UNIT II Technology development and transfer.pptx

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A regulatory agency (regulatory body, regulator) or independent agency (independent regulatory agency) is a government authority that is responsible for exercising autonomous dominion over some area of human activity in a licensing and regulating capacity.

These are customarily set up to strengthen safety and standards, and/or to protect consumers in markets where there is a lack of effective competition. Examples of regulatory agencies that enforce standards include the Food and Drug Administration in the United States and the Medicines and Healthcare products Regulatory Agency in the United Kingdom; and, in the case of economic regulation, the Office of Gas and Electricity Markets and the Telecom Regulatory Authority in India.

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1. UNIT- II Technology development and transfer

2. Contents WHO guidelines for Technology Transfer(TT): Terminology, Technology transfer protocol. Quality risk management Transfer from R & D to production (Process, packaging and cleaning), Granularity of TT Process (API, excipients, finished products, packaging materials) Documentation, Premises and equipment's, qualification and validation, quality control, analytical method transfer, Approved regulatory bodies and agencies, Commercialization - practical aspects and problems (case studies), TT agencies in India - APCTD, NRDC, TIFAC, BCIL, TBSE / SIDBI; TT related documentation - confidentiality agreement, licensing, MoUs, legal issues.

3. Technology Transfer(TT): Introduction 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”. Transfer of technology requires : Documented, planned approach. Trained and knowledgeable personnel. Compliant quality system. Documentation of data covering all aspects of development, production and quality control. Usually there is a Sending unit (SU) , a receiving unit (RU) and the unit managing the process, which may or may not be a separate entity.

4. Most products’ processes/technology are transferred to another location at some point during their life cycle. This transfer occurs in stages, starting with development and scaling up to manufacture, production, and launch, and ending with post-approval. Technology transfer is a systematic mechanism that governs the transfer of any process, along with its documentation and professional experience, from development to manufacture or across manufacturing locations.

5. Some of the responsibilities outlined in this document for the SU may also be considered to be part of the management unit responsibilities. The guidelines address the following areas Transfer of development and production (processing, packaging and cleaning). Transfer of analytical methods for quality assurance and quality control. Skills assessment and training. Organization and management of the transfer. Assessment of premises and equipment. Documentation; and qualification and validation .

6. Scope of Guidelines: Technology transfer aims to ensure that scientific and technological developments are accessible to a wider range of users who can then further develop and exploit the technology into new products, processes, applications, materials, or services.

7. The guidelines for SU and RU: This includes: (a) Transfer of development and production (processing, packaging and cleaning). (b) Transfer of analytical methods for QA and QC. (c) Skills assessment and training of personnel. ( d) Organization and management of the transfer. e) Assessment of premises and equipment. (f ) Documentation, qualification and validation.

8. This guidance is applicable for all technology transfer from R & D to manufacturing plant, from exhibit scale to Validation batches or one manufacturing site to other own sites or contract manufacturing site (Site Transfer Products). Legal & Economic implications: Intellectual property rights Royalties Pricing Conflict of interest Confidentiality

9. Facets of technology transfer The transfer of technology could happen in following ways Government labs to private sector firms. Between private sector firms of same country. Between private sector firms of different country. From academic to private sector firms.

10. Importance of Technology Transfer in Pharmaceutical Industry To elucidate necessary information to transfer technology from R&D to actual manufacturing by sorting out various information obtained during R&D. To elucidate necessary information to transfer technology of existing products between various manufacturing places. To exemplify specific procedures and points of concern for the two types of technology transfer in the above to contribute to smooth technology transfer. This is applies to the technology transfer through R&D and production of drug substances or drug products and the technology transfer related to post marketing changes in manufacturing places .

11. Reasons for technology transfer Lack of manufacturing capacity: The developer of technology may only have manufacturing equipment which is suitable for small scale operation, and must collaborate with another organization to do large scale manufacturing. Lack of resources to launch product commercially:  The original inventor of technology may only have the resources to conduct early-stage research such as animal studies and toxicology study, but doesn’t have the resources to take technology through its clinical and regulatory phases.

12. Lack of marketing and distribution capability:  The developer of 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. Exploitation in a different field of application:  Each partner may have only half of the solution i.e. the developer of the technology might be capable of exploiting the technology itself in the field of diagnostic applications and may grant exploitation right to commercial partner for the exploitation of therapeutics application . Reasons for technology transfer

13. Steps in technology transfer Development of technology by R & D [Research Phase] Development Phase Production Phase (Optimization and Production) Technology Transfer Documentation Barriers of Technology Transfer

14. Research Phase - Development of technology by R & D 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. For this different test and compatibility studies are done. B . Identification of specification and quality by R&D Generally it should be considered by R & D the quality of product should meet the specifications of an innovator product. For this different stability studies are carried out for innovator product and for product which is to be manufactured.

15. Development Phase (Technology transfer from R&D to production): R &D provides technology transfer dossier (TTD) document to product development laboratory which contains all information of formulation and drug product as given below: Master formula card (MFC) Master Packaging Card (MPC) Master formula Standard Test Procedures Specifications Development report Packaging development report Development report

16. Production Phase (Optimization and Production) A) Validation studies Production is implemented after various validation studies verify that, it is able to consistently manufacture product based on transferred manufacturing formula with a higher degree of stability. Research and development department transferring technology should take responsibility for validation such as performance qualification, cleaning validation and process validation unique to subject drugs.

17. B) Scale-up for production Scale up involves the transfer of technology during the small scale development of the product and processes. It is essential to consider the production environment and system during development of process. Different operations e.g. dispensing, sifting, blending, compaction/dry granulation/wet granulation, compression, coating are used in the formulation of solid dosage form.

18. B) Scale-up for production Contin.. From blending to film coating, each process is easy for pharmaceutical professionals to be absorbed in the particular part of the manufacturing process for which they are directly responsible.  Effective technology transfer helps to provide process efficiency and control and maintain product quality.

19. C) Considerations of different parameters for scale-up: Before starting scale-up, we also considered different parameters that should be optimum for successful technology transfer. These were: Flexibility, Cost, Dependability, Innovation and Product Quality. It was important to realize that good communication was critical for formulation and process transfer to be successful . D) Selection of method: The method for batch fabrication was selected on the basis of data given from R&D. Granulation, blending; compression and coating were critical parameters for technology transfer.

20. Technology Transfer Documentation: 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. 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.

21. The development report contains: Data of pharmaceutical development of new drug substances and drug products at stages from early development phase to final application of approval. ii) Information of raw materials and components. iii) Design of manufacturing methods. iv)Change in histories of important processes and control parameters. v) Specifications and test methods of drug substances. vi) Validity of specification range of important tests such as contents impurities and dissolution. vii) Verifications of results.

22. 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.

23. 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. D) Exhibit After taking scale up batch of the product, manufacturing of exhibit batches take place. In case of exhibit, batch sizes are increased along with equipment and their process is involved. They are done for filing purposes in different regulatory agencies.

24. Barriers of Technology Transfer Lack of 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 pre-qualification : 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.

25. Unsuccessful or incomplete Process Validation. High rates of batch rejections, excessive labour requirements, increased cost of product etc. Incomplete Documentation. Product does not show specifications as intended. Delayed regulatory approval and/or product launch. Barriers of Technology Transfer

26. Transfer Type Sending Unit (SU) Receiving Unit (RU) For Registration purpose Development Lab Manufacturing Unit of--Own site-CMO Site For Higher Efficiency (Within Manufacturing Unit) Manufacturing Unit of Own site (Small scale -CMO Site (Small scale) Manufacturing Unit of Own site (Large scale) -CMO Site (Small scale) For Site transfer activity Own site-1/ CMO Site-1 wn Site-2-CMO Site-2 This Guidance is also applicable for all manufacturing processes and Analytical Methods transferred from a Sending unit (SU) to a receiving Unit (RS)

27. Example of documentation commonly required for the technology transfer The table below provides an example of documentation commonly required for the technology transfer. Aspect Related documentation Regulatory process Regulatory process description, Applicable regulatory documentation. Starting materials (active pharmaceutical ingredients {APIs}) and excipients) Drug Master File (DMF), API Master File (APIMF), Active Substance Master File (ASMF) Material Safety Data Sheets, Product development report, Storage conditions, Stability data, Forced stability data Specifications, Supplier qualification References . 29

28. Aspect Related documentation Batch manufacturing Master of executed batch record Scale up information , Risk assessment , Critical process parameters, In-process control specification, Scale up protocol and report Process validation. Packaging Packaging material specification , Master of executed packaging record, Validation Sampling plan, Acceptance Quality Level (AQL) for products and defects Packaging validation.

29. Aspect Related documentation Finished product Specification Product Dossier . Formulation Formulation development reports, Master formula Material, Compatibility/interaction studies, Specifications for delivery devices. Equipment and instruments List of equipment and instruments, Preventive maintenance information Overview of qualification .

30. Aspect Related documentation Analytical procedures Analytical test procedures, Analytical procedure development, Analytical procedure, Validation Standard test procedures, Instrument specifications. Cleaning Cleaning validation master plan , Cleaning procedure development and cleanability Cleaning procedures, Health Based Exposure Level (Permitted daily exposure) information reports, Analytical procedures validation for cleaning, Cleaning validation reports and recovery study reports .

31. Aspect Related documentation Other documents Recalls and complaint reports , Bio-batch information Pilot batch information, History of changes and change management, Hold time protocols and reports

32. Responsibilities of technology transfer The technology team consist of following R&D process technologist(FR&D and AR&D) Packaging Development Department (PDD) Quality control department Quality assurance department Production department Engineering representative

33. Responsibilities

34. Terminology

35. Terminologies used in technology Transfer Active pharmaceutical ingredient (API) : Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when so used becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.

36. Good manufacturing practice That part of quality assurance which ensures that pharmaceutical products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. Process validation Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets its predetermined specific actions and quality characteristics.

37. Quality Assurance(QA): Quality assurance is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product . It is the totality of the arrangements made with the objective of ensuring that pharmaceutical products are of the quality required for their intended use. Quality control(QC) : Quality control covers all measures taken, including the setting of specifi cations, sampling, testing and analytical clearance, to ensure that starting materials, intermediates, packaging materials and finished pharmaceutical products conform with established specifications for identity, strength, purity and other characteristics.

38. Acceptance criteria : Measurable terms under which test results will be considered acceptable. Change control (C/C): A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure that the system is maintained in a validated state. Drug master file (DMF) Detailed information concerning a specific facility, process or product submitted to the drug regulatory authority, intended for the incorporation into the application for marketing authorization.

39. Commissioning: The setting up, adjustment and testing of equipment or a system to ensure that it meets all the requirements, as specified in the user requirement specification, and capacities as specified by the designer or developer. Commissioning is carried out before qualification and validation. Corrective action (C/A) : Any action to be taken when the results of monitoring at a critical control point indicate a loss of control.

40. Qualification Action of proving and documenting that any premises, systems and equipment are properly installed, and/or work correctly and lead to the expected results. Qualification is often a part (the initial stage) of validation, but the individual qualification steps alone do not constitute process validation.

41. Design qualification (DQ): Documented evidence that the premises, supporting systems, utilities, equipment and processes have been designed in accordance with the requirements of good manufacturing practices (GMP). Installation qualification (IQ): The performance of tests to ensure that the installations (such as machines, measuring devices, utilities and manufacturing areas) used in a manufacturing process are appropriately selected and correctly installed and operate in accordance with established specifications.

42. Operational qualification (OQ): Documented verification that the system or subsystem performs as intended over all anticipated operating ranges. Performance qualification (PQ): Documented verification that the equipment or system operates consistently and gives reproducibility within defined specifications and parameters for prolonged periods. Design space The multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality

43. Gap analysis Identification of critical elements of a process which are available at the SU but are missing from the RU. Good Manufacturing Practices (GMP) That part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. Inter-company transfer A transfer of technology between sites of different companies. Intra-company transfer A transfer of technology between sites of the same group of companies.

44. In-process control (IPC) Checks performed during production in order to monitor and, if necessary, to adjust the process to ensure that the product conforms to its specifications. The control of the environment or equipment may also be regarded as a part of in-process control. Quality risk management (QRM) Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the pharmaceutical product throughout the product life-cycle.

45. Receiving unit (RU) The involved disciplines at an organization where a designated product, process or method is expected to be transferred. Sending unit (SU) The involved disciplines at an organization from where a designated product, process or method is expected to be transferred. Technology transfer report (TTR) A documented summary of a specific technology transfer project listing procedures, acceptance criteria, results achieved and conclusions. Any deviation should be discussed and justified.

46. Validation It is a documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. Spiking The addition of a known amount of a compound to a standard, sample or placebo, typically for the purpose of confirming the performance of an analytical procedure. Transfer of technology (TOT): A logical procedure that controls the transfer of an established process together with its documentation and professional expertise to site capable of reproducing the process and its support functions to a predetermined level of performance

47. Validation master plan (VMP) A high-level document that establishes an umbrella validation plan for the entire project and summarizes the manufacturer’s overall philosophy and approach, to be used for establishing performance adequacy. It provides information on the manufacturer’s validation work programme and defines details of and timescales for the validation work to be performed, including a statement of the responsibilities of those implementing the plan. Validation protocol (or plan) (VP ) A document describing the activities to be performed in a validation, including the acceptance criteria for the approval of a manufacturing process – or a part thereof – for routine use.

48. Validation report (VR) A document in which the records, results and evaluation of a completed validation programme are assembled and summarized. It may also contain proposals for the improvement of processes and/or equipment Standard operating procedure(SOP): An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material (e.g. equipment operation, maintenance and cleaning, validation, cleaning of premises and environmental control, sampling and inspection).

49. General Principles of Technology Transfer

50. General Principles of Technology Transfer The basic requirements of TT are Quality risk management Documented approach Logical approach Skilled and trained staff Sending unit(SU) Receiving unit(RU)

51. The following general principles are to be followed for the successful technology transfer The project should be attain the quality parameters based on QRM. The facilities and equipment's available in SU and RU should be similar. The trained and skilled staffs should be available at RU RU should reproduce the documented evidence of transferred product, process or manufacturing method against the predetermined specification of SU. Reporting of out of specification results and error by the SU and SU The clarify of transfer process should be maintained. The legal implications like royalities,intellectual property rights ,conflict of interests should be conveyed prior and during the transfer.

52. Technology transfer protocols

53. Technology transfer protocols The following steps should be followed as per the technology transfer. Purpose and Objective of the transfer Scope of the transfer Skilled personnel and their responsibilities. A parallel comparison of materials, methods and equipment between SU and RU. The transfer stages with documented evidence that each critical stages has been satisfactorily accomplished before the next commences. Identification of critical control points.

54. Technology transfer protocols Experimental design and acceptance criteria for analytical methods. Information on trial production batches, qualification batches and process validation. Change control for any process deviations encountered. Analysis of finished product. Documented reports of analysis. Arrangements for keeping retention samples of active ingredients , intermediates and finished products, and information on reference substances where applicable; Conclusion, including signed-off approval by project manager.

55. Technology transfer protocols The SU should give the process and its supporting functions with the relevant validation documentation . In most cases, an existing process is transferred and documentation is already available. The SU should provide criteria and information on hazards and critical steps associated with the product, process, or method to be transferred so that a QRM exercise can be conducted at the RU prior to transfer in terms of premises, equipment, and support services (purchasing and inventory control mechanisms, quality control procedures, documentation, computer validation, site validation, equipment qualification, water for pharmaceutical production and waste management).

56. Technology transfer protocols The SU and RU should jointly validate the following validation protocols, which have been satisfactorily completed. Installation qualification and operational qualification data for manufacturing and packaging equipment at the RU site and analytical equipment. Qualification of the rooms for both manufacture and packaging at the RU site. The SU and the RU should jointly implement and evaluate any training programmes that may be required unique to the product, process, or method to be transferred, such as analytical procedures or equipment use.

57. Technology transfer protocols The SU and RU should work together to carry out the transfer procedure using a checklist and/or flow diagram that shows the sequence of steps to be followed during the technology transfer. The SU and the RU should work together to develop and implement any training programs that are required for the product, process, or method to be transferred, such as analytical procedures or equipment usage, and to evaluate training outcomes

58. Granularity of TT Process (API, excipients, finished products, packaging materials)

59. Active pharmaceutical ingredients (API) Complete information of API for formulation process, It includes : API solubility study data and impact of pH on solubility API Melting point and Polymorphism data. API toxicological data. Bulk and tap density with detail method of evaluation. Nature of hygroscopicity. Water content Loss on drying Limit of impurities Microbiological factors

60. Active pharmaceutical ingredients (API) contin .. The following are examples of the information which may typically be provided; Impact of API particle size on product performance Effect of API quality attributes variation on product performance API degradation study -Acid, alkali, temperature, light etc. Effect of different API vendors on product performance if multiple vendors are planned . API COA (in house and Vendor) of at least 3 batches and stability data

61. Active pharmaceutical ingredients (API) The SU should provide the RU with the open (applicant’s) part of the API master file (APIMF or drug master file (DMF) or active substance master file (ASMF)), or equivalent information and any relevant additional information on the API of importance for the manufacture of the pharmaceutical product. The following are examples of the information which may typically be provided; however the information needed in each specific case should be assessed using the principles of QRM. Manufacturer and associated supply chain; Step of the API to be transferred;

62. Active pharmaceutical ingredients (API) Contin.. Flow chart of synthesis pathway, outlining the process, including entry points for raw materials, critical steps, process controls and intermediates; Where relevant, definitive physical form of the API (including photomicrographs and other relevant data) and any polymorphic and solvate forms. solubility profile if relevant, pH in solution partition coefficient, including the method of determination.

63. Active pharmaceutical ingredients (API) Contin.. intrinsic dissolution rate, including the method of determination; particle size and distribution, including the method of determination; bulk physical properties, including data on bulk and tap density, surface area and porosity as appropriate; water content and determination of hygroscopicity, including water activity data and special handling requirements;

64. Active pharmaceutical ingredients (API) Contin.. Microbiological considerations (including sterility, bacterial endotoxins and bioburden levels where the API supports microbiological growth) in accordance with national, regional or international pharmacopeial requirements; Specifications and justification for release and end-of-life limits; Summary of stability studies conducted in conformity with current guidelines, including conclusions and recommendations on retest date; List of potential and observed synthetic impurities, with data to support proposed specifications and typically observed levels;

65. Active pharmaceutical ingredients (API) Contin.. Information on degradants, with a list of potential and observed degradation products and data to support proposed specifications and typically observed levels; Potency factor, indicating observed purity and justification for any recommended adjustment to the input quantity of API for product manufacturing, providing example calculations; and Special considerations with implications for storage and or handling, including but not limited to safety and environmental factors (e.g. as specified in material safety data sheets) and sensitivity to heat, light or moisture.

66. Active pharmaceutical ingredients (API) Contin.. Stability data of three batches including pilot bio batch Hold time Study data & if stability data of hold time batch if done Residual solvent data of development batches, if any organic solvents are used. Specific Environmental condition during Mfg., like Temp, RH, Sodium light, Oxygen scavengers, silica bags, triple laminated bags or any other condition of bulk storage as well as samples handling for sample to QC. Product Development history with respect to issues faced Dry Mixing.

67. Process Information Regarding the information of process and testing the following information should provided by the SU. Requirement of facility Requirement of equipment's Requirement of skilled person Detail information of raw materials Storage guideline and handling of raw materials and finished goods.

68. Process Information Manufacturing process Process flow charts Process optimization Detail master batch records Method of addition of raw materials and excipients Detail intermediate products. Reaction conditions Environmental factors Analytical methods Standardization process Assay procedure Finished goods testing

69. Validation protocols Process validation Equipment validation Annual audits and reviews Change control , critical point and corrective actions. Quality control and assurance. Process Information

70. Granulation Process 1. Challenges study for deciding factor for optimize high & low kneading, Impeller & chopper speed & its effect on physical & chemical parameters of tablets . 2. Impact of granulation challenges on property of finished product and granulometry like bulk density, Tapped Density, PSD (Probability,severity,detectability) Flow property of granules. 3. Granulation end point criteria /characteristic/organoleptic properties/Wet milling requirement if any .

71. Dry Mixing Challenge study for Mixing time vs Blend uniformity ,Bulk density, LOD & Theoretical Water content of dry mix / blend. Binder preparation and Addition Challenge study for binder quantity optimization, Binder addition rate & Solvent quantity optimization study. Viscosity of binder solution Effect of Hold time of binder at particular duration shall be studied, depends on nature binder, concentration etc.

72. Excipients

73. Excipients The excipients to be used have a potential impact on the final product. The duty of SU is to provide detail information of excipients to RU. The following information which may typically be provided; Description of functionality, with justification for inclusion of any antioxidant, Preservative or any excipient above recommended guidelines; manufacturer; Special considerations with implications for storage and/or handling, including but not limited to safety and environmental factors (e.g. as specified in material safety data sheets) and sensitivity to heat, light or moisture solubility.

74. Specifications, i.e. monographs and additional information that may affect product processing or quality for compendia excipients, or a complete listing of specifications, including analytical methods and justification for release limits for non-compendial excipients. Detail of manufacturer and supplier. Category of excipients Dosage form available Description and Solubility. Excipients Contin..

75. For transdermal dosage form Lipophilicity, partition coefficient Particle size and distribution Specific gravity Water content Dissolution and detail process. For solid dosage form Bulk density and taped density profile with detail method of evaluation Compaction properties. Particle size and distribution. Water content and loss of drying. Complete information of Excipient for formulation process, it includes:

76. Complete information of Excipient for formulation process, it includes: For semisolid dosage form Melting point Range of pH Viscosity Specific gravity For liquid dosage form Range of pH Viscosity Specific gravity Water content

77. For parenteral formulation Range of pH Viscosity, specific gravity, water content Osmotic pressure, ionic strength. For aerosol/inhaled dosage form: Solubility Bulk and tap density Particle size and distribution Water content Complete information of Excipient for formulation process, it includes:

78. FINISHED PRODUCTS

79. Finished Products The finished product is a final product that has completed all stages of production and manufacturing. The finished product should be stored in specific container and labeling is mandatory. The finished product storage and handling guidelines are to be informed to RU along with the detail specification and analytical test procedure. Predetermine specifications should be analyzed and detail standardization process should be transferred.

80. For inhaled dosage forms Solubility profile Bulk physical properties, including data on bulk and tap density, surface area and porosity as appropriate . Water content and determination of hygroscopicity, including water activity data and special handling requirements. Microbiological considerations in accordance with regional pharmacopoeial requirements.

81. For Solid Dosage Forms Solubility profile Bulk physical properties, including data on bulk and tap density, surface area and porosity as appropriate . Water content and determination of hygroscopicity, including water activity data and special handling requirements. Microbiological considerations in accordance with regional pharmacopoeial requirements .

82. For semi-solid/topical dosage forms Solubility profile melting point range pH range Specific density/gravity Viscosity and/or visco elasticity Moisture content range Microbiological considerations in accordance with regional pharmacopoeial requirements.

83. For parenteral dosage forms Solubility profile Specific density/gravity Osmolarity Moisture content range Microbiological considerations in accordance with regional pharmacopoeial requirements. pH range ionic strength

84. For Transdermal dosage forms Specific density/gravity Solubility profile Viscosity and/or visco elasticity Moisture content range Microbiological considerations in accordance with regional pharmacopoeial requirements. information on adhesives supporting compliance with peel, sheer and adhesion design criteria partition coefficient, including the method of determination

85. For liquid dosage forms Specific density/gravity Viscosity and/or visco elasticity Moisture content range Microbiological considerations in accordance with regional pharmacopoeial requirements.

86. Transfer from R & D to production (Process, packaging and cleaning )

87. Transfer from R & D to production Introduction It should be established at the outset whether the intention is to perform single-batch manufacture, continuous production or campaigns, and whether the RU can accommodate the intended production capacity. Consideration should be given to the level and depth of detail to be transferred to support production and any further development or process optimization at the RU as intended under the transfer project plan. The SU and the RU should jointly develop a protocol for the transfer of relevant information related to the manufacturing process under consideration from the SU to the RU, as well as the development of an equivalent process at the RU.

88. Process The SU should provide a detailed characterization of the product, including its qualitative and quantitative composition, physical description, method of manufacture, in-process controls and specifications, packaging components and configurations, and any special safety and handling considerations. The SU should provide any information on the history of process development which may be required to enable the RU to perform any further development and/or process optimization intended after successful transfer. Such information may include the following:

89. Information on clinical development , e.g. information on the rationale for the synthesis, route and form selection, technology selection, equipment, clinical tests, and product composition; Information on scale-up activities : process optimization, statistical optimization of critical process parameters, pilot report and/or information on pilot-scale development activities indicating the number and disposition of batches manufactured; and Process

90. Information or report on full-scale development activities, indicating the number and disposition of batches manufactured, and deviation and change control reports which led to the current manufacturing. The SU should provide to the RU information on any health, safety and environmental issues associated with the manufacturing processes to be transferred, and resulting implications, e.g. need for gowning or protective clothing. Process

91. The SU should provide to the RU information on current processing and testing, including : a detailed description of facility requirements and equipment ; process technology selection; information on starting materials, and storage requirements for raw materials and finished products; description of manufacturing steps (narrative and process maps or flow charts), including qualification of in-processing hold times and conditions, order and method of raw material addition and bulk transfers between processing steps; description of analytical methods;

92. in-process controls, including, e.g. identification of critical performance aspects for specific dosage forms, identification of process control points, product quality attributes and qualification of critical processing parameter ranges, statistical process control (SPC) charts; validation information, e.g. validation plans and reports, and annual product reviews; stability information; and an authorized set of SOPs and work instructions for manufacturing .

93. Packaging

94. Packaging: Information on packaging to be transferred from the SU to the RU include Suitable container Proper closure system Packaging material Process of packaging Design of packaging Proper labeling Relevant information mentioned in package and label. Based on the information provided, the RU should perform a suitability study for initial qualification of the packaging components.

95. Packaging: For quality control testing of packaging components, specifications should be provided for drawings, artwork, material . The information is provided by SU should be analyzed at RU for packaging either the packaging is suitable,safe,protective and compatible to the finished product or not. Packaging should be suggested in such a manner that the final product should not decompose or affected by the environmental factors. The product should not be oxidized and should be protected from sunlight. The container should not react with the product and the efficacy of the product should not altered by any means after packaging.

96. Cleaning

97. Cleaning: During the manufacturing process, pharmaceutical products and APIs can be contaminated by other pharmaceutical products or APIs if the plant is processing different products. To minimize the risk of contamination and cross-contamination, operator exposure & environmental effects, adequate cleaning procedures are essential. The SU should provide information on cleaning to minimize cross-contamination.

98. Cleaning: Cleaning procedures and their validation are site-specific. In order for the RU to define its cleaning strategy the SU should provide information on cleaning at the SU to minimize cross-contamination due to residues from previous manufacturing steps, operator exposure and environmental impact, including: information on solubility of active ingredients, excipients and vehicles; existing cleaning procedures

99. Additional information should be provided, as appropriate and where available, example cleaning validation reports (chemical and microbiological); information on cleaning agents used (efficacy, evidence that they do not interfere with analytical testing for residues of APIs, removal of residual cleaning agents); and recovery studies to validate the sampling methodology . Based on the information provided by the SU, cleaning procedures should be designed at the RU, taking into account relevant characteristics of the starting materials (e.g. potency, toxicity, solubility, corrosiveness and temperature sensitivity), manufacturing equipment design and configuration, cleaning agent and products residue.

100. Documentation for transfer of technology (TOT) Some of the important documents required in technology transfer are Technology transfer protocol, qualification protocol Training protocols report Standard operating procedure Technology transfer report Analytical method transfer protocol Validation report Process validation report, stability report Cleaning validation protocol and report Validation master plan Master batch record.

101. Documentation: The documents used in technology transfer are presented in table. Documentation for transfer of technology (TOT) Key task Documentation provided by SU Transfer documentation Project definition Project plan and quality plan (where separate documents), protocol, risk assessments, gap analysis Project implementation plan TOT protocol Quality agreement Facility assessment Plans and layout of facility, buildings (construction, finish) Qualification status (DQ, IQ, OQ) and reports Side-by-side comparison with RU facility and buildings; gap Analysis Qualification protocol and report

102. Documentation for transfer of technology (TOT) Key task Documentation provided by SU Transfer documentation Health & Safety assessment Product-specific waste management plans Contingency plans . Skill set analysis and training SOPs and training documentation (product-specific operations, analysis, testing) . Training protocols, assessment results Analytical method transfer Analytical method specifications and validation, including in-process quality control. Analytical methods transfer protocol and report

103. Documentation for transfer of technology (TOT) Key task Documentation provided by SU Transfer documentation Starting material Evaluation Equipment selection and transfer Specifications and additional information on APIs, excipients Inventory list of all equipment and systems, including makes, models, qualification status (IQ, OQ, PQ). Drawings, manuals, logs, SOPs (e.g. set-up, operation, cleaning, maintenance, calibration, storage) Side-by-side comparison with RU equipment (makes, models, qualification status) Gap analysis. Qualification and validation protocol and report

104. Key task Documentation provided by SU Transfer documentation Process transfer: manufacturing and packaging Reference batches (clinical, dossier, bio-batches) Development report (manufacturing process rationale), History of critical analytical data Rationale for specifications, Change control documentation, Critical manufacturing process Parameters Process validation reports Drug master file. API validation status and report(s) Product stability data Current master batch manufacturing and packaging records List of all batches produced Deviation reports, Investigations, complaints, recalls Annual product review History of process development at RU, Experiences at RU should be recorded for future reference Provisional batch mfg. document (RU to develop) Provisional batch packaging document (RU to develop) Description of process at RU (narrative, process map, flow chart) Process validation protocol and report

105. Documentation for transfer of technology (TOT) Key task Documentation provided by SU Transfer documentation Cleaning Cleaning validation, Solubility information; therapeutic doses; category (toxicology); existing cleaning SOPs; validation reports chemical and micro; agents used; recovery study Product- and site-specific cleaning SOPs at RU Cleaning validation protocol and report

106. Premises and Equipment

107. Premises The SU should provide information to the RU on the Plant layout, construction and finish of all buildings and services . Heating Ventilation and air-conditioning, Temperature, Relative humidity, power system, water system Compressed air related information should be provided to RU before the production.

108. Premises Contin.. The SU should provide information on relevant h ealth, safety and environmental issues , including: inherent risks of the manufacturing processes (e.g. reactive chemical hazards, exposure limits, fire and explosion risks). health and safety requirements to minimize operator exposure (e.g. atmospheric containment of pharmaceutical dust).

109. Differences in building, construction layout and services between the SU and the RU should be listed and compared in view of the following considerations: buildings and services at the RU should be capable of accommodating the product, process or method under transfer to the agreed quality standard and production volume in compliance with GMP. Quality control laboratories should be equipped and capable of testing all APIs, excipients, intermediate and finished products, packaging components and cleaning validation samples; Premises Contin..

110. Buildings intended for production of a highly sensitizing nature (e.g. penicillin's and cytotoxic materials) should be dedicated for this purpose and located in a different facility from other production units; Health, safety and environmental issues, including waste management, emergency planning, minimization of operator exposure and environmental impact, should be addressed at the RU in compliance with any regulatory or company-developed rules, regulations and limits. Premises Contin..

111. Equipment Equipment The SU should provide a list of equipment, makes and models involved in the manufacture, filling, packing and/or control of the product, process or method to be transferred, together with existing qualification and validation documentation. Relevant documentation may include: • Drawings; • Manuals; • Maintenance logs; • Calibration logs; and • SOPs (e.g. equipment set up, operation, cleaning, maintenance, calibration, storage).

112. The RU should review the information provided by the SU together with its own inventory list including the qualification status (IQ, OQ, PQ) of all equipment and systems, and perform a side by-side comparison of equipment at the two sites in terms of their functionality, makes, models and qualification status. Based on the side-by-side comparison, the RU should perform a gap analysis to identify requirements for adaptation of existing equipment, or acquisition of new equipment, to enable the RU to reproduce the process being transferred. Equipment Contin..

113. GMP requirements should be satisfied, and intended production volumes and batch sizes (e.g. same, scaled-up or campaign) should be considered. Factors to be compared include: minimum and maximum capacity material of construction critical operating parameters critical equipment components (e.g. filters, screens, temperature/pressure sensors) and range of intended use. Equipment Contin..

114. The facility- and building-specific location of all equipment at the RU should be considered at the time of drawing up process maps or flow charts of the manufacturing process to be transferred, including movement of personnel and material. The impact of manufacturing new products on products currently manufactured with the same equipment should be determined. Equipment Contin..

115. New equipment should be designed and constructed to facilitate the process and ease cleaning and maintenance operations. Any newly acquired equipment should undergo a qualification protocol up to and including OQ level. Applicable operating procedures for set-up, operation, cleaning, storage and maintenance should be developed by the conclusion of OQ. Supporting documents such as drawings of equipment and piping installations, manuals, maintenance logs and calibration logs should be retained. Equipment Contin..

116. Qualification and Validation

117. General Qualification and validation of facilities, equipment, systems and procedures are essential to demonstrate that all critical stages of the transfer project have been completed successfully, enabling the RU to reproduce the product, process or method routinely to the specifications agreed with the SU. Validation performed as part of the transfer project should be documented in a validation master plan (VMP). The VMP should identify the stages which need to be validated and define acceptance criteria.

118. For intra-company transfers, the RU should operate under the same VMP as the SU. For inter company transfers, a VMP should be in place at the RU before the transfer. The RU should prepare a validation protocol (VP) for each sequential step. Successful execution of each VP should be documented in a validation report (VR). The steps required for this purpose have been described in this guideline for buildings, services and equipment, manufacturing, packaging and cleaning and analytical testing. General

119. In brief, the following basic steps apply equally to each of these areas: The SU should provide information on materials, systems and procedures involved in the manufacturing of the product, process or method to be transferred; The RU should review the information provided by the SU, and audit its current systems, equipment and processes , including non-process related practices and support services that impact the process; General

120. General Based on this review, the RU should either accept the information provided or develop it further to prepare site-specific procedures, SOPs, training programmes and protocols which will form the basis of the qualification and validation ; and relevant staff, e.g. operators and analysts, should be trained in any new processes as required. Once the required systems and procedures have been commissioned at the RU, and successful training has been documented,

121. Qualification and validation of facility and equipment should be executed, followed by validation of analytical test methods, process validation for manufacturing and packaging, and cleaning validation. The RU should review the gap analysis and prepare, where appropriate, VPs for the facility, services and equipment. Both new and existing equipment should satisfy the VPs associated with purchase and design specifications, factory acceptance tests (FAT) if possible, IQ and OQ. Performance qualification, including a further assessment of operating parameters with relation to product characteristics, should be established on commencement of trial batches. Successful completion of qualification and validation should be documented in a report.

122. Quality control

123. Quality control Transfer of analytical methods should accommodate all the analytical testing required to demonstrate compliance of the product to be transferred with the registered specification. Transfer of analytical methods used to test pharmaceutical products, their ingredients and cleaning (residue) samples, needs to be in place before process validation studies of manufacturing operations can be carried out.

124. Quality control SU's responsibilities The SU's responsibilities for the transfer of analytical methods are to: provide method-specific training for analysts and other quality control staff; provide acceptance criteria and validation protocols for any RU training exercises; assist in analysis of quality control testing results; define and justify all methods to be transferred for testing a given product, ingredient or cleaning sample;

125. SU's responsibilities define experimental design, sampling methods and acceptance criteria; provide any validation reports for methods under transfer, and demonstrate their robustness; provide data for the equipment used and any standard reference samples; and provide approved SOPs used in testing. Quality control

126. The RU's responsibilities are to: Review analytical methods provided by the SU, and formally agree on acceptance criteria before execution of the transfer protocol; Ensure that the necessary equipment for quality control is available and qualified at the RU site. Equipment should be replicated where possible, but it is accepted that different models, e.g. spectrometers and chromatographs, could already be in place; Ensure that adequately trained and experienced personnel is in place for analytical testing;

127. Quality control RU's responsibilities Provide a documentation system capable of recording receipt and testing of samples. suggested analytical training protocol would be as follows: SU and RU analysts assay two retained samples from SU. SU and RU analysts then assay two sub-potent samples (available from SU or spiked).

128. RU's responsibilities SU and RU analysts assay samples taken from RU production; RU analyst provides sufficient replicate analyses to enable a significance test against the established method at the SU site; and a similar exercise should be undertaken for analysis of low levels of APIs. All training activities and outcomes should be documented.

129. Analytical method transfer

130. Technology Transfer— Analytical Method Analytical methods used to test pharmaceutical products, starting materials, packaging components and cleaning (residue) samples, if applicable, should be implemented at the testing laboratory before testing of samples for process validation studies is performed by the RU. Analytical method transfer should be performed providing all the information regarding analytical testing.

131. Technology Transfer— Analytical Method A protocol defining the steps should be prepared for transfer of analytical methods. The analytical methods transfer protocol should include a description of the objective, scope and responsibilities of the SU and the RU; a specification of materials and methods; the experimental design and acceptance criteria; documentation (including information to be supplied with the results, and report forms to be used, if any); procedure for the handling of deviations; references; signed approval; and details of reference samples (starting materials, intermediates and finished products ).

132. Responsibilities of SU The SU should provide the following information for analytical method transfer . The methods of analysis and testing raw materials, finished products. Training for analyst and staff Details of equipment's used for the testing. Testing parameters. Experimental principle, design and methods. Quality control testing results. Validation reports. Technology Transfer— Analytical Method

133. Responsibilities of RU ❖ Review analytical methods provided by the SU , and formally agree on acceptance criteria before execution of the transfer protocol. ❖ Ensure that the necessary equipment for QC is available and qualified at the RU site. The equipment used by the RU during the analytical transfer should meet appropriate specifications to ensure the requirements of the method or specification are met. ❖ Ensure that adequately trained and experienced personnel are in place for analytical testing.

134. Responsibilities of RU Review analytical methods provided by the SU , and formally agree on acceptance criteria before execution of the transfer protocol. ❖ Ensure that the necessary equipment for QC is available and qualified at the RU site. The equipment used by the RU during the analytical transfer should meet appropriate specifications to ensure the requirements of the method or specification are met. ❖ Ensure that adequately trained and experienced personnel are in place for analytical testing.

135. The RU’s responsibilities are to: Provide a documentation system capable of recording receipt and testing of samples to the required specification using approved test methods, and of reporting, recording and collecting data and designation of status (approved, rejected, quarantine); ❖ Execute the method transfer protocol; ❖ Perform the appropriate level of validation to support the implementation of the methods; and ❖ Generate and obtain approval of transfer reports.

136. RU’s responsibilities It is recommended to perform the demonstration of analytical methods by SU-QC to RU-QC and based on mutual agreement, Standard testing procedure shall be prepared for a method validation/ verification (as applicable) study by RU QC. ❖ Sending Unit shall transfer Analytical method to receiving unit in concurrence to relevant regulatory guideline and GMP aspects . ❖ Possible experimental designs and acceptance criteria for the main analytical testing methods.

137. WHO has clearly mentioned about the possible experimental designs for analytical testing. The test are Identification test Content uniformity Solubility Assay or percentage purity of components Dissolution parameter Qualitative and quantitative test for microbiological assays. Limit test for impurities Residue recovery The responsibilities from both sending unit and receiving unit should be performed and should prepare the report jointly to execute the transfer protocol.

138. Cleaning Therapeutic category and toxicological assessment; and Existing cleaning procedures. ❖ Cleaning validation reports (chemical and microbiological); ❖ Information on cleaning agents used (efficacy, evidence that they do not interfere with analytical testing for residues of APIs, removal of residual cleaning agents) ❖ Recovery studies to validate the sampling methodology

139. Technology Transfer— Analytical Method Analytical Method –Dissolution Dissolution at different RPM of paddle / basket. Dissolution profile time point (Release and stability). Effect of temperature of dissolution media. Effect of change over (from acid to buffer) -time / rinsing method on dissolution. Effect of pH of dissolution media on dissolution. Dissolution method Manual vs Autosampler study data . For capsule product, dissolution with & without sinker, with and without enzyme.

140. Analytical Method Transfer Validation Blend Uniformity -Blend Assay -impact of Sample Size . FP Assay and FP CU method comparison. PSD -Type of Sieve / Sieve Shaker / Time / Quantity of sample . Impact of sonication time study on assay /Blend uniformity Storage condition for standards, impurities and any specific information/precautions for handling Method validation and transfer data.