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.

1. This presentation is compiled by “ Drug Regulations” a Not for
Profit organization from publicly available material on the world
wide web.
Visit www.drugregulations.org
www.drugregulations.org 1

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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  The F D A in July 2008 issued a final regulation that
made 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.  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. www.drugregulations.org 19

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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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,
 Supplier's name,
 Material lot number,
 Storage conditions, and
 Corresponding expiration date.

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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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. This presentation is compiled by “ Drug Regulations” a Not for
Profit organization from publicly available material on the world
wide web.
Visit www.drugregulations.org
www.drugregulations.org 72