QUALITY

1. QUALITY • "THE TOTALITY OF FEATURES AND CHARACTERISTICS OF A PRODUCT OR SERVICE THAT BEAR UPON ITS ABILITY TO SATISFY STATED OR IMPLIED NEEDS" Or • "QUALITY IS THE SUM OF ALL THE FACTORS THAT ENABLE OWNERSHIP SATISFACTION AND BRING CUSTOMERS BACK TO BUY A PRODUCT OR SERVICE AGAIN AND AGAIN"

2. HISTORY • Till late sixties, quality of pharmaceuticals or chemicals was considered to be responsibility of the head of the testing laboratory who was called chief analyst. A report of the sample, whether or not it complied with statutory standards was all that was considered necessary for evaluating quality. Knowledge of how the product was made or how well the product would keep on storage , i. e. stability of the product was not considered to be anyone’s responsibility. With the introduction of antibiotics, which are unstable under varying climatic conditions, knowledge of the stability of products and providing shelf life under different storage conditions was called for.

3. HISTORY • Thalidomide babies tragedy (thalidomide given to pregnant ladies for morning sickness; children born with deformed limbs)led to implementation of CGMP, official first in 1963 in USA. • Safety & efficacy underlying CGMP regulation was a reaction to ‘ elixir of death ‘ episode.( sulphanilamide elixir with ethylene glycol base) • J.J.Hospital tragedy in1986( glycerine containing ethylene glycol)led to statutory enforcement of GMP in the form of an amendment to Sch M .

4. Quality in Medicines • Chemicals and pharmaceuticals are unique because, • a) their quality cannot be judged by the consumer, • b) their quality cannot be guaranteed by testing of the final product because tests are done only on a small sample of a batch. • c) there are risks in chemical & pharmaceutical production such as cross contamination, mix-ups, wrong labeling etc. These may not be detected by routine testing and corrected in time. • d) quality requirements are stringent since they have to take into account efficacy, safety and stability of the product.

5. Quality in Medicines • Assurance means that product design (at R&D stage) must be appropriate for the product’s intended use. • Even before manufacture, the safety & efficacy of the product must be unambiguously established. • The stability, both physical & pharmaceutical, must be clearly shown.. • The quality of input materials & of finished product must be specified • The proposed manufacturing process must be validated to show that it will yield the product of the quality specified for it. • GMP, GLP & GCP requirements are taken into account & followed. • Adequate quality control measures are taken to ensure that input materials are not released for use, & end products are not released for sale until their quality has been controlled, evaluated & judged to be satisfactory as per established procedures. • Assurance goes further to maintain records of the final distribution outlets, on-going stability testing of retention samples of every product & systematic evaluation of complaints.

6. Quality System • Includes- • Batch Release • Product Quality Reviews • Complaint reviews • Discrepancy/ failure investigations • Change Control • CAPA (Corrective And Preventive Action) Reprocess/ Rework • Validation/ Revalidation • Rejects • Stability Failures/ Out of trend data • Quarantine products • Documented GMP & Job Related Training • Reprocessed, reworked, returned, salvaged product

7. QUALITY ASSURANCE • Addressed in section14 of Sch.M(14.1 subsection containing a to e points. • Taking care of the matters that influence individually or collectively the quality of a product in the form of resources, organizational structure, procedures, processes & control measures is assuring the quality of the product. Basically, the determination of quality requirements for a product & the mfg. of the product conforming to these requirements together constitute quality assurance.

8. QUALITY CONTROL • Quality control is a part of GMP & is concerned with sampling, specifications ,Inspection & testing & with procedures that ensure that input materials are not released for use, & end products are not released for sale until their quality has been evaluated & judged to be satisfactory. • Quality control function should be independent of production & should be responsible only to top management.

9. Laboratory Control System • Includes measures and activities related to laboratory procedures, testing, analytical methods development, validation / verification, stability program • Adequate laboratory facilities • Adequately staffed laboratories (supervisory and bench personnel) • Qualified and trained • Reference Standards (primary; secondary) • Microbiological cultures • Instrumentation as per testing requirements • Adequate Microbiology facility to support the site requirements • Qualified Microbiologist • Retention Sample Handling and Controls • Stability Management Program

10. Laboratory Control System • Written Documents- • Approved specifications • Approved procedures for sampling, testing, approval / rejection • Trending – OOT • Laboratory controls followed and documented • Out of Specifications (OOS) • Approved procedure (SOP) covering OOS • Investigation of “OOS” results in a timely manner as per SOP and documented. CAPA identified and implemented. • “OOS” review included in Product Quality Reviews

11. Laboratory Control System • Validation / Qualification • Method validation/ revalidation • Equipment Qualification / Maintenance - AMC • Calibration: written procedures, schedule, documentation - OOC • Validation and Security for computerized handling of test results and related data • Excel sheet usage and validation

12. QUALITY CONTROL • QUALITY CONTROL AREA • Addressed in section 5 of Sch M( From 5.1 to 5.4 points) • Requirements of personnel in QC are listed in section 6.

13. QUALITY CONTROL LABORATORY • General Requirements • Ensure that the control laboratories are designed, equipped & maintained to suit all the activities to be carried out in them.(e.g. analytical , instrumental, packaging material testing, microbiological, sterility testing, pyrogen testing etc.) • Thought should be given to locating the laboratory suitably to avoid unnecessary ‘to’ing & ‘fro’ing between lab & production area.QC personnel shall have access to production areas for sampling & investigation.(16.9) • Lay out should be such that 1) there is no accumulation of dust & dirt & efficient & easy cleaning of both premises & equipments is possible. • Laboratory should be well lit with lighting arrangements suited to the operations conducted in the specific area. The maximum use of natural lighting should be possible but direct sunlight should be avoided.

14. QUALITY CONTROL LABORATORY • Operations involving the use of significant quantities of flammable liquids should have flame –proof electrical fittings and other in-built safety features including emergency crash panels or doors. • Exhausts provided in fume cupboard should be powerful enough to remove hazardous & poisonous gases resulting from chemical operations. Asbestos gloves, pair of tongs with long arms, safety goggles should be available near muffle furnace & fume cupboard. Fume cupboards should be fitted with ceramic bases & drainage within the hood. • The entire laboratory should be air-conditioned; determinations done at temperatures above 30deg. will not give accurate results. Volumetric glassware is calibrated at about 25deg. • The fittings & service pipes in the laboratory should be such that they can withstand corrosion from gases& chemicals used in analytical work & from the laboratory effluents. They should be appropriately colour coded.

15. QUALITY CONTROL LABORATORY • Central wash areas, piped hot water, distilled water facilities should be provided. Granite top with epoxy resin finish is recommended for carrying out analysis. • At least 10% of the total laboratory area should be set aside for storage of chemicals, glassware, solvents & gas cylinders. There should be secure storage for poisonous chemicals.(16.3) • Reserve samples of products should be stored in a special room away from fumes, chemicals & strong light. It must provide conditions of temp. & humidity consistent with the storage conditions mentioned on the labels of the products.(16.17) • Pharmacopoeias, ref. std., working std., ref. spectra, other ref. material & technical books should be available.(16.14)

16. QUALITY CONTROL Following are the imitations of mere testing • If a reject is discovered it is expensive: as all of the value has already been added! • Inspection following production is the most inconvenient time to identify a reject. • Stability studies showed that compliance of the product with its specifications at the time of manufacture was no guarantee of its stability in the market place. • Faulty equipment or lapses in manufacturing operations could result in non- homogeneity and variations in the batch may not be detected in samples taken from the batch.. • Testing has its presumptive nature . i. e. tests are done for only those ingredients or impurities or decomposition products which are likely to be present in it. Therefore QC should be backed by support system of QA to ensure customer protection & satisfaction.

17. QUALITY CONTROL SYSTEM • Quality control system is addressed in section 16 of Schedule M ((16.1 to 16.14)

18. QUALITY CONTROL SYSTEM Principal Duties • To prepare detailed sops, STPs, & instructions in writing for carrying out each test & analysis .(16.4) • To release or reject each batch of raw materials.(16.6) • To release or reject semi finished products if necessary(16.6) • To release or reject packaging & labeling materials & the final containers in which drugs are to be packed. (16.6) • To release or reject each batch of finished product that is ready for distribution

19. QUALITY CONTROL SYSTEM • To evaluate the adequacy of the conditions under which raw materials, semi finished products & finished products are stored. • To evaluate the quality & stability of finished products & when necessary of raw materials & semi finished products. • To establish shelf life & storage requirements on the basis of stability tests related to storage conditions.(16.10) • To establish & when necessary revise , control procedures & specifications(16.5 &16.13)

20. QUALITY CONTROL SYSTEM • To examine returned products as to whether such products should be released , reprocessed or destroyed. To evaluate all complaints by QA incharge(16.11) • Ref./Retained samples to be kept for a period of 3months (1Year) after expiry of each batch.(16.7)

21. QUALITY CONTROL SYSTEM • SOP for sampling, inspection & testing of RM, Intermediates, FP,PM & for environmental monitoring should be available. • To review production records to ensure that the authorized manufacturing process has been followed.(BMR should be signed by head of quality control unit to guarantee that the “batch has been manufactured, tested & analysed & in accordance with the manufacturing procedures & written instructions as per the master formula. • To approve or reject any procedure or specification which is likely to affect product quality.“Master formula records shall be prepared & endorsed by head of production & quality control.” • To approve or reject products manufactured under contract manufacturing or a loan license arrangement with outside parties. (Quality audit for vendors should be carried out.)

22. QUALITY CONTROL SYSTEM • Certificate of Analysis should be as per sch U-III. Formats are • A- For tablets & capsules • B-Parenteral preparations • C-other drugs • D- Raw materials • E- containers, packing materials etc.

23. Vendor Audit for contract manufacture& analysis • Contract Manufcture and Analysis ( discussed in Drug Rules) • Contract giver must bear the ultimate responsibility for ensuring that the product as manufactured by the contract acceptor (loan licensee) meets all agreed specifications and legal requirements. Both the parties must agree in writing on the arrangements for ensuring quality of input materials, for in-process checks, finished product testing & final release of the product. There should be clear indications of the responsibilities of the giver & the acceptor. • The contract giver should assure himself that the contract acceptor has the resources to carry out satisfactorily the work entrusted to him; for which he should carry out Vendor assessment. Manufacturing, analytical & distribution records should be kept by, or be available to , the contract giver.

24. Functions of Quality Control QC Dept also provides Analytical method validation data, stability data, QC related data in MFR, CTD. QA dept plays vital role in preparing QMS, QA audits & inspection, document control ,Quality Risk assessment, customer complaints investigation, assessment , Product recall procedures etc.