors to minimize cross-contamination of products and errors in labeling and packaging, and the integrity of production and quality control records however, they do little to minimize within batch and batch to batch variation in the output of production.  Therefore, it is an important function of the in-process quality assurance program to ensure that finished dosage form have uniform purity and quality within a batch and between batches.  This is accomplished by identifying critical steps in the manufacturing process and controlling them within defined limits.

16.  Prime responsibility of maintaining product quality during production rests with the manufacturing department.  Removal of responsibility from manufacturing for producing a quality product can result in imperfect composition, such as: ● ingredients missing ● subpotent or superpotent addition of ingredients ● mixup of ingredients ● mistakes in packaging or filling, such as product contamination ● mislabeling or deficient package ● lack of conformance to product registration.

17.  Quality assurance should check the original containers of released raw materials for cleanliness before they are taken to the production department.  Most raw materials, however, are weighed in an environmental control weighing area, where they are transferred to a secondary container that circulates only inside the production department.  This secondary container should be properly labeled with a sticker that bears all the information on the original container label.  Only released raw materials with proper reassay dates should be allowed to enter the production department.  Raw materials intended for use in specific products should be stacked and stored together in an approximate staging area with proper identification (name, dosage form, item number, lot number, weight and signatures).

18. ● If the raw material is kept in the store for long period, controlling tests during manufacturing must be carried out for assurance of its purity and validity. ● Raw materials do not pass these controlling tests must be quarantined, identified by special labels, not to be used and be returned to the quarantine store for damage under concerning committee supervision.

19. Raw materials processing
● Only released, properly labeled raw materials are allowed in the in-processing area.
● Depending on the nature of the product, quality assurance personnel should check and verify that the temperature and humidity in the area are within the specified limits required for the product.
● If the temperature and/or humidity is beyond the specified limits, production must be informed and corrective actions taken.
● The specified in-process procedures is to be checked, at each step in the process, according to written in-process quality assurance procedures.

20. ● Quality assurance personnel should verify and document the proper equipment, addition of ingredient, mixing time, drying time, filtering, and mesh size of sieves used in screening.
● At certain points, samples are to be taken to the quality control laboratory for potency assay and any other testing that is necessary to ensure batch uniformity and purity.
● Containers of in-process raw materials are labeled with product name, item number, lot number and gross, tare and net weights of the contents.

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