SCHEDULE-B

CONDITIONS FOR GRANT OF A LICENSE TO MANUFACTURE BY WAY OF FORMULATION

SECTION-1

PREMISES

1. Location and surroundings

1.1 Location.-- The premises shall be located preferably in an industrial area and in any case not in any [Omitted] residential or commercial area.

1.2 Surroundings.-- Premises shall be situated in an environment that, when considered together with measures to protect the manufacturing processes, presents minimum risk of causing any contamination of materials or products, It shall be away form filthy surroundings and shall not be adjacent to an open sewerage, drain, public lavatory or any factory which produces a disagreeable or obnoxious odor or fumes or large quantities of soot, dust or smoke which may contaminate the drugs being manufactured or adversely affect their quality. Existing units shall keep the surroundings under their control to be clean.

1.3 Size.-- The size of the plot shall not be less than 2000 square yards.

2. Building layout and its pre-approval.-- The building shall be of adequate size and suitable design and construction in view of the need for drugs to be manufactured and to suit the operations to be carried out. The site and layout plan of building shall be got approved form the Central Licensing Board or person authorized by it in this behalf before starting construction of the building and any minor subsequent changes in the layout plan will be communicated as and when made with a revised updated layout plan at the time of renewal of Drug Manufacturing License.

3. Building design and construction (General)
3.1 General.-- The layout and design shall aim at minimizing the risk of errors, facilitate good sanitation and permit effective cleaning and maintenance in order to avoid cross-examination, build-up of dust or dirt, and in general, any adverse effect on the quality of products.

3.2 Services.-- Electrical supply, lighting, temperature and humidity controls and ventilation shall be appropriate and such that they doe not adversely effect directly or indirectly, either the pharmaceutical products during their Manufacture ands storage, or the accurate functioning of equipment.

3.3 Protection against insects.-- Premises shall be designed and equipped so as to afford maximum protection against the entry of insects or other animals.

3.4 Surfaces.-- In areas where raw materials, in-process materials or drugs are exposed, the following general condition shall apply to the extent necessary to prevent contamination, namely:--
(i) floors, walls, and ceilings permit easy cleaning, brick, cement blocks, and other porous materials are sealed;

(ii) floors, walls, ceiling, and other surfaces are hard, smooth, and free of sharp corners where extraneous material can collect;

(iii) joints are sealed between walls, ceiling and floors;

(iv) pipes, light fittings, ventilation points and other services do not create surfaces that can not be cleaned; and

(v) screened and trapped floor drains are provided if required.

4. Storage areas
4.1 Capacity.-- Storage area shall be properly defined of sufficient capacity to allow orderly storage of various categories of materials and products; staring and packaging materials, intermediates bulk and finished products, products in quarantine, and, released, rejected, returned, or recalled products.

4.2 Design.-- Storage areas shall be designed or adapted to ensure good storage conditions. In particular, they shall be clean and dry, suitably lit and maintained within acceptable temperature limits which should be commensurate with storage requirements of the drugs. Where special storage conditions are required (e.g., controlled temperature and humidity) these shall be provided, checked, and monitored.

4.3 Bays.-- Receiving and dispatch bays shall protect materials and products from the weather. Reception areas shall be designed and equipped to allow containers of incoming materials to be cleaned if necessary before storage.

4.4 Quarantine.-- Well defined quarantine areas shall be provided for the incoming materials, in process materials and finished drugs. Where quarantine status is ensured by storage in separate areas, these areas shall be clearly marked and their access restricted to authorized personnel. Any system replacing the physical quarantine shall be given equivalent security.

4.5 Sampling.-- There shall normally be a separate sampling area for starting materials. If sampling is to be performed in the storage area, it shall be provided in such a way as to prevent contamination or cross-contamination.

4.6 Rejected Materials.-- Segregation in a separate area shall be provided for the storage of rejected, recalled, or returned materials or products.

4.7 Special Materials.-- Highly active materials, narcotics, other dangerous drugs, and substances presenting special risks of abuse, fire, or explosion shall be stored in safe and secure areas.

4.8 Packaging Materials.-- Printed packaging materials are considered critical to the conformity of the pharmaceutical product to its labelling, and special attention shall be paid to the safe and secure storage of these materials.

4.9 Weighing Area.-- The weighing of starting materials on the basis of estimation of yield shall be carried out in separate weighing areas designed for that use with provisions for dust control. Separate provisions shall be made for materials posing high risks of contamination, like steroids and antibiotics especially penicillin.

5. Production Department
5.1 General Facilities.-- A production Department shall be provided which shall have all necessary facilities including:--
(i) adequate number of appropriately qualified and trained technical personnel;
(ii) adequate and properly planned areas;
(iii) suitable equipment, instruments and containers for manufacture including their validation where necessary;
(iv) clearly defined manufacturing processes shown to be capable of consistently manufacturing pharmaceutical products of the required quality and complying with their specifications;
(v) validated critical steps of manufacturing processes;
(vi) procedures and instructions for working approved by the Quality Control Department;
(vii) suitable storage places for in-process materials;
(viii) adequate number of technically trained and skilled personnel and equipment for in-process controls;
(ix) skilled operators trained to carry out procedures correctly, the record of training should be available; and
(x) appropriate air handling system to avoid contamination and cross-contamination.

5.2 Dedicated facilities for production
Dedicated and self-contained facilities for the production of particular drugs shall be provided in addition to the general facilities such as high sensitizing materials (e.g. pencillin) or biological preparations (e.g. live microorganisms) or cytotoxic substances or radiopharmaceutical or veterinary immunological preparations or sterile products or for that matter such other highly active pharmaceutical products, antibiotics, hormones as may be identified by the Central Licensing Board at any stage in order to minimize the risk of a serious medial hazard due to cross contamination. veterinary products containing ingredients similar to those used for human health and of the same quality can be manufactured in the same premises used for manufacture of pharmaceutical products, however, simultaneously human drugs shall not be manufactured. Non-pharmaceutical products, technical positions, such as pesticides shall not be manufactured in the same premises already used for the manufacture of pharmaceutical products. In exceptional cases of emergency, the principle of campaign working in the same facilities may be allowed by the Central Licensing Board provided that specific precautions are taken and the necessary validations are made.

5.3. General requirements for production areas
(i) Layout.-- The production area shall preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.

(ii) Adequacy.-- The adequacy of the working and in process storage space shall permit the orderly and logical placement of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid cross contamination, and to minimize the risk of omission error or wrong application of any of the manufacturing or control steps.

(iii) Surfaces.-- Starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (wells, floors and ceilings) shall be smooth and free from cracks and open joints shall not shed particulate matter, and shall permit easy and effective cleaning and, if necessary, disinfection.

(iv) Services.-- Pipework, light fittings, ventilation points and other services shall be designed and sided to avoid the creation of recesses that are difficult to clean. As far as possible, for maintenance purposes, they shall be accessible from outside the manufacturing areas.

(v) Drains.-- Drains shall be of adequate size and equipped to prevent backflow. Open channels shall be avoided.

(vi) Environmental Controls.-- Production areas shall be effectively ventilated, with air-control facilities (including control of temperature and, where necessary, humidity and filtration) appropriate to the products handled, to the operations undertaken, and to the external environment. these areas shall be regularly monitored during production and non-production periods to ensure compliance with their design specifications.

(vii) Packaging.-- Area(s) for the packaging of pharmaceutical products shall be specifically designed and laid out so as to avoid mix-ups or cross-contamination.

(viii) Light.-- Production areas shall be well lit, particularly where visual on-line controls are carried out.

6. Ancillary areas
6.1 Rest rooms.-- Rest and refreshment rooms shall be separate from other areas.

6.2 Changing rooms.-- Facilities shall be provided for changing and storing clothes and for washing and toilet purposes which shall be easily accessible and appropriate for the number of users. Toilets shall not communicate directly with production or storage areas.

6.3 Workshops.-- Maintenance workshops shall preferably be separated from production areas. Whenever parts and tools are stored in the production area, they shall be kept in rooms or lockers reserved for that use.

6.4 Animal house.-- Animal houses shall be well isolated form other areas, with separate entrance (animal access) and air-handling facilities.

2.1. General.-- The all necessary equipment shall be provided which shall be so designed, constructed, located installed and maintained as to suit the operations to be carried out, and the layout and design of equipment must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt, and, in general, any adverse effect on the quality of products.

2.2 Layout.-- The equipment shall be so laid that:--
(a) permits it to function in accordance with its intended use. Parts in contact with raw materials in-process materials, or drugs are accessible to cleaning or ar removable;

(b) permits cleaning of adjacent areas and does not interfere with other processing operation, and in also minimizes circulation of personnel and optimizes flow of material;

(c) prevents the contamination of drugs by other drugs, and by foreign material such as rust, lubricant, and particles coming from the equipment; and

(d) the base of immovable equipment is adequately sealed along point of contact with the floor.

2.3. Construction.-- The equipment shall be so constructed that it does not add extraneous material to the drug and for that:
(a) the surfaces that come in contact with raw materials, in-process materials, or drugs are smooth and are made of material that is non-toxic, corrosion resistant, non-reactive to the drug being manufactured, and capable of withstanding repeated cleaning or sanitizing;

(b) the design is such that the possibility of a lubricant or other maintenance material contaminating the drug is minimum;

(c) wooden equipment and equipment made of material that is prone to shed particles or to harbour bacteria do not come in contact or contaminate raw materials, in-process, or drugs, and

(d) chain drives and transmission gears are enclosed or properly covered.

2.4 Piping.--All service piping and devices shall be clearly labelled to indicate the contents and, where applicable, the direction of flow, and special attention be paid to the provision of non-interchangeable connections or adopters for dangerous gases and liquids.

2.5 Tanks.-- Tanks used in processing liquids and ointments are equipped with fittings that can be dismantled and cleaned and are provided with appropriate covers.

2.6 Filters.-- Filter assemblies are designed for easy dismantling.

2.7 Cleaning equipment.-- Washing and cleaning equipment shall be provided which shall not be a source of contamination.

2.8 Defective equipment.-- Defective equipment shall, if possible, be removed from production and quality control areas, at least, be clearly labelled as defective.

3.1. General.-- The Quality Control Department shall be independent with adequate number of trained personnel and under the authority of a person who shall be a full time employee.

3.2 Laboratories.-- Adequate laboratory facilities shall be proved with necessary equipment and instrument, glassware, chemicals, reagents etc, suited to testing procedures of drugs to be manufactured.

3.3. Area.-- The quality control laboratories shall have adequate areas which shall:--
(i) be separated from production areas, and the areas where biological, microgiological or radioisotope test methods are employed shall be separated from each other.

(ii) be designed to suit the operations to be carried out in them and sufficient space shall be given to avoid mix-ups and cross-contamination;

(iii) be so designed so that it takes into account the suitability of construction materials, fume prevention and ventilation and separate air handling units and other requirements shall be provided for biological, microbiological, sterility testing and radioisotope laboratories;

(iv) have separate room for highly sensitive instruments to protect these against electrical interference, vibrations, contact with excessive moisture and other external factors or where there is need to isolate the instrument; and

(v) have appropriate facilities to store samples and records.

3.4 Facilities.-- The quality control laboratory shall have:
(i) satisfactory equipment required for test and analysis of drugs intended to be manufactured, protocols for test and analysis of drugs to be manufactured including their validation where necessary;

(ii) have adequate other facilities and approved procedures for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products and where applicable for monitoring environmental conditions for goods manufacturing practice purposes;

(iii) written procedures specifically:--
(a) validation of methods of manufacture and quality control testing;
(b) validation of equipment and instruments and cleaning procedures;
(c) stability testing of the active pharmaceutical substances and the finished drugs; and
(d) determining the shelf life of both raw materials and finished drugs.

(iv) validation studies conducted for important equipment or instruments, methods of manufacture and quality control and cleaning procedures in accordance with predefined protocols. A written report summarizing results and conclusions shall be available.

(v) separate facilities for the bulk storage of volatile and inflammable materials.

4.1 General.-- The documents shall:--
(i) be designed and prepared, complying with the relevant parts of the drug registration approvals;
(ii) be approved, signed, and dated by appropriate authorized persons and shall not be changed without authorization;
(iii) have unambiguous contents and shall clearly state the title, nature, and purpose, and they shall be laid out in an orderly fashion and be easy to check, reproduced documents shall be clear and legible.

4.2 Specifications and Testing Procedures.-- Following documents shall be available:--
(i) Reference Bodies.-- Pharmacopoeias, reference standards, reference spectra, and other reference materials, where necessary;
(ii) Testing Procedures.-- validated testing procedures in the context of available facilities and equipment;
(iii) Specifications.-- Appropriately authorized and dated specifications including tests on identity, content, purity, and quality, for starting and packaging materials and finished products; and where appropriate, for intermediate or bulk products. Specifications for water, solvents, and reagents (e.g., acids and bases) used in production shall also be included.

4.3 Specification for Starting and Packaging Materials.-- Specifications for starting and primary or printed packaging materials shall include, if applicable:--
(i) the designated name (if applicable, the International Non-proprietary Name) and internal code reference;
(ii) the reference, if any, to a pharmacopoeial monograph;
(iii) qualitative and quantitative requirements with acceptance limits; and
(iv) packaging material shall conform to specifications, with emphasis placed on the compatibility of the material with the drug products it contains.

4.4 Specifications for Finished Products.-- Specification for finished products shall include:--
(i) the designated name of the product and the code reference where applicable;
(ii) the designated name(s) of the active ingredients(s) (if applicable, the International Non-proprietary Name);
(iii) the label claim or the reference to the formula;
(iv) a description of the dosage form;
(v) directions for sampling and testing or it reference to procedures;
(vi) the qualitative and quantitative requirements with acceptance limits;
(vii) the storage conditions and precautions where applicable; and
(viii) the shelf-life.

4.5 Master formula.-- A formally authorized master formula shall exist for each product and batch size to be manufactured, which shall include;
(i) the name of the product, with a product reference code relating to its specification;
(ii) a description of the dosage form, strength of the product, and batch size;
(iii) a list of all starting materials to be used (if applicable, with the International Non-proprietary Name), with the amount of each described, using the designated name and a reference that is unique to that material (mention shall be made by any substance that may disappear in the course of processing) and a reference number or code number to its quality control testing;
(iv) a statement of the expected final yield with the acceptance limits, and of relevant intermediate yields where applicable;
(v) a statement of the processing location and the principal equipment to be used;
(vi) detailed step-wise processing instructions (e.g. checks, on materials, pre-treatment, sequence for adding materials, mixing times, temperatures);
(vii) the instructions for any in-process controls with their limits;
(viii) where necessary, the requirements for storage of the products, including the container, the labelling, and any special storage conditions; and
(ix) any special precautions to be observed.

4.6 Packaging Instructions.-- Formally authorized packaging instructions shall exist for each product, pack size, and type which shall normally include, or made reference to:--
(i) the name of the product;
(ii) a description of its pharmaceutical for, strength and method of application where applicable;
(iii) the pack size expressed in terms of the number, weight, or volume of the product in the final container;
(iv) a complete list of all the packaging materials required for a standard batch size, including quantities, sizes, and types, with the code of reference number relating to the specifications for each packaging materials;
(v) where appropriate an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product have been marked;
(vi) special precautions to be observed, including a careful examination of the packaging area and equipment in order to ascertain the line clearance before operations begin;
(vii) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; and
(viii) details of in-process controls with instructions for sampling and acceptance limits.

4.7 Standard Operating Procedures and Records.-- There shall be standard operating procedures for:--
(i) the receipt of each delivery of staring material and primary and printed packaging material;
(ii) the internal labelling, quarantine, and storage of starting materials packaging materials, and other materials as appropriate;
(iii) each instrument and price of equipment. These shall be placed in close proximity to the equipment;
(iv) sampling, which specify the person(s) authorized to take samples, and the sampling instructions shall include;
(a) the method of sampling and the sampling plan;
(b) the equipment to be used;
(c) any precautions to be observed to avoid contamination of the material or any deterioration in its quality;
(d) the amount of sample to be taken;
(e) instructions for any required sub-division of the samples;
(f) the type of sample container to be used, and whether they are for aseptic sampling or for normal sampling; and
(g) any specific precautions to be observed, especially in regard to the sampling of sterile or noxious material;

(v) describing the details of the batch (lot) numbering system, with the objective of ensuring that each batch of intermediate, bulk, or finished product is identified with a specific batch number;
(vi) for batch numbering that are applied to the processing stage and to the respective packaging stage shall be related to each other;
(vii) for batch numbering shall assure that the same batch numbers will not be repeatedly used; this applies also to reprocessing.

4.8 There shall be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed shall be recorded and shall include:--
(a) name of the material or drug and, where applicable, dosage form;
(b) batch number and, where appropriate, the manufacture and/or supplier;
(c) references to the relevant specifications and testing procedures;
(d) test results, including observations and calculations, and reference to any specifications (limits);
(e) dates of testing;
(f) initials of the persons who performed the testing;
(g) initials of the persons who verified the testing and the calculations, where appropriate;
(h) a clear statement of release or rejection and the dated signature of the designated responsible person.

4.9 There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used and facilities to be cleared and such written procedures shall be followed.

4.10 Written standard operating procedures and the associated records of actions taken shall be available, for:--
(a) equipment assembly and validation;
(b) analytical apparatus and calibration;
(c) maintenance, cleaning and sanitization;
(d) personnel matters including qualifications, training, clothing, hygiene;
(e) environmental monitoring;
(f) pest control;
(g) complaints;
(h) recalls;
(i) returns.

4.11 Labels

4.11.1 Labels firmly affixed or security attached to containers, equipment or working areas shall be clear and unambiguous and shall indicate the status like "quarantined" "accepted" "rejected" "clean," etc.

4.11.2 All finished drugs shall be labelled in accordance with the approval of Registration board and with at least the following information:--
(a) the name of the drug;
(b) a list of the active ingredients, showing the amount of each present, and a statement of the net contents, e.g., number of dosage units, weight or volume;
(c) the batch number assigned by the manufacturer;
(d) the expiry date;
(e) any special storage conditions or handling precautions that may be necessary;
(f) direction for use, and warnings and precautions that may be necessary; and
(g) the name and address of the manufacturer or the company or the person responsible for placing the drug on the market.

4.11.3 The label or accompanying document of reference standards shall indicate concentration, date of manufacture, expiry date, date the closure is first opened and storage conditions, where appropriate.

4.12 Batch Processing Records
4.12.1. A Batch Processing Record shall be maintained for each batch processed. It shall be based on the relevant portions of the approved Master Formula and Processing Instructions.

4.12.2 Before starting any processing a check shall be performed and recorded that the equipment and work station are clear of previous products, documents or materials not required for the planned process and that equipment is clean and suitable for use.

4.12.3. During processing, the following information shall be recorded and, after completion, the record shall be dated and signed in agreement by the person responsible for the processing operations:
(a) the name of the drug;
(b) the number of the batch being manufactured;
(c) dates and times of commencement, of significant intermediate stages and of completion of production;
(d) initials of the operator of different significant steps of production and, where appropriate, of the person who checked each of these operations (e.g. weighting);
(e) the batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added);
(f) any relevant processing operation or event and major equipment used;
(g) a record of the in-process controls and the initials of the person (s) carrying them out, and the results obtained;
(h) the amount of drug obtained at different stages of manufacture (yield) explaining any significant deviations from the expected yield;
(i) notes on special problems including details, with signed authorization, for any deviation from the Master Formula.

5.1 Sanitation.-- A written sanitation program shall be available which will include instructions on the sanitary production of drugs and the handling of materials used in the production of drugs, and, in particular, indicating the following cleaning procedures for the premises and the equipment used in the production of the drug, namely:--
(i) cleaning requirements applicable to all production areas of the plant, with emphasis on manufacturing areas that require special attention.
(ii) cleaning requirements applicable to processing equipment;
(iii) clearing intervals;
(iv) cleaning materials, their concentration, and the equipment to be used;
(v) responsibilities of outside contractors, if any;
(vi) disposal procedure for waste material and debris;
(vii) pest control measures;
(viii) precautions required to prevent contamination of a drug when rodenticides, insecticides, and fumigation agents are used;
(ix) microbial and environmental monitoring procedures and limits in areas where susceptible products are manufactured; and
(x) the personnel responsible for carrying out cleaning procedure.

5.2 Hygiene
5.2.1. Minimum requirements of health, hygiene behaviour and clothing for personnel shall be available in writing in order to ensure the clean and sanitary production of the drug.

5.2.2. No person who is affected with or is a carrier of a disease in a communicable form, or has an open lesion on any exposed surface of the body shall be employed for areas where a drug during any stage of its production is exposed.

5.2.3. Minimum requirements of health shall be available in writing and shall provide for:--
(i) pre-employment medical examination;
(ii) assessment of an employee’s health prior to return to his place of employment following illness involving a communicable disease;
(iii) action to be taken in the event of a positive diagnosis or a case suspected of being hazardous to consumers of the products; and
(iv) routine supervisory check system of employees.

5.2.4. The hygiene program shall clearly define clothing requirements and hygiene procedures for company personnel and visitors including the following:--
(i) Where a potential for the contamination of a raw materials, in-process material, or drug exists, individuals shall wear clean clothing and protective covering;
(ii) Eating, smoking, or any unhygienic practice shall not be permitted in production areas;
(iii) Requirements concerning personal hygiene, with emphasis on hand hygiene;
(iv) Requirements concerning cosmetics and jewelry worn by employees.