Regulatory Requirements - Good Manufacturing Practices (GMPs) represent the minimum requirements that must be satisfied when producing pharmaceuticals for human or veterinary use. They mandate a high degree of control over all stages of the manufacturing process, from ordering the raw materials through to packaging and dispatching the finished goods. All aspects of production must be described in written procedures, and all production activities must be thoroughly documented as they are carried out.

GMPs may be viewed as the third element of a trio of ''GXP'' regulatory requirements, which comprise also Good Laboratory Practice (GLP) and Good Clinical Practice (GCP).

Under GMP, manufacturers are also expected to embrace novel technologies as they emerge, where these offer significant quality improvements. Examples are the use of more accurate engineering control systems, surface coating materials which are easier to clean and sanitize, and more sensitive techniques for chemical analysis. It is not that innovation must be embraced for its own sake; the cost of a novel measure must be considered in relation to the quality improvement it brings. However, the industry ''benchmark'' standards do evolve over time, hence prevalent use of the acronym cGMP (current GMP).

1. Quality Management

For an organization to be compliant with cGMP, the most fundamental requirement is to have an effective quality management structure. Quality should be the responsibility of all persons involved in manufacturing, but the system must be defined and overseen by an independent Quality Unit, which is separate from all production activities. The manager of this Quality Unit should report to a senior level of the organizational hierarchy, and should not be subordinate to the production manager. The quality unit should be involved in all quality-related matters, and should review and approve all quality-related documents.

The quality unit should fulfill the functions of quality control (QC) and of quality assurance (QA), though these may be organized as separate units if desired - depending on the size and structure of the company. The QC function normally comprises the analytical work carried out to ensure that specifications are met - e.g. for raw material quality, equipment cleanliness or air quality. QA has a more wide-ranging role and has been defined (in the Q7A guideline) as ''the sum total of the organized arrangements made with the object of ensuring that all active pharmaceutical ingredients (APIs) are of the quality required for their intended use and that quality systems are maintained''.

One important Quality Unit responsibility is to ensure that internal audits, or self-inspections, are regularly performed to determine whether established procedures are being followed and whether the cGMP regulations and guidelines are being observed. The audit findings and/or corrective actions should be documented and brought to the attention of responsible management.

Regular quality-reviews of APIs should be conducted at least annually, comprising in-process control and test results, batch failures, deviations, nonconformances, process or analytical changes, stability results, complaints, and returns. The results of these reviews should be evaluated and an assessment made as to whether any corrective action is required.

2. Principal Requirements of GMP

The main provisions can be divided into requirements for Personnel, Materials, Premises and Equipment, and Processes.

2.1. Personnel

Personnel are often the most significant source of variance in a process, and most failures can ultimately be traced to human errors. A drug manufacturer should therefore employ an adequate number of personnel with the necessary qualifications and practical experience to perform and/or supervise the required tasks. The structure of the company should be set out clearly in an organization chart, and all personnel should have specific duties recorded in written job descriptions. Training in the particular operations that the employee performs, and in the cGMP regulations that relate to his/her function, should be conducted regularly by qualified instructors. Records of such training should be maintained, and its effectiveness should be periodically assessed. Appropriate clean protective apparel should be provided, and staff should practice good sanitation and health habits.

2.2. Materials

All process materials must be carefully controlled to ensure they are only used in those processes for which they have been approved. This means maintaining proper storage facilities, where clear distinctions are made between materials which are quarantined, approved, or rejected/returned. Appropriate specifications should be developed for all starting materials, reagents, processing aids, solvents, water, and primary packaging materials, as well as for the final APIs and key intermediates. Each individual batch or lot should be uniquely identified and evaluated against its specifications before being approved for use in any process. The evaluation should normally be carried out by the quality unit; however, for some of the earlier less critical manufacturing steps, it may be performed by production personnel, following QU-approved procedures. All incoming materials should be sampled, and at least one identity test performed. In many cases it is acceptable to rely on a supplier's Certificate of Analysis as evidence of the required quality, as long as confidence in that supplier can be justified on the basis of a quality audit or other evaluation process and of satisfactory experience. Randomly selected lots of all incoming materials should be subjected to full specification testing from time to time. Whenever a material is used in a process, its lot number and the precise amount dispensed should be recorded on the batch production record, so that all materials are traceable back to their original sources. Records should also be kept on the disposition of each lot.

2.3. Buildings, Facilities, and Process Equipment

Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance, and appropriate operations, and to minimize the potential for contamination. There should be defined areas, or other control systems, for distinct operations such as receipt, sampling, quarantine, storage, processing, packaging, and laboratory activities. Adequate lighting should be provided in all areas. Adequate ventilation, air filtration, and exhaust systems are required for those environments where the final API is isolated, dried, or packaged. Such areas should have smooth, continuous, and impermeable surfaces, with no sharp corners. API processes should ideally be physically segregated from one another; if this is not possible, then adequate procedures should be established which prevent cross-contamination.

Utilities such as steam, gas, compressed air, heating, ventilation, and air-conditioning should be qualified and appropriately monitored wherever they may affect product quality. Drawings for these systems should be available, and appropriate operating limits should be established.

All processing equipment should be of appropriate design and adequate size, and suitably located for its intended use, cleaning, sanitation, and maintenance. Any surfaces which directly contact the raw materials or products should be constructed of unreactive materials which will not adversely affect the quality of the API (e.g., steel equipment may not be appropriate for processing corrosive materials such as hydrochloride salts). All instruments should be regularly calibrated to ensure they consistently operate within defined tolerances.

Critical equipment and facilities should be formally qualified to demonstrate their suitability for the required operations and their conformance to predetermined specifications. Qualification will normally be conducted in different phases, beginning with a Design Qualification (DQ), in which the manufacturer's designs, blueprints, and specifications are compared with the user's own requirements to assess whether the basic concept will meet the defined process demands. Once the item has been installed and commissioned, it should go through the Installation Qualification (IQ) stage, which is a checklist to confirm that all the necessary functionality (switches, gauges, electrical connections, etc.) is present and of a suitable standard. The next stage is an Operational Qualification (OQ), in which the equipment is set to work on a typical task or process (usually employing inert materials), and details of its performance are collected and assessed. Finally, in the Performance Qualification (PQ), a trial run of a real process is conducted. (This PQ may be performed as part of the validation of that particular process.)

All equipment should be subject to a regime of planned preventative maintenance, to ensure that it continues to operate within its specifications, and to detect and rectify any potential problems at an early stage before they cause any batch failures.

In some cases it may be necessary to dedicate the equipment to particular processes, most notably for the production of highly sensitizing products such as penicillins.

Equipment should normally be cleaned to a satisfactory standard after each individual batch to prevent cross-contamination between batches and, most importantly, between different products. Equipment dedicated to one process or used for a multibatch campaign of the same product may be cleaned less frequently, but this should be justified on a case-by-case basis.

Companies are expected to establish their own cleanliness criteria based on an assessment of their own circumstances. Normally the criteria will include the requirement for no visible residue on the equipment surface. Where the surface is not completely accessible for visual inspection, some indirect means should be established, such as a rinse test or a swab test, with defined residue limits. Such limits should be rational, practical, achievable, and verifiable. For example, some companies operate on the 10 ppm principle, whereby limits are set to ensure that the following product cannot be contaminated with more than 10 ppm of the previous product. Other companies set limits to ensure that the maximum daily dose of the following product cannot be contaminated by more than 0.1 % of the minimum daily dose of the previous product.

Cleaning after each process should be defined in written procedures, which should be validated to ensure that they consistently achieve the defined standards. Cleaning validation involves identifying the areas of the equipment which are most difficult to clean and demonstrating that they are in fact cleaned to the required standard over a number of consecutive (usually three) runs. This may involve dismantling the equipment to some extent to reach otherwise inaccessible areas. However, cleaning validation need only be performed on a ''worst-case'' basis, that is, on those processes which are judged to present the greatest cleaning difficulties.

2.4. Processes

The production of each batch of API or intermediate should be closely documented to provide as complete a record as possible of the circumstances of its manufacture. To ensure uniformity from batch to batch, master production instructions should be prepared, dated, and signed by one person and independently checked, dated, and signed by another person in the quality unit. The master instructions should give details of all process materials required, including packaging and labeling, with their quality specifications and amounts. The major production equipment should be specified, along with detailed production instructions, including sequences, allowable ranges for process parameters, sampling instructions, in-process controls, time limits for completion of individual steps, and expected yield ranges at appropriate phases. Each individual batch should conform as far as possible to these master instructions, with any deviations being recorded, investigated, and evaluated.

Each individual batch production record should identify the operators and supervisors involved with the batch, record equipment numbers, the dates and times of each critical operation, the lot numbers of each ingredient used and the precise amounts dispensed, the actual results recorded for critical process parameters and in-process controls, actual yields at appropriate phases, details of any process deviations, and results of release testing.

2.5. Process Validation

A formal validation is required for all operations determined to be critical to the quality and purity of the API. Process validation is often a very time consuming and laborious activity; therefore, many companies perform it only on the final synthetic steps, relying on quality control and other GMP measures to assure the quality of the earlier, less critical intermediates. A written validation protocol should be established that specifies how the validation of a particular process will be conducted. This should identify the critical product attributes of the API (e.g., analytical specifications, physical form), and the critical process parameters (e.g., temperatures, stoichiometry) which may affect these attributes. For each critical parameter a normal operating range, a proven acceptable range, and, where appropriate, edge of failure limits, should be established. A series of consecutive validation runs (usually three) is then undertaken to establish that the process consistently falls within the defined ranges for each parameter and that the product consistently meets its quality specifications.

Validation studies should normally be completed before any commercial distribution of the API (Prospective Validation). For most new drugs, FDA approval will be withheld until the agency is satisfied that an adequate validation has been performed.

Once a process has been validated, strict controls must be enforced to prevent unauthorized changes. Any proposed changes to the process should be formally evaluated for the effect they may have on the critical quality attributes of the API. If a process change is judged to be major, i.e., it has the potential to influence the quality of the product, then its introduction should be preceded by a revalidation of the process. Minor changes which are judged unlikely to affect product quality may be implemented without formal revalidation, provided they give an equivalent input to the process. (For example, if the starting material is obtained from a new supplier, it should meet the same qualitative and quantitative specifications as that from the previous supplier.) Each process should be reviewed on a regular (perhaps annual) basis to assess how far it has shifted since its last validation, and a judgment should be made as to whether revalidation is required.

Read more about this topic in Ullmann's

This article is an excerpt from the Ullmann's Encyclopedia of Industrial Chemistry which celebrates its 100^th anniversary in 2014. More about the topic can be found in the encyclopedia article on Good Manufacturing Practices. More concept articles on general interest topics in industrial chemistry and chemical engineering can be found on the Ullmann's Academy homepage