This article gives the recommendations for Phase I Investigational Drugs
Introduction
Consistent with the FD&C Act (§ 501(a) (2) (B)), CGMP must be in effect for the manufacture of each batch of investigational drug used during phase 1 clinical trials. Manufacturers should establish manufacturing controls based on identified hazards for the manufacturing setting that follow good scientific and QC principles. The following manufacturing controls are applicable to the manufacture of phase 1 investigational drugs and in some specific manufacturing situations. These recommendations provide flexibility to the manufacturers in implementing CGMP controls appropriate to their specific situation and application.
A. Personnel
All personnel should have the education, experience, and training or any combination thereof to enable each individual to perform their assigned function. In particular, personnel should have the appropriate experience to prepare the phase 1 investigational drug and be familiar with QC principles and acceptable methods for complying with the statutory requirement of CGMP, such as the recommendations described in this guidance.
B. QC Function
Every manufacturer should establish a written plan that describes the role of and responsibilities for QC functions.
For example, a written plan should provide, at a minimum, for the following functions
Although quality is the responsibility of all personnel involved in manufacturing, we recommend that you 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.
However, in very limited circumstances and depending on the size and structure of an organization, all QC functions may be performed by the same individual(s) performing manufacturing. For example, in some small operations, it may be necessary to have the same individual perform both manufacturing and QC functions, including release or rejection of each batch. However, in such circumstances, we strongly recommend that another qualified individual not involved in the manufacturing operation conduct an additional periodic review of manufacturing records and other QC activities.
When activities such as testing, commonly performed by dedicated QC personnel in commercial manufacture, are performed by manufacturing personnel in phase 1 studies, adequate controls should be in place (e.g., segregation of testing from manufacturing) so as to not contaminate testing or negatively affect test results.
C. Facility and Equipment
Any facility used for manufacturing phase 1 investigational drugs should have adequate work areas and equipment for the intended task.
Each facility should provide the following described work area and equipment:
We recommend that you identify all equipment used for a particular process and document such use in the manufacturing record. You should follow the provisions described under Sterile Products/Aseptically Processed Products for phase 1 investigational drugs prepared using aseptic processing. Use of procedural controls in a facility promotes orderly manufacturing and aids in preventing contamination, cross contamination and mix-ups.
D. Control of Components, and Containers and Closures
You should 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, labeled) until you have examined or tested the materials, as appropriate, and released them for use in manufacturing. It is important to handle and store such materials in a manner that prevents degradation or contamination.
The manufacturer should be able to identify and trace all materials used in the manufacture of a phase 1 investigational drug from receipt to use in the manufacture of each batch. We recommend that you keep a record (e.g., log book) containing relevant information on all materials. At a minimum, recorded relevant information would include receipt date, quantity of the shipment, supplier's name, material lot number, storage conditions, and corresponding expiration date.
The manufacturer should 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.
We recommend that you 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, we recommend that you test for the incomplete specified attribute of the material. For each batch of the API (or drug substance), you should perform confirmatory identity testing.
E. Manufacturing and Records
The manufacture of phase 1 investigational drugs should follow written manufacturing and process control procedures that provide for the following records.
A record of manufacturing data that details the materials, equipment, procedures used, and any problems encountered during manufacturing. We recommend that manufacturers retain records sufficient to replicate the manufacturing process. Similarly, if the manufacture of a phase 1 investigational drug batch is initiated but not completed, we recommend that the record include an explanation of why manufacturing was terminated.
A record of changes in procedures and processes used for subsequent batches along with the rationale for any changes
A record of the microbiological controls that have been implemented (including written procedures) for the production of sterile-processed phase 1 investigational drugs that are covered by this guidance.
You should 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
F. Laboratory Controls
1. Testing
Laboratory tests used in manufacturing (e.g., testing of materials, in-process material, packaging, drug product) should be scientifically sound (e.g., specific, sensitive, and accurate), suitable and reliable for the specified purpose. You should perform tests under controlled conditions and follow written procedures describing the testing methodology. You should maintain records of all test results, procedures, and changes in procedures.
You should perform laboratory testing of the phase 1 investigational drug to evaluate quality attributes including those that define the identity, strength, potency, purity, as appropriate. Specified attributes should be monitored, and acceptance criteria applied appropriately. For known safety-related concerns, specifications should be established and met. 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
To ensure reliability of test results, we recommend that you calibrate laboratory equipment at appropriate intervals and maintain the equipment according to established written procedures. We recommend that personnel verify that the equipment is in good working condition when samples are analyzed (e.g., system suitability).
You should retain a representative sample from each batch of phase 1 investigational drug. We recommend retention of both the API and phase 1 investigational drug in containers used in the clinical trials. When feasible, we recommend that the sample consist of a quantity 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). We recommend that you appropriately store and retain the samples for at least two years following clinical trial termination, or withdrawal of the IND application.
2. Stability
We recommend initiation of a stability study using representative samples of the phase 1 investigational drug to 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).
G. Packaging, Labeling and Distributing
The phase 1 investigational drug should be suitably packaged to protect it from alteration, contamination, and damage during storage, handling, and shipping. You should establish written procedures for controlling packaging, labeling, and distribution operations. We recommend the use of appropriate measures (e.g., product segregation, label reconciliation, verify operations by a second person, confirmatory laboratory testing, QC review) to achieve effective control especially in situations where the potential for mix-ups is more likely (e.g., use of placebo, blinded trials, multiple strengths).
As it relates to phase 1 clinical trials, distribution includes the transport of a phase 1 investigational drug covered by this guidance to clinical investigators. You should handle phase 1 investigational drugs in accordance with labeled conditions (e.g., temperature) to ensure retention of the quality of the product. A distribution record of each batch of phase 1 investigational drug must be sufficiently detailed to allow traceability and facilitate recall of the phase 1 investigational drug if necessary
H. Recordkeeping
As indicated in previous sections, manufacturers should keep complete records relating to the quality and operation of the manufacturing processes, including but not limited to:
Equipment maintenance and calibration
Under § 312.57(c), sponsors must 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.
Cgmp recommendations, phase i investigational drugs,
