Raw materials
Buildings and facilities.
GMPs under the 21 Code of Federal Regulations (CFR) Part 211.42 state that buildings or areas used in the receiving, storage, and handling of raw materials should be of suitable
size, construction and location to allow for the proper cleaning, maintenance, and operation (7). The common theme for this
section of CFR Parts 210 and 211 is the prevention of errors and contamination. In principle, the requirements for buildings and facilities
used in early phase manufacturing are not significantly different than those for later phases or even commercial production.
However, there are some areas that are unique to early clinical trial manufacturing.
Control of materials.
The CFR regulations under Part 211.80 provide good direction with respect to lot identification, inventory, receipt, storage, and
destruction of materials (7). The clear intent is to ensure patient safety by establishing controls that prevent errors or
cross-contamination and ensure traceability of components from receipt through clinical use. In general, the requirements
for the control of materials are identical across all phases of development, so it is important to consider these requirements
when designing a GMP facility within a laboratory setting.
For example, all materials must be assigned a unique lot number and have proper labeling. An inventory system must provide
for tracking each lot of each component with a record for each use. Upon receipt, each lot should be visually examined for
appropriate labeling and for evidence of tampering or contamination. Materials should be placed into quarantine or in the
approved area or reject area with proper labeling to identify the material and prevent mix-ups with other materials in the
storage area. Provision should be made for materials with special storage requirements (e.g., refrigeration, high security).
The storage labeling should match the actual conditions that the material is being stored and should include expiry/retest
dates for approved materials. Although such labeling is inconvenient for new materials where the expiration or retest date
may change as more information is known, this enables personnel to be able to determine quickly whether a particular lot of
a material is nearing or exceeding the expiration or retest date. General expiry/retest dates for common materials should
be based on manufacturer's recommendation or the literature.
Finally, there are clear regulatory and environmental requirements for the destruction of expired or rejected materials. It
is important to observe regional and international requirements regarding the use of animal sourced materials (12). It is
recommended to use materials that are not animal sourced and that there be available certification by the raw material manufacturers
that they contain no animal sourced materials. If animal sourced raw materials must be used, then certifications by the raw
material manufacturers that they either originate from certified and approved (by regulatory bodies) sources for use in human
pharmaceuticals, or that the material has been tested to the level required for acceptance by regulatory agencies (following
US, EU, or Japanese guidelines, as applicable) is required.
Receipt and approval
Specifications.
It is a GMP requirement that all raw materials for the manufacture of drug product have appropriate specifications to ensure
quality. The compendial requirements should be used for setting specifications provided the material is listed in at least
one pharmaceutical compendium (e.g., US, European, and Japanese Pharmacopeias). It is important that the use of materials meeting the requirements of a single compendium is acceptable for use in early
phase clinical studies conducted in the US, Europe, and Japan. For example, a material that meets USP criteria and is used in the manufacture of a drug product should be acceptable for use in early clinical studies in the European
Union. In the absence of a pharmaceutical compendium monograph, the vendor specification and/or alternative compendial specifications
such as USP's Food Chemical Codex should guide specification setting. In any case, the sponsor is responsible for the establishment
of appropriate specifications. Therefore, it is the authors' position that good practice is to have at least a basic understanding
of the manufacture, chemistry, and toxicology of the materials to guide appropriate specification setting.
Material testing and evaluation.
The minimum testing required for incoming materials is visual inspection and identification. However, as mentioned above,
the appropriate tests should be determined for the material based on the knowledge of the manufacture, chemistry, and toxicology.
If the vendor is qualified, then the certificate of analysis may be acceptable in conjunction with the visual inspection and
identification testing (see "Vendor Qualification" section below).
Approval for use.
Ideally, manufacture of a bulk drug product should begin with approved material specifications and with materials that are
fully tested and released. However, there are circumstances where it may not be feasible to start manufacture with approved
specifications and fully tested and released materials, including API. Manufacturing prior to final release (sometimes called
manufacturing "at risk") may be acceptable, however, because the quality system ensures that all specifications are approved,
test results are within specifications, and all relevant documents are in place before the product is released for administration
to humans. The "risk" must lie fully with the manufacturer and not with the patient.
Vendor qualification.
Vendors supplying excipients, raw materials, or API must be qualified by the sponsor. Appropriate qualification should depend
on the stage of development and an internal risk assessment. For, example if a vendor has a history of supplying the pharmaceutical
industry and the material is to be used in early development, a paper assessment (e.g., a questionnaire) should be sufficient.
If a supplier does not have a history of supplying the pharmaceutical industry, a risk assessment should be performed and
depending on the outcome a site audit may be required prior to accepting material for use.
Ideally, vendors should be qualified prior to using raw materials for manufacture. However, it is acceptable for qualification
to proceed in parallel as long as documentation/risk assessments are available prior to product release and as in the previous
section all risk lies with the manufacturer and not the patient.
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