1. QUALITY CONTROL AND QUALITY ASSURANCE Ridwan Islam

2. Quality Control  The concept of total quality control [or total quality management (TQM)] refers to the process of striving to produce a perfect product by a series of measures requiring an organized effort by the entire company to prevent or eliminate errors at every stage of production.

3. Quality must be built into a drug product during product and process design and it is influenced by the-  physical plant design  space  ventilation  cleanliness and  sanitation during routine production.

4. It considers-  raw material management and control  in-process and product control  specifications and tests for the active ingredients, excipients and the product itself  freedom from microbial contamination  proper storage of the product  containers or packaging materials to ensure that the container closure systems provide functional protection of the product against such factors as-  moisture (e.g. Hydrolysis of aspirin)  oxygen (e.g. vitamin B12)  light (e.g. Na-nitroprusside)  volatility  drug-package interaction

5. Quality Assurance  The assurance of product quality depends on more than just proper sampling and adequate testing of finished products. Quality must be maintained throughout the procedure.   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

6. such as-  ingredient missing  sub-potent or super-potent addition of ingredients  mistakes in packaging or filling  product contamination  mislabeling

7.  Quality assurance personnel must establish control or checkpoints to monitor the quality of the product as it is processed and upon completion of manufacture. These begin with raw materials and component testing and include in-process control (IPC), packaging, labeling and finished product testing as well as stability monitoring.

8. Raw Material Control:  Active or therapeutic material: Current Good Manufacturing Practices (CGMP) suggests that ‘components’ must be-  -received  -sampled  -tested and  -stored in a reasonable way  -rejected materials must be disposed of Appropriate records of these steps must be maintained.

9.  In practice, the manufacturer physically inspects and assigns lot numbers to all raw materials received and quarantines them until they are approved for use. Each raw material is sampled and is sent to the quality control laboratory for testing according to the written procedures.

10.  For example, quality assurance specifications of Acetaminophen (Paracetamol) are given below: Mol. Wt. 151.16

11. Chemical Formulap-hydroxyacetanilide, p-acetoaminophenol, etc Description White, odorless, crystalline powder, possessing a slightly bitter taste Solubility Soluble in boiling water and in sodium hydroxide, freely soluble in alcohol Identity By- A) IR- scan conforms to reference standard B) UV- scan conforms to reference standard C) FeCl 3 -violet-blue color is produced Melting range168-172 ºC pH5.3-6.5 WaterNMT 0.5% (by % LOD, for e.g.) Residue on ignitionNMT 0.1% (by sulfurated ash technique) Heavy metalNMT 0.001% (by Atomic Absorption Spectroscopy) Assay98-101% (as specified in B.P/U.S.P)

12. If acceptable, the raw material is moved to release storage area. It should be properly stickered to indicate the:  item number,  name of the material,  lot number,  date of release  re-assay date and  signature of the quality assurance officer.

13. In general, a typical raw material has a purity requirement of 97%. Its specifications normally include:  solubility  identification  melting range  loss on drying  residue on ignition

14.  Any raw material not meeting specifications must be isolated from the acceptable materials, stickered as a rejection and disposed promptly.  Raw materials should be analyzed by instrumental techniques, such as:  spectrophotometry  thin layer chromatography  high-pressure liquid chromatography, etc.

15.  Inactive or Inert Materials: Physical characteristics, such as  Color  Odor  Particle size, etc and Some chemical specifications, such as  Heavy metal content  Arsenic content  Water content  Presence of microbes  Residue on ignition and  pH, etc are checked.

16. In-process control or In-process Quality Control (IPQC):  It is an important function of the in-process quality assurance program to ensure that finished dosage forms 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.

17.  Quality Control before Start-Up:  To assure that finished products meet high standards of quality and purity, an effective sanitation program is required at all facilities where such products are manufactured.  -Successful extermination program must be enforced within and outside the plant to control insects and rodents.  -personal cleanliness, proper hair covering and clothing are required.

18.  -adequate ventilation is important. The manufacturing department is designed with dust collectors, air filters  (for e.g. HEPA filter-To qualify as HEPA by US government standards, an air filter must remove (from the air that passes through) 99.97% of particles that have a size of 0.3 µm), etc.  -proper temperature and proper humidity are other important factors.  -Manufacturing equipment and utensils should be thoroughly cleansed and maintained according to specific written directions to preclude the carryover of drug residues from previous operation.  -all dust producing operations should be provided with adequate exhaust systems to prevent cross- contamination.

19.  Quality Assurance during Manufacturing Process:  A variable group of tests are widely used for in- process control. Such in-process tests are designed to ensure control of problems that can arise during finished dosage form manufacturing.  Current Good Manufacturing Practices (CGMP) require that in-process quality assurance be adequately documented throughout all stages of manufacturing.

20. For parenteral products, the in-process quality controls are:  checking the bulk solution, before filling, for drug content  pH  color  clarity  checking the filled volume of liquid or filled weight of sterile powder for injection in the final container  testing for leakage in the sealed ampoules  submitting the product for sterility testing or other predetermined biological tests to establish the safety of the product.

21. For Solid Dosage forms, the in-process quality controls are:  Physical appearance checking  Color and odor  Determining drug content of the formulation  Thickness of tablet  Friability of tablet  Hardness of tablet  Weight variation among tablets and capsuls  Disintegration and/or dissolution time of tablet

23. For Liquid Dosage forms, the in-process quality controls are:  Volume check for liquids  Viscosity of liquid and  pH of liquid dosage form. For Semisolid preparations, the following in-process quality controls are available:  checking of homogeneity of drug content prior to filling operations  determining the particle size of the preparation  checking the appearance, viscosity, specific gravity, sediment volume and other specified physical parameters at prescribed intervals  testing for leakage on the containers

24. Packaging Materials Control:  The USP defines the container closure system as the device that holds the drug and is or may be in direct contact with the drug. The immediate container is that which is in direct contact with the drug at all times. The closure is a part of the container.

25. The packaging materials should not interact physically or chemically with the finished product to alter the strength, quality or purity beyond specified requirements. The following features are to be considered in developing container specifications:  Moisture and vapor tightness  Toxicity and chemical/physical characteristics of materials needed in container construction  Physical and chemical changes of container upon prolonged contact with the product  Compatibility between the container and the product

26. Labels Control:  Appropriate labeling carrying the name of the product, quantity of the product, item number, lot number and manufacturing and expiry date, etc must be ensured.

27. Finished Product Control:  Final testing of finished product is made in the quality control laboratories. These tests are designed to determine compliance with specifications. It is, therefore, an important factor for quality assurance.  This testing ensures that each product contains the amount of drug claimed on the label, that the drug is stable in the formulation in its specific final container closure system for its expected shelf life, and that dosage units contain no toxic foreign substances.

29. 5 M’s of Quality  Man  Material  Machinery  Manuals/Methodology ( SOP)  Motivation

30. Control of records:  Two records must be prepared and maintained in accordance with established procedures:  Master Formula Record  Batch Production Record

31. Master Formula Record  Documentation of the component materials and processing steps, together with production operation specifications and equipments to be used, make up master formula record.  Master formula record for each product should be prepared endorsed and dated by responsible individual and should be individually checked, endorsed and dated by another competent and responsible individual.  It has to be done to assure that each batch of a product can be identically reproduced.

32. Master Formula Record  Master formula record shall include the following information: 1) The name of the product, a description of the dosage form and its strength. 2) The complete list of ingredients 3) The quantity by weight or volume of each ingredient. If variations in the quantity of a particular ingredient is permitted, an adequate statement should be provided in the record

33. 4. The standards or specifications of each ingredient used in the product. 5. An appropriate statement concerning any calculated excess of an ingredient. 6. Manufacturing and control instructions, specifications, precautions and special notations to be followed. 7. A detailed description of the closures, containers, packaging and labeling materials.

34. Batch Production Record  Batch production record should be prepared, maintained and controlled for each batch of product.  They should be retained for a period of FIVE years after distribution has been completed.  The batch production record shall contain an accurate reproduction of the manufacturing formula, procedure and product specifications.

35. Batch Production Record  The records include:  Date, specific code or identification number of each ingredient employed  Weights or measures of components and products in the course of processing  Result of in-process control testing  Endorsement of individual performing and supervising each step of operation.

36.  In addition, a lot number is assigned that permits the identification of all procedures performed on the lot and their results. This lot number appears on the label of the product.  This procedure facilitates a search for the details of manufacture and control history of any particular product.

37. Quality Assurance highlights  According to QA, products are designed and developed in a way that takes account of the requirements of GMP and other associated codes such as those of good laboratory practice (GLP) and good clinical practice (GCP)  Product and control operations are clearly specified in a written form and GMP requirements are adopted.  All necessary controls on starting materials, intermediate products, and bulk products and other in- process controls, calibrations, and validations are carried out

38.  The finished products is correctly processed and checked according to the defined procedures  Products are not sold or supplied before the authorized persons have certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control and release of products.  Satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical products are stored by the manufacturer, distributed and subsequently handled so that quality is maintained throughout their shelf life

39.  There is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the quality assurance system.  Evaluation and Analysis of the Deviations,  Stability studies,  Registration of documents,  Complaint handling,  Documentation of the process from staring material to the end user and its storage.

40. Control of Bulk Materials: Specifications:  The main purpose of establishing specifications is to ensure that the characteristics of the finished dosage forms conform to appropriate standards of  Identity  Purity  Potency  Quality

41. Standard of identity  IR Spectra for chlorothiazide dispersed in mineral oil should exhibit maxima only at the same wavelengths as that of reference standard  UV spectra of propranolol.HCl in methanol should exhibit maxima and minima at the same wave length as that of reference standard. The respective absorptive values at the maximum wavelength do not differ by more than 2.5%  A solution of quinidine gluconate in dilute sulfuric acid exhibits vivid blue fluorescence

42. Standard of quality  The specific rotation of propranolol hydrochloride is between -1ºC and + 1ºC.  The refractive index of clofibrate is between 1500 and 1505 at 20ºC  The specific gravity of ethanol is between 0.812 and 0.816 at 15.5ºC

43. Standards of Purity  A solution of Ouabain yields no precipitate with tannic acid or with iodine to indicate the absence of alkaloids  The residue on ignition of propranolol.HCl is not more than 0.1%  After drying quinidine gluconate at 105ºC for 1 hour, it loses not more than 0.5% of its weight.

44. Standard of potency  Chlorthiazide contains not less than 98% and not more than 100.5% of Chlorthizide  Ouabain contains not less than 95% and not more than 100.5% of ouabain  Quinidine gluconate contains not less than 99% and not more than 100.5% of total alkaloidal salt.

45. 10 GOLDEN RULES OF GMP Get the facility design right from the start Rule #1 Validate processes Rule #2 Write good procedures and follow them Rule #3 Identify who does what Rule #4 Keep good records Rule #5

46. Train and develop staff Rule #6 Practice good hygiene Rule #7 Maintain facilities and equipment Rule #8 Build quality into the whole product lifecycle Rule #9 Perform regular audits Rule #10

47. Not following a procedureAbsence of a procedureProcedure out-of-dateNot following a schedule, program or plan COMMON AUDIT FINDINGS..

48. Internal audits schedule lateUntrained personnelNo GMP trainingNo job specific training COMMON AUDIT FINDINGS..

49. Risk of mix-ups and contaminationUnauthorized entry of personnelPoor housekeeping/ cleaning COMMON AUDIT FINDINGS..

50. Poor design of drainsPoor temperature controlDoors and windows left openIncorrect crossing out of data COMMON AUDIT FINDINGS..

51. Not completing records at the time of actionArea not identified with batch number, product and activityItems not labelledPipework not labelled COMMON AUDIT FINDINGS..

52. Damage to facility/ equipmentRedundant and broken equipmentNot using penUse of correction fluid COMMON AUDIT FINDINGS..

53. No organization chartNo job descriptionNo training record COMMON AUDIT FINDINGS..

54.  Items not labelled Unauthorized entry of personnel  monitoring

55. Dust mask smoke mask gogglesgloves moustache & beard cover