Quality should be the responsibility of all persons involved in manufacturing. Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.
The system for managing quality should encompass the organizational structure, procedures, processes and resources, as well as activities to ensure confidence that the API will meet its intended specifications for quality and purity. All quality-related activities should be defined and documented.
There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. The quality unit can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.
The persons authorized to release intermediates and APIs should be specified. All quality-related activities should be recorded at the time they are performed. Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented.
No materials should be released or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g., release under quarantine as described in Section X (10) or the use of raw materials or intermediates pending completion of evaluation).
Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality-related complaints, recalls, and regulatory actions).
Responsibilities of the Quality Unit(s)
The quality unit(s) should be involved in all quality-related matters. The quality unit(s) should review and approve all appropriate quality-related documents. The main responsibilities of the independent quality unit(s) should not be delegated. These responsibilities should be described in writing and should include, but not necessarily be limited to:
" Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of the manufacturing company
" Establishing a system to release or reject raw materials, intermediates, packaging, and labeling materials
" Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution
" Making sure that critical deviations are investigated and resolved
" Approving all specifications and master production instructions
" Approving all procedures affecting the quality of intermediates or APIs
" Making sure that internal audits (self-inspections) are performed
" Approving intermediate and API contract manufacturers
" Approving changes that potentially affect intermediate or API quality
" Reviewing and approving validation protocols and reports
" Making sure that quality-related complaints are investigated and resolved
" Making sure that effective systems are used for maintaining and calibrating critical equipment
" Making sure that materials are appropriately tested and the results are reported
" Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates, where appropriate
" Performing product quality reviews
Responsibility for Production Activities
The responsibility for production activities should be described in writing and should include, but not necessarily be limited to:
" Preparing, reviewing, approving, and distributing the instructions for the production of intermediates or APIs according to written procedures
" Producing APIs and, when appropriate, intermediates according to pre-approved instructions
" Reviewing all production batch records and ensuring that these are completed and signed
" Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and the conclusions are recorded
" Making sure that production facilities are clean and, when appropriate, disinfected
" Making sure that the necessary calibrations are performed and records kept
" Making sure that the premises and equipment are maintained and records kept
" Making sure that validation protocols and reports are reviewed and approved
" Evaluating proposed changes in product, process or equipment
" Making sure that new and, when appropriate, modified facilities and equipment are qualified
Internal Audits (Self Inspection)
To verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule.
Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner.
Product Quality Review
Regular quality-reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least:
" A review of critical in-process control and critical API test results
" A review of all batches that failed to meet established specification(s)
" A review of all critical deviations or nonconformances and related investigations
" A review of any changes carried out to the processes or analytical methods;
" A review of results of the stability monitoring programme
" A review of all quality-related returns, complaints and recalls
" A review of adequacy of corrective actions
The results of this review should be evaluated and an assessment made of whether corrective action or any revalidation should be undertaken. Reasons for such corrective action should be documented. Agreed corrective actions should be completed in a timely and effective manner.
Personnel
A) Personnel Qualifications
B) There should be an adequate number of personnel qualified by appropriate education, training, and/or experience to perform and supervise the manufacture of intermediates and APIs.
The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing.
Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates to the employee's functions. Records of training should be maintained. Training should be periodically assessed.
C) Personnel Hygiene
D) Personnel should practice good sanitation and health habits.
Personnel should wear clean clothing suitable for the manufacturing activity with which they are involved and this clothing should be changed, when appropriate. Additional protective apparel, such as head, face, hand, and arm coverings, should be worn, when necessary, to protect intermediates and APIs from contamination.
Personnel should avoid direct contact with intermediates or APIs. Smoking, eating, drinking, chewing and the storage of food should be restricted to certain designated areas separate from the manufacturing areas.
Personnel suffering from an infectious disease or having open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of APIs.
Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions should be excluded from activities where the health condition could adversely affect the quality of the APIs until the condition is corrected or qualified medical personnel determine that the person's inclusion would not jeopardize the safety or quality of the APIs.
Consultants
Consultants advising on the manufacture and control of intermediates or APIs should have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained.
Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants.
(Extracted from Guidance for Industry: Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research [CBER])