At a time when bio-business is booming, pharmaceutical companies are playing safe with the development of active pharmaceutical ingredients (APIs). APIs are nothing but active chemicals used in the manufacturing of drugs. The fact that there are medications that contain more than one active ingredient spell the market value of APIs
Scientists insist on Good Manufacturing Practices (GMP) for the development of APIs under an appropriate system that stresses quality and purity, which are considered to be part and parcel of active ingredients. GMP comprises of receipt of materials, production, packaging, re-packaging, labeling, re-labeling, quality control, release, storage and distribution of APIs and other related controls.
It may sound strange to learn that the legal classification of active pharmaceutical ingredients may vary from region to region or country to country. When a material is classified as an API in a region or country, the manufacturers are expected to develop the material in accordance with the legal classification prevailing in that particular region or country.
APIs are commonly manufactured by chemical synthesis, extraction and cell culture/fermentation. It can also be developed by recovery from natural sources or any combination of above mentioned processes.
For the production of API, manufacturers commonly employ a material known as 'API Starting Material'. An API Starting Material may be an article of commerce or a material purchased from one or more suppliers under contract or commercial agreement. One can even produce this material sitting at the comfort of home.
What is significant is that API starting materials normally have defined chemical properties and a structure. This material is incorporated as a major structural fragment into the API.
However, once a company initiates the development of API, it is expected to designate and document the rationale behind it. For synthetic processes this is known as the point at which "API starting materials" are entered into the process. For other processes, including fermentation, extraction and purification, this rationale should be established on a case by case basis.
From the point of establishment of rationale, appropriate GMP should be applied to these intermediate and/or API manufacturing steps. The process of applying GMP includes the validation of critical steps determined to impact the quality of an API.
Quality management
No doubt, manufacturers always strive to bring out quality products, thanks to the die-hard competition amongst them prevailing in the country. As part of the quality management, each manufacturer should establish, document, and implement an effective mechanism incorporating active participation of management and appropriate manufacturing personnel.
The quality management system should encompass the organizational structure, procedures and processes and resources. Special care must be taken to infuse confidence into the minds of manufacturing personnel that active ingredient will meet its intended specifications for quality and purity. Also, all quality related activities should be defined and documented.
Apart, the quality management team has to ensure procedures to notify regulatory inspections, serious GMP deficiencies, product defects and related actions to responsible management in a timely manner.
Above all, there should be a quality unit/(s) that is independent of production, fulfilling both quality assurance and quality control responsibilities. The quality units may be in the form of separate QA and QC. This unit/(s) may either consist of a group or have only an individual, largely depending upon the size and structure of the organization.
The company should take all measures to not to release or use materials before the satisfactory completion of evaluation by the quality unit/(s), unless there are appropriate systems in place to allow for such use. The company is also expected to specify the persons authorized to release intermediates and APIs.
Quality control:
The quality control should be maintained in all quality-related matters. The quality control 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;
.Establishing a system to release or reject raw materials, intermediates, packaging and labeling materials;
.Making sure that critical deviations are investigated and resolved;
.Approving all specifications and master production instructions;
.Approving all procedures potentially impacting the quality of intermediates or APIs, etc.
Production activities
.The responsibility for production activities should also be described in writing. It 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; etc.
Internal audits:
In order to verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule.
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. It should include at least:
.A review of critical in-process control and critical API test results;
.A review of all batches which failed to meet established specifications;
.A review of results of the stability monitoring programme;
.A review of all quality related returns, complaints and recalls; and
.A review of adequacy of corrective actions.
Personnel qualifications
There should be adequate number of eligible personnel 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.
As a matter of fact, qualified individuals are expected to conduct training sessions regularly. The training sessions should cover the particular operations that the employees perform and GMP, as it relates to the employees' functions. Records of training should be maintained. It is important that companies assess the practical effectiveness of the training periodically.
Personnel hygiene:
Personnel involved in the process of development of active ingredients should practice good sanitation and health habits. These personnel should wear clean clothing suitable for the manufacturing activity. Depending up on the need, this clothing should be changed. Additional protective apparel, such as head, face, hand, and arm coverings should be worn when necessary to protect intermediates and APIs from contamination.
Consultants
Consultants, who are appointed to advise on the manufacture and control of intermediates or APIs, should have sufficient education, training, and experience, or any combination thereof.
Design and construction: Buildings and facilities used to manufacture the intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance, and operations as appropriate to the type and stage of manufacture. Facilities should be designed in such a way as to minimize potential contamination. Where microbiological specifications have been established for the intermediate or API, facilities should also be designed to limit exposure to objectionable microbiological contaminants as appropriate.
Process equipment:
Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size, and suitably located for its intended use, cleaning, sanitization (where appropriate) and maintenance.
The required equipments should be constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the intermediates and APIs beyond the official or other established specifications. Production equipment should only be used within its qualified operating range.
Major equipments, including reactors and storage containers and permanently installed processing lines used during the production of an intermediate or API should be appropriately identified. Some of the other points to be considered for the continuous improvement of the product quality of APIs are:
.Complaints and Recalls
.Quality Management
.Laboratory Controls
.Repackaging, re-labeling if necessary
.Documentation, etc.
(The author is expert in chemicals and pharmaceuticals based in Mumbai)