The cliché of the three Ds — documents, documents, and more documents — is apt for FDA PAI inspections. Historically, regulatory agencies have relied heavily on cross-checking documents to ascertain the state of compliance with the cGMP regulations. The documents of critical importance are the batch records that contain
detailed information about the batch history. It is often difficult for a firm to “fudge” these documents, although
many have tried. What is important to understand here is that the entire batch record is cross-checked with the purchase requisitions, delivery documents, testing documents, and final release documents. It is almost impossible to create a system that would fool the FDA inspectors.
The firms are advised that a low level of due diligence will expose the trial of doing paperwork. Included in the batch
records are the date of manufacture, the identity of major equipment and lines used, specific identification of each
a batch of a component or in-process material used, weights and measures of components used in the course of processing, in-process and laboratory control results, an inspection of the packaging and labeling area before and after
use, a statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of
processing, complete labeling control records, including specimens or copies of all labeling used, description of
drug product containers and closures, any sampling performed, identification of the persons performing and
directly supervising or checking each significant step in the operation, any deviation report resulting from an investigation made according to 21 CFR 211.192, and results of examinations made in accordance with 21 CFR 211.134 (packaging and labeling inspections).
Change control is the procedural system through which changes are reviewed, justified, documented,
approved, and implemented in conformance with regulatory and corporate requirements. To support a strong
change control system, the firms must have a series of documents available that include a summary of all
changes made to date that affect the manufacturing process being considered for approval; individual reports that
are written to review, justify, approve, and implement specific changes that affect the manufacturing process being
considered for approval; any change control reports for facilities, manufacturing processes, and cleaning processes; or analytical laboratory methods that are related to the NDA/ANDA process being submitted.
As it is routine that changes are made in the development timeline, a rigid change control system may not work all the time.
It is therefore recommended that the firms must have available for the FDA investigators a history of changes
made, along with justification for the changes. It is important for the firms to know that the investigators arriving
at the site may not have a copy of the filing made to the FDA, such as the CMC section of the application. Firms
are advised to have a “third” copy available. The requirements of the CMC section are given below; these requirements also apply to supplements, except that the information required in the supplement is limited to that needed to support the change being submitted.
1. Batch production record
2. Specifications and test procedures for each
component and for the drug product
3. Names and addresses of the sources of the active and non-compendial inactive components of the container closure system for the drug product
4. Results of any test performed on the components used in the manufacture of the drug product and on the drug product.
5. Name and address of each contract facility involved in the manufacture, processing, packaging, or testing of the drug product and identification of the operation performed by each contract facility.
6. Proposed or actual master production record, including a description of the equipment to be used for the manufacture of a commercial lot of the drug product or a comparably detailed description of the production process for a representative batch of the drug product, must be provided for all initial NDAs; ANDAs must contain a proposed or actual master production record
1. Development History Report
A historic summary of the development of the product serves many purposes. The foremost purpose is to apprise
the investigators of the scope of the inspection. The investigators learn more about the product from the history of
its development than from the analysis report of the finished product. This shows the awareness of the firm about
the development process.
This document should include a description of the API, the formulation, and the analytical methods. These sections should be clearly marked or presented in separate binders. The summary section should highlight how the bio batch is linked to the full-scale batch with respect to validation and scale-up of production. This section also offers an opportunity for the firm to address the issues that it considers critical.
2. Deviation Records
Deviations are inevitable, whether they occur in the production or the testing of the product; obviously, a broader
standard is used during development than in full-scale production. The important thing is that all deviations
should be recorded, a justification should be provided for the decision to deviate, and a description of its potential
effect on the quality of the product should be provided. Of most significance to the FDA is the reason for entering
into a deviation: Is it because the process was not adequately characterized or validated? Or was it because of
inevitable circumstances, such as a breakdown in the system? A logbook describing deviations is one way the firm
may show to the FDA its diligence in ensuring compliance with the cGMP regulations. Nothing makes the FDA more
suspicious than a blank log stating that there were no deviations. In addition, these log reports offer an excellent
medium for internal QA audits. Firms need to understand that the purpose of cGMP compliance is ensuring the
quality and safety of the product, not necessarily adhering to a particular process or composition. Obviously, the
requirements of validation make it necessary that any deviation converted into regular practice must be properly
3. Installation, Operational, and Performance Qualification
The IQ/OQ/PQ documents pertaining to all manufacturing equipment, analytical equipment, or systems should be
available for inspection. In many instances, firms consider their development laboratories as not needing to be as
rigidly compliant with these documentation requirements as their manufacturing facilities are. This creates serious
problems at PAI if the development laboratory produces a bio batch. Furthermore, the process or method transfer
becomes a serious problem if unqualified equipment or processes are used in the development cycle. Firms are
strongly urged to treat their development laboratory as if they were cGMP-compliant facilities.
4. Organizational Chart
Organizational charts establish that an adequate number of personnel are available to perform and supervise the
manufacture, processing, packaging, or holding of a drug product (21 CFR 211.25), that a proper chain of responsibility has been established in supervisors of manufacturing processes, and that there is the appropriate separation of responsibilities for manufacturing operations and the quality unit. These charts should be available for both the development organizations and the commercial manufacturing organizations.
5. Products List
To evaluate how the product submitted may be affected by the manufacturing of other products on the same premises, a complete list of all products manufactured should be provided to the PAI team on the first day of inspection.
The FDA considers cross-contamination issues critical should there be a serious objection raised, the PAI team
will refuse to continue the audit. Firms are strongly urged to review the cGMP guidelines and the guidance documents provided by the FDA: Some basic rules about cephalosporins, penicillins, hormones, and biological
products are well known; however when in doubt, do not hesitate to write the FDA to seek clarification before
beginning the production of a new product. It is noteworthy that a single batch of a forbidden entity in the premises may render the premises unsuitable forever if proper validation could not be performed. For example, if a penicillin or cephalosporin product is manufactured on the premises, these premises can no longer be used for any other
product, as it would be difficult to prove the absence of contaminants.
Site plan drawings should be available for facilities used in clinical trial material production as well as for those at
which commercial products will be produced. These drawings quickly show how the facility is constructed and
controlled and include the floor plan, which shows the proper segregation of areas by walls, airlocks, and doors;
these plans are useful to demonstrate people and equipment flow, showing that clean personnel and equipment
do not cross paths with dirty personnel and equipment.
Also, there should be a broader facility and grounds plan showing the relative position and location of various buildings in the facility. This is particularly useful where multiple buildings are used to finish the product or to test it, as the security of the batch in transit and the possibility of contamination are key issues to be resolved. In addition,
drawings of the utility systems, such as the heating, ventilation, air-conditioning systems, and water systems,
should be available. Firms are advised that they may request the FDA to review these drawings before the visit,
perhaps at the time of installation, to make sure that the basic guidelines are adhered to.
7. Stability Data
Some of the most significant data that the PAI team confirm is the stability profile of the product; most likely the
raw data would be examined if the presentation of the summary data appears flawed.
SOPs relevant to basic systems and operations should be provided in a neatly arranged folder starting with the master validation plan, product, personnel, and process management. A comprehensive index should be attached.
9. Training Records
It is a cGMP requirement (21 CFR 211.25 a, b) that personnel have education, training, or experience that
enables them to perform their assigned task. These training records should include the training curriculum for each
individual, as well as the list of completed courses. These records should be made available for all personnel who
manufacture, process, package, test, or release clinical trial materials and commercial products. Firms are strongly reminded that in most inspections the FDA finds this to be one of the weakest areas. For example, some of
the common FDA citations for training violations include lack of formal training documentation, lack of training in
GMP regulations on an ongoing basis, lack of a formal job function training program, lack of a system for evaluating or monitoring employees to ensure that training was effective, no provision for retraining individuals on a
periodic basis to ensure that employees remain familiar with the requirements applicable to them, no provision for
training employees on recently revised procedures, and no provision for ensuring that employees were trained before
they perform job functions. Training records should also include details about how the new employees are trained
to follow the company’s SOPs, rules, and other regulations. The SOP reading and understanding records, therefore, form vital evidence that the FDA examines to ensure that all employees have received adequate training in performing their tasks. Awareness and understanding of what is considered critical depend on the role the employee
plays; for example, compliance with good laboratory practices (GLP) or good clinical practice may be relevant
to some, but not all, employees. Safety training, job function training, and documentation training are additional
10. Validation Records
Validation protocols may include test parameters, product characteristics, production equipment specifications, and
settings, and decision points on what constitutes acceptable test results. Three types of validation protocols should
be available during the PAI: cleaning, manufacturing process, and analytical methods. Any data associated with a
completed protocol should also be made available. Also, if there had been any retrospective validation, these data
should also be available.
11. Technology Transfer and Scale-Up
The goal of technology transfer and scale-up is to show, through process control, that any modifications made from
conception to implementation have been appropriately evaluated and documented and that the product is safe,
pure, and effective. The technology transfer master plan comprises three components: the documents, the writing
style, and the illustration of equivalents. The development stage documents are often abbreviated, and the files are
not necessarily as complete as in the case of full-scale production; also, in addition, the language used often differs as the audience changes from a scientist to a line worker. It is important also to show how the equivalent processes were selected; for example when using a small dryer, how can the use of a large fluid bed dryer be labeled
12. Quality Policy
The quality policy is a global document for the company that covers such issues as recalls, employee training and
certification, and overall impact analysis of product and process changes. Customer expectations, materials
specifications and laws and regulations may also affect the number of personnel needed and the way quality functions are subdivided into manageable work units. Of the importance of inclusion in the quality systems description
are the documenting controls, including clearance and issuance of production records, procedures, specifications,
and so forth; internal and vendor audits; sampling, examination, and approval of materials, including packaging
and labeling (often administered by the laboratory component of the department); Material Review Board representatives; verifying yields and other critical production data through production record audits; the finished product release; accompanying FDA investigators and external auditors; administering or contributing to cGMP, safety, or other required training programs; ensuring the investigations of product failures, process deviations, laboratory out-of-specification findings, and consumer complaints; monitoring approval and implementation of corrective action plans and change controls; on-site verification of the performance of critical production operations such as clearing labeling equipment and lines; reviewing and approval of the product development records and documents transferring a product from development to commercial production; validation/qualification protocols and summary reports acceptance; and annual cGMP review.
In addition, some functions are delegated to the engineering group to complete, and these include statistical process
control and trend analyses; calibration of instruments and equipment, including out-of-specification follow-up; and
analysis of reports of extraordinary maintenance and preventative maintenance failures.
13. Vendor Approval
The ISO 9001 and ISO 9002 Quality Standards require manufacturers to select vendors on the basis of their
ability to meet purchase specifications. By ISO 9004 definition, this includes meeting regulatory requirements
and safety standards. The FDA’s cGMP regulations 21 CFR 211.84(a) through (e) require a manufacturer to test
and approve or reject components, drug product containers, and closures. 21 CFR 211.84(d)(2) requires the manufacturer to test each component for conformity with written specifications for purity, strength, and quality or
to accept the supplier’s report of analysis. 21 CFR 211.84(d)(3) requires the manufacturer to test containers
and closures for conformance with all appropriate written procedures or to accept the supplier’s report of analysis. Reports showing compliance with the firm’s vendor approval policy are required at the time of PAI.
14. Outside Contractors
When any work is contracted out, whether, in the manufacture or testing phase, the FDA will hold the firm where
the deviation or deviations that occurred responsible for violations of the cGMP regulations (21 CFR 210 and 211)
that pertain to those services. However, the contractor and the application holder will be held jointly responsible for processes performed by the contractor to the extent that each party contributed to the violations. The performance of each party will be considered in determining whether one or both parties are subject to regulatory action for failure to comply with cGMPs. It is in the best interest of the applicant to perform due diligence in the selection of any contractor, as well as to audit the contractors to ensure they meet the regulatory requirements and the contractual commitments.