• GMP:- GMPs define a quality system that manufacturers use as they build quality into their products. For example, approved drug products developed and produced according to GMP are safe, properly identified, of the correct strength or potency, pure, and of high quality.

GUIDELINES

  • GMPs are enforced in the United States by the U.S. Food and Drug Administration (FDA), under Title 21 CFR.
  • The European Union GMP – EU-GMP.
  • The World Health Organization – WHO GMP.
  • In the United Kingdom the Medicines Act (1968) covers most aspects of GMP in what is commonly referred to as “The Orange Guide”.
  • In ICH there is a separate Guideline belongs to GMP for active pharmaceutical ingredients– ICH Q7.
  • In India Schedule-M covers the most aspects of GMP.
  • Numerous version of GMP around the world available, Wording may differ in those but same principles are applicable.

Part-211:- contain 11 Subparts

 

  1. Responsibilities of quality control unit
  • There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products.
  • There should be an authority to review records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated.
  • Adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to the quality control unit.
  • The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.
  • The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed.
  1. b) Personnel qualifications
  • Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions.
  • Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee’s functions.
  • Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.
  • Each person responsible for supervising the manufacture, processing, packing, or holding of a drug product shall have the education, training, and experience, or any combination thereof, to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess.
  • There shall be an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each drug product
  1. c) Personnel responsibilities
  • Personnel engaged in the manufacture, processing, packing, or holding of a drug product shall wear clean clothing appropriate for the duties they perform.
  • Protective apparel, such as head, face, hand, and arm coverings, shall be worn as necessary to protect drug products from contamination.
  • Only personnel authorized by supervisory personnel shall enter those areas of the buildings and facilities designated as limited-access areas.
  • Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions that may adversely affect the safety or quality of drug products shall be excluded from direct contact with components, drug product containers, closures, in-process materials, and drug products until the condition is corrected or determined by competent medical personnel.
  • SUBPART C—BUILDINGS AND FACILITIES
  • Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations.
  • Any such building shall have adequate space for the orderly placement of equipment and materials to prevent mix-ups between different components, drug product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination.
  • Adequate lighting shall be provided in all areas.
  • Adequate ventilation shall be provided.
  • Drains shall be of adequate size and, where connected directly to a sewer, shall be provided with an air break or other mechanical device to prevent back-siphonage.
  • Adequate washing facilities shall be provided, including hot and cold water, soap or detergent, air driers or single-service towels, and clean toilet facilities easily accessible to working areas.
  • Building shall be free of infestation by rodents, birds, insects, and other vermin.
  • Trash and organic waste matter shall be held and disposed of in a timely and sanitary manner.
  • Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firm’s operations as are necessary to prevent contamination or mix-ups
  • There shall be written procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents. Such written procedures shall be designed to prevent the contamination of equipment, components, drug product containers, closures, packaging, labeling materials, or drug products and shall be followed. Rodenticides, insecticides, and fungicides shall not be used unless registered and used in accordance with the Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 135).
  • Any building used in the manufacture, processing, packing, or holding of a drug product shall be maintained in a good state of repair.
  • SUBPART D—EQUIPMENT
  • Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.
  • Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.
  • Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product.
  • Records shall be kept of maintenance, cleaning, sanitizing, and inspection.
  • Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.
  • Appropriate controls shall be exercised over computer or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel
  • SUBPART E—CONTROL OF COMPONENTS AND DRUG PRODUCT CONTAINERS AND CLOSURES
  • There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures; such written procedures shall be followed.
  • Components and drug product containers and closures shall at all times be handled and stored in a manner to prevent contamination.
  • Bagged or boxed components of drug product containers or closures shall be stored off the floor and suitably spaced to permit cleaning and inspection.
  • Upon receipt and before acceptance, each container or grouping of containers of components, drug product containers, and closures shall be examined visually for appropriate labeling as to contents, container damage or broken seals, and contamination.
  • Components, drug product containers, and closures shall be stored under quarantine until they have been tested or examined, whichever is appropriate, and released. Storage within the area shall conform to the requirements of §211.80.
  • Each lot of components, drug product containers, and closures shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit.
  • Representative samples of each shipment of each lot shall be collected for testing or examination. The number of containers to be sampled, and the amount of material to be taken from each container, shall be based upon appropriate criteria such as statistical criteria for component variability.
  • Samples shall be collected in accordance with the following procedures:
  1. The containers of components selected shall be cleaned when necessary in a manner to prevent introduction of contaminants into the component.
  2. The containers shall be opened, sampled, and resealed in a manner designed to prevent contamination of their contents and contamination of other components, drug product containers, or closures.
  3. Sample containers shall be identified so that the following information can be determined: name of the material sampled the lot number, the container from which the sample was taken, the date on which the sample was taken, and the name of the person who collected the sample.
  4. Containers from which samples have been taken shall be marked to show that samples have been removed from them.
  • Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality.
  • Any lot of components, drug product containers, or closures that meets the appropriate written specifications of identity, strength, quality, and purity and related tests under paragraph (d) of this section may be approved and released for use. Any lot of such material that does not meet such specifications shall be rejected.
  • Components, drug product containers, and closures approved for use shall be rotated so that the oldest approved stock is used first.
  • Components, drug product containers, and closures shall be retested or reexamined, as appropriate, for identity, strength, quality, and purity and approved or rejected by the quality control unit in accordance with §211.84 as necessary, e.g., after storage for long periods or after exposure to air, heat or other conditions that might adversely affect the component, drug product container, or closure.
  • Rejected components, drug product containers, and closures shall be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable
  • Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements
  • Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product.

 

  • SUBPART F—PRODUCTION AND PROCESS CONTROLS
  • There shall be written procedures for production and process control designed
  • These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units.
  • 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 batch shall be formulated with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient.
  • When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product. Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. Such deviation shall be justified and documented
  • 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.
  • 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.
  • To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations 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.
  • Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of all aseptic and sterilization processes.
  • Written procedures shall be established and followed prescribing a system for reprocessing batches that do not conform to standards or specifications and the steps to be taken to insure that the reprocessed batches will conform to all established standards, specifications, and characteristics.
  • Reprocessing shall not be performed without the review and approval of the quality control unit.
  • SUBPART G—PACKAGING AND LABELING CONTROL
  • There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials; such written procedures shall be followed. Labeling and packaging materials shall be sampled, and examined, tested upon receipt and before use in packaging or labeling of a drug product.
  • Any labeling or packaging materials meeting appropriate written specifications may be approved and released for use. Any labeling or packaging materials that do not meet such specifications shall be rejected to prevent their use in operations for which they are unsuitable.
  • Any labeling or packaging materials meeting appropriate written specifications may be approved and released for use. Any labeling or packaging materials that do not meet such specifications shall be rejected to prevent their use in operations for which they are unsuitable.
  • Labeling materials issued for a batch shall be carefully examined for identity and conformity to the labeling specified in the master or batch production records.
  • There shall be written procedures designed to assure that correct labels, labeling, and packaging materials are used for drug products;
  • Packaged and labeled products shall be examined during finishing operations to provide assurance that containers and packages in the lot have the correct label.
  • A representative sample of units shall be collected at the completion of finishing operations and shall be visually examined for correct labeling.
  • Results of these examinations shall be recorded in the batch production or control records.
  • To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability testing described in §211.166
  • Expiration dates shall appear on labeling of drug products
  • SUBPART H—HOLDING AND DISTRIBUTION
  • Written procedures describing the warehousing of drug products shall be established and followed. They shall include:
  1. Quarantine of drug products before release by the quality control unit.
  2. Storage of drug products under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality, and purity of the drug products are not affected.
  • Written procedures shall be established, and followed, describing the distribution of drug products. They shall include:
  1. A procedure whereby the oldest approved stock of a drug product is distributed first. Deviation from this requirement is permitted if such deviation is temporary and appropriate.
  2. A system by which the distribution of each lot of drug product can be readily determined to facilitate its recall if necessary.
  • SUBPART I—LABORATORY CONTROLS
  • The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms required
  • Any deviation from the written specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified
  • Any sampling and testing plans shall be described in written procedures that shall include the method of sampling and the number of units per batch to be tested; such written procedure shall be followed.
  • There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include
  • Testing of the drug product in the same container-closure system as that in which the drug product is marketed;
  • An adequate number of batches of each drug product shall be tested to determine an appropriate expiration date and a record of such data shall be maintained
  • Accelerated studies, combined with basic stability information on the components, drug products, and container-closure system, may be used to support tentative expiration dates provided full shelf life studies are not available and are being conducted.
  • An appropriately identified reserve sample that is representative of each lot in each shipment of each active ingredient shall be retained
  • The reserve sample consists of at least twice the quantity necessary for all tests required to determine whether the active ingredient meets its established specifications.
  • For a drug product, the reserve sample shall be retained for 1 year after the expiration date of the drug product containing the active ingredient.
  • SUBPART J—RECORDS AND REPORTS
  • Any production, control, or distribution record that is required to be maintained in compliance with this part and is specifically associated with a batch of a drug product shall be retained for at least 1 year after the expiration date of the batch.
  • All records required under this part, or copies of such records, shall be readily available for authorized inspection during the retention period at the establishment where the activities described in such records occurred.
  • The identity and quantity of each shipment of each lot of components, drug product containers, closures, and labeling; the name of the supplier; the supplier’s lot number(s) if known; the receiving code as specified in §211.80; and the date of receipt.
  • To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person. The preparation of master production and control records shall be described in a written procedure and such written procedure shall be followed.
  • Master production and control records shall include
  1. The name and strength of the product and a description of the dosage form;
  2. The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product and a statement of the total weight or measure of any dosage unit;
  3. A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling;
  4. Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed.
  • All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed.
  • Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed.
  • The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow-up.
  • Laboratory records shall include complete data derived from all tests necessary to assure compliance with established specifications and standards, including examinations and assays.

 

  • SUBPART K—RETURNED AND SALVAGED DRUG PRODUCTS
  • Returned drug products shall be identified as such and held. If the conditions under which returned drug products have been held, stored, or shipped before or during their return, or if the condition of the drug product, its container, carton, or labeling, as a result of storage or shipping, casts doubt on the safety, identity, strength, quality or purity of the drug product, the returned drug product shall be destroyed unless examination, testing, or other investigations prove the drug product meets appropriate standards of safety, identity, strength, quality, or purity.
  • Drug products that have been subjected to improper storage conditions including extremes in temperature, humidity, smoke, fumes, pressure, age, or radiation due to natural disasters, fires, accidents, or equipment failures shall not be salvaged and returned to the marketplace. Whenever there is a question whether drug products have been subjected to such conditions, salvaging operations may be conducted only if there is evidence from laboratory tests and assays (including animal feeding studies where applicable) that the drug products meet all applicable standards of identity, strength, quality, and purity.