Dr.A.B.Ram Jyothis MD (Hom) Pharm.
Quality Analyst, Department of Quality Assurance.
Fr.Muller Homoeopathic Pharmaceutical Division
Deralakatte Post, Mangalore – 574160
E mail: PHARMAKON@rediffmail.com
The Good Manufacturing Practice (GMP) code of Homoeopathic pharmaceuticals for this country had been under consideration for many years. A draft of GMP regulations was prepared in August 2005 and was circulated to members of Federation of Homoeopathic Manufactures of India and Drug Technical Advisory Board.
The Indian code of Good Manufacturing Practices for Homoeopathic pharmaceutical industries was amended in 31st October, 2006 in the form of Schedule M-1 of Drugs and Cosmetic Rules of 1945 as per a Gazette notification, dated 31st October, 2006 so that all the Homoeopathic manufactures have sufficient time to prepare them in implementing the standards set out in the said notification. Good Manufacturing Practices are designed to ensure that the entire process, from the purchase of raw materials from approved suppliers manufactured through the detailed, defined production processes, using appropriate facilities and trained personnel operating in well designed building, having proper quality control measures to the final distribution outlets, results in the achievement of consistent and uniformly good quality.
It is a professional way of life for the pharmacist and ethical commitment to public from the pharmaceutical industry besides being value addition to the business. If pharmacist accept the social responsibility for the manufacture, distribution and sale of safe, effective and defect – free drug products we will go well beyond the elementary requirements of Schedule M I and in fact, implementation will be almost automatic. It is however necessary to appreciate the philosophy of quality assurance of which GMP is an essential element and in order to do that a brief review of earlier approaches to the achievement of quality in the Homoeopathic Pharmaceutical industry would be helpful.
Until as recently as the late nineties it was believed that quality could be controlled in the laboratory and pronounced upon by the head of the testing laboratory who was called the Chief Analyst or Chief Chemist. Even today, this view persists in some quarters. A sample which may or may not have been representative of bulk, was usually given to the laboratory or testing. A report of whether or not it complied with statutory or other standards was all that was considered necessary for evaluating quality. Knowledge of how the product was made or how well the product would keep on storage was not considered a part of the unction of the Chief Analyst, in fact, quality of the product was not even considered to be anyone’s responsibility.
The ever increasing demand for Homoeopathic pharmaceutical products throughout the world, which may be stored under varying climatic conditions, called for knowledge of the stability of products and the first systematic efforts at providing shelf – life under different storage conditions were made. Stability studies showed that compliance of the product with its specifications at the time of manufacture was no guarantee of its stability in market place. Testing of the end- product was unavoidable but was proving to be of limited value.
In any case, testing has, among others, one big limitation; information about a batch of product or even material is obtained by analysis of samples which are expected to be representative of the batch. This assumption is valid only when the batch is homogeneous or when the bulk is made to a process known to yield a uniform product; faulty equipment or lapses in manufacturing operations could result in non homogeneity and variations in the batch may not be detected in sample taken from the batch. The other limitation of testing is its presumptive nature i.e. tests are done for only those ingredients or components which are presumed o be there. One does not look for substances which are present because of a mix –up or wrong labeling or any other bad manufacturing practice. Likewise, the analysis of any raw material is limited to only those impurities which are presumed or likely to be present in it.
Evolving Concept of Total Quality Management (TQM):
Given this situation where the extent and reliability of testing were limited, the manufacturing process had to be closely monitored before a verdict could be given on the quality of product. The concept of Quality Control was taking root and the Chief Quality Analyst in his new role as the Quality Control Manager had to approve the manufacturing methods for aspects which could impinge on the quality of final product. Changes in the process or of supplies of input materials also had to be approved. Increasing public awareness and concern led to legislation in many parts of the world to control the manufacture and sale of pharmaceutical products in order to give confidence to people that medicines on sale were safe and effective. Regulatory agencies were expecting from the industry not merely Quality Control but also Quality Assurance.
Today Assurance means the product design (at the research and development stage) must be appropriate or the product’s intended use. In other words, even before manufacture, the safety and efficacy of he product must be unambiguously established, the stability, both physical and pharmaceutical, must be clearly shown, the quality of input materials and of the finished product must be specified and the proposed manufacturing process must be validated to show that it will yield the product of the quality specified for it. Subsequently, Good Manufacturing Practices designed to ensure that the entire process, from the purchase of approved materials through the detailed, defined production processes, using appropriate facilities and trained personnel operating in well –designed building , through the Quality Control measures to the final distribution outlets, results in the achievement of consistent and uniformly good quality.
The management of quality of Homoeopathic Pharmaceuticals has interrelated aspects such as Quality Control and Quality Assurance. The relationship between them and their fundamental importance to the production and control of pharmaceutical products should be clearly understood. GMP forms the core of this complex web of activities and so finds a place in the Drug and Cosmetics Act.
In order to achieve the objectives of Total Quality Management, the following steps have to be followed:
1. A product which is effective, safe and stable for its expected life should be developed.
2. The quality of the product should be defined in the form of specifications.
3. A process should be devised and documented by following which the products (inclusive of its pack) of quality defined for it will be obtained.
4. GMP requirement should be included in the documented production and control operations.
5. The quality of the raw and packing materials required to produce the product should be defined in the form of specifications.
6. Arrangements should be made for the supply and use of the right starting and packing materials.
7. Manufacture should be done strictly according to the defined and documented process to yield the finished product which:
a) Contains the correct ingredients in the correct proportions,
b) Complies with the defined specifications of both product and pack, and
c) Bears correct label.
8. The finished product should be stored, distributed and subsequently handled in such a manner that its quality is maintained throughout its designated shelf-life.
9. Managerial responsibilities should be clearly specified in job descriptions.
10.There should be participation and commitment of staff in all departments and at all levels within the organisation, the suppliers of materials and the distributors of the products.
Importance of Documentation:
An essential element of Total Quality Management is good documentation. Clearly written documentation prevents errors that may arise in oral or casually written communication and provides assurance that all quality-related activities are carried out exactly the way they have been planned and approved. Schedule M 1 apparently calls for a manual or a collection of departmental manuals which describes in great detail the system of quality management in the Pharmaceutical Company. The international standard ISO 9000 goes a step further and prescribes documentation covering the entire spectrum of quality related functions in the whole organization.
Broadly, all documents relating to quality fall into one or more of the following categories:
1. Documents required for the achievement of product quality such as specifications, manufacturing instructions, standard operating procedures etc.
2. Documents required for the effective operation of the quality management system such as quality assurance procedures, departmental procedures etc.
3. Records which (a) Give information on the actions taken at all stages of manufacture and at all other relevant stages pertinent to the quality of the final product. (b) Provide confirmation of performance, and (c) Provide a history of each batch of product, including its distribution.
Documents should be designed, prepared, reviewed and distributed with care. They should be written in some detail and in simple language that can be understood by the user. They should be approved, signed and dated by appropriate authorized persons. Documents should be regularly reviewed and kept up to date. No document should be amended without authorization. In the case of permanent amendments, the amended document should be replaced at the earliest opportunity by a newly prepared and authorized document. The superseded or outdated document should be removed from active use and a copy retained in a master file for reference.
The Schedule M 1 requirement consists of a set of documents which describe clearly the systems of control of materials, processes and products and the procedures in the various departments, which together constitute the quality management system. Such a compilation is not merely to be kept for reference and inspection, but should be used often, because it will be the “Quality Bible” of the Pharmaceutical Company. It should cover all the interacting activities and techniques related to handling of materials, manufacture and quality control.
The manual will serve both the Company and the drugs control administration. For the former, it will be a statement of commitment that things will be done the way management has decided, in order to provide assurance to it and the public who buy the products of the Company. For the regulatory authorities, the manual provides visible and authentic evidence of the systems in operation in the Company and obviates the need to obtain verbal information on them with the probability of getting conflicting versions from the operating people.
What should be the contents of a quality assurance manual? Obviously, it will depend on the size of the Pharmaceutical company and the scale of its operations. At the lease, it should cover the following:
1. A brief description of the overall system of manufacture and control, starting from the receipt of input materials up to the distribution of finished products.
2. Details of the procedures to be followed in each and every department of the factory (including those not directly involved in manufacturing such as sanitation services, building maintenance etc): The procedures should give the sequence of operations and the responsibilities of the persons in charge of these activities. They should clearly indicate who does what, when and how.
3. Documents to be used for recording data collected in the course of performing the various activities. Where pr-printed forms are employed it would be useful to have specimens of them attached to the relevant procedures.
4. Reporting systems indicating whom to inform and when, what to with the information and so on.
The writing of a manual should be entrusted to a group of technical people with adequate of knowledge of production and quality control and with the ability to express in clear and simple language. To the extent possible, the procedures should be in the form of instructions in the imperative and as numbered steps. The details should be precise and unambiguous. A document should be so written that, if necessary, part of it can be revised without having to rewrite the whole. The manual should be drafted, checked and finalized by the group (mentioned earlier) and reviewed and approved by the heads of production and quality control.
The greatest value of a quality assurance manual is in establishing a high degree of quality credibility with the consumers and the government authorities but it is more important to establish credibility within the organization. This is best done by making the manual accessible to whoever wants or needs it. It should be read and followed by staff at all levels and referred to whenever a doubt arises on quality-related activities or when an audit of the quality system is being done However, it should not be allowed to become outdated or act as a constraint on improvement and innovation. At any time it should accurately reflect the measures being taken by the Company to achieve its quality objectives.
Implementation of Total Quality Management Systems:
The inevitable questions that arise are “is it possible to implement Total Quality management Systems in Homoeopathic Pharmaceuticals?” and “will it prove to be an expensive exercise?” The short answer to the first is “Yes” and to the second “No”. How then does one go about it? As far as industry is concerned the first requirement is top management commitment, which must be translated into a quality policy. The policy should have as its objective of manufacture of products which consistently meet the requirements of good quality in every way in the interest of the consumer. Quality is to be attained by the use of quality assurance system involving people at all levels and disciplines within the company. The next step is a statement of this policy, its explanation to the management team and an undertaking from the team that the policy will be implemented. The third step is the organization of a quality assurance function in the Company.
In doing this it must be remembered that:
1. Responsibility for product quality must retain with the production and control functions; it must not be allowed to shift to the quality assurance unit.
2. Persons in all quality related functions should be given the opportunity to perform efficiently and must at all times have the management backing they need.
3. Systems and procedures must be prevented from failing, by independent checks. Reviews by the quality assurance unit.
4. The quality assurance unit must be independent of the production and control functions and must report at a management level no lower than them.
Once the objectives of the quality assurance unit have been defined, work should start on the basic requirements of GMP which have been detailed in Schedule M 1. The bulk of the GMP requirements can be met without capital investment and in most cases with a one-time expenditure. All that is necessary is a team of articulate people from Production and Quality Control devoting time and getting down to devising and writing up the systems and procedures. The same team could then form the nucleus of the quality assurance group or unit which will take over the responsibility for implementing the systems and auditing from time to time to ensure compliance. The success of the quality assurance programme will ultimately depend on the people who operate the systems; proper and continual training of people should therefore receive management attention all the time. Along with creating and improving product quality there must be a conscious effort at improving the quality of work in all areas. The company environment should support high quality employee performance.
The organizational set-up for quality management deserves mention here. As mentioned earlier the two key persons who are jointly responsible for quality are the heads of production and quality control. They should be independent of each other and have sufficient authority in their spheres of work and control. The head of quality control (in charge of quality evaluation) should be allowed to function impartially and without fear. The approval or rejection of materials, products, specifications and procedures which impact on the quality of the product should be the sole responsibility of the quality control manager.
The increasing involvement of the QC Manager in all matters affecting quality has to be recognized; the historical legacy of looking upon Quality Control as a mere laboratory manager has to slowly change to that of an adviser on quality matters but this transition is not going to be easy. The inevitable clash of egos between the one who produces the product and the one who evaluates it can be resolved only if the QC Manager has tact, patience and above all, knowledge of not only his own function but also of many other functions in the organization. It should be remembered that Quality is a constant effort and it should come from a team work.
1. Extraordinary Gazzate, Schedule M-1, Good manufacturing Practices for Homoeopathic Pharmacuetical Industries,October 2006.
2. R, S.Iyer, Schedule M and Beyond, Good Manufacturing Practices, Indian Drug Manufacturers Association, 1997.
3. Sidney H. Willig and James R. Stoker ‘Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control’, Bhalani publishing House, Oct 1991.
4. WHO, Geneva, WHO technical Report Series,WHO Expert committee onSpecification for Pharmaceutical Preparations,2005.