TECHNOLOGY TRANSFER PROCESS IN PHARMACEUTICAL INDUSTRIES ( IP-2/ UNIT 2)

TECHNOLOGY TRANSFER PROCESS IN PHARMACEUTICAL INDUSTRIES

1. TECHNOLOGY TRANSFER PROCESS IN PHARMACEUTICAL INDUSTRIES

2. CONTENTS INTRODUCTION / WHAT IS TECHNOLOGY TRANSFER? FACETS OF TECHNOLOGY TRANSFER CONSTITUENTS OF TECHNOLOGY TRANSFER TECHNOLOGY TRANSFER FROM VARIOUS SECTORS TECHNOLOGY TRANSFER PROCESS FLOW CHART GUIDELINES / IMPORTANCE OF TECHNOLOGY TRANSFER WHY / REASONS OF TECHNOLOGY TRANSFER AND WHEN IT WILL BE DONE? FACTORS AND BARRIERS INFLUENCING ON TECHNOLOGY TRANSFER APPROCHES TO OVERCOME THE BARRIERS TECHNOLOGY TRANSFER PROCESS AND ITS STEPS AND PROCEDURE TECHNOLOGY TRANSFER TEAM & RESPONSIBILITY TECHNOLOGY TRANSFER DOCUMENATION TECHNOLOGY TRANSFER CHECKLIST TECHNOLOGY TRANSFER DOCUMENATION PROBLEMS IN TECHNOLOGY TRANSFER TECHNOLOGY TRANSFER OF TEST METHODS EXAMPLE OF TECHNOLOGY TRANSFER PROBLEMS IN TABLETS MANUFACTURING

3. INTRODUCTION / WHAT IS TECHNOLOGY TRANSFER? Transfer of technology is defined as “a logical procedure that controls the transfer of any process together with its documentation and professional expertise between development and manufacture or between manufacture sites” Technology transfer is both integral and critical to the drug discovery and development process for new medicinal products

4. Technology Transfer is helpful to develop dosage forms in various ways as it provides efficiency in process, maintains quality of product, helps to achieve standardized process which facilitates cost effective production. It is the process by which an original innovator of technology makes its technology available to commercial partner that will exploit the technology. Technology transfer is both integral and critical to drug discovery and development for new medicinal products. In pharmaceutical industry, “Technology Transfer” refers to the processes of successful progress from drug discovery to product development, clinical trials and ultimately full-scale commercialization. “ Technology transfer” refers to the processes that are needed for successful progress from drug discovery to product development to clinical trials to full- scale commercialization or it is the process by which a developer of technology makes its technology available to commercial partner that will exploit the technology. Technology transfer is important for such research to materialize on a larger scale for commercialization especially in the case of developing product. Technology transfer includes not only the patentable aspects of production but also includes the business processes, such as knowledge and skills.

5. Technology Transfer Process Regulatory Submission Drug Discovery & D evelopment Phases Lead Candidate Compounds Drug Nominated First time to man Lead Optimization Concept Testing Full Development Phase I Phase II Phase III Launch Phase IV Production R&D Technology Transfer Drug Substance Drug Product Analytical Tests &Methods

6. Facets of technology transfer The transfer of technology could happen in any of following ways: 1 . Government labs to private sector firms. 2 . Between private sector firms of same country. 3 . Between private sector firms of different country. 4 . From academia to private sector firms. 5 . Academia, government and industry collaborations

7. CONSTITUENTS OF TECHNOLOGY TRANSFER 6P

8. Proper Research – By proper research we mean firstly that in which the result are reproducible and issues such as scale up, stability etc. and other practical now has been addressed, also that in which problem were taken up in first place Proper work- This refer to institutional and guidelines regarding IP Protection licensing modalities etc. which must be in place beforehand. In the absence of these, decision get delayed, lack of fairness in decision e.g. case of X institute, which came up with good technology but since no guidance were there, kept running around for two years and then gave up. Pricing – most difficult and critical area of Transfer of technology. Too high price can put off buyer, leaving the technology unsold. Too price a result in revenue loss. There are basically two model regarding pricing 1 )Price charged for a technology should depend upon market force i.e . impact of the technology irrespective of amount spent on developing it. 2 )Price charged should include all expenses involved in developing it.

9. Publicity – It is important to identify and then approach buyer i.e. adopt targeted Publicity and not blanket publicity. Specific journal, website, letters to manufacturer, personal selective visit etc. are some common approach which help in locating buyer Partnership – this means working along with industry. Industry takes it up, manufacturer and makes available to society. Partnership are important to ensure your technology is successfully adopted simply conveying the details may not be sufficient. People’s Acceptance – It is no use trying to develop a technology which people will not accept e.g. due to religious reason/social concern etc. genetically modified food, irradiated vegetables processed beef in India, improved capsule made of non- vegetarian material. LIST OF INSTITUTE IN INDIA ASSISSTING IN TECHNOLOGY TRANSFER Asia pacific Centre for Transfer of technology ( APCTT) Technology Bureau for small enterprises ( TBSE) National Research & Development corporation Foundation for Innovation and Technology Transfer

10. TECHNOLOGY TRANSFER FROM VARIOUS SECTORS Start-up Firms R&D Firms Universities Research Institutes Research Development IDEA Larger Companies Production Manufacturing Distribution MARKET (Commercialization)

11. TECHNOLOGY TRANSFER PROCESS FLOW CHART TECNOLOGY TRANSFER PROCESS

12. GUIDELINES/ IMPORTANCE OF TECHNOLOGY TRANSFER To elucidate necessary information to transfer technology from R&D to actual manufacturing by sorting out various information obtained during R&D. Demonstration of necessary information to technology transfer from research and development to actual manufacturing. To elucidate necessary information to transfer technology of existing products between various manufacturing places. To exemplify specific procedures and points of concern for smooth technology transfer. For the smooth manufacturing of commercialized products. This is applicable to the technology transfer through R&D and production of drug (chemically synthesized drug substances and drug products) and the technology transfer related to post- marketing changes in manufacturing places. The ultimate goal for successful technology transfer is to have documented evidence that the manufacturing process for drug substance and drug products are robust and effective in producing the drug and drug products complying with the registered specifications and Good Manufacturing Practice requirement. General impact of the technology transfer program. i . Improvement of the research pertinence and its promotion in foreign countries. ii. Contribution with the creation and consolidation of research groups and centers for technology development, involving the training of young research students. iii. Promote interdisciplinary projects to be developed in the region of interest.

13. Why/ Reasons of technology transfer? Many reasons exist why a company would like to transfer its technology to other parties: 1) Due to lack of manufacturing capacity, the developer of the technology may only have manufacturing equipment that suitable for lab and small scale operations and must partner with another organization to do large scale manufacturing. 2) Due to lack of resources to launch product commercially. The original inventor of technology may only have resources to conduct early-stage research and Phase-I and II clinical trials. 3) Due to lack of marketing distribution and distribution capability . The developer of the technology may have fully developed the technology and even have obtained regulatory approvals and product registrations, but it may not have the marketing and distribution channels and must collaborate with another organization that has the capability. 4) Forming alliances with partners that can progress the development of the technology to take it to market. 5) Forming alliances with partners with manufacturing capability. 6 )Forming alliances with partners with marketing and distribution capability. 7 )Exploitation in a different field of application.

14. WHEN TECHNOLOGY TRANSFER IS DONE ? • Idea to Discovery Lab • Discovery Lab to Development Lab • Development Lab to Pilot Plant • Kilo Lab to Pilot Plant • Pilot Plant to Semi-works (other pilot plant) • Pilot Plant to Manufacturing • Manufacturing to Manufacturing Various stages of formulation development were as follows • Preformulation studies. • Bench scale - (1/1000th of X) • Lab scale – (1/100th of X) • Scale up- (1/10th of X or 0.1M whichever is maximum) • Commercial (X) Where X is the final commercial scale batch size.

15. FACTORS INFLUENCING TECHNOLOGY TRANSFER Drivers for Technology Transfer – (A) Good business and manufacturing practices – The company’s success is primarily the result of its adoption of good business and manufacturing practices, particularly in the areas of product identification and formulation technology. • Potential for competitive pricing – Balance cost to remain competitive by having higher private sector prices and very low public sector prices. • Strategic planning – Create an enabling environment for vertical integration, with prospects for higher capacity utilization and eventual lowering of production costs. • Strong economy and environment – For technology transfer to be successful there needs to be supportive business and scientific environment in the recipient country, and that environment should include skilled workers, economic and political stability, supportive regulatory environment, market size and potential and a well developed national infrastructure of natural resources and transport. • Transparent and efficient regulation – Pharmaceuticals are necessarily a high regulated industry, the regulatory function must be efficient and transparent for technology transfer to be economically viable.

16. Opportunities for contingency supply – Multinational pharmaceutical companies are inclined to transfer technology to local manufacturers with the potential to receive when they foresee an inability to meet time scales and volume demand from large procurers. • Access to new machinery, training, know-how and business partnership – This makes the prospect of technology transfer very desirable to local pharmaceutical manufacturers since the technology, equipment, etc. could be applied profitably beyond the initial purpose . ( B) Barriers of Technology Transfer • Lack of efficiency – Automation of production processes to improve efficiency and lower costs. • Low market share – Local producers face significant challenges in meeting International Quality Standards and capturing a critical market share. Greater market share would increase profitability. • Cost of prequalification – There is benefit in meeting International Standards since it opens up the opportunity for trading across the entire world. • Labour issues – The pharmaceutical sector demands relatively skilled labour . High labour turns over and absenteeism owing to unattractive conditions of service is negative contributor

17. Approaches to overcome barriers in technology transfer 1. Commercializing publicly funded technologies: The basic pattern envisioned is to give institutions receiving public research funds the right to obtain and exploit patents on inventions developed in the course of research. 2 . Research tool patents and freedom to operate for the public sector: Patents sometimes make it difficult for public researchers to carry out their research or to make the products of that research available. It is intensified by the tendency of some publicly funded research laboratories to avoid use of a patented technology without permission even in nations where no relevant patent is in force. 3 . Web access and scientific publication: Limited access to scientific journals led to enormous problems for developing nations scientists. 4 . National security issues and restrictions on exports of particular technology: International controls designed to protect national security and to prevent the proliferation of important technologies also restrict the flow of technologies. 5 . Inadequate funding in important areas and possible treaties: There are areas of research of importance to the developing world that are being funded inadequately. 6 . Co-operative research agreements: Global support for public sector research might be encouraged is through co-operative research agreements designed to meet specific goals. It would seem more feasible to focus efforts on technologies of significant social benefit to the developing nations. 7 . Possible treaty on scientific access: There has also been a proposal for an international treaty on access to knowledge and technology negotiated on the basis of the type of reciprocity found in normal international trade negotiations. The concept is mean to be non- zero sum in the sense that, like free trade in goods, free trade in scientific ideas benefits all, and such arrangements could be made bilaterally as well as multilaterally.

18. Technology Transfer Process Technology transfer is both integral and critical to the drug discovery and development process for new medicinal products. The decision to transfer products between manufacturing sites is frequently driven by economics . Key stages of the process include data collection, data review, regulatory impact with particular emphasis on any change approvals, analytical validation, pilot or full-scale process batch, stability set down (if required). Technology Transfer Flow chart . Technology Transfer Manufacturing production QC Department QA Packing Production Analytical Department Formulation Department Engineering Department Packing Department

19. REPRESENTATION OF TECHNOLOGY TRANSFER PROCESS Research & Development Analytical Development & Validation Product Development Laboratory Quality Assurance & Quality control Setting of Parameters & Documentation Production & Commercialization

20. TECHNOLOGY TRANSFER PROCESS The processes are classified into the three categories. • Research Phase – Quality by design • Development Phase – Research for Factory Production – Consistency between Quality & Specification – Assurance of consistency through development & manufacturing – Technology Transfer from R&D to Production • Production Phase – Validation & Production – Feed back from Production & Technology Transfer of Marketed Products

21. Process Development EHS Study pilot Scale-Up Trail Production Site Evaluation Industrial Scale-Up & Tech Transfer Industrial production Sequence Selection Route Selection Recipe Development Regulatory Compliance Preclinical Phase Clinical Phase Post Approval

22. STEPS IN TECHNOLOGY TRANSFER PROCESS During development of a formulation, it is important to understand the procedure of operations used, critical and non-critical parameters of each operation, production environment, equipment and excipients availability should be taken into account during the early phases of development of formulation so that successful scale up can be carried out. (A) Development of technology by R&D. (Research Phase) (a)Design of procedure and selection of excipients by R&D ( b) Identification of specifications and quality by R&D ( B) Technology transfer from R&D to production (Development Phase) (a) Master Formula Card (MFC) ( b) Master Packing Card ( c) Master Formula ( d) Specifications and Standard Test Procedures (STP’S) ( C) Optimization and Production (Production Phase) (a) Validation Studies ( b) Scale up for production ( D) Technology Transfer Documentation (a) Development Report ( b) Technology Transfer Plan ( c) Report ( E) Exhibit

23. TECHNOLOGY TRANSFER PROCESS Cont... (A) Development of technology by R&D. (Research Phase) (a) Design of procedure and selection of excipients by R&D– Selection of materials and design of procedures is developed by R&D on the basis of innovator product characteristics. ( b) Identification of specifications and quality by R&D– Quality of product should meet the specifications of an innovator product.

24. TECHNOLOGY TRANSFER PROCESS Cont... B ) Technology transfer from R&D to production (Development Phase) R &D provides technology transfer dossier (TTD) document to product development laboratory, which contains all information of formulation and drug product as follows ( a)Master Formula Card (MFC ) – Includes product name along with its strength, generic name, MFC number, page number, effective date, shelf life and market. ( b )Master Packing Card – Gives information about packaging type, material used for packaging, stability profile and shelf life of packaging. (c)Master Formula – Describes formulation order and manufacturing instructions. (Process order and environment conditions) ( d )Specifications and Standard Test Procedures (STP’S ) – Helps to know active ingredients and excipients profile, in-process parameters, product release specifications and finished product details.

25. TECHNOLOGY TRANSFER PROCESS Cont... ( C) Optimization and Production (Production Phase) (a)Validation Studies – Production is implemented after validation studies that can verify that process is able to stabilize the product based on transferred manufacturing formula. Manufacturing department accepting technology is responsible for validation and the R&D department transferring technology should take responsibility for validation such as performance qualification, cleaning and process validation. ( b) Scale up for production – Involves the transfer of technology during small scale development of the product and processes. It is essential to consider the production environment and system during development of process. Operators should concentrate on keeping their segment of the production process running smoothly.

26. TECHNOLOGY TRANSFER PROCESS Cont... ( D) Technology Transfer Documentation Generally interpreted as document indicating contents of technology transfer for transferring and transferred parties. Each step from R&D to production should be documented, task assignments and responsibilities should be clarified and acceptance criteria for completion of technology transfer concerning individual technology to be transferred. It is duty of Quality Assurance department to check and approve the documentation for all processes of technology transfer. (a) Development Report– The R&D report is a file of technical development, and R&D department is in-charge of its documentation. This report is an important file to indicate rationale for the quality design of drug substances and its specifications and test methods. The development report is not prerequisite for the application for approval; it can be used at the pre approval an inspection as valid document for quality design of new drug. The development report contains (1) Data of pharmaceutical development of new drug substances and drug products at stages from early development phase to final application of approval. ( 2) Information of raw materials and components. ( 3) Design of manufacturing methods. ( 4) Change in histories of important processes and control parameters. ( 5) Specifications and test methods of drug substances. ( 6) Validity of specification range of important tests such as contents impurities and dissolution. ( 7) Verifications of results.

27. TECHNOLOGY TRANSFER PROCESS Cont. .. (b) Technology Transfer Plan – The technology transfer plan is to describe items and contents of technology to be transferred and detailed procedures of individual transfer and transfer schedule, establish judgment criteria for the completion of the transfer. The transferring party should prepare the plan before the implementation of the transfer and reach an agreement on its contents with the transferred party. ( c) Report – Completion of technology transfer is to be made once data are taken accordingly to the technology plan and are evaluated to confirm that the predetermined judgment criteria are met. Both transferring and transferred parties should document the technology transfer report. ( E) Exhibit After taking scale up batches of the product, manufacturing of exhibit batches takes place. In case of exhibit, batch sizes are increased along with equipments and their processes. This is done for filling purpose in regulatory agencies.

28. TECHNOLOGY TRANSFER PROCEDURE 1. Procedure for Manufacturing and Packaging: • After the completion of three validation/commercial batches, R&D shall prepare the technology transfer dossier (TTD), which shall be reviewed by Head- Production, Head-QC, Head- Engineering and approved by Head-QA . • The dossier shall contain the details of unitary formula, process flow chart, raw material and packing material specifications, in-process and finished product specifications, master formula card, safety parameters, critical process steps, critical process parameters and their specifications and measured response, process validation protocol, process validation report, stability data, deviation and change controls, product development report. • After successful transfer of technology (manufacturing process), manufacturing of the respective product is the responsibility of production department. If any problem arises, QA shall investigate and refer to R&D through investigation report in the form of Inter Office Communication (IOC). • Any deviation in the process shall be supported by deviation/change control form as applicable. • For third party and loan license products, respective organization will provide the TTD to QA and manufacturing process shall be demonstrated to production personnel on minimum of two or three batches.

29. TECHNOLOGY TRANSFER PROCEDURE Cont.... 2 . Procedure for Analytical Method Transfer: A) For Drug Product: • Analytical method transfer shall be initiated by analytical department for all the validated methods. • Analytical department analyst along with quality control analyst has to perform analysis as per the analytical method transfer protocol. • The transfer activity shall be established on the optimization batch or process batch with the final formula. • Analytical method transfer activity shall be initiated with analytical method transfer protocol prepared by AR&D, reviewed by DQA/QC and finally approved by QA. • The analytical method transfer protocol shall explain the transfer activities of the drug product and also the parameters that shall be transferred are Assay, Dissolution, Related substances, Content uniformity and Residual solvents. • In case of multiple strengths, analytical method transfer shall be performed for lower strength. • All chromatograms, record of results and other information have to be interlinked and records have to be maintained. • A report has to made with summarized results and conclusions and the same shall be reviewed by Head-DQA and Head-QC, approved by Head-QA. • The analytical method transfer process is considered to be completed upon the certification by analytical department, quality control & quality assurance that the method under consideration meets the acceptance criteria. • Finally analytical method transfer report shall be prepared.

30. TECHNOLOGY TRANSFER PROCEDURE Cont.... 2 . Procedure for Analytical Method Transfer: B ) For Drug Substances: i ) Non Pharmacopoeial Methods: The vendor has to transfer the analytical methods to QC. In case, if the analytical method transfer activity was not performed by the vendor the same shall be prepared by AR&D as per the STP. ii ) Pharmacopoeial Methods: The vendor has to transfer the analytical methods to QC. If the methods are same as per respective pharmacopoeia, the method suitability shall be performed by AR&D. Suitability of the analytical method shall verified by performing the specificity (RRT verification) and precision study (Triplicate) and the same shall be reviewed by DQA and communicated to QC. • Analytical method transfer protocol and report shall be prepared. • The analytical method transfer protocol shall explain the transfer activities of the drug substance and also the parameters that shall transferred are assay, residual solvents and related substances. • All chromatograms, record of results and other information have to be interlinked and records have to be maintained. • A drug substance analytical method transfer report has to be made with summarized results with conclusions as per drug product method transfer report. • The limits and parameters described for drug product/drug substance are indicative, but shall altered based on customer’s requirements and nature of drug product/drug substances to be followed as per respective analytical method transfer protocol. • Documentation for analytical method transfer activity shall be done by analytical R&D department.

31. TECHNOLOGY TRANSFER TEAM The technology transfer team consists of – R&D Process Technologist – QA Representative – Production Representative – Engineering Representative – QC Representative

32. Constitution of technology transfer team and their responsibilities Technology Transfer Team member Responsibilities Process Technologist a ) Central focus for transfer activities. b ) Collates documentation from donor site c ) Performs initial assessment of transferred project for Feasibility , Compatibility with site capabilities and Establishes resource requirements. QA Representative a ) Reviews documentation to determine compliance with marketing authorization (MA). b ) Reviews analytical methods with QC to determine capability , equipment training requirements. c ) Initiates conversion of donor site documentation into local systems or format . d ) Initiates or confirms regulatory requirements, e.g., change to manufacturing license ; variations to MA if process changes needed, etc. Production Representative a ) Reviews process instructions (with process technologist) to confirm capacity and capability. b ) Considers any safety implications, e.g., solvents; toxic; sanitizing materials. c ) Considers impact on local standard operating procedures (SOPs). d ) Considers training requirements of supervisors or operators.

33. Constitution of technology transfer team and their responsibilities Cont... Technology Transfer Team member Responsibilities Engineering Representative a ) Reviews (with production representative) equipment requirement . b ) Initiates required engineering modifications, change or part purchase. c ) Reviews preventative maintenance and calibration impact , e.g ., use of more aggressive ingredients; more temperature sensitive process, and modifies accordingly. QC Representative a ) Reviews analytical requirement. b ) Availability with instruments. c ) Responsible for analytical method transfer for drug substance and drug product.

34. TECHNOLOGY TRANSFER DOCUMENATION 1. Organization for Technology Transfer 2. Research and Development Report 3. Product Specification File 4. Technology Transfer Plan 5. Technology Transfer Report 6. Verification of Results of Technology Transfer

35. TECHNOLOGY TRANSFER CHECKLIST It consists of • Production master formula • Manufacturing instructions • Dispensing instructions • Analytical methods • Previous process validation • Previous analytical validation • Cleaning instructions and previous cleaning validation • Stability reports • Excipients specifications and source • Active specifications and source • Primary packaging material specifications and source • Packaging instructions • Process deviations file, Analytical deviations file • Reject and rework file • Specimen manufacturing batch record.

36. PROBLEMS IN TECHNOLOGY TRANSFER 1. Problems during the technology justification and selection stage. i . Wrong selection of technology based on misjudgment when preparing a business case for a technology transfer project. ii. Cost of buying, installing, operating and maintaining the technology is also high. iii. The technology selected is also complex for easy understanding and assimilation of the transferee. iv. The technology needs extensive adaptation to suit local conditions. 2 . Problems during the planning stage. i . Transferor (seller) underestimates the problems in transferring the technology to a developing country setting. ii. Transferor does not fully understand transferee needs. iii. Transferee managers are not involved in the planning which is carried out only by the transferor. iv. Too much attention is paid to the hardware to be purchased and not enough attention is paid to skills and information acquisition. v. Overestimation of the technological capabilities of the transferee by the transferor thereby leading to unrealistic expectations on how well the transferee can meet target dates. vi. Poor market demand forecasting by the transferee of the outputs to be produced by using the transferred technology. vii. The objectives of the transferor and transferee are not compatible. viii. Mechanisms chosen for implementing the transfer are not appropriate.

37. PROBLEMS IN TECHNOLOGY TRANSFER Cont... 3 . Problems during negotiations. i . Differences in negotiation approaches and strategies. ii . Lack of trust between the transferor and transferee. iii . Goal incompatibility during negotiations. iv . Inability to reach agreements on pricing, product and marketing strategies. v . Both parties try to achieve results in an unrealistically short period of time. 4 . Problems during technology transfer implementation. i . Shortage of experienced technology transfer managers. ii. Lack of trust in transferor developed systems by the transferee . iii. Inability to achieve quality targets. iv. Delay in obtaining supplementary materials, from the local environment, needed for quick implementation. v . High cost and poor quality of locally available materials needed to implement the technology transferred. vi. Inadequate tracking of the technology during implementation. vii. Cost overrun due to poor implementation.

38. Success of Technology Transfer Its depends on • Communication – Open communication between all team members – Direct communication between technical members – Effective and timely communication with regulators • Sending and Receiving Unit – Technology transfer is not a “one way street” – The sending unit and receiving unit must be equally involved in the process to ensure success • Team work at all time

39. Technology Transfer of Test Methods Test methods subject to technology transfer include the following • Test methods for drug substances • Test methods for drug products • Test methods for raw materials and components • Test methods for in-process tests • Test methods for drug residue tests • Test methods for environmental tests

40. Technology Transfer Plan • For technology transfer of test methods, it is required to clarify validation range and acceptance criteria of conformity of technology transfer regarding individual test methods to be transferred. • The validation range (e.g. full validations, reproducibility, etc.) should be judged on the basis of results of evaluation of technologies, facilities and equipments of transferred party, and the range may be influenced by information to be contained in the technology transfer documentation. • To compare test results, samples (including dose range, number of batches, etc.), specific test methods and evaluation methods to be used in the transferring and transferred parties should be specified.

41. Technical information to be described in or attached to the technology transfer plan Information of Raw Materials Summary including physical and chemical properties and stability • Name and structural formula • Stability data Specifications and test methods • Specific test methods and specifications • Change history of specifications and test methods and its rationale • Results of analytical validation List of reference standards (Test results should be attached.) Information of toxicity and stability for laboratory use List of subject samples for comparative evaluation and their test results

42. Information of Drug Substances Summary including physicochemical properties and stability • Name and structural formula • Elucidation of chemical structure • Possible isomers • Physical and chemical properties (including physicochemical properties) • Stability data (including severe test data)

43. Batch records • Chemical synthesis methods of subject batches • Analytical data of batches • Impurity profile of representative batch

44. Specifications and test methods • Specific test methods and specifications (including items related to efficacy such as particle size distribution, polymorphism, crystallinity, and hygroscopicity) • Change history of specifications and test methods and their rationales • Results of analytical method validation

45. Information of Drug Products Summary including formula and stability • Elucidation of dissolution profile • Stability data (including severe test data) • Storage conditions and expiry date (if established ) Analytical data of batches Specifications and test methods • Specific test methods and specifications (including items related to efficacy such as particle size distribution and hygroscopicity ) • Change history of specifications and test methods and its rationale • Results of analytical method validation List of reference standards ( Test results should be attached.)

46. Information on Implementation of Technology Transfer Persons in charge of planning, checking and settlement of technology transfer Test methods (test method number Objectives Persons in charge of transferring and transferred parties Training plan (including explanation of test methods and demonstration) Plan of comparative evaluation study • Samples: Lot No. (including rationale for the number of lots), storage condition during test, and handling after the completion of the test (disposal or return to the transferred party , etc .) • Test period • Number of repeated tests • Handling of data (Handling method) • Retest and handling of outlier • Acceptance criteria • Storage of raw data (storage department, storage place, and duration

47. Items Concerning Manufacturing Methods • Information on manufacturing methods (synthetic routes and purification methods) • Information on operating conditions (control parameters and acceptable range) • Information on important processes and parameters (identification of processes and parameters which will affect quality) • Information on in-process control • Information on reprocess and rework (places and methods)

48. Items Concerning Facilities and Equipments • Information on equipment cleaning (cleaning methods, cleaning solvents, and sampling methods) • Information on facilities (selection of materials, capacity, and equipment types, and necessity of special equipments .

49. Items Concerning Test Methods and Specifications • Information on specifications and test methods of drug substances, intermediates, and raw materials (physical and chemical, microbiological, endotoxin and physicochemical properties, etc.) • Validations for test methods of drug substances and intermediates

50. Problem in tablets are either related to imperfections in any one or more of the following during transfer of technology I . Tableting Process II . Excipient III . Machine

51. PROCESS RELATED PROBLEMS : • CAPPING: It is due to air-entrapment in the granular material. • LAMINATION: It is due to air-entrapment in the granular material. • CRACKING: It is due to rapid expansion of tablets when deep concave punches are used.

52. EXCIPIENT RELATED PROBLEMS : • CHIPPING: It is due to very dry granules. • STICKING: It is due to excess moisture present in the granules. • PICKING: It is due to the improper drying of the granules . • BINDING: It is due to the excessive binder present in the granules.

53. MACHINE RELATED PROBLEMS : • DOUBLE IMPRESSION: It is due to free rotation of the punches, which have some engraving on the punch faces.

54. CAPPING: Capping happened when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling. Reason : Capping is usually due to the air– entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die.

55. CAPPING RELATED TO ‘FORMULATION’ (GRANULATION ) Sr.No. CAUSES REMEDIES 1 . Large amount of fines in the granulation Remove some or all fines through 100 to 200 mesh screen 2 . Too dry or very low moisture content Moisten the granules suitably. Add hygroscopic substance ( leading to loss of proper binding action). e.g .: sorbitol, methyl- cellulose or PEG- 4000. 3 . Not thoroughly dried granules. Dry the granules properly. 4 . Insufficient amount of binder or Increasing the mount of binder OR Adding dry binder such gelatinized improper binder. as pre- gelatinized starch, gum acacia, powdered sorbitol , PVP , hydrophilic silica or powdered sugar. 5 . Insufficient or improper lubricant. Increase the amount of lubricant or change the type of lubricant. 6 . Granular mass too cold to compress firm. Compress at room temperature.

56. CAPPING RELATED TO ‘MACHINE’ (DIES, PUNCHES AND TABLET PRESS) Sr.No CAUSES REMEDIES 1. Poorly finished dies Polish dies properly. Investigate other steels or other materials. 2. Deep concave punches Use flat punches. or beveled-edge faces of punches. 3. Lower punch remains below Make proper setting of the face of die during ejection. lower punch during ejection. 4. Incorrect adjustment of Adjust sweep-off blade correctly sweep - off blade. to facilitate proper ejection. 5. High turret speed. Reduce speed of turret ( Increase dwell time).

57. Lamination / Laminating • Definition: ‘Lamination’ is the separation of a tablet into two or more distinct horizontal layers. • Reason: Air–entrapment during compression and subsequent release on ejection. • The condition is exaggerated by higher speed of turret.

58. LAMINATION RELATED TO FORMULATION (GRANULATION) Sr . No CAUSES REMEDIES 1 . Oily or waxy materials in granules Modify mixing process. Add adsorbent or absorbent. 2 . Too much of hydrophobic lubricant Use a less amount of lubricant or e.g .: Magnesium- stearate. change the type of lubricant LAMINATION RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Sr . No. CAUSES REMEDIES 1. Rapid relaxation of the peripheral Use tapered dies, i.e. upper part of the die regions of a tablet, has an outward taper of 3° to 5°. on ejection from a die. 2 . Rapid decompression Use pre-compression step. Reduce turret speed and reduce the final compression pressure.

59. CHIPPING • Definition: ‘Chipping’ is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations. • Reason: Incorrect machine settings, specially mis-set ejection take- off.

60. CHIPPING RELATED TO FORMULATION (GRANULATION) Sr . No CAUSES REMEDIES 1. Sticking on punch faces Dry the granules properly or increase lubrication . 2. Too dry granules. Moisten the granules to plasticize. Add hygroscopic substances. 3. Too much binding causes chipping at bottom . Optimize binding, or use dry binders. CHIPPING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Sr . No CAUSES REMEDIES 1. Groove of die worn at Polish to open end , reverse or replace the die. compression point. 2 . Barreled die (center of the die Polish the die to make it cylindrical wider than ends) 3. Edge of punch face turned Polish the punch edges inside / inward 4 . Concavity too deep to compress properly. Reduce concavity of punch faces. Use flat punches.

61. MOTTLING • Definition: ‘Mottling’ is the term used to describe an unequal distribution of colour on a tablet, with light or dark spots standing out in an otherwise uniform surface. • Reason: One cause of mottling may be a coloured drug, whose colour differs from the colour of excipients used for granulation of a tablet.

62. CAUSES AND REMEDIES OF MOTTLING: Sr.No . CAUSES REMEDIES 1 . A coloured drug used along with Use appropriate colourants . colourless or white - coloured excipients . 2. A dye migrates to the surface of Change the solvent system, granulation while drying. Change the binder, Reduce drying temperature and Use a smaller particle size. 3 . Improperly mixed dye, Mix properly and reduce size especially during if it is of a larger size to prevent ‘Direct Compression’. segregation. 4 . Improper mixing of a Incorporate dry colour additive coloured binder solution. during powder blending step, then add fine powdered adhesives such as acacia and tragacanth & mix well and finally add granulating liquid.

63. Double impression • Definition: ‘Double Impression’ involves only those punches, which have a monogram or other engraving on them. • Reason : At the moment of compression, the tablet receives the imprint of the punch. Now, on some machines, the lower punch freely drops and travels uncontrolled for a short distance before riding up the ejection cam to push the tablet out of the die, now during this free travel, the punch rotates and at this point, the punch may make a new impression on the bottom of the tablet, resulting in ‘Double Impression’. • If the upper punch is uncontrolled, it can rotate during the short travel to the final compression stage and create a double impression.

64. CAUSES AND REMEDIES OF DOUBLE IMPRESSION: Sr . No. CAUSE REMEDIES 1 . Free rotation of either upper punch - Use keying in tooling, i.e. inset a key or lower punch during ejection of a tablet. alongside of the punch, so that it fits the punch and prevents punch rotation . - Newer presses have anti-turning devices , which prevent punch rotation.

65. THANK YOU