GMP Production and Process Controls

GMP Production and Process Controls



WRITTEN PROCEDURES; DEVIATIONS:

(a)    There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.

(b)    Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.
    The procedures for production and process control are to be reviewed and approved by quality control. It will be essential to that:

a.    The various requirements referenced in the CGMP regulations (especially the other subsections of Subpart F) have been adequately addressed.

b.    The documents are in compliance with the relevant sections of any NDA and ANDA.

    The FDA is currently reevaluating approval requirements with respect to production changes. The objectives are to reduce the work load at the FDA, harmonize via ICH, and allow quicker implementation of changes. The status is somewhat confused by the ICH approach, which primarily focuses on stability requirements while the FDA also addresses levels of approval (Annual Report, Change being Effected, Prior Approval). Due to lack of consensus between the ICH parties, the ICH project is currently on hold. The situation further compounded by the issuance by the FDA of two similar but not identical proposals in November and December 1994 (see Suggested Readings 16 and 19). The November guideline developed by the Scale-Up and Post Approval Change (SUPAC) Expert Working Group of the Chemistry Manufacturing Controls coordinating Committee of the Center for Drug Evaluation and Research was limited to immediate release solid dosage forms. Guidelines on other dosage form will be issued.

CHANGE CONTROL

    Change control should include changes to raw materials, packaging, components, labeling, expiration dating, formulation, production process, production equipment (including major maintenance), critical plant systems, facilities, computerized systems, specifications, and test methods.
    The procedure will involve multiple disciplines including sales and marketing, medical, legal, regulatory affairs, R&D, technical services, and maintenance, as well as QC/QA. No all functions will need to be involved with all changes. The evaluation of the change, which must be documented, will include:
•    Clear definition of the proposed change with the reason for the change.
•    Identification of potential impact and the evaluations to be performed, such as accelerated stability, revalidation, retraining.
•    Regulatory impact (all countries involved) approvals required.
•    Schedule for implementation.
•    Definition of who needs to approve the change and a record of their concurrence.
•    Post introduction review to confirm that the change did not have any adverse impact.
    Evaluation of change control should be part of the QA plant audit.

CHARGE-IN OF COMPONENTS
(a)    The batch shall be formulated with the intent to provide not less that 100 percent of the labeled or established amount of active ingredient.

(b)    Components for drug product manufacturing shall be weighed, measured, or subdivided as appropriate. If a component is removed from the original container to another, the new container shall be identified with the following information:

    (1)    Component name or item code
    (2)    Receiving or control number
    (3)    Weight or measure in new container   
    (4)    Batch for which component was dispensed, including its product name, strength, and lot number.

(c)    Weighing, measuring, or subdividing operations for components shall be adequately supervised. Each container of component dispensed to manufacturing shall be examined by a second person to assure that:

(1)    The component was released by the quality control unit.
(2)    The weight or measure is correct as stated in the batch production records.
(3)    The containers are properly identified.

(d)    Each component shall be added to the batch by one person and verified by a second person.

EQUIPMENT IDENTIFICATION
(a)    All compounding and storage containers, processing lines and major equipment used during the production of a batch of a drug product shall be properly identified at all times to indicate their contents and, when necessary, the phase of processing of the batch.

(b)    Major equipment shall be identified by a distinctive identification number or code that shall be recorded in the batch production record to show the specific equipment used in the manufacture of each batch of a drug product. In cases where only one of a particular type of equipment exists in a manufacturing facility, the name of the equipment may be used in lieu of a distinctive identification number or code.


SAMPLING AND TESTING OF IN-PROCESS MATERIALS AND DRUG PRODUCTS
(a)    To assure batch uniformity and integrity of drug products, written procedures shall be established to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Such control procedures shall include, but are not limited, to the following, where appropriate:

    (1)    Tablet or capsule weight variation
    (2)    Disintegration time
    (3)    Adequacy of mixing to assure uniformity and homogeneity
    (4)    Dissolution time and rate
    (5)    Clarity, completeness, or pH of solutions

(b)    Valid in-process specifications for such characteristics shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate. Examination and testing samples shall assure that the drug product and in-process material conforms to specifications.

(c)    In-process materials shall be tested for identity, strength, quality and purity as appropriate, and approved or rejected by the quality control unit, during the production process, e.g., at commencement or completion of significant phases or after storage for long periods.

PROCESS VALIDATION
    The FDA in "Guidelines on General Principles of Process Validation "defines process validation as "establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics." The designing of quality into a product and its production processes, coupled with supporting validation data, increase the potential for consistently achieving quality standards and reduces dependence on both in-process and end-product testing.