Quality control laboratory.

quality control of pharmaceutical products

1. A SEMINAR ON QUALITY CONTROL LABORATORY PREPARED BY: HELI N KARNAVAT GUIDED BY: M.PHARM SEM-1 Ms.KRUPA THULA ROLL NO:3 Assistant Professor PMRA M.Pharm LJ INSTITUTE OF PHARMACY AHMEDABAD 1

2. CONTENTS INTRODUCTION RESPONSIBILITIES OF PERSONNELS ROUTINE CONTROL INSTRUMENTS REAGENTS SAMPLING PLANS STANDARD TEST PROCEDURES PROTOCOL DATA GENERATION AND STORAGE QUALITY CONTROL DOCUMENTS R ETENTION SAMPLE RECORDS AUDITS OF QUALITY CONTROL FACILITIES 2

3. HISTORY OF QC LAB: GLP is a formal regulation that was created by the FDA (United states food and drug administration) in 1978. Although GLP originated in the United States , it had a world wide impact. Non-US companies that wanted to do business with the United states or register their pharmacies in the United States had to comply with the United States GLP regulations. They eventually started making GLP regulations in their home countries. In 1981 an organization named OECD (organization for economic co-operation and development ) produced GLP principles that are international standard. 3

4. Quality Control Area.-(as per schedule M) Quality Control Laboratories shall be independent of the production areas. Separate areas shall be provided each for physico-chemical, biological, microbiological or radio-isotope analysis. Separate instrument room with adequate area shall be provided for sensitive and sophisticated instruments employed for analysis. Quality Control Laboratories shall be designed appropriately for the operations to be carried out in them. Adequate space shall be provided to avoid mix-ups and cross-contamination. Sufficient and suitable storage space shall be provided for test samples, retained samples, reference standards, reagents and records. 4

5. Continued… The design of the laboratory shall take into account the suitability of construction materials and ventilation. Separate air handling units and other requirements shall be provided for biological, microbiological and radioisotopes testing areas. The laboratory shall be provided with regular supply of water of appropriate quality for cleaning and testing purpose. Quality Control Laboratory shall be divided into separate sections i.e. for chemical, microbiological and wherever required, biological testing. These shall have adequate area for basis installation and for ancillary purposes. The microbiology section shall have arrangements such as airlocks and laminar air flow work station, wherever considered necessary. 5

6. INTRODUCTION QUALITY CONTROL: Quality control deals with the system which accepts or rejects any activities or parameters which affects the quality of product and thus prevent quality deficiency. Q.C. is not confined to only laboratory operation but must be involved in all decisions, concerning with the quality of the product” 6

7. AS PER WHO DEFINITION: Q.C . is the part of GMP concerned with sampling, specification, and testing and with the organization, documentation and release procedure which ensure that the necessary and relevant tests are actually carried out and those materials are not released for use, nor product released for sale or supply, until their quality has bee satisfactory. 7

8. WHO guidelines for Q.C laboratory: S hould be separated from production areas . Areas where biological, microbiological or radioisotope test methods are employed should be separated from each other . Control laboratory should be designed to suite the operations to be carried out in them. There should be adequate suitable storage space for samples, reference standards and records. 8

9. QUALITY CONTROL LABORATORY ABOVE SHOWN IS THE OVERVIEW OF A QUALITY CONTROL LABORATORY OF A REPUTED PHARMACEUTICAL COMPANY. 9 Figure:1.1- Quality Control Laboratory

10. RESPONSIBILITIES OF PERSONNELS 10

11. LABORATORY DIRECTOR Responsible for overall operation and administration of the laboratory, including employment of competent qualified personnels. To ensure that laboratory develops and uses a quality system approach to laboratory testing that provides accurate and reliable patient test results. Ongoing monitoring of each testing process used in laboratory to identify potential problems that could result in errors. 11

12. Continued… Take corrective action. Evaluate the corrective actions taken, to make sure that they were effective and will not occur again. To ensure that testing systems in laboratory provides quality services in all aspects of test performance. 12

13. Lab technicians To operate laboratory equipment and computers and performs other assigned work, in accordance to documented laboratory procedures. To perform chemical analysis. Responsible for operation of GC, Spectrophotometers, balances, computers, etc. Responsible to be cross trained to perform special laboratory functions. C arry out sampling, testing, measuring, recording and analysing  .  provide all the required technical support to enable the laboratory to function effectively whilst adhering to correct procedures and health and safety guidelines . 13

14. Continued… performing laboratory tests in order to produce reliable and precise data to support scientific investigations; carrying out routine tasks accurately and following strict methodologies to carry out analyses; preparing specimens and samples; constructing, maintaining and operating standard laboratory equipment, for example centrifuges, titrators, pipetting machines and pH meters; 14

15. Continued… ensuring the laboratory is well-stocked and resourced; recording and sometimes interpreting results to present to senior colleagues keeping up to date with technical developments, especially those which can save time and improve reliability. following and ensuring strict safety procedures and safety checks. 15

16. ROUTINE CONTROL INSTRUMENTS 16

17. Normally practiced routine control includes: The lab and instruments should be cleaned daily. All the instruments should be validated and checked and the results should be recorded. The samples arrived in the lab should be noted in incoming register. Humidity and temperature of the lab should be recorded daily. Log books should be filled correctly for every instrument used. The results of the tests should be recorded appropriately. Any fault in the instruments should be immediately reported to the Q.C manager. 17

18. INSTRUMENT RELATED TERMS VERIFICATION: a quality control process used to evaluate whether a product, service or system complies with the regulations, specifications or conditions implied by the standard. VALIDATION: is a quality assurance process of establishing evidence that provides high degree of assurance that the product meets its intended standards. 18

19. Continued… CALIBRATION: the set of operations that establishes the relationship between values indicated by an instrument or system and the corresponding known values of reference standard. EQUIPMENT QUALIFICATION: the action of proving that any equipment works properly and actually gives accurate and reliable results. 19

20. Reagents Reagent quality control records must be retained for 5 years. Reagents shall be used and controlled according to manufacturer’s recommendations. All reagents and chemicals, including solvents and materials used in tests and assays, should be of appropriate quality .   Reagent should be purchased from reputable, approved suppliers and should be accompanied by the certificate of analysis, and the material safety data sheet. 20

21. Preparation of reagents in laboratory responsibility for this task should be clearly specified in the job description of the person assigned to carry it out prescribed procedures should be used which are in accordance with published pharmacopoeial or other standards where available. Records should be kept of the preparation and standardization of volumetric solutions. 21

22. The labels of all reagents should clearly specify: Name; content; manufacturer; date received and date of opening of container; concentration; storage condition; expiry date or retest date 22

23. 23 FIGURE 1.2 REAGENT LABELS

24. The labels for volumetric solutions prepared in the laboratory should clearly specify: N ame ; M olarity(concentration ); D ate of preparation and initials of technician/analyst; D ate of standardization and initials of technician/analyst; S tandardization factor. 24

25. T ransportation and subdivision of reagents: W henever possible they should be transported in the original containers; W hen subdivision is necessary, clean containers should be used and appropriately labelled . All reagent containers should be visually inspected to ensure that the seals are intact, both when they are delivered to the store and when they are distributed to the units. 25

26. Continued...   Reagents that appear to have been tampered with should be rejected; however, this requirement may exceptionally be waived if the identity and purity of the reagent concerned can be confirmed by testing. Water should be considered as a reagent. The appropriate grade for a specific test should be used as described in the pharmacopoeias or in an approved test when available. Precautions should be taken to avoid contamination during its supply, storage and distribution. The quality of the water should be verified regularly to ensure that the various grades of water meet the appropriate specifications . 26

27. Continued… Stocks of reagents should be maintained in a store under the appropriate storage conditions (ambient temperature, under refrigeration or frozen). The store should contain a supply of clean bottles, vials, spoons, funnels and labels, as required, for dispensing reagents from larger to smaller containers. Special equipment may be needed for the transfer of larger volumes of corrosive liquids. The person in charge of the store is responsible for looking after the storage facilities and their inventory and for noting the expiry date of chemicals and reagents. Training may be needed in handling chemicals safely and with the necessary care. 27

28. Sampling plan: Sampling is an activity which is of crucial significance to the quality control in Pharmaceutical and Healthcare industry where necessary to take the samples. Sampling at the end of a manufacturing process provides a check on the adequacy of the quality control procedures of the manufacturing department . Sampling plan is detailed outline of which measurement will be taken at what times,on which material,in what manner,and by whom . In quality control activity “sampling” is one of the major activity   28

29. Continued… In QC laboratory ; Procedure available for receiving, storage and handling of samples for analysis. Sample receiving procedure should be documented and keep it. Each sample having distinct identification number and information for its storage with handling and labeling. Storage condition facilities in laboratory like refrigerator and absence of light. Detailed description of sub sampling of samples for analysis. Reserve samples should be retained for additional testing if quantity is adequate. 29

30. Continued… Sampling may be required for different purposes for example; Acceptance of batches Clearance of batches In process controls Stability studies Complaints The control that applied to the samples may be; Checking the identity of materials Performing complete Pharmacopoeia or testing Performing the special test 30

31. Sampling kit The QC person may require the tools and equipment for collecting the samples (Sampling kit). The tools are knives, pliers, saws, hammers, wrenches etc. to open packages, barrels and containers. Not used the complicated tools for sampling of samples. Pipette with suction bulb use for liquid of low viscosity. Glass rod can be used for highly viscous liquid Spatulas and scoops used for granules. When it is necessary to take sample of materials at three different strata (Top, Middle, Bottom) sampling stick used. 31

32. Continued… All tools and implements should be kept scrupulously clean before use, washed it thoroughly with water or suitable solvents and then dried. It will be better if more than one set of sampling kits are available in clean and dry condition. 32

33. Types of sampling: Single sampling. Double sampling. Continuous Sampling. Sequential Sampling 33

34. Single sampling: A single sampling plan is defined by sample size, n, and the acceptance number c. Say there are N total items in a lot. Choose n of the items at random. If at least c of the items are unacceptable, reject the lot. N=LOT NUMBER For a single sampling plan, one sample of items is selected at random from a lot and the disposition of the lot is determined from the resulting information. These plans are also denoted as (n,c) plans since there are n observations and the lot is rejected if there are more than c defectives. Single sample plans are the most common and easiest plans to use. However, they are not the most efficient in terms of the average number of samples needed. 34

35. 35 Inspect n pieces in a sample If the number defective found in sample Accept the lot Equals or exceeds r Does not exceed c Do not accept lot n= sample size, c= allowable no. of defect in the sample, r= rejection no. F ig:1.3 SINGLE SAMPLING CHART.

36. DOULE SAMPLING Double and multiple sampling plans were invented to give a questionable lot another chance. For example, if in double sampling the results of the first sample are not conclusive with regard to accepting or rejecting, a second sample is taken. Application of double sampling requires that a first sample of size n1 is taken at random from the (large) lot. The number of defectives is then counted and compared to the first sample's acceptance number a1 and rejection number r1. Denote the number of defectives in sample 1 by d1 and in sample 2 by d2, then: If d1≤a1, the lot is accepted. If d1≥r1, the lot is rejected. If a1<d1<r1, a second sample is taken. 36

37. Continued… If a second sample of size n2 is taken, the number of defectives, d2, is counted. The total number of defectives is D2=d1+d2. Now this is compared to the acceptance number a2 and the rejection number r2 of sample 2. In double sampling, r2=a2+1 to ensure a decision on the sample. If D2≤a2, the lot is accepted. If D2≥r2, the lot is rejected. 37

38. 38 Inspect first sample,n1 pieces Does not exceed , c1 Do not accept lot Equals or exceed r2 Does not exceed c2 Accept lot Inspect asecond sample , n2 pieces Equals or exceeds , r1 If the no. of defectives in the first sample Exceeds c1 but does not exceed r1 If the no. of defectives in combined sample Fig:1.4 DOUBLE SMAPLIN CHART

39. CONTINUOUS SAMPLING C ontinuous sampling is used where product flow is continuous and not easily grouped in lots. Two parameters exist for continuous sampling. One is the frequency (f) and the second is the clearing number (i ). 39

40. Continued… Carrying out a continuous sampling plan is simple and can be carried out in 3 steps. 1. Inspect all i data. 2. If no defects are found, randomly sample fraction f of data and check again for defects. 3. Whenever a defect is found, correct the flaw and repeat step 1. 40

41. SEQUENTIAL SAMPLING Sequential sampling is different from single, double or multiple sampling. Here one takes a sequence of samples from a lot. How many total samples looked at is a function of the results of the sampling process. The sequence can be one sample at a time, and then the sampling process is usually called item-by-item sequential sampling. One can also select sample sizes greater than one, in which case the process is referred to as group sequential sampling. 41

42. STANDARD TEST PROCEDURE An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material but of a more general nature (e.g. equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master batch production documentation. Sampling: - There shall be written Standard Operating Procedures for sampling which include the person(s) authorized to take the samples. 42

43. Continued… The sampling instruction shall include: (a) The method of sampling and the sampling plan, (b) The equipment to be used, (c) any precautions to be observed to avoid contamination of the material or any deterioration in its quality, (d) The quantity of samples to be taken, (e) instructions for any required sub-division or poling of the samples, (f) The types of sample containers to be used, (g) any specific precautions to be observed, especially in regard to sampling of sterile and hazardous materials. Testing: There shall be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed shall be recorded. 43

44. 44 Physical Analysis : Description : Diameter :Measure the diameter of approximately 6 tablet using Vernier calipers. Thickness : Measure the diameter of approximately 6 tablet using Vernier calipers. Hardness :Check the hardness of approximately 6 tablet using hardness tester . Friability :Note the accurate weight of 20 tablet. Keep it into drum of friability apparatus and allow to rotate for 100 revolution at 25 RPM. Disintegration :Place one tablet in each tube of basket rack assembly of disintegration apparatus and observe the time period for complete disintegration.

45. Identification : Identification Test by HPLC. The retention time of the major peak in the chromatogram of sample preparation should correspond to that of in the chromatogram of working std preparation in the assay. Assay: Mobile Phase: Take 45volume of water in 55 volume of Acetonitrile and add 0.1 volume of triethylamine. Adjust pH 3.5 using phosphoric acid and filter it. Standard Preparation : Dilute 69.3mg amlodipine besilate (50mg amlodipine)+ 54.39 mg Lisinopril (equal to Lisinopril Anhydrous ) working standard in mobile phase to obtain 50ml Further dilute 5 ml in 25 ml in mobile phase to get final concentration amlodipine 200 ppm / ml and Lisinopril Anhydrous 200 ppm/ml 45

46. Test Preparation : Accurately weight of fine tablet powder equvalent to 10 mg Amlodipine +10 mg Lisinopril Anhydrous and dissolve in 50 ml to mobile phase to get final concentration amlodipine 200 ppm / ml and Lisinopril Anhydrous 200 ppm/ml. Column: C18 Flow rate: 1.0 ml / min. Wavelength : 215 nm Run Time : 15 min. Procedure: Inject 20  l of standard preparation and test preparation separately. And calculate the %assay for each tablet individually . Calculation: % Assay = Area of Sample X Std. Dilution X Potency Area of Std Sample Dilution 100 Limit : 90 % to 110 % 46

47. PROTOCOL 47

48. DEFINITION   Protocol is a system of rule about the correct way to act in formal situation . Each study shall have an approved written protocol that clearly indicates the objective and all methods for the conduct of study. 48

49. WHAT SHOULD A PROTOCOL CONTAIN??? Every protocol needs to focus specifically on one type of experiment to be performed. Title and statement of the purpose of the study Identification of the test and control articles by names, chemical number or code number. The name of the sponsor and the name and address of the testing facility at which the study is being conducted. The procedure for identification of the system 49

50. Continued… Type and frequency of test, analysis and measurements to be made. Records to be maintained. The date of approval of the protocol by the sponsor and the dated signature of the study director. 50

51. Continued… Each study shall have an approved written protocol that clearly indicates the objectives and all methods for the conduct of the study. The protocol shall contain, as applicable, the following information: The requirement to indicate “all methods for the conduct of the study” does not mean that all laboratory SOPs must be reiterated in the protocol; it is sufficient if the protocol indicates “what” will be done and “when” it will be done. Laboratory SOPs describe “how” each study activity is to be performed. 51

52. Continued… The description shall include specifications for acceptable levels of contaminants that are reasonably expected to be present in the materials and are known to be capable of interfering with the purpose or conduct of the study if present at levels greater than established by the specifications. Each dosage level, expressed in milligram per kilogram of body weight or other appropriate units, of the test or control article to be administered and the method and frequency of administration. The type and frequency of tests, analyses, and measurements to be made. 52

53. DATA GENERATION AND STORAGE RECORDS 53

54. Continued… Storage facility for records should reflect the need to preserve confidentially, integrity and logical retrieval. Thought should be given to the susceptibility of the records to damage from fire (heat), flood (humidity), electric or magnetic fields, dust, solvents etc. It is the responsibility of laboratory staff to ensure all relevant documentation is kept for the specified timeframes and to archive large quantities of documentation that is to be kept long term but not necessarily looked at on a regular basis. 54

55. PURPOSE The purpose of this procedure is to describe the requirements for the retention of laboratory documentation under GMP and the disposal of such documentation. 55

56. RETENTION SAMPLES 56

57. DEFINITION A sample from every batch of product made and the chemicals and components that make up a finished good are kept for a set period of time for use as reference material should be a problem with a specific product or batch. 57

58. CONDITIONS TO BE MET The sample shall consist of at least twice the quantity necessary for all tests required to determine its compliance with specification . The sample shall be stored in controlled room temperature expect where the product labeling or specification states otherwise . The sample shall be stored in the same primary container enclosure system in which the product is marked or shipped, or in one that has essentially the same characteristic . The sample shall be securely stored in accordance with their labels requirements and segregated from other material . The conditions in the store area must be supervised and recorded . 58

59. DOCUMENTATION 59

60. Continued… Documentation is an essential part of the quality management System. The laboratory should establish and maintain procedures to control and review all documents (both internally generated and from external sources) that form part of the quality documentation. 60

61. THE PROCEDURES SHOULD ENSURE Each document, whether a technical or a quality document, has a unique identifier, version number and date of implementation; Appropriate , authorized SOPs are available at the relevant locations, e.g. near instruments; Documents are kept up to date and reviewed as required; Any invalid document is removed and replaced with the authorized, revised document with immediate effect. 61

62. Continued… A revised document includes references to the previous documents. Old, invalid documents are retained in the archives to ensure traceability of the evolution of the procedures; any copies are destroyed. All relevant staff are trained for the new and revised SOPs Quality documentation, including records, is retained for a minimum of five years. 62

63. RECORDS 63

64. DEFINITION Any production, control, or distribution record that is required to be maintained in compliance with this part and is specifically associated with a batch of a drug product shall be retained for at least 1 year after the expiration date of the batch . Quality management records should include reports from internal (and external if performed) audits and management reviews, as well as records of all complaints and their investigations, including records of possible corrective and preventive actions 64

65. CLOSURE AND LABELLING RECORDS The identity and quantity of each shipment of each lot of components, Drug product containers, closures, and labeling; The name of the supplier ; The supplier’s lot number(s) if known; The receiving code and the date of receipt. The name and location of the prime manufacturer, if different from the supplier, shall be listed if known. 65

66. MASTER PRODUCTION AND CONTROL RECORDS The master manufacturing records should clearly identify : Name of product, Product type, Strength Ingredients to be added, Name , alphanumeric code , A mounts or dosage unit or percentage Amount of each ingredient for a batch Sequence of adding ingredients 66

67. Continued… Equipment to be utilized designated by name and, where appropriate, by number processing steps with details of conditions such as time, temperature, speed Special precautions and hazardous conditions which exist and the necessary safety equipment to be used Theoretical yields and actual yields (action levels) Space for signature and date of operator/supervisor performing or checking each significant step. 67

68. THANK YOU 68