This presentation is compiled by “ Drug Regulations” a Not forProfit organization from publicly available material on the ...
   Background                                                                    Laboratory Controls-Stability   New Ru...
   A phase 1 clinical trial includes the initial introduction of an    investigational new drug product, including biolog...
   In phase 2 and phase 3 clinical trials substantially greater    number of subjects are exposed to the drug product   ...
   Section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351 (a)(2)(B))    requires drugs, which include IND products, to compl...
   The preamble to a final rule published in the Federal Register of    September 29, 1978 (43 FR 45014) (the 1978 final ...
   These typically are characterized by    ◦ Large, repetitive, commercial batch production (e.g., those regulations that...
   The preamble further stated :   „„The Commissioner finds that, as stated in § 211.1, these CGMP    regulations apply ...
   On February 21, 1991, FDA issued a guidance document entitled    „„Preparation of Investigational New Drug Products (H...
   For several reasons, FDA believed that production of phase 1    investigational drugs should be exempted from complyin...
   First   Investigational drugs remain subject to the statutory requirement that    deems a drug adulterated if „„* * *...
   Second   FDA oversees drugs for use in phase 1 trials through its existing    IND authority.   Every IND must contai...
   Third   Under this IND authority, FDA has the option to place an IND on    clinical hold if the study subjects would ...
   Thus,   Even though FDA is exempting phase 1 drug products from    compliance with the specific requirements of the C...
   FDA believed this change in the CGMP regulations (parts 210 and    211) was appropriate because many of the issues pre...
   Additionally, many of the specific requirements in the regulations in part 211    do not apply to the conditions under...
   The F D A in July 2008 issued a final regulation thatmade early phase 1 clinical drug development safe and    efficien...
   Consequently, in the final rule, FDA amended the scope section of the drug    CGMP regulations in part 210          to...
www.drugregulations.org   19
   Included:       Recombinant and non-recombinant products       Vaccines       Allergenic products       In vivo di...
   Excluded:       Human cell or tissue products       Clinical trials for device approval       Products manufactured...
   Maintain Quality & Safety of Investigational Drug by       Established or standardized QC procedures       Following...
   Alternatives to meet the objectives are acceptable.   Ensure that methods, facilities, and manufacturing    controls ...
   Consider the hazards and associated risks from the    manufacturing environment when drug is manufactured    in labora...
   A   comprehensive        and   systematic   evaluation   of   the    manufacturing setting to identify potential hazar...
   Manufacturing environment should have adequate work areas    that are properly equipped and controlled for the specifi...
   Use different Technologies to meet CGMP    Requirements :    ◦ Use of disposable equipment and process aids to reduce ...
   Use different Technologies to meet CGMP    Requirements :    ◦ Use of closed process equipment (i.e., the phase 1     ...
   Personnel need appropriate education, experience    and training   Appropriate experience to prepare the phase 1    i...
   Need a written plan that describes the role and responsibilities of the QC    function.   Examine materials and compo...
   Quality is the responsibility of all personnel involved in    manufacturing.   However, assign an individual(s) to pe...
   Can use laboratories that are not expressly or solely designed for    their manufacture, can use shared facilities, ac...
   Adequate work areas and equipment for the    intended task.   Each facility should provide :    ◦ Sufficient space, c...
   Appropriate   equipment     to   maintain   an   air    cleanliness classification suitable to the operation    perfor...
   Equipment: Disposables, Prepackaged Materials, Closed Systems (can potentially    alleviate the need for stricter room...
   Establish written procedures describing the   Handling,   Review,   Acceptance, and   Control of material (i.e., c...
   Identify and trace all materials used in the manufacture from receipt    to use in the manufacture of each batch.   K...
   Establish acceptance criteria for specified attributes on each    material.   For some materials, all relevant attrib...
   Examine      the    certificate   of   analysis   (COA)     and/or   other    documentation on each lot of material to...
   Follow written manufacturing and process control procedures:   Manufacturing data should detail:    ◦ Materials,    ◦...
   Maintain record of changes in procedures and processes used    for subsequent batches along with the rationale for any...
   Laboratory tests should be scientifically sound (e.g., specific,    sensitive, and accurate), suitable and reliable. ...
   Monitor specified attributes and acceptance criteria applied    appropriately.   Establish specifications for known s...
   Maintain the equipment according to established written    procedures.   Verify the equipment is in good working cond...
   Sample quantity , where feasible , should be adequate to    perform additional testing or investigation if required at...
   Initiate stability study   Use representative samples of the phase 1 investigational    drug   Monitor the stability...
   Package the drug suitably to protect it from alteration,    contamination, and damage during storage, handling, and   ...
   Distribution includes the transport of a phase 1    investigational drug .   Handle phase 1 investigational drugs in ...
   Keep complete records relating to the quality and operation of the    manufacturing processes, including but not limit...
   Manufacture only one phase 1 investigational drug at any given    time.   Area could be used for multiple purposes, i...
   Examples of procedural controls could include   procedures for clearing the room of previous product materials,   pr...
   The manufacturing process is critical to ensure the correct    composition, quality, and safety .   Difficult to dist...
   Implement appropriate equipment and controls in    manufacturing   Ensure that unit operations with safety-related fu...
   Evaluate the manufacturing environment for susceptibility to    contaminate the environment with biological substances...
   Multi-product facilities should have in place cleaning and    testing procedures that ensure prevention and/or detecti...
   Consider additional or specialized controls.   It may not be possible to follow each recommendation of the    guidanc...
   Manufacture of multiple batches will allow manufacturing and    testing information to accumulate in an accelerated ma...
   Take special precautions for Sterile Products.   Implement appropriate controls for aseptic processing to    ensure a...
   Conduct aseptic manipulation in an aseptic workstation under    laminar airflow conditions that meet Class A, ISO 5. ...
   Disinfect the entire aseptic workstation e.g.,    ◦ before aseptic manipulation, or    ◦ between different operations ...
   Disinfect the surface of nonsterile items with sterile disinfectant    solution before placing them in the laminar flo...
   Verify that the equipment is suitable for its intended .   Perform appropriate calibration of temperature probes used...
   Ensure that release of drug by the QC unit, or designated individual,    includes an acceptable review of manufacturin...
   Where is the clinical trial?   ICH Q7A   EMEA   Raw material identity testing   Quality Agreements   Quality Unit...
   Drug device combination products   Need to follow QSR and Design Controls   Quality Systems and documentation:   Us...
   Different Quality Agreement for phase 1contractors, or Development    Agreement or Scope of Work?   Can you use the p...
   The final FDA rule exempts investigational drugs used in phase 1    studies (as described in 21 C.F.R. § 312.21 of FDA...
   FDA believes that many of the issues presented by the production of    investigational drugs intended for use in the r...
   The exempt phase 1 drugs are, however, still required to meet the    statutory (as opposed to regulatory) requirements...
   With respect to general guidance, it notes that adherence to CGMP    during manufacture of phase 1 investigational dru...
   The guidance further notes it is the manufacturer’s responsibility to    provide and use methods, facilities, and manu...
This presentation is compiled by “ Drug Regulations” a Not forProfit organization from publicly available material on the ...
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CGMP for IND phase I products

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A phase 1 clinical trial includes the initial introduction of an investigational new drug product, including biological drug products, into humans. Such studies are conducted to establish the basic safety of the drug, and are designed to determine the metabolism and pharmacologic actions of the drug in humans. The total number of subjects in a phase 1 clinical trial is limited generally to no more than 80 subjects.
This presentation covers the CGMP’s for Investigation New Drugs for Phase I. The presentation has been compiled from publicly available material on the world wide web by “ Drug Regulations” a not for profit organization.

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CGMP for IND phase I products

  1. 1. This presentation is compiled by “ Drug Regulations” a Not forProfit organization from publicly available material on the world wide web. Visit www.drugregulations.org www.drugregulations.org 1
  2. 2.  Background  Laboratory Controls-Stability New Rule for IND Phase I ( 2008 amendment)  Packaging , Labelling & Distribution Scope of the new rule & guidance  Special Manufacturing Situations- Multi product General points throughout the guidance Facility. Steps to establish appropriate manufacturing  Special Manufacturing Situations-Biological & Bio environment Technology Products. Personnel  Special Manufacturing Situations-Adventitious Agent QC Function Control Facilities  Special Manufacturing Situations- Gene Therapy & Equipment Cellular Therapy Products. Control of Components, and Containers and  Special Manufacturing Situations- Sterile Products Closures  Other Considerations Manufacturing & Records  Contract Manufacturing & Testing Laboratory Controls- Testing  Summary www.drugregulations.org 2
  3. 3.  A phase 1 clinical trial includes the initial introduction of an investigational new drug product, including biological drug products, into humans. Such studies are conducted to establish the basic safety of the drug, and Are designed to determine the metabolism and pharmacologic actions of the drug in humans. The total number of subjects in a phase 1 clinical trial is limited generally to no more than 80 subjects. www.drugregulations.org 3
  4. 4.  In phase 2 and phase 3 clinical trials substantially greater number of subjects are exposed to the drug product The effectiveness of the drug product is also tested in addition to safety. During phase 2 or phase 3, drug products may also be made available for treatment use through one of several mechanisms for expanded access to investigational drugs. www.drugregulations.org 4
  5. 5.  Section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351 (a)(2)(B)) requires drugs, which include IND products, to comply with current good manufacturing practice. If not the Drug is deemed adulterated. FDA‟s general CGMP regulations for human drugs are set forth in parts 210 and 211. Based on this statutory requirement manufacturers were required to follow CGMP. ( 21 CFR parts 210 and 211) www.drugregulations.org 5
  6. 6.  The preamble to a final rule published in the Federal Register of September 29, 1978 (43 FR 45014) (the 1978 final rule) issuing these regulations expressly stated that the CGMP regulations applied to investigational drug products also. However certain requirements in part 211, which implement § 501(a)(2)(B) of the FD&C Act, are directed at the commercial manufacture. www.drugregulations.org 6
  7. 7.  These typically are characterized by ◦ Large, repetitive, commercial batch production (e.g., those regulations that address validation of manufacturing processes (§ 211.110(a)), and ◦ Warehousing (§ 211.142)) Therefore these were not appropriate for the manufacture of most investigational drugs used for phase 1 clinical trials. www.drugregulations.org 7
  8. 8.  The preamble further stated : „„The Commissioner finds that, as stated in § 211.1, these CGMP regulations apply to the preparation of any drug product for administration to humans or animals, including those still in investigational stages. It is appropriate that the process by which a drug product is manufactured in the development phase be well documented and controlled in order to assure the reproducibility of the product for further testing and for ultimate commercial production. The Commissioner is considering proposing additional CGMP regulations specifically designed to cover drugs in research stages‟‟ (43 FR 45014 at 45029). Such additional regulations have never been issued. www.drugregulations.org 8
  9. 9.  On February 21, 1991, FDA issued a guidance document entitled „„Preparation of Investigational New Drug Products (Human and Animal)‟‟ (56 FR 7048) (the 1991 guidance). That document, however, did not discuss all manufacturing scenarios, and Did not clearly address small- or laboratory-scale production of drug products for use in phase 1 clinical trials. Additionally, the 1991 guidance did not fully discuss FDA‟s expectations on appropriate approaches to manufacturing controls for batches produced during drug development. www.drugregulations.org 9
  10. 10.  For several reasons, FDA believed that production of phase 1 investigational drugs should be exempted from complying with the specific regulatory requirements set forth in parts 210 and 211. These reasons are given in succeeding slides. www.drugregulations.org 10
  11. 11.  First Investigational drugs remain subject to the statutory requirement that deems a drug adulterated if „„* * * the facilities or controls used for, Its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practices. To assure that such drug meets the requirements as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess‟‟ (section 501(a)(2)(B) of the act (21 U.S.C. 351(a)(2)(B))). www.drugregulations.org 11
  12. 12.  Second FDA oversees drugs for use in phase 1 trials through its existing IND authority. Every IND must contain, among other things, a section on chemistry, manufacturing, and control information that describes the Composition, manufacture, and control of the investigational drug product (§ 312.23(a)(7) (21 CFR 312.23(a)(7))) Submission of this information, along with other information required in the IND, informs FDA of the steps that the manufacturer is taking to ensure the safety and quality of the investigational drug. www.drugregulations.org 12
  13. 13.  Third Under this IND authority, FDA has the option to place an IND on clinical hold if the study subjects would be exposed to unreasonable and significant risk or if the IND does not contain sufficient information to assess the risks to subjects (21 CFR 312.42). FDA also may terminate an IND if the methods, facilities, and controls used for the manufacturing, processing, and packing of the investigational drug are inadequate to establish and maintain appropriate standards of identity, strength, quality, and purity as needed for subject safety (21 CFR 312.44(b)(1)(iii)). www.drugregulations.org 13
  14. 14.  Thus, Even though FDA is exempting phase 1 drug products from compliance with the specific requirements of the CGMP regulations, FDA retains the ability to take appropriate actions to address manufacturing issues. For example, in addition to the authority to put an IND on clinical hold or terminate an IND, FDA may initiate an action to seize an investigational drug or enjoin its production if its production does not occur under conditions sufficient to ensure the identity, strength, quality, and purity of the drug, which may adversely affect its safety www.drugregulations.org 14
  15. 15.  FDA believed this change in the CGMP regulations (parts 210 and 211) was appropriate because many of the issues presented by the production of investigational drugs intended for use in the relatively small phase 1 clinical trials are different from issues presented by the production of drug products for use in the larger phase 2 and phase 3 clinical trials or for commercial marketing. www.drugregulations.org 15
  16. 16.  Additionally, many of the specific requirements in the regulations in part 211 do not apply to the conditions under which many drugs for use in phase 1 clinical trials are produced. For example, the concerns underlying the regulations‟ requirement for ◦ Fully validated manufacturing processes, ◦ Rotation of the stock for drug product containers, ◦ The repackaging and relabeling of drug products, and ◦ Separate packaging and production areas Are generally not concerns for these very limited production investigational drug products used in phase 1 clinical trials. www.drugregulations.org 16
  17. 17.  The F D A in July 2008 issued a final regulation thatmade early phase 1 clinical drug development safe and efficient by enabling a phased approach to complying with current good manufacturing practice (CGMP) statutes and FDA investigational requirements. www.drugregulations.org 17
  18. 18.  Consequently, in the final rule, FDA amended the scope section of the drug CGMP regulations in part 210 to make clear that production of investigational drugs for use in phase 1 clinical trials conducted under an IND need not comply with the regulations in part 211. However, once an investigational drug product has been manufactured by, or for, a sponsor and is available for use in a phase 2 or phase 3 study, the same investigational drug product used in any subsequent phase 1 study must be manufactured in compliance with part 211. www.drugregulations.org 18
  19. 19. www.drugregulations.org 19
  20. 20.  Included:  Recombinant and non-recombinant products  Vaccines  Allergenic products  In vivo diagnostics  Plasma derivatives Blood and blood components (but must comply with 21 CFR 600-660)  Gene therapy and somatic cellular therapy  APIs used in phase 1
  21. 21.  Excluded:  Human cell or tissue products  Clinical trials for device approval  Products manufactured for phase 1 and 2 clinical trials  Already approved products  PET drugs (21 CFR 212)
  22. 22.  Maintain Quality & Safety of Investigational Drug by  Established or standardized QC procedures  Following appropriate CGMP  Well-defined, written procedures  Adequately controlled equipment and manufacturing environment  Accurately and consistently recorded data from manufacturing (including testing)
  23. 23.  Alternatives to meet the objectives are acceptable. Ensure that methods, facilities, and manufacturing controls used ensure that appropriate standards of safety, identity, strength, quality, and purity are met. Consider carefully how to best ensure the implementation of standards, practices, and procedures that conform to CGMP for their specific product and manufacturing operation.
  24. 24.  Consider the hazards and associated risks from the manufacturing environment when drug is manufactured in laboratory facilities. Consider contamination or cross contamination with other substances (e.g. chemicals, biologicals, adventitious agents) that may be present from previous or concurrent research or manufacturing activities.
  25. 25.  A comprehensive and systematic evaluation of the manufacturing setting to identify potential hazards. ◦ Product environment, ◦ Equipment, ◦ Process, ◦ Personnel, ◦ Materials Appropriate actions prior to and during manufacturing to eliminate or mitigate potential hazards to safeguard the quality of the phase 1 investigational drug.
  26. 26.  Manufacturing environment should have adequate work areas that are properly equipped and controlled for the specific operation(s) . Given the diversity of products and requisite manufacturing operations, not all environments may be acceptable for the manufacture of the specific phase 1 investigational drug under consideration. In these situations, use of more suitable facilities is recommended.
  27. 27.  Use different Technologies to meet CGMP Requirements : ◦ Use of disposable equipment and process aids to reduce cleaning burden and chances of contamination ◦ Use of commercial, pre-packaged materials (e.g., Water For Injection (WFI), pre-sterilized containers and closures) to eliminate the need for additional equipment or for demonstrating CGMP control of existing equipment.
  28. 28.  Use different Technologies to meet CGMP Requirements : ◦ Use of closed process equipment (i.e., the phase 1 investigational drug is not exposed to the environment during processing) to alleviate the need for stricter room classification for air quality . ◦ Use of contract or shared CGMP manufacturing facilities and testing laboratories (including specialized services).
  29. 29.  Personnel need appropriate education, experience and training Appropriate experience to prepare the phase 1 investigational drug Experience & Training in QC principles Experience & Training in acceptable methods for complying with the statutory requirement of CGMP.
  30. 30.  Need a written plan that describes the role and responsibilities of the QC function. Examine materials and components Review and approval of manufacturing and testing procedures and acceptance criteria Releasing or rejecting batches Investigating unexpected results or errors An individual independent of manufacturing preferred. Same individual performing the manufacturing and the QC functions acceptable in small operations. ◦ Another qualified individual independent of manufacturing must conduct periodic reviews
  31. 31.  Quality is the responsibility of all personnel involved in manufacturing. However, assign an individual(s) to perform QC functions independent of manufacturing responsibilities. Especially for the cumulative review and release of phase 1 investigational drug batches.
  32. 32.  Can use laboratories that are not expressly or solely designed for their manufacture, can use shared facilities, academic institutions Need to conduct a comprehensive and systematic evaluation of the manufacturing setting to identify potential hazards Focus on contamination and cross-contamination with other substances Identify appropriate actions prior to and during manufacturing that eliminate or mitigate those hazards Assess contract facilities to ensure effective quality control functions
  33. 33.  Adequate work areas and equipment for the intended task. Each facility should provide : ◦ Sufficient space, clean environment, appropriate construction ◦ Appropriate lighting, ventilation, and heating ◦ Appropriate cooling, plumbing, washing, and sanitation
  34. 34.  Appropriate equipment to maintain an air cleanliness classification suitable to the operation performed in the area. For example, appropriate air handling systems (e.g., laminar flow hoods) to aid in preventing contamination and cross-contamination.
  35. 35.  Equipment: Disposables, Prepackaged Materials, Closed Systems (can potentially alleviate the need for stricter room classification…) “Appropriate” space, lighting, cooling, ventilation, cooling, heating, plumbing, washing, and sanitation Identify all equipment used for a particular process and document it in the record Equipment that will not react with, add to, or be absorbed by the phase 1 drug Equipment properly maintained, cleaned, calibrated and sanitized following written procedures Procedural controls to prevent contamination and cross contamination Air cleanliness suitable to the operations “Use of procedural controls in a facility promotes orderly manufacturing and aids in preventing contamination…”
  36. 36.  Establish written procedures describing the Handling, Review, Acceptance, and Control of material (i.e., components, containers, closures) used in the manufacture of a phase 1 investigational drug. Materials should be controlled (e.g., segregated, labelled) until examined or tested and released. It is important to handle and store such materials in a manner that prevents degradation or contamination.
  37. 37.  Identify and trace all materials used in the manufacture from receipt to use in the manufacture of each batch. Keep a record (e.g., log book) containing relevant information on all materials. At a minimum, record Receipt date, Quantity of the shipment, Suppliers name, Material lot number, Storage conditions, and Corresponding expiration date.
  38. 38.  Establish acceptance criteria for specified attributes on each material. For some materials, all relevant attributes or acceptance criteria may not be known at the phase 1 stage of product development. However, attributes and acceptance criteria selected for assessment should be based on scientific knowledge and experience for use in the specific phase 1 investigational drug. The material attributes and acceptance criteria will be reviewed in the IND application.
  39. 39.  Examine the certificate of analysis (COA) and/or other documentation on each lot of material to ensure that it meets established acceptance criteria for specified attributes. For some (e.g., human and animal derived material), documentation should include information on sourcing and/or test results for adventitious agents, as appropriate. If documentation for a material is incomplete for a specified attribute, test for the incomplete specified attribute of the material. For each batch of the API (or drug substance), perform confirmatory identity testing.
  40. 40.  Follow written manufacturing and process control procedures: Manufacturing data should detail: ◦ Materials, ◦ Equipment, ◦ Procedures used, and ◦ Any problems encountered during manufacturing. Retain records sufficient to replicate the manufacturing process. Include an explanation of why manufacturing was terminated if manufacture is initiaited but not completed.
  41. 41.  Maintain record of changes in procedures and processes used for subsequent batches along with the rationale for any changes. Maintain record of the microbiological controls that have been implemented (including written procedures) for the production of sterile-processed drugs. Follow the recommendations for use of aseptic techniques and the control of in-process materials, components, and container closures designed to prevent microbial and endotoxin contamination.
  42. 42.  Laboratory tests should be scientifically sound (e.g., specific, sensitive, and accurate), suitable and reliable. Perform tests under controlled conditions and Follow written procedures describing the testing methodology. Maintain records of all test results, procedures, and changes in procedures. Perform laboratory testing to evaluate quality attributes including those that define the identity, strength, potency, purity, as appropriate.
  43. 43.  Monitor specified attributes and acceptance criteria applied appropriately. Establish specifications for known safety-related concerns, and meet them. For some phase 1 investigational drug attributes, all relevant acceptance criteria may not be known at this stage of development. This information will be reviewed in the IND submission. Calibrate laboratory equipment at appropriate intervals to maintain reliability of test results
  44. 44.  Maintain the equipment according to established written procedures. Verify the equipment is in good working condition when samples are analysed (e.g., system suitability). Retain a representative sample from each batch of phase 1 investigational drug. Retain both the API and phase 1 investigational drug in containers used in the clinical trials.
  45. 45.  Sample quantity , where feasible , should be adequate to perform additional testing or investigation if required at a later date (e.g., twice the quantity necessary to conduct release testing, excluding testing for pyrogenicity and sterility). Store appropriately and retain the samples for at least two years following clinical trial termination, or withdrawal of the IND application.
  46. 46.  Initiate stability study Use representative samples of the phase 1 investigational drug Monitor the stability and quality of the phase 1 investigational drug during the clinical trial (i.e., date of manufacture through date of last administration) IND regulations require information sufficient to assure the drug product’s stability during the planned studies (see 21CFR 312.23(a)(7)(iv) (b)).
  47. 47.  Package the drug suitably to protect it from alteration, contamination, and damage during storage, handling, and shipping. Establish written procedures for controlling packaging, labelling, and distribution operations. Use appropriate measures to achieve effective control ◦ e.g., product segregation, label reconciliation, verify operations by a second person, confirmatory laboratory testing, QC review) This is essential in situations where the potential for mix- ups is more likely (e.g., use of placebo, blinded trials, multiple strengths).
  48. 48.  Distribution includes the transport of a phase 1 investigational drug . Handle phase 1 investigational drugs in accordance with labelled conditions (e.g., temperature) to ensure retention of the quality of the product. Maintain a distribution record of each batch sufficiently detailed to allow traceability and facilitate recall if necessary (§ 312.57(a))
  49. 49.  Keep complete records relating to the quality and operation of the manufacturing processes, including but not limited to: ◦ Equipment maintenance and calibration ◦ Manufacturing records and related analytical test records ◦ Distribution records ◦ QC functions ◦ Component records ◦ Deviations and investigations ◦ Complaints Maintain retain records for at least two years after a marketing application is approved for the drug, or If an application is not approved for the drug, until two years after shipment and delivery of the drug for investigational use is discontinued and FDA is notified. (Under § 312.57(c), )
  50. 50.  Manufacture only one phase 1 investigational drug at any given time. Area could be used for multiple purposes, including manufacture of other investigational products or laboratory research. Place appropriate cleaning and procedural controls in place to ensure that there is no carry-over of materials or products, or mix- ups. The design of an area should promote ◦ The orderly handling of materials and equipment, ◦ The prevention of mix-ups, and ◦ The prevention of contamination of equipment or product by substances, previously manufactured products, personnel, or environmental conditions.
  51. 51.  Examples of procedural controls could include procedures for clearing the room of previous product materials, product segregation, component segregation, and use of unique product identifiers. Evaluate periodically the procedural controls for their effectiveness. Take appropriate corrective action when indicated by the evaluation or when other events warrant.
  52. 52.  The manufacturing process is critical to ensure the correct composition, quality, and safety . Difficult to distinguish changes in quality attributes, or predict the impact of observed changes in quality attributes on safety. Knowledge and understanding of a phase 1 investigational drug is limited Comprehensive product characterization is often unavailable, especially for products that are difficult to characterize. Carefully control and record the manufacturing process Record appropriate testing to reproduce a comparable phase 1 investigational drug as may be necessary.
  53. 53.  Implement appropriate equipment and controls in manufacturing Ensure that unit operations with safety-related functions perform their function with a high degree of assurance. Complement these functions with specific testing. Use testing for safety-related purposes such as ◦ Viral loads, ◦ Bio burden, ◦ Detoxification of bacterial toxins, ◦ Virus clearance
  54. 54.  Evaluate the manufacturing environment for susceptibility to contaminate the environment with biological substances, including microbial adventitious agents (e.g., bacterial, viral, mycoplasm), that may remain from previous research or manufacturing activities. Some pathogenic microorganisms, spore-forming microorganisms, transgenic animals and plants, live viral vaccines, and gene therapy vectors, warrant additional containment considerations. Discuss these with the agency.
  55. 55.  Multi-product facilities should have in place cleaning and testing procedures that ensure prevention and/or detection of contamination by adventitious agents. To the extent possible, use dedicated equipment and/or disposable parts. For multi-product areas, establish procedures ◦ to prevent cross-contamination, and ◦ to demonstrate removal of the previously manufactured product from shared equipment and work surfaces, especially if live viral and vector processing occurs in a manufacturing area.
  56. 56.  Consider additional or specialized controls. It may not be possible to follow each recommendation of the guidance. Include justification for adopting additional controls or alternative approaches to the recommendations in this guidance in the records on the phase 1 investigational drug. In some cases, products may be manufactured as one batch per subject in phase 1 clinical trials.
  57. 57.  Manufacture of multiple batches will allow manufacturing and testing information to accumulate in an accelerated manner. Monitor manufacturing performance to ensure product safety and quality. Conduct and document internal performance reviews when manufacturing multiple batches . Review to assess whether the manufacturing process is optimal to ensure overall product quality. Based on the review Implement appropriate modifications or corrective actions.
  58. 58.  Take special precautions for Sterile Products. Implement appropriate controls for aseptic processing to ensure a sterile phase 1 investigational drug. Use FDA guidance on aseptic processing. Particular manufacturing controls are detailed in succeeding slides.
  59. 59.  Conduct aseptic manipulation in an aseptic workstation under laminar airflow conditions that meet Class A, ISO 5. Perform all manipulations of sterile products and materials under aseptic conditions. Conduct a process simulation using bacterial growth media . Perform environmental monitoring of the aseptic workstation during processing. Such monitoring may include microbial monitoring by settling plates or by active air monitoring.
  60. 60.  Disinfect the entire aseptic workstation e.g., ◦ before aseptic manipulation, or ◦ between different operations during the same day Ensure proper workstation installation and placement to allow appropriate airflow. Ensure that items within a laminar airflow aseptic workstation do not interrupt the unidirectional airflow Disinfect gloves or change them frequently when working in the laminar flow hood .
  61. 61.  Disinfect the surface of nonsterile items with sterile disinfectant solution before placing them in the laminar flow hood. Document and follow all procedures intended to maintain the sterility . Demonstrate that the test article does not interfere with the sterility tests (e.g., USP <71>) Employ aseptic technique and control of microbiological impurities in components designed to prevent microbial and endotoxin contamination. Train personnel in using aseptic techniques.
  62. 62.  Verify that the equipment is suitable for its intended . Perform appropriate calibration of temperature probes used to monitor the sterilization cycle; Use suitable and qualified biological indicators; Retain maintenance and cycle run log records . Demonstrate that the sterilization method for sterile components and disposable equipment is suitable. Create documentation that supports the appropriate use and shelf life of sterile components and equipment
  63. 63.  Ensure that release of drug by the QC unit, or designated individual, includes an acceptable review of manufacturing records that demonstrate aseptic procedures and precautions were followed. Ensure that final drugs are not released until acceptable results of sterility testing are known. When positive results are obtained for sterility testing perform an investigation to determine the cause of contamination followed by corrective action, if warranted. Notify the person responsible for the associated clinical trials so appropriate action can be taken.
  64. 64.  Where is the clinical trial? ICH Q7A EMEA Raw material identity testing Quality Agreements Quality Unit Facility QP Audits, release of lots, and stability extensions Expectations of other territories Expectations of potential partners What else will the material be used for? Is it a phase 1/phase 2 trial
  65. 65.  Drug device combination products Need to follow QSR and Design Controls Quality Systems and documentation: Use same or different Quality System for Phase 1 Separate Training for Phase 1 Assay Qualification Audit Program Document Review Staffing Additional requirements such as QC plan, hazard assessment, multi- product use periodic assessment of procedural control, Documentation of scientific rational Where will phase 2 work be done? Is there enough information to ensure an efficient and successful tech transfer?
  66. 66.  Different Quality Agreement for phase 1contractors, or Development Agreement or Scope of Work? Can you use the pilot or non-GMP facility at contractors? (less $$$ and time constraints) Documentation practices at contractor Deviation and Change approval practices Assessment or Audit Use sites you may have not used previously New facilities specific to Phase 1
  67. 67.  The final FDA rule exempts investigational drugs used in phase 1 studies (as described in 21 C.F.R. § 312.21 of FDA’s IND regulations) from the Current Good Manufacturing Practice (“CGMP”) requirements in 21 C.F.R. Part 211. This exemption does not apply to an investigational drug for use in a phase 1 study once the investigational drug has been made available for use by or for the sponsor in a phase 2 or phase 3 study, or the drug has been lawfully marketed. If the investigational drug has been made available in a phase 2 or phase 3 study or the drug has been lawfully marketed, the drug used in the phase 1 study must comply with part 211.
  68. 68.  FDA believes that many of the issues presented by the production of investigational drugs intended for use in the relatively small phase 1 trials are different from the issues presented by the production of drug products for use in larger phase 2 or 3 trials or for commercial marketing. Additionally, many of the specific requirements in the regulations in part 211, such as those relating to stock rotation, repackaging, or relabeling, do not apply to the conditions under which many drugs for use in phase 1 are produced.
  69. 69.  The exempt phase 1 drugs are, however, still required to meet the statutory (as opposed to regulatory) requirements for CGMP. To help companies determine what is required to comply with these statutory requirements, FDA issued a guidance document discussing CGMP for phase 1 drugs. This guidance provides both specific, detailed information for complying with CGMP, as well as general guidance.
  70. 70.  With respect to general guidance, it notes that adherence to CGMP during manufacture of phase 1 investigational drugs occurs mostly through: (1) well-defined, written procedure; (2) adequately controlled equipment and manufacturing environment; and (3) accurately and consistently recorded data from manufacturing (including testing).
  71. 71.  The guidance further notes it is the manufacturer’s responsibility to provide and use methods, facilities, and manufacturing controls to ensure that the phase 1 investigational drug meets appropriate standards of safety, identity, strength, quality, and purity and That manufacturers should consider carefully how to best ensure the implementation of standards, practices, and procedures that conform to CGMP for their specific product and manufacturing operation.
  72. 72. This presentation is compiled by “ Drug Regulations” a Not forProfit organization from publicly available material on the world wide web. Visit www.drugregulations.org www.drugregulations.org 72

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