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CURRENT GOOD MANUFACTURING PRACTICES
« on: April 17, 2014, 12:40:03 PM »
 CURRENT GOOD MANUFACTURING PRACTICES

 NOTIFIED ON MAY 15, 1998 UNDER DRUGS ACT 1976 AND
 DRUGS (LICENSING, REGISTERING AND ADVERTISING) RULES 1976.
 
 PUBLISHED BY:
 MINISTRY OF HEALTH,
 GOVERNMENT OF PAKISTAN
 ISLAMABAD
 
 No.F.9-19/96-Lic.
 Government of Pakistan
 Ministry of Health
 *****
 Islamabad, the  15th May 1998
 S.R.O. 470(I)/98, - In  exercise of the powers conferred by section 43   of the Drugs Act, 1976(XXXI of  1976), the Federal Government of   Pakistan to direct that the following further amendments shall be made   in the Drugs (Licensing, shall be made in the Drugs  (Licensing ,   Registering and Advertising) Rules , 1976, the same having been    previously published as required by sub-section (3) of the said section,   namely  :-
 In the aforesaid Rules-
 I. For rule 2 the following shall be substituted, namely :-
 2. Definitions In these rules, unless there is anything repugnant in the    subject or context:-
 (a) “active pharmaceutical ingredient” means a substance   pharmacologically active  compound (ingredient);
 (b) “airlock” means an enclose space with two or more doors, which is    interposed between two or more rooms of differing classes of cleanliness   for  the purpose of controlling the airflow between those rooms when   they need to be  entered and an airlock is designed for and used by   either people or goods;
 (c) “authorized person responsible for the release of batches of product   for  sale:
 (d) “basic manufacture” means manufacturer of a drug from basic raw   material to  a product which is ready for use as a staring material for   the formulation of a  finished drug or for repacking and such   manufacture may involve chemical ,  bio-chemical, photochemical, microbial or such other processes or a combination  of any of such processes;
 (e) “batch (or lot)” means a defined quantity of starting material,   packaging  material, or finished product processed in a single process   or series of  processes so that it could be expected to be homogeneous,   in the case of  continuous manufacture the batch must correspond to   complete to be homogeneous,  in the case of continuous manufacture the   batch must correspond to a defined  fraction of the production ,   characterized by its intended homogeneity, and to complete certain   stages of manufacture it may sometimes be necessary to divide  a batch   into a number of sub-batches, which are later brought to form a final    homogeneous batch;
 (f) “batch number (or lot number)” means a distinctive combination of   numbers  and or letters which specifically identifies a batch on the   labels , the batch  to be trace and revived.
 (g) “batch numbering system” means a standard operating procedure   describing  the details of the batch numbering;
 (h) “batch records” means all documents associated with the manufacture   of a  batch of bulk product or finished product showing a history of   each batch of  product and of all circumstances pertinent to the quality   of the final product;
 (i) “biological agents” means micro-organisms, including genetically   engineered  microorganisms, cell cultured and endoparasites, whether   pathogenic or not ;
 (j) “biological agents” means micro-organisms, including genetically   engineered  micro organisms, cell culture and end parasites, including   final packing;
 (k) “calibration” means the set of operations that established, under   specified  conditions, the relationship between values indicated by an   instruments or  meaning system for especially weighing, recording, and   controlling, or the  values relationship between values indicated by an   instrument or measuring  system for especially weighing, recording, and   controlling, or the values  represented by a material measure, and the   corresponding known values of a  reference standard and the limits for   acceptance of the results;
 (l) “Clean area” means an area with defined environments control of   particulate  and microbial contamination, constructed and used in such a   way as to reduce  and or eliminate introduction, generation, and   retention of contaminants within  the area ;
 (m) “compounding” means scientific combination of two or more   ingredients with  a view to make a finished;
 (n) “consignment or delivery” means the quantity of starting material,   or of a  drug product, made by one manufacturer and supplied at one time   in response to  a particular request or order, a consignment may   comprise one or more packages  or containers and may include material   belonging to more than one batch;
 (o) “critical process” means a process that may cause variation in the   quality  of the pharmaceutical product;
 (p) “cross-contamination” means of a starting material, intermediate   product,  or finished product with another starting martial or drug   during production;
 (q) “finished product” means a product that has undergone al stags of    production, including packaging in its final container and labeling;
 (r) “Form” means a form set forth in Schedule A;
 (s) “formulation” means all operations involved in converting a drug   into a  final pharmaceutical dosage form ready for use as a finished   drug including  compounding, processing, formulating, filling, packing,   finishing, labeling,  and other like processes;
 (t) “good manufacturing practices for pharmaceutical products” means   part of  quality assurance which:-
 (u) “half-finished product” means any material or mixture of materials   that has  to undergo further manufacture;
 (v) “in-process control” means checks performed during production in   order to  monitor and if necessary to adjust the process to ensure that   the product  conforms to its specifications and control of the environment or equipment may  also be regarded as a part of in-process control;
 (w) “intermediate product” means partly processed material that must   undergo  further manufacturing steps before it becomes a bulk product;
 (x) “large-volume parenteral” means sterile solutions intended for parenteral  application with a volume of more than 100 ml one container   of the finished  dosage form;
 (y) “manufacturer” means all operations of production , quality control,    release, storage and the related controls;
 (z) “manufacturer” means a company that carries out at least one step of    manufacturer;
 (aa) “manufacturer authorization” means a document, issued by the Drug    Registration Board set up under the Drugs Act, 1976, as a certificate of   drug  registration;
 (ab)“master formula” means a document or set of documents specifying the    starting materials with their quantities and the packaging materials ,   together  with a description of the procedures and precautions required   to produce a  specified quantity of a finished product as well as the   processing  instructions, including the in-process controls;
 (ac) “master record” means a documents or set of documents that as a   basis for  the batch documentation (blank batch record);
 (ad) “new drug” means drug that has not been commonly sold or distributed to  the public in Pakistan and is introduced for the first time;
 (ae) “Ordinance” means  the Drug s Ordinance, 1976(IV of 1976)
 (af) “Packing” means  all operations, including filling and labeling   which a bulk drug has to undergo  in order to become a finished product;
 Note : Sterile filling  would not normally be regarded as part of packaging, the bulk product being the  filled , but not the finally packaged, primary container.
 (ag) “Packing material”  means any a material, including printed material, employed in the packing of a  pharmaceutical product, excluding any outer packaging used for transportation  or shipment and packaging material are referred to as primary or secondary  according to   whether or not they are intended to be in direct contact with the product;
 (ah) “Pharmaceutical product” means any drug intended for human use or    veterinary use presented in its finished dosage form or as a starting   material  for use in such a dosage form;
 (ai) “Processing instruction or procedures” means as defined include   (ab) of  this section;
 (aj) “production” means all operations involved in the preparation of a    pharmaceutical product;
 (ak) “Purity” means the degree to which other chemical or biological   entities  are present in any substance;
 (al) “quality assurance” means the totality of the arrangements made   with the  object of ensuring that pharmaceutical products are of the   quality required for  their intended use and so incorporates good manufacturing practices , Quality  Control and other factors including design and development and good laboratory  practices;
 (am) “quality control” means the part of good manufacturing practices   concerted  with sampling, specifications, and necessary and relevant   tests are actually  carried out and that materials are not released for   use, nor finished products  released procedures which ensure that the   necessary and relevant tests are  actually carried out and that   materials are not released for use , nor finished  products released for   sale or supply until their quality has been judged to be satisfactory   and it is involved in all decision concerning the quality of the    product;
 (an) “quarantine” means status of starting or packing materials, intermediates,  or bulk or finished products isolated physically or by other effective means  while a decisions concerning the quality of the product;
 (ao) “ reconciliation” means a comparison, making due allowance for   normal  variation between the amount of product or used and the amount   actually  produced or used and the amount actually produced or used;
 (ap) “recovering or blending” means the introduction of all or part of   previous  batches or of redistilled solvents and similar prints of the   requires quality  into and the batch at defined stage of manufacture;
 (aq) “repacking “ means all operations involved in the transfer of a   drug from  a larger container or packing into smaller xontanes or pickings including  filling, packing and labeling with a view to make it   ready for retail sale or  wholesale, but does not includes any compounding , or processing with a view to  formulate it in any dosage form;
 “Retail Sale” means a sale other than wholesale.
 (as)”reprocessing” means the reworking of all or part of a barh of product of  an unacceptable quality from a refined sage of production so   that its quality  may be rendered acceptable by one or more additional   operators;
 (at)“returned product” means finished product sent back to the   manufacturer or  distributor.
 (au) “schedule” means schedule to these rules:
 (av) “semi-basic manufacture means manufacture from an intermediate   substance  of a drug to be used as starting material for the formulation   of a finished  drug or to be used for repacking;
 (aw) “specification” means the requirements with which the products or    materials udder or obtained during manufacture must confirm as specified   in the  Drugs (Specification) Rules, 1978;
 (ax) “standard operating procedure” means an authorized written procedure  including instructions for performing operations not necessarily specific to a  given product or material but of amore general nature such as control sampling  and inspection, and certain standard operating procedures may be used to  supplement specific master batch production documentation;
 (ay) “Starting material” means any substance used in the production of    pharmaceutical product but excluding packing materials;
 (az) “system” means a regulated pattern of interacting activities and    techniques which are united to form an organized whole;
 (ba) “validation” means the documents fact of proving that any procedure    process, equipment, material, activity or system works correctly and   actually  leads to the expected results ; and
 (bb) “wholesale” means sale to a person who purchases for the purpose of    selling again and includes sale to a hospital or dispensary, or to   medical,  educational or research institute.
 
 11. In rule 16:-
 A. in clause(a) for the Schedule B the following shall be substituted,   namely:-
 SCHEDULE-B
 
 CONTENTS
 SECTION-I
 Premises
 1. Location and Surroundings
 1.1 Location
 1.2 Surroundings
 
 2. Building Layout And Its Pre-Approval
  3. Building Design And Construction (General)
  3.1 General
 3.2 Services
 3.3 Protection Against Insects etc
 3.4 Surfaces
 
 4. Storage Area
  4.1 Capacity
 4.2 Design
 4.3 Bays
 4.4 Quarantine
 4.5 Sampling
 4.6 Rejected Material
 4.7 Special Material
 4.8 Packaging Material
 4.9 Weighing Area
 
 5. Production Department
  5.1 General Facilities
 5.2 Dedicated Facilities for Production
 5.3 General Requirements for Production
 (i) Layout
 (ii) Adequacy
 (iii) Surfaces
 (iv) Services
 (v) Drains
 (vi) Environmental Controls
 (vii) Packaging
 (viii) Light
 
 6. Ancillary Area
  6.1 Rest Rooms
 6.2 Changing Rooms
 6.3 Workshop
 6.4 Animal House
 
 SECTION-2EQUIPMENT FOR PRODUCTION 
 2.1 General
 2.2 Layout
 2.3 Construction
 2.4 Piping
 2.5 Tanks
 2.6 Filters
 2.7 Cleaning Equipment
 2.8 Defective Equipment
 
 SECTION-3QUALITY CONTROL DEPARTMENT
  3.1 General
 3.2 Laboratories
 3.3 Areas
 3.4 Facilities
 (i) Equipment
 (ii) Others
 (iii) Written Procedures
 (iv) Validation
 (v) Storage
 
 SCHEDULE-BCONTITIONS FOR GRANT OF A LICENSE TO  MANUFACTURE DRUGS   BY WAY OF FORMUATION
 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 congested 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 from filthy surroundings and   shall not be adjacent to an open  sewerage, drain, public lavatory or   any factory which products. It shall be  away from filthy surroundings   and shall be adjacent to an open sewerage, drain, public lavatory or   any factory which products 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 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 carries   out. The site and layout  plan of building shall be not approval from   the central Licensing Board or person  authorized by it in this behalf   before starting construction of the building  and any minor subsequent   change 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 minimization the risk   of  errors, facilitate good sanitation and permit effective cleaning and   maintained  in order to avoid cross contamination , 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 do not   adversely  effect, directly or indirectly either the pharmaceutical   products during their  manufacture and storage, or the accurate   functioning of equipment.
 
 SECTION-4DOCUMENTATION
  4.1 General
 4.2 Specifications & Testing Procedures
 (i) Reference Books
 (ii) Testing Procedures
 (iii) Specifications
 4.3 Specifications for Starting and Packing Materials
 4.4 Specifications For Starting and Packaging Materials
 4.5 Mater Formula
 4.6 Packing Instructions
 4.7 Standard Operating Procedures (SOPs) and Records
 4.8 S.O. Ps for Testing
 4.9 S.O.Ps for Sanitation
 4.10 S.O.Ps Miscellaneous
 4.11 Labels
 4.12 Batch Processing records
 
 SECTION-5SANITAON AND HYGIENE
  5.1 Sanitation
 5.2 Hygiene
 
 3.4 Surfaces : In arrears where raw materials, in-process materials or   drugs  are exposed, the following general condition shall apply to the   extent  necessary prevent contamination, namely :-
 (i) floors, walls, and ceilings/permit easy cleaning, brick , cement   blocks,  and other porous materials are sealed;
 (ii) floors, walls, ceilings, and other surfaces are hard, smooth, and   free of  sharp corners where extraneous material can collect;
 (iii) joints are sealed between walls, ceilings 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 virus categories of materials and   products in  quarantine, and released, rejected, returned ,or recalled   products.
 4.2 Design: Storage areas shall be designed or adapted to ensue 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 area 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 physician quarantine shall be given   equivalent security.
 4.5 Sampling: These shall normally be a separate sampling area for   starting  materials. If sampling is to be performed in the storage area,   it shall be  provided for the storage of rejected, recalled, or   returned materials, or  products.
 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 an secure areas.
 4.8 Packaging Materials : Printed packing materials are considered   critical to  the conformity of the pharmaceutical product to its   labeling, and special  attention shall paid to 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 provide 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) Procedure and instructions for working approval 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 operations 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 provide in addition to the general facilities such as   highly  sanitizing materials (e.g., penicillin) or biological   preparations (e.g., love  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 identifies by the Central   Licensing Board at any stage in order to minimize the  risk of a serious   medical 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 use for   manufactured  of pharmaceutical products, however, simultaneously human   drugs shall not be  manufactured. Non-pharmaceutical products, technical   poisons, such as  pesticides shall not be manufactured.   Non-Pharmaceutical products , however ,  simultaneously human drugs   shall not be manufactured in the same premises  already use 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 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 working   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 (walls, floors,  and ceilings) shall be smooth and free from   cracks and open joints shall not  shed particulate matter, and shall   permit easy effective cleaning and , if  inaccessible, disinfection.
 (iv) Services : Pipe work, 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    back-flow. 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  regulatory monitored during   production and non-production periods to ensure compliance with design   specifications.
 (vi) Packaging : Area (s) for the packing of pharmaceutical products   shall be  specifically designed and laid out so as to avoid mix-ups or   cross  contamination.
 (vii) 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 Workshop : Maintenance workshop shall perfectly 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 houses :Animal houses shall be well isolated from other   areas, with  separate entrance (animal access) and air-handing facilities.
 
 
 SECTION – 2EQUIPMENT FOR PRODUCTION 
 2.1 General: The all  necessary equipment shall be provided which shall   be so designed, constructed,  located installed and maintained as to   suit the operation 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  material, in-process materials, or drugs are   accessible to cleaning or are  removable;
 (b) Permits cleaning of adjacent areas and does not interfere with other    processing operations, and it also minimizes circulation of personnel   and  optimizes flow of material;
 (c) Prevents the contamination of drugs by other drugs, by dust, 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 points of    contact with their 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 with  standing 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 harbor  bacteria do not come in contact or   contaminate raw material, in- process  materials, or drugs; and
 
 (d) Chain drives and transmission gears are enclosed or properly   covered.
 2.4 Pining: All service  piping and devices shall be clearly labeled to   indicate the contents and, where  applicable, the direction of flow and   special attention is paid to the  provision of non-interchangeable   connection or adopter 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 form production and quality  control areas, at least, be clearly   labeled as defective.
 
 SECTION – 3QUALITY CONTROL DEPARTMENT
  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 provided 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,   microbiological 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 good 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.
 
 (vi) Validations 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.
 
 (vii) Separate facilities for the bulk storage of   volatile and inflammable  materials.
 
 SECTION – 4DOCUMENTATION
  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 document 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 material 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 Specifications 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 pharmacopoeia   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 product 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 ingredient(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 a   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 specifications;
 (ii) a description of  the dosage form, strength   of the product, and batch size; specifications;
 (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 of  any substance   that may disappear in the course of processing) and a reference  number   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,  pretreatment, 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 labeling, 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 or 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 being;
 (vii) a description of the packaging operations, 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 starting   material and primary and printed packaging material;
 (ii) the international labeling, quarantine, and storage of starting materials,  packaging materials, and other materials, as appropriate;
 (iii) each instrument and piece 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 included;
 (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 stage 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   manufacturer 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 labeled 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 my 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 time of commencement of significant   intermediate stage 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.  weighing);
 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 fro the expected yield;
 i) notes on special problems including details,   with signed authorization, for  nay deviation from the Master Formula.
 
 SECTION – 5SANITATION AND HYGIENE
  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 premised and the equipment used in the  production of 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) cleaning intervals;
 (iv) cleaning materials, their concentration, and   the equipment to bused;
 (v) responsibilities of outside contractors, if   any;
 (vi) disposal procedures 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 procedures.
 5.2. Hygiene:
 5.2.1 Minimum  requirements of health, hygienic behavior 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 for, 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 in writing and shall  provide for : -
 (j) 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 material, 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.
 B in clause (c), in  sub-clause (i) : -
 
 (a) for the words “ twelve months” the words   “three years” shall be  substituted; and
 (b) for the word “drug” the words “type of drugs   to be manufactured” shall be  substituted; and
 C in clause (e), for  the words “sufficient experience in testing of drugs” the words “three years  experience in testing of types of drugs intended to be manufactured” shall be substituted;
 
 III. in rule 20, in clause (a), for the “Schedule B II” the following new  Schedule B II shall be substituted, namely : -
 
 SCHEDULE B-II
 GOOD MANUFACTURING PRACTICES (GMPS) FOR  LICENSE TO   MANUFACTURE BY WAY OF FROMULATION
 CONTENTS
 PART – I
 GENERAL CONDITIONS 
 SECTION – I                  1 Responsibility of  licensee for drugs fitness   for use
 SECTION – 2                   2. Quality assurance system
 SECTION – 3                    3. Quality control
 3.1 Quality Control  Department
 3.2 Basic requirements
 3.3 Control procedures.
 3.1 General
 3.3.2 Sampling
 3.3.3 Test requirement for starting and packaging   materials
 3.3.4 Test requirement for in-process controls
 3.3.5 Test Requirement for Finished Products
 3.3.6 Production record/batch review
 3.3.7 Stability studies
 3.4 Self inspection
 3.4.1 General
 3.4.2 Items for self inspection
 3.4.3 Self inspection team
 3.4.4 Frequency of self inspection
 3.4.5 Self inspection report
 3.5 Quality Audit
 3.5.1 Audit by independent specialist
 3.5.2 Supplier’s audits
 3.5 Complaints
 3.6.1 Review of complaints
 3.6.2 Person authorized
 3.6.3 Written procedures
 3.6.4 Recording defects and investigation
 3.6.5 Investigation
 3.6.6 Follow-up action
 3.6.7 Recording measures
 3.6.8 Review for Reviewing Problem
 3.7 Product recalls
 3.7.1 System
 3.7.2 Authorized person
 3.7.3 Written procedures
 3.7.4 Recall with promptness
 3.7.5 Distribution records
 3.7.6 Recording and progress
 3.7.7 Evaluation
 3.7.8 Storage of recalled drugs
 3.7.9 All concerned to be informed
 SECTION – 4                    4. Personnel
 4.1 General
 4.2 Written duties
 4.3 GMP awareness
 4.4 Prohibition of unauthorized person
 4.5 Duties of Heads of Departments
 4.6 Duties of Production Incharges
 4.7 Duties of Quality Control Incharges
 4.8 Training
 4.8.1 Written programme
 4.8.2 Training appropriate to duties
 4.8.3 Specific training
 4.8.4 Understanding concepts
 4.8.5 Visitor and untrained personnel discouraged
 4.9 Personal hygiene
 4.9.1 Health examination
 4.9.2 Practices in personal hygiene
 4.9.3 Illnesses
 4.9.4 Reporting health problems
 4.9.5 Avoiding direct contact with materials
 4.9.6 Appropriate clothing and covering
 4.9.7 Foods and drinks prohibited
 SECTION – 5GOOD PRACTICES IN MANUFACTURING PROCESSING                 5.1 General  responsibility of licensee
 SECTION – 6MATERIALS                    6.1 Material general
 6.1.1 Quarantine
 6.1.2 Appropriate storage
 6.2 Starting materials
 6.2.1 Purchase
 6.2.2 Purchase from producer or established   supplier
 6.2.3 Checking of containers
 6.2.4 Damaged container
 6.2.5 Delivery from different batches
 6.2.6 Labeling
 6.2.7 Identity of contents
 6.2.8 Released materials to be used
 6.2.9 Correct dispensing
 6.2.10 Checking
 6.2.11 Labeling
 6.3 Packaging materials
 6.3.1 Purchase
 6.3.2 Printed materials
 6.3.3 Reference numbers
 6.3.4 Obsolete materials
 6.3.5 Checking before delivery
 6.4 Intermediate and bulk products
 6.4.1 Storage
 6.4.2 Handling
 6.5 Finished pharmaceutical products
 6.5.1 Quarantine
 6.5.2 Release
 6.6 Rejected and recovered materials
 6.6.1 Storage and disposal
 6.6.2 Reprocessing
 6.6.3 Batch recovers
 6.6.4 Additional testing of reprocessed material
 6.7 Recalled and returned products
 6.7.1 Recalled products
 6.7.2 Returned goods
 6.8 Reagents and culture media
 6.9 Reference standards
 6.9.1 Testing prepared reference standard
 6.9.2 Use
 6.9.3 Working standards
 6.9.4 Storage
 6.10 Waste materials
 6.10.1 Storage
 6.10.2 Disposal
 6.11 Miscellaneous
 SECTION – 7
 7.1 Processing operations
 7.1.1 General
 7.1.2 Material handling
 7.1.3 Avoiding deviation
 7.1.4 Yield checks
 7.1.5 Avoiding mix-ups
 7.1.6 Labeling
 7.1.7 Unauthorized entry prohibited
 7.1.8 In price controls
 7.2 Prevention of cross-contamination and   bacterial
 Contamination in production
 7.2.1 Precautions against dust
 7.2.2 Measures against contamination
 7.2.3 Cross contamination checks
 7.2.4 Microbiological monitory
 7.3 Processing operations intermediate and bulk
 Products
 7.3.1 Pre-Processing cleanliness checks
 7.3.2 In-process controls
 7.3.3 Defective equipment
 7.3.4 Cleaning containers
 7.3.5 Yield deviations
 7.3.6 Product pipelines
 7.3.7 Water pipes
 7.3.8 Equipment calibration
 7.3.9 Repair or maintenance
  7.4 Packaging  operations
 7.4.1 Avoiding mix-ups
 7.4.2 Pre-packaging checks
 7.4.3 Labeling packaging line
 7.4.4 Process continuity
 7.4.5 Printing operation checks
 7.4.6 Label verification
 7.4.7 Resistant printing on labels
 7.4.8 On-line packaging checks
 7.4.9 Product re-introduction on packaging line
 7.4.10 Discrepancies to be investigated
 7.4.11 Destruction of un-used packaging materials

 SECTION – 8
 
Sanitation and hygiene
 
SECTION – 9
 
Validation
 9.1 General
 9.2 Process validation
 9.2.1 Validation of critical processes
 9.2.2 Validation of new master formula
 9.2.3 Validation of equipment or materials
 
 SECTION – 10
 
                  10.1 Documents
 10.1.1 Maintenance of documents
 10.1.2 Recording actions
 10.1.3 Documentation system
 10.1.4 Status identification
 10.1.5 Product labeling
 10.1.6 Reference standards identification
 10.1.7 Specification approvals
 10.1.8 Revision of specification
 10.1.9 Packaging material specification
 10.1.10 Starting material re-assay
 10.2 Specification for intermediate and bulk products
 10.3 Batch processing records
 10.3.1 General
 10.3.2 Checking work station
 10.3.3 Recording process operation
 10.4 Batch packaging  records
 10.4.1 General
 10.4.2 Pre-packaging line checks
 10.4.3 Recording packaging Operation
 10.4.4 Recording packaging batch numbers
 10.4.5 Analytical records
 10.4.6 Finished product release procedure
 10.4.7 Recording batch distribution
 10.4.8 Standard operating procedures
 10.4.9 Equipment logbooks
 10.4.10 Equipment utilization records
 
PART – II
 ADDITIONAL CONDITIONS FRO MANUFACTURE  OF STERILE PRODUCT
 SECTION -1
 
                  General
 1.1 Air Classification System for manufacture of sterile products
 Manufacture of sterile  preparations
 2.1 manufacturing operations
 2.2 Terminally sterilized products
 2.3 Products sterilized by filtration
 2.4 Products manufactured under aseptic conditions
 3 Personnel
 3.1 General
 3.2 Personnel training
 3.3 Entry restricted
 3.4 Hygiene and cleanliness
 3.5 Use of protective garments
 3.6 Clothing requirements
 3.7 Protective garments in grade B room
 3.8 Washing of clothing
 3.9 Prohibitions
 
SECTION – 2
 
                  4 Maintenance of clean area
 4.1 General
 4.2 Airlock system
 4.3 Air supply system
 4.4 Maintenance of equipment
 4.5 Water supply
 
SECTION – 3
 
                  5 Equipment maintenance
 5.1 Documentation
 
SECTION – 4
 
                  6 Sanitation
 6.1 Procedure
 6.2 Use of disinfectants and detergents
 6.3 Fumigation
 6.4 Monitoring of clean areas
 
SECTION – 5
 
                  7 Processing
 7.1 Precautions against contamination
 7.2 Preparation of live organisms
 7.3 Simulation of aseptic operations validation
 7.4 Monitoring water supply sources
 7.5 Activities in clean areas kept minimum
 7.6 Care of stating materials
 7.7 Care against fibers
 7.8 Care after final cleaning of materials
 7.9 Interval between operations to be minimal
 7.10 Sterilization of gases used
 7.11 Disburden to be minimal
 7.12 Asepsis of articles in clean areas
 7.13 New processes to be validated
 
SECTION – 6
 
                  8 Sterilization
 8.1 General
 8.2 Validation
 8.3 Suitability of process
 8.4 Care for biological indicates
 8.5 Sterilized non-sterilized products
 9 Sterilization by heat
 9.1 Recording sterilization cycle
 9.2 Sufficient time allowed to reach required temperature
 9.3 Precautions drugging cooling
 10 Sterilization by moist heat
 10.1 General
 10.2 Wrapping materials
 11 Sterilization by dry heat
 12 Sterilization by radiation
 12.1 General
 12.2 Outside contractor
 12.3 Measurement of radiation
 12.4 Validation
 12.5 Handling procedures
 13 Sterilization by ethylene oxide
 13.1 General
 13.2 Ensure contact between gas and microbial cells
 13.3 Equilibrium with humidity and temperature
 13.4 Monitoring each cycle
 13.5 Biological indicators
 13.6 Record maintenance
 13.7 Validation
 14 Filtration of pharmaceutical products that can not
 Be sterilized in the final container
 14.1 General
 14.2 Using double filter layer
 14.3 Eliminate fibers
 14.4 Checking integrity of filters
 14.5 Frequency of use of filter
 14.6 Filter safety
 15 Finishing of sterile products
 15.1 General
 15.2 Use of vacuum
 15.3 Inspection of containers
 16 Quality control
 16.1 Sterility testing
 16.2 Sterility test as the last measures
 16.3 Monitoring end toxin
 SCHEDULE –II
  GOOD MANUFACTURING  PRACTICES (GMPS) FOR LICENSE TO
 MANUFACTURE BY WAY OF FROMULATION
  PART – I
 GENERAL CONDITIONS  SECTION – 1 
 1. Responsibility of licensee  for drug’s fitness for use.
 The licensee shall  assume the responsibility for the quality of the   furs manufactured by it to  ensure that they are fit for their intended   use, comply with the requirements  of the Ordinance and rules made there   under and do not place patients at risk  due to inadequate safety,   quality or efficacy. To achieve the quality objective  reliably, there   shall be a comprehensively designed and correctly implemented  system of   quality assurance incorporating good manufacturing practices nod    quality control. It shall be fully documented and its effectiveness   monitored.  All parts of the quality assurance system shall be   adequately staff with  competent personnel and shall have suitable and   sufficient premises, equipment,  and facilities.
 
 SECTION – 2
 
 2. Quality assurance system.
 The licensee shall have a system of quality assurance appropriate to   the  manufacture of drugs which shall ensure that: -
 (a) drugs are designed  and developed in a way that takes into account   the requirements of good  manufacturing practices and other associated   codes as may be notified form time  to time;
 (b) production and control operations are clearly specified in a   written form  and good manufacturing practices requirements are adopted   and followed;
 (c) managerial responsibilities are clearly specified in job   description;
 (d) arrangements are made for the manufacture, supply, and use of the   correct  starting and packaging materials;
 (e) all necessary controls on starting materials, intermediate   products, and  bulk products and other in process controls, calibrations   and validations are  carried out;
 (f) the finished products are correctly processed and checked,   according to the  defined procedures;
 (g) finished drugs are not sold or supplied before the authorized   person(s) has  certified that each production batch has been produced   and controlled in  accordance with the requirements of the good   manufacturing practices and the  relevant rules made under the Ordinance   relevant to the production, control and  release of drugs as well as of   conditions of registration;
 (h) satisfactory arrangements exist to store in appropriate storage   conditions;
 (i) there is a procedure for self inspection and or quality audit at    appropriate intervals that regularly reviews the effectiveness and    applicability of the quality assurance system and that such a procedure   is  followed; and
 (j) a system exist in the form of written Standard Operating   Procedures  according to which complaints about marketed products are   examined, the causes  of quality defects investigated, and appropriate   measure taken in respect of  the defective products and to prevent   recurrence and that system is followed.
 
 SECTION – 3
 
 3. Quality control.
 3.1. Quality control  department: The licensee shall maintain and   satisfactory run its quality  control department which is independent of   other departments and under the  authority of a person with the   required qualifications and experience and with  adequate facilities to   ensure that all the quality control arrangements are effectively and   reliably carried out.
 3.2. Basic requirements: The basic requirements to be met for quality   control  shall be as follows: -
 (a) During the period of validity of license, adequate facilities,   trained  personnel and approved procedures are available for sampling,   inspecting, and  testing stating materials, packaging materials, and   intermediate, bulk, and  finished products, and where appropriate for   monitoring environmental  conditions for good manufacturing practices   purposes;
 (b) Samples of starting materials, packaging materials, intermediate   products,  bulk products and finished products are taken by methods and   personnel approved  of by the quality control department;
 (c) Test methods are validated;
 (d) Records are made manually and or by recording instruments   demonstrating  that all the required sampling, inspecting, and testing   procedures have  actually been carried out and that any deviation has   been fully recorded and  investigated;
 (e) The finished products contain ingredients complying with the   qualitative  and authorization, the ingredients shall be of the required   purity, in their  proper container, and correctly labeled;
 (f) Record are made of the results of inspecting and testing materials   and  intermediate, buck, and finished precuts against specification and   product  documentation and an assessment of deviations from specified   procedures;
 (g) No batch of product is released for sale prior to certification by   the  authorized person(s) that it is in accordance with the   requirements of the  rules;
 (h) Sufficient samples of starting materials and products are retained   to  permit future examination of the product if necessary and the   retained product  is kept in its final pack unless the pack is   exceptionally large; and
 (i) All quality control procedures are established, validated and   implemented;  the reference standard for substances are evaluated,   maintained, and stored,  correct labeling of containers of materials and   product is ensured; the  stability of the active pharmaceutical   ingredients and products is monitored,  complaints related to the   quality of the product are investigated and environmental monitoring is   conducted. All these operations shall be carried  out in accordance   with written procedures and where necessary, recorded,  provided that   the Central Licensing Board may allow other arrangements if it is    considered so necessary for an effective quality control system of the    licensee.
 3.3 Control Procedures.
 3.3.1 General: All tests and analysis and analysis conducted shall be   in  accordance with the instructions given in the relevant written test   procedures.  The result shall be checked by the supervisor before the   material or product is  released or rejected.
 3.3.2 Sampling: The samples shall: -
 (a) be representative of the batches of material from which they are   taken and  in accordance with approved written procedure;
 (b) be taken in a manner so as to avoid contamination or other adverse   effects  on quality, and the containers that have been sampled shall be   marked  accordingly and carefully resealed after sampling;
 (c) be taken with care to guard against contamination or mix-up of, or   by, the  material being sampled, all sampling equipment that comes into   contact with the  material shall be clean, and some particularly   hazardous or potent materials  may require special precautions;
 (d) be taken with equipment which shall be cleaned and, if necessary,    sterilized before and after each use and stored separately from other    laboratory equipment; and
 (e) bear a label indication: -
 (i) the name of the sampled material;
 (ii) the batch or lot number;
 (iii) identify the container from which the sample has been taken
 (iv) the signature of the person who has taken the sample; and
 (v) the date of sampling.
 3.3.3 Testing requirement for starting and packaging materials.
 (i) Test before use: Before releasing a starting or packaging material   for use,  the quality control manager shall ensure that the materials   have been tested  for conformity with specifications for identity,   strength, purity, and other  quality parameters.
 (ii) Identity from each container: An identity test shall be conducted   on a  sample from each container of starting material.
 (iii) Examination of each batch: Each batch (lot) of printed packaging    materials shall be examined following receipt.
 3.3.4 Test requirement  for in-process controls.
 Records of testing: In-process control records shall be maintained and   form a  par------ of the batch records.
 
 3.3.5 Test requirements for finished products:
 (i) Testing each batch: For each batch of drug product, there shall be   an appropriate  laboratory determination of satisfactory conformity to   its finished product  specifications prior to release.
 (ii) Rejection of failed products: Products failing to meet the   established  specifications or any other relevant quality criteria may   be revalidated and  shall be rejected if they do not qualify   revalidation protocols.
 (iii) Reprocessing: Reprocessing may be performed, if feasible, but   the  reprocessed product shall meet all specifications and other quality   criteria  prior to its acceptance and release.
 3.3.6 Production record and batch review.
 (i) Review of Records: Production and control records shall be   reviewed and any  divergence or failure of a batch to meet its   specifications shall be thoroughly  investigated, the investigation   shall, if necessary, extend to other batches of  the same product and   other products that may have been associated with the specific failure   or discrepancy, and a written record of the investigation  shall be made   and shall include the conculsio0n and details of follow-up  action.
 (ii) Retention of  Samples: Retention samples from each batch of   finished product shall be kept  for at least one year after the expiry   date. Finished products shall usually be  kept in their final packaging   and stored under the recommended conditions. If exceptionally large   packages are produced, smaller samples might be stored in  appropriate   container. Samples of active starting materials shall be retained  for   five years. Other starting materials (other than solvents, gases, and    water) shall be retained for minimum of two years if their stability   allows;  Retention samples of materials and products shall be of a size   sufficient to  permit at least tow full re-examinations.
 3.3.7 Stability studies:
 (i) The quality control department shall: -
 (a) evaluate the quality and stability of finished pharmaceutical   products and,  of starting materials and intermediate products; and
 (b) establish expiry dates and shelf-life specifications on the basis   of  stability tests related to storage conditions.
 (ii) A written program for ongoing stability determination shall be   developed  and implemented to include elements such as: -
 (a) a complete description of the drug involved in the study;
 (b) the complete testing parameters and methods describing all tests   for potency,  purity, and physical characteristics and documented   evidence that these test  indicate stability.
 (c) Provision for the inclusion of a sufficient number of batches;
 (d) The testing of each drug;
 (e) Provision for special storage conditions;
 (f) Provision for adequate sample retention; and
 (g) A summary of all the data generated, including the evaluation and   the  conclusions of the study.
 (iii) Stability of the finished product shall be evaluated and   documented prior  to marketing and following and significant changes in   the processes, equipment,  primary packaging materials, etc.
 3.4 Self-inspection:
 3.4.1 General: The  licensee shall conduct repeated self inspection   with a view to evaluate its own  compliance with good manufacturing   practices in all aspects of production and  quality control; The self   inspection program shall be designed to detect any shortcomings in the   implementation of good manufacturing practices and to  recommend the   necessary corrective actions; Self inspections shall be performed    routinely, and may be, in addition, performed on special occasions, e.g.   in the  case of product recalls or repeated rejections or when an   inspection by the  Central Licensing Board is required; The team   responsible for self inspection  shall consist of personnel who can   evaluate the implementation of good  manufacturing practices   objectively; all recommendations for corrective action shall be   implemented; The procedure for self-inspection shall be documented,  and   there shall be an effective follow-up program.
 3.4.2 Items for self inspection: Written instructions for self   inspection shall  be established to provide a minimum and uniform   standard of requirements and  shall include questionnaires on good   manufacturing practices requirements  covering at least the following   items, namely;
 (a) personnel;
 (b) premises including personnel facilities;
 (c) maintenance of buildings and equipment;
 (d) storage of starting materials and finished products;
 (e) equipment;
 (f) production and in-process controls;
 (g) quality control;
 (h) documentation;
 (i) sanitation and hygiene;
 (j) validation and verification programs;
 (k) calibration of instruments or measurement systems;
 (l) recall procedures;
 (m) complaints management;
 (n) labels control; and
 (o) results of previous self-inspections and any corrective steps   taken.
 3.4.3 Self-inspection team: Management shall appoint a self-inspection   team of  members from inside or outside the company who are expert in   the field of  inspection and familiar with good manufacturing practices.
 3.4.4 Frequency of self-inspection: The frequency at which   self-inspections are  conducted may depend on company requirements but   it shall be at least once  every year.
 3.4.5 Self-inspection report: A report shall be made at the completion   of  self-inspection which shall include: -
 (a) self-inspection results;
 (b) evaluation and conclusion; and
 (c) recommended corrective actions.
 
 3.4.6 Follow-up actions: The company management shall evaluate both   the  self-inspection report and the corrective actions as are necessary.
 3.5 Quality audit:
 3.5.1 Audit by independent specialist: It may be useful to supplement    self-inspection with a quality audit which consists of an examination   and  assessment of all or part of a quality system with the specific   purpose of  improving it; a quality audit is usually conducted by   outside or independent  specialists or a tem a designated by the   management for this purpose; such  audits may also be extended to   suppliers and contractors.
 3.5.2 Supplier’s audits: The quality control department shall have   responsibility  together with other relevant departments for approving   suppliers who can  reliably supply starting and packaging materials that   meet established  specifications.
 3.6 Complaints:
 3.6.1 Review of complaints: All complaints and other information   concerning  potentially defective products must be carefully reviewed   according to written  procedures.
 3.6.2 Person authorized: A person responsible for handling the   complaints and  deciding the measures to be taken shall be designated,   together with sufficient  supporting staff to assist him and if this   person is different from the  authorized person, the latter shall be   made aware of any complaint,  investigation, or recall.
 3.6.3 Written procedures: There shall be written procedures describing   the  action to be taken including the need to consider a recall, in the   case of a  complaint concerning a possible product defect.
 3.6.4 Recording defects and investigation: Any complaint concerning a   product  defect shall be recorded with all the original details and   thoroughly  investigated; The person responsible for quality control   shall normally be  involved in the study of such problems.
 3.6.5 Investigation: If a product defect is discovered or suspected in   a batch,  consideration shall be given to whether other batches shall   be checked in order  to determine whether they are also affected; in   particular, other batches that  may contain reprocessed product from the   defective batch shall be investigated.
 3.6.6 Follow up action: Where necessary, appropriate follow-up action,   possibly  including product recall, shall be taken after investigation   and evaluation of  the compliant.
 3.6.7 Recording measures: All the decisions and measures taken as a   result of a  complaint shall be recorded and referenced to the   corresponding batch record.
 3.6.8 Review for recurring problems: Complaint record shall be   regularly  reviewed for any indication of specific or recurring problems   that require  attention.
 3.7 Product recalls.
 3.7.1 System: There shall be a system to promptly and effectively   recall from  the market the products known or suspected to be defective.
 3.7.2 Authorized person: A person responsible for the execution and    coordination of recalls shall be designated, as well as sufficient staff   to  handle all aspects of the recalls with the appropriate degree of   urgency; this  person shall normally be independent of the sales and   marketing organization;  if this person is different from the authorized   person the latter shall be jade aware of any recall operation.
 3.7.3 Written procedures: There shall be established written   procedures,  regularly checked and updated for the organization of any   recall activity.  Recall operations shall be capable of being initiated   promptly at least down to  the level of the health institutions and all   sale channels including whole sale  and where possible retail sale and a   public notice if required.
 3.7.4 Recall with promptness: All competent authorities to whom a   given product  may have been distributed shall be promptly informed of   any intention to recall  the product because it is, or was suspected of   being, defective.
 3.7.5 Distribution records: The distribution records shall be readily   available  to the person(s) responsible for recalls, and they shall   contain sufficient  information on wholesalers and directly supplied   customers(including, for  exported products, those who have received   samples for clinical tests and  medical samples) to permit and effective   recall.
 3.7.6 Recording of progress: The progress of the recall process shall   be  recorded and a final report issued, including a reconciliation   between the  delivered and recovered quantities of the products.
 3.7.7 Evaluation: The effectiveness of the arrangements for recalls   shall be  evaluated from time to time.
 3.7.8 Storage of recalled drugs: An instruction shall be included to   store  recalled products in a secure segregated area while their fate is   decide.
 3.7.9 All concerned to be informed: The Central Licensing and   Registration  Boards and other concerned government authorities shall be   immediately informed  if it is intended to recall product(s) or if a   product has been recalled.  Effective system shall be maintained to   inform the doctors, pharmacists and  public of the recalled products.
 
 SECTION - 4 Personnel 
 4.1 General: The  licensee shall provide: -
 (a) sufficient qualified personnel to fulfill all its responsibilities   required  under these rules; and
 (b) organization chart.
 4.2 Written duties: All responsible staff shall have their specific   duties  recorded in written descriptions and adequate authority to carry   out their  responsibilities. There shall be no gaps or unexplained   overlaps in the  responsibilities of personnel concerned with the   application of good  manufacturing practices. Individual   responsibilities shall be clearly  understood by the individuals   concerned;
 4.3 Good manufacturing practices awareness: All personnel shall be   aware of the  principles of good manufacturing practices that affect   them and receive initial  and continuing training, including hygiene   instructions, relevant to their  needs.
 4.4 Prohibition of unauthorized persons: Steps shall be taken to   prevent  unauthorized people from entering production, storage, and   quality control  areas, and personnel who do not work in these areas   shall not use them as a  passageway.
 4.5 Duties of heads of departments: The heads of the production and   quality  control departments may have shared, or jointly exercised the   following  responsibilities relating to quality, namely: -
 (a) the authorization of written procedures and other documents,   including  amendments;
 (b) the monitoring and control of the manufacturing environment;
 (c) plant hygiene;
 (d) process validation and calibration of analytical apparatus;
 (e) training, including the application and principles of quality   assurance;
 (f) the approval and monitoring of suppliers of materials;
 (g) the approval and monitoring of contract manufacturers;
 (h) the designation and monitoring of storage conditions for materials   and  product;
 (i) the retention of records;
 (j) the monitoring of compliance with good manufacturing practices    requirements;
 (k) the inspection, investigation, and taking of samples in order to   monitor  factors that may affect product quality.
 4.6 Duties of production in charge: The head of the production   department may  have the following responsibilities, namely: -
 (a) to ensure that products are produced and stored according to the    appropriate documentation in order to obtain the required quality;
 (b) to approve the instructions relating to production operations   including the  in process controls, and to ensure their strict   implementation;
 (c) to ensure that the production records are evaluated and signed by a    designated person before they are made available to the quality   control  department;
 (d) to check the maintenance of the department, premises, and   equipment;
 (e) to ensure that the appropriate process validations and   calibrations of  control equipment are performed and recorded and the   reports made available;  and
 (f) to ensure that the required initial and continuing training of   production  personnel is carried out and adapted according to need.
 4.7 Training:
 4.8.1 Written programmed: The training shall be provided in accordance   with a  written program for all the personnel whose duties required   them to work in the  production areas, as the case may be, in the   control laboratories (including  the technical, maintenance, and   cleaning personnel), and for other personnel  whose activities could   affect the quality of the product.
 4.8.2 Training appropriate to duties: Besides basic training on the   theory and  practice of good manufacturing practices, newly recruited   personnel shall  receive training appropriate to the duties assigned to   them, continuing  training shall also be given, and its practical   effectiveness shall be  periodically assessed, training programs shall   be available, approved by the  head of either production or quality   control, as appropriate, and training  records shall be kept.
 4.8.3 Specific training: Personnel working in areas where   contamination is a  hazard, such as clean areas or areas where highly   active, toxic, infectious, or  sensitizing materials are handled, shall   be given specific training.
 4.8.4 Understanding concepts: The concept of quality assurance and all   the  measures capable of improving its understanding and implementation   shall be  fully discussed during the training sessions.
 4.8.5 Visitors or untrained personnel discouraged: Visitors or   untrained  personnel shall be discouraged entry into the production and   quality control  areas.
 4.9 Personal hygiene:
 4.9.1 Health examination: All personnel, prior to and during   employment, as may  be appropriate, shall undergo health examinations   and personnel conducting  visual inspections shall also undergo periodic   eye examinations.
 4.9.2 Practices in personal hygiene: All personnel shall be trained in   the practices  of personal hygiene, a high level of personal hygiene   shall be observed by all  those concerned with manufacturing processes,   personnel shall be instructed  particularly to wash their hands before   entering productions areas, and signs  to this effect shall be pasted   and instructions observed.
 4.9.3 Illnesses: Any person shown at any time to have an apparent   illness or  open lesions that may adversely affect the quality of   products shall not be  allowed to handle starting materials, packaging   materials, in process  materials, or drug products until the condition   is no longer judge to be a  risk.
 4.9.4 Reporting health problem: All employees shall be instructed and    encouraged to report to their immediate supervisor any conditions,   relating to  plant, equipment, or personnel, that they consider may   adversely affect the  products.]
 4.9.5 Avoiding direct contact with materials: Direct contact shall be   avoided  between the operator’s hands and starting materials, primary   packaging  materials, and intermediate or bulk product.
 4.9.6 Appropriate clothings and covering: To ensure protection of the   product  form contamination, personnel shall wear clean body coverings   appropriate to  the duties they perform, including appropriate hair   covering, and used clothes,  if re-usable, shall be stored in separate   closed containers until properly laundered and, if necessary,   disinfected or sterilized.
 4.9.7 Foods and drinks prohibited: Smoking eating, drinking, chewing,   and  keeping plants, food, drink smoking material, and personal   medicines shall not  be permitted in production, laboratory, and storage   areas or in any other areas  where they might adversely influence   product quality.
 
 
 SECTION – 5GOOD PRACTICES IN MANUFACTURING PROCESSING. 5.1 General responsibility of licensee: The licensee shall follow Good   Manufacturing Practices in production  of drugs under which it shall be   ensured that: -
 (a) all manufacturing processes which shall be defined are   systematically  reviewed in the light of experience, and shown to be   capable of consistently  manufacturing pharmaceutical products of the   required quality that comply with  their specifications;
 (b) critical steps of manufacturing processes and any significant   changes made  to the processes are validated;
 (c) all necessary facilities are continued to be made available,   including:-
 (i) appropriately qualified and trained personnel;
 (ii) adequate premises and space;
 (iii) suitable equipment and services;
 (iv) correct materials, containers, and labels;
 (v) approved procedures and instructions;
 (vi) suitable storage and transport; and
 (vii) adequate personnel, laboratories, and equipment of in-process   controls  under the responsibility of the             
production management.
 (d) instructions and procedures are written in clear and unambiguous language,  specifically applicable to the facilities provided and followed in letter and  spirit;
 (e) operators receive training and refresher courses at regular intervals to  carry out procedures correctly, and records of such training are maintained;
 (f) records are made, manually and or by recording instruments, during manufacture to show that all the steps required by the defined procedures and  instructions have in fact been taken and that the quantity and quality of the  product are as expected, and any significant deviations are fully recorded and  investigated;
 (g) records covering manufacture and distribution, which enable the complete  history of a batch to be traced, are retained in a comprehensible and  accessible form;
 (h) the proper storage and distribution of the products minimizes any   risk to  their quality; and
 (i) the written system to recall any batch of product from sale or   supply is  followed whenever a recall is necessitated.
 
 SECTION – 6MATERIALS
  Material general:
 6.1.1 Quarantine: All incoming materials and finished products shall   be  quarantined immediately after receipt or processing, until they are   released  for use or distribution.
 6.1.2 Appropriate storage: All materials and product shall be stored   under the  appropriate conditions established by the manufacturer and in   an orderly manner  to permit batch segregation and stock rotation by a   first-in, first-out rule.
 Starting materials:
 6.2.1 Purchase: The purchase of starting materials is an important   operation  that must involve staff who have a particular and thorough   knowledge of the  products and suppliers and a pharmacist with some   experience of production may  be preferred.
 6.2.2 Purchase from producer or established suppliers: Starting   materials shall  be purchased directly from the producer or only from   established suppliers.
 6.2.3 Checking of Containers: For each consignment, the containers   shall be  checked for integrity of package and seal and for correspondence between the  order, the delivery note, and the supplier’s   labels, and, containers shall be  cleaned where necessary and labeled,   if required, with the prescribed data.
 6.2.4 Damaged container: Damage to containers and any other problem   that might  adversely affect the quality of a materials shall be   recorded and reported to  the quality control department and investigated.
 6.2.5 Delivery from different batches: If a delivery of material is   made up of  different batches, each batch shall be considered as   separate for sampling,  testing, and release.
 6.2.6 Labeling: Starting materials in the storage area shall be   appropriately  labeled, and labels shall bear at least the following   information, namely: -
 (a) the designated name of the product and the internal code reference   where  applicable;
 (b) the batch number(s) given by the supplier and on receipt by the   manufacture,  if any;
 (c) where appropriate, the status of the contents such as on   quarantine, on  test, released, rejected, returned, and recalled; and,
 (d) where appropriate, and expiry date or a date beyond which   retesting is  necessary. When fully computerized storage systems are   used appropriate system  shall be developed for the identification of   above referred information.
 6.2.7 Identity of contents: There shall be appropriate procedures or   measures  to ensure the identity of the contents of each container of   starting material,  and bulk containers from which samples have been   drawn shall be identified.
 6.2.8 Released materials to be used: Only starting materials released   by the  quality control department and with in their shelf-life shall be   used.
 6.2.9 Correct dispensing: Starting materials shall be dispensed only   by  designated persons, following a written procedure to ensure that the   correct  materials are accurately weighed or measured in to clean and   properly labeled  containers.
 6.2.10 Checking: Each dispensed material and its weight or volume   shall be  independently checked and the check recorded.
 6.2.11 Labeling: Materials dispensed for each batch of the final   product shall  be kept together and conspicuously labeled as such.
 6.3 Packaging materials:
 6.3.1 Purchase: The purchase, handling and control of primary and   printed  packaging materials shall be as for starting materials.
 6.3.2 Printed materials: Particular attention shall be paid to printed    packaging materials which shall be stored in secure conditions so as   to exclude  the possibility of unauthorized access, cut labels and other   printed materials  shall be stored and transported in separate closed   containers so as to avoid  mix-ups and packaging materials shall be   issued for use only by designated personnel following an approved and   documented procedure.
 6.3.3 Reference numbers: Each delivery or batch of printed or primary   packaging  material shall be given a specific reference number or   identification mark.
 6.3.4 Obsolete materials: Outdated or obsolete primary packaging   material or  printed packaging material shall be destroyed and its   disposal be recorded.
 6.3.5 Checking before delivery: All products and packaging materials   to be used  shall be checked on delivery to the packaging department for   quantity, identity,  and conformity with the packaging instructions.
 6.4 Intermediate and bulk products:
 6.4.1 Storage: Intermediate and bulk products shall be kept under   appropriate  conditions.
 6.4.2 Handling: Intermediate and bulk products purchased as such shall   be handled  on receipt as though they were starting materials.
 6.5 Finished pharmaceutical products:
 6.5.1 Quarantine: Finished pharmaceutical products shall be held in   quarantine  until their final release, and thereafter they shall be   stored as usable stock  under conditions established by the manufacturer.
 6.5.2 Release: The evaluation of finished products and the   documentation  necessary for release of a product for sale, as per requirement of these rules,  shall be followed.
 6.6 Rejected and recovered materials:
 6.6.1 Storage and disposal: Rejected materials and products shall be   clearly  marked as such and stored separately in restricted areas, and   they shall either  be returned to the suppliers or, where appropriate,   reprocessed or destroyed,  and then action shall be approved by   authorized personnel and recorded.
 6.6.2 Reprocessing: The reprocessing of rejected products shall be   exceptional,  it is permitted only if the quality of the final product   is not affected, if  the specifications are met, and if it is done in   accordance with a defined and  authorized procedure after evaluation of   the risks involved and record shall be kept of the reprocessing and a   reprocessed batch shall be given a new batch  number.
 6.6.3 Batch recovery: The introduction of all or part of earlier   batches,  conforming to the required quality, in to a batch of the same   product at a  defined stage of manufacture shall be authorized   beforehand, this recovery  shall be carried out in accordance with a   defined procedure after evaluation of  the risks involved, including any   possible effect on shelf-life and the recovery shall be recorded.
 6.6.4 Additional  testing of reprocessed materials: The need for   additional testing of any  finished product that has been reprocessed ,   or into which a recovered product  has been incorporated, shall be   considered by the quality control department.
 6.7 Recalled and returned products:
 6.7.1 Recalled products: Recalled products shall be identified,   clearly marked  as such and stored separately in a secure area until a   decision is taken on  their fate.
 6.7.2 Returned goods; Products returned from the market shall be   destroyed  unless it is certain that their quality is satisfactory, they   may be considered  for resale, relabelling, or bulking with a   subsequent batch only after they have  been critically assessed by the   quality control department in accordance with a written procedure. The   nature of the product, any special storage conditions if  requires, its   condition and history, and the time elapsed since it was issued  shall   be taken into account in this assessment, where any doubt arises over   the  quality of the product, it shall not be considered suitable for   reissue or  re-use, although basic chemical reprocessing to recover the   active ingredient  may be possible, and any action taken shall be   appropriately recorded.
 6.8 Reagents and culture media:
 6.8.1 All reagents and culture medial shall be recorded upon receipt   or  preparation.
 6.8.2 Reagents made up in the laboratory shall be prepared according   to written  procedures and appropriately labeled, the label shall   indicate the  concentration, standardization factor, shelf-life, the   date when  re-standardization is due, and the storage conditions and the   label shall be  signed and dated by the person preparing the reagent.
 6.8.3 Both positive and negative controls shall be applied to verify   the  suitability of culture media, and the size of the inoculum used in   positive  controls shall be appropriate to the sensitivity required.
 6.9 Reference standards:
 6.9.1 Testing of prepared reference standard: Reference standards may   be  available in the form of official reference standards and reference   standards  prepared by the producer shall be tested, released, and then   stored in the same  way as official standards, and they shall be kept   under the responsibility of a designated person in a secured area.
 6.9.2 Use: Official reference standards shall be used only for the   purposed  described in the appropriate testing method submitted for   registration  purposes.
 6.9.3 Working standards: Secondary or working standards may be   established by  the application of a appropriate tests and checks at   regular intervals to  ensure standardization, and all in-house reference   standards shall be based on  official reference standards, when   available.
 6.9.4 Storage: All reference standards shall be stored and used in a   manner  that will not adversely affect their quality.
 6.10 Waste materials:
 6.10.1 Storage: Provision shall be made for the proper and safe   storage of  waste materials awaiting disposal, and toxic substances and   flammable  --------------- shall be stored in suitably designed and   separate enclosed  cupboat---------
 6.10.2 Disposal: Waste material shall not be allowed to accumulate,   and  -----------collected in suitable receptacles for removal to   collection points  --------------- buildings and disposed of safely and   in a sanitary manner at  regular and -------------intervals.
 6.10.3 Effluent Control: There shall be a effluent control system.
 6.11 Miscellaneous: Rodenticides, insecticides, fumigating agents, and    sanitizing-----shall not be permitted to contaminate equipment,   starting  materials, packaging-------in-process materials, or finished   products.
 
 SECTION – 7
  7.1 Processing  operations:
 7.1.1 General: Productions operations must follow clearly defined   procedures  with the objective of obtaining products of the requisite   quality.
 7.1.2 Material  handling: All handling of materials and products such   as receipt and  quarantine, sampling, storage, labeling, dispensing,   processing, packaging, and  distribution shall be done in accordance   with written procedures or  instructions and, where necessary, recorded.
 7.1.3 Avoiding deviation: Any deviation from instructions or   procedures shall  be avoided as far as possible and if deviations occur,   they shall be approved  in writing by a designated person, with the   involvement of the quality control  department.
 7.1.4 Yield checks: Check on yields and re-conciliation of quantities   shall be  carried out as necessary to ensure that yields are within   acceptable limits.
 7.1.5 Avoiding mix-ups: Operations on different products shall not be   carried  out simultaneously or consecutively in the same room unless   there is no risk of  mix-up or cross contamination.
 7.1.6 Labeling: At all times during processing, all materials, bulk   containers,  major items of equipment, and where appropriate the rooms   used shall be labeled  or otherwise identified with an indication of the   product or material being  processed and its strength, where   applicable, and the batch number, and where applicable this indication   shall also mention the stage of production.
 7.1.7 Unauthorized entry prohibited: Access to the production premises   shall be  restricted to authorized personnel.
 7.1.8 Inprocess controls: In-process controls are mostly performed   within the  production area and they shall not carry any risk for the   quality of the  product.
 7.2 Prevention of cross-contamination and bacterial contamination in    production:
 7.2.1 Precautions against dust: When dry materials and products are   used in  production, special precautions shall be taken to prevent the   generation and  dissemination of dust. This applies particularly to the   handling of highly  active or sensitizing materials.
 7.2.2 Measures against contamination: Contamination of a starting   material or  of a product by another material or product shall also be   avoided and  similarly, cross-contamination shall be avoided by   appropriate technical or  organizational measures, as may be necessary   by production segregated areas,  namely: -
 (a) conducting production in segregated areas;
 (b) providing appropriate airlock, pressure differentials and dust   extraction;
 (c) minimizing the risk of contamination caused by re-circulation or   re-entry  of untreated or insufficiently treated air;
 (d) wearing and keeping protective clothing in areas where products   with  special risk of cross-contamination are processed;
 (e) using, cleaning and decontamination procedures of known   effectiveness, as  in-effective cleaning of equipment is a common source   of cross-contamination;
 (f) encourage using a “closed system” of production;
 (g) testing for residues where necessary;
 (h) using cleanliness status labels on equipment, showing the name of   the  previous product.
 7.2.3 Cross contamination checks: Measures to prevent cross-contamination and  their effectiveness shall be checked periodically according to standard  operating procedures.
 7.2.4 microbiological monitoring: Production areas where susceptible   products  are processed shall undergo periodic microbiological   monitoring and the bio  burden shall be kept within the specified   limits.
 7.3 Processing operations intermediate and bulk products:
 7.3.1 Pre-processing and cleanliness checks: Before any processing   operation is  started, steps shall be taken to ensure that the work area   and equipment are  clean and free from any starting materials,   products, product residues, labels,  or documents not required for the   current operation.
 7.3.2 Inprocess controls: Necessary in-process controls and   environmental  controls shall be carried out and recorded.
 7.3.3 Defective equipment: Means shall be instituted for indicating   failures of  equipment or of services, such as water or gas, to   equipment. Defective  equipment shall be withdrawn from use until the   defect has been rectified.
 7.3.4 Cleaning containers: Containers for filling shall be cleaned   before  filling and attention shall be given to avoiding and removing   any contaminants  such as glass fragments and metal particles.   Production equipment shall be  cleaned according to detailed written   procedures and stored only under clean  and dry conditions.
 7.3.5 Yield deviations: Any significant deviation from the expected   yield shall  be recorded and investigated.
 7.3.6 Product pipelines: Checks shall be carried out to ensure that   pipelines  and other pieces of equipment used for the transportation of   products form one  area to another are connected in a correct manner.
 7.3.7 Water pipes: Pipes used for conveying distilled or deionizer   water and,  where appropriate, other water-pipes shall be sanitized   according to written  procedures that detail the action and limits for   microbiological contamination  and the measures to be taken.
 7.3.8 Equipment calibration: Measuring, weighing, recording control   equipment  and instruments shall be serviced and calibrated at   pre-specified interclass  and records maintained. To ensures   satisfactory functioning instruments shall  be checked daily or prior to   use for performing analytical tests and the date  of calibration and   the date when re-calibration is due shall be clearly indicated.
 7.3.9 Repair and maintenance: Repair and maintenance operations shall   not  present any hazard to the quality of the products.
 7.4 Packaging operations:
 7.4.1 Avoiding mix-ups: When the program for packaging operations is   being set  up particular attention shall be given to minimizing the risk   of cross contamination,  mix-ups, or substitutions, and different   products shall not be packaged in  close proximity unless there is   physical segregation or these of electronic surveillance.
 7.4.2 Pre-packaging checks: Before packaging operations are begun,   steps shall  be taken to ensure that the work area, packaging lines,   printing machines, and  other equipment are clean and free from any   products, materials, or documents  previously used and not required for   the current operation, and the line  clearance shall be performed   according to an appropriate checklist and  recorded.
 7.4.3 Labeling of packaging line: The name and batch number of the   product  being handled shall be displayed at each packaging station or   line.
 7.4.4 Process continuity: Normally, filling and sealing shall be   followed as  quickly as possible by labeling, and if labeling is   delayed, appropriate  procedures shall be applied to ensure that no   mix-up or mislabeling can occur.
 7.4.5 Printing operation checks: The correct performance of any   printing, code  numbers or expiry dates, done separately or in the   course of the packaging.
 shall be checked and recorded, and attention shall be paid to printing   by hand  which shall be rechecked at regular intervals.
 7.4.6 Label verification: Special care shall be taken when cut labels   are used  and when overprinting is carried out off-line and in   hand-packaging operations,  roll-feed labels are normally preferable to   cut labels in helping to avoid  mix-up. On-line verification of all   labels by automated electronic means can be helpful in preventing   mix-up, but checks shall be made to ensure that electronic code   readers, label counters, or similar devices are operation  correctly.
 7.4.7 Fast colour printing on labels: Printed and embossed information   on  packaging materials shall be distinct and resistant to fading or   erasing .
 7.4.8 On-Line packaging checks: On-line control of the product during   packaging  shall include at least check on: -
 (a) the general appearance of the packages;
 (b) whether the packages are complete;
 (c) whether the correct products and packaging materials are used;
 (d) whether any overprinting is correct;
 (e) the correct functioning of line monitors and
 (f) sample taken from the packaging line shall not be returned unless    inspection is done in close the packaging proximity of line.
 7.4.9 Product re-introduction on packaging line: Products that have   been  involved in an unusual event during packaging shall be   re-introduced into the  process only after special inspection,   investigation, and approval by  authorized personnel and a detailed   record shall be kept of this operation.
 7.4.10 Discrepancies to be investigated; Any significant or unusual   discrepancy  observed during reconciliation of the amount of bulk   product and printed  packaging materials and the number of units   produced shall be investigated and  satisfactorily accounted for before   release.
 7.4.11 Destruction of un-used packaging materials: Upon completion of a    packaging operation, unused batch-coded packaging materials shall be   destroyed  and the destruction recorded, and a documented procedure   shall be followed if  encoded printed materials are returned to stock.
 
 SECTION – 8
  8. Sanitation and  hygiene:
 General: A high level of sanitation and hygiene shall be practiced in   every  aspect of the manufacture of drug products, the scope of   sanitation hygiene  covers personnel, premises, equipment and apparatus,   production materials and  containers, products for cleaning and   disinfection, and anything that could  become a source of contamination   to the product, and potential sources of  contamination shall be   eliminated through and integrated comprehensive program  of sanitation   and hygiene. (For sanitation and hygiene please also refer to  Section   59 Schedule B-I and Section 4.9 of Schedule.
 
 SECTION – 9 
 Validation:
 9.1 General: Validation studies shall be conducted in accordance with    pre-defined protocols. A written report summarizing recorded results   and  conclusions shall be prepared and stored. Processes and procedures   shall be  established on the basis of a validation study and undergo   periodic  re-validation to ensure that they remain capable of achieving   the intended  results, and particular attention shall be accorded to the   validation of  processing, testing, and cleaning procedures.
 9.2 Process validation to be performed as per written procedures:
 9.2.1 Validation of critical processes: Critical processes shall be   validated,  prospectively or retrospectively.
 9.2.2 Validation of new master formula: When any new master formula or   method  of preparation is adopted, steps shall be taken to demonstrate   its suitability  for routine processing, and, the defined process, using   the materials and  equipment specified, shall be shown to yield a   product consistently of the  required quality.
 9.2.3 Validation of equipment and materials: Significant amendments to   the  manufacturing process, including any change in equipment or   materials that may  affect product quality and or the re-producibility   of the process shall be  validated.
 SECTION -10Documents
                  10.1.1 Maintenance of documents: Documents, as required under these   rules,  shall be meticulously maintained and regularly reviewed and kept   up to date, and when a document has been revised, a system shall exist   to prevent inadvertent use of the superseded version.
 10.1.2 Records of action: Records shall be made or completed when any   action is  taken and in such a way that all significant activities   concerning the  manufacture of pharmaceutical products are traceable.   The batch record shall be  retained for at least on year after the   expiry date of the finished product.
 10.1.3 Documentation systems: Data may be recorded by electronic data    processing systems or by photographic or other reliable means. Master   formulae  and detailed standard operating procedures relating to the   system in use shall  be available and the accuracy of the records shall   be checked and if  documentation is handled by electronic   data-processing methods, only authorized persons shall be able to enter   or modify data in the computer, and there shall  be a record of changes   and deletion; access shall be restricted by passwords or  other means   and the entry of critical data shall be independently checked and  data   shall also be readily available.
 10.1.4 Status identification: Labels applied to containers, equipment,   or  premises shall be unambiguous and in the company’s agreed format.   the labels of  different colors to indicate the status such as   “quarantined”, “accepted”,  “rejected”, or “clear” may also be used in   addition to the wording.
 10.1.5 Product labeling: All finished products shall be labeled in   accordance  with the Drug (Labeling and Packing) Rules 1986
 10.1.6 Reference standard identification: For reference standards, the   label or  accompanying documents shall indicate concentration, date of   manufacture,  expiry date, and storage conditions, where appropriate.
 10.1.7 Specification approvals: Each specifications shall be approved   and  maintained by the quality control unit.
 10.1.8 Revision of specification: Periodic revisions of the   specifications may  be necessary to comply with new edition of the national pharmacopoeia or other  official compendia or the Drugs (Specifications) Rules 1978.
 10.1.9 Packaging material specification: Packaging material shall   conform to  specification, with emphasis placed on the compatibility of   the material with  the drug product it contains.
 10.1.10 Starting material re-assay: Documents describing testing   procedures  shall state the required frequency for re-assaying each   starting material, as  determined by its stability.
 10.2 Specifications for Intermediate and bulk products:
 Specification for intermediate and bulk products shall be available if   these  are purchased or dispatched, or if data obtained from   intermediate products are  used in the evaluation of the finished   product, and the specifications shall be  similar to specifications for   starting materials or for finished products.
 10.3 Batch processing records:
 10.3.1 General: A batch processing record shall be kept for each batch    processed based on the relevant parts of the currently approved master   formula,  and the method of preparation of such records shall be   designed to avoid  transcription errors.
 10.3.2 Checking work station: Before any processing beings, a check   shall be  made that the equipment and work station are clear of previous   products,  documents, or materials not required for the planed process,   and that the  equipment is clean and suitable for use, and this check   shall be recorded.
 10.3.3 Recording process operation: During processing, the following    information shall be recorded at the time each action is taken, and   after  completion the record shall be dated and signed by the person   responsible for  the processing operations, namely: -
 (a) the name of the product;
 (b) the number of the batch being manufactured;
 (c) date and time of commencement of significant intermediate stages,   and of  completion of production;
 (d) the name of the person responsible for each stage of production;
 (e) the initials of the operator(s) of different significant steps of    production and, where appropriate, of the person(s) who checked each of   these  operations (e.g. weighing);
 (f) the batch number and or analytical control number and the quantity   of each  starting material actually weighed including the batch number   and amount of any  recovered or reprocessed material added;
 (g) any relevant processing operation or event and the major equipment   used;
 (h) the in-process controls performed, the initials of the person(s)   carrying  them out, and the result obtained;
 (i) the amount of product obtained at different and pertinent stage of   manufacture  (yield,) together with comments or explanations for   significant deviations from  the expected yield; and
 (j) notes on special problems including details, with signed   authorization for  nay deviation from the master formula.
 10.4 Batch packaging records:
 10.4.1 General: A batch packaging record shall be kept for each batch   or part  batch processed based on the relevant parts of the packaging   instruction, and  the method of preparing such records shall be designed   to avoid transcription  errors.
 10.4.2 Pre-packaging line check: Before any packaging operation   beings, checks  shall be made that the equipment and work station are   clear of previous  products, document s or material not required for the   planned packaging  operations, and that equipment is clean and suitable   for use. These checks  shall be recorded.
 10.4.3 Recording of packaging operation: The following information   shall be  recorded at the time each action is taken, and the date and   the person  responsible shall be clearly identified by signature or   electronic password  namely: -
 
 (a) the name of the product, the batch number, and the quantity of   bulk product  to be packed, as well as the batch number and the planned   quantity of finished  product obtained, the quantity actually obtained,   and the reconciliation;
 (b) the date(s) and time(s) of the packaging operations;
 (c) the name of the responsible person carrying out the packaging   operation;
 (d) the initials of the operator s of the different significant steps;
 (e) the checks made for identity and conformity with the packaging   instruction,  including the results of in-process controls;
 (f) details of the packaging operations carried out, including   references to  equipment and the packaging lines used, and, when   necessary, the instructions  for keeping the product un-packed or a   record of returning product that has not  been packaged to the storage   area;
 (g) whenever possible, samples of the printed packaging materials   used,  including specimens bearing the batch number, expiry date, and   any additional  overprinting;
 (h) notes on any special problems, including details of any deviation   from the  packaging instructions, with written authorization by an   appropriate person;  and
 (i) the quantities and reference number or identification of all   printed  packaging materials and bulk product issued, used, destroyed,   or returned to  stock and the quantities of product obtained to permit   an adequate  reconciliation.
 10.4.4 Recording batch numbers: Batch-number allocation shall be   immediately  recorded in a logbook, and the record shall included date   of allocation,  product identity, and size of batch.
 10.4.5 Analytical records: Analysis records shall include at least the    following, namely: -
 (a) the name of the material or product and, where applicable, dosage   form;
 (b) the batch number and, where appropriate, the manufacturer 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) the initials of the persons who performed the testing;
 (g) the initials of the persons who verified the testing and the   calculations,  where
 appropriate; and
 (h) a clear statement of release or rejection (or other status   decision) and  the dated
 signature of the designated responsible person.
 10.4.6 Finished product release procedure: Written release and   rejection  procedures shall be available for materials and products, and   in particular for  the release for sale of the finished product by an   authorized person.
 10.4.7 Recording batch distribution: Records shall be maintained of   the  distribution of each batch of a product in order to facilitate the   recall of  the batch if necessary.
 10.4.8 Standard operating procedures: Standard operating procedures   and associated  records of actions taken or, where appropriate,   conclusions reached shall be  available at the premises for : -
 (a) equipment assembly and validation;
 (b) analytical apparatus and calibration;
 (c) maintenance, cleaning, and sanitization;
 (d) personnel matters including qualification, training, clothing, and   hygiene;
 (e) environmental monitoring;
 (f) pest control;
 (g) complaints;
 (h) recalls; and
 (i) returns.
 10.4.9 Equipment logbooks: Logbooks shall be kept with major and   critical  equipment as identified by the licensee and shall record, as   appropriate, any  validations, calibrations, maintenance, cleaning, or   repair operations  including dates and the identity of the people who   carried out these  operations.
 10.4.10 Equipment utilization record: The use of major and critical   equipment  and the areas where products have been processed shall be   appropriately  recorded in chronological order.
 
 
 
 PART – II
 ADDITIONAL CONDITONS FOR MANUFACTURE OF STERILE PRODUCTS. 
 In additional to the  general conditions manufacture of drugs by way   of formulation as described in  Part – II of this Schedule, the   following additional conditions shall be  followed for the manufacture   of sterile products.
 
 SECTION – 1
 1. General
 1.1 The production of sterile preparations shall be carried out in   clean areas,  entry to which shall be through airlocks for personnel   and/or for goods. Clean  areas shall be maintained to an appropriate   standard of cleanliness and  supplied with air that has passed through   filters of an appropriate efficiency.
 1.2 The various operations of component preparation (such as   containers and  closures), product preparation, filling, and sterilization shall be carried out  in separate areas within the clean area.
 1.3 Clean areas for the production of sterile products are classified   according  to the required characteristics of the ark in grades A,B,C,   and D as given in  the table
 TABLE
 Air classification system for manufacture of sterile products
 Maximum number of  Maximum number
 particles permitted per m3 of viable micro-organisms
 permitted per m3
 Grade 0.05µm >5µm
 A 3500 none less than 1
 (Laminar-airflow
 workstation)
 B 3500 none 5
 C 350 000 2 000 100
 D 3 500 000 20 000 500
 
 Notes:-
 • Laminar-airflow systems shall provide a homogeneous air speed about    0.30±20%m/s for vertical flow and about 0.45±20%m/s for horizontal flow   but  precise air speeds will depend on the type of equipment.
 • In order to reach the B,C, and D air grades, the number of air   changes shall  generally be higher than 20 per hour in a room with a   good airflow pattern and  appropriate HEPA (high efficiency particulate   air) filters.
 • Low values for contaminants are reliable only when a large number of   air  samples are taken.
 • The guidance given for the maximum permitted number of particles   corresponds  approximately to the United States Federal Standard 209E as   follows: Class 100  (grades A and B), Class 10 000 (grade C), and Class   100 000 (Grade D).
 It may not always be  possible to demonstrate conformity with   particular air standards at the point  of fill when filling is in   progress, owing to the generation of particles or  droplets from the   product itself.
 1.4 Area Grades: Area  grades must be selected by the manufacturer on   the basis of validation runs  e.g., sterile media fills as identified   below.
 
 2. Manufacture of sterile preparations
 2.1 Manufacturing Operations Classifications are here divided into   three  categories:
 (a) Terminally sterilized products: those in which the preparation is   sealed in  its final container and terminally sterilized;
 (b) Products sterilized filtration: the preparation is sterilized by    filtration;
 (c) Products manufactured under aseptic conditions: those in which the    preparation can be sterilized neither by filtration nor terminally and    consequently must be produced from sterile starting materials in an   aseptic  way.
 2.2 Terminally sterilized products: Solutions shall generally be   prepared in  grade C environment in order to give low microbial and   particulate counts,  suitable for immediate filtration and   sterilization. Solution preparation could  be allowed in a grad D environment if additional measures are taken to minimize contamination,   such as the use closed vessels. For parenteral, filling shall be  done   in a laminar-airflow workstation (grade A) in grade C environment. The    preparation of other sterile products, e.g., ointments, creams,   suspensions,  and emulsion, and filling of containers shall generally be   done in a grade C  environment before terminal sterilization.
 2.3 Products sterilized by filtration: The handling of starting   materials and  the preparation of solutions shall be done in grade C   environment. These  activities could be allowed in a grade D environment   if additional measures are  taken to minimize contamination, such as   the use of closed vessels prior to  filtration. After sterile   filtration, the product must be handled and dispensed into containers   under aseptic conditions in a grade A or B area with a grade B  or C   background respectively.
 2.4 Products manufactured under aseptic conditions: The handling of   starting  materials and all further processing shall be done in a grade A   or B area with  a grade B or C background respectively.
 
 3. Personnel
 3.1 General: Only the minimum number of personnel required shall be   present in  clean areas, and it is particularly, important during   aseptic processes.  Inspections and control shall be conducted from   outside the areas as far as  possible.
 3.2 Personnel training: All personnel, including those concerned with   cleaning  and maintenance, employed in such areas shall receive regular   training for disciplines  relevant to the correct manufacture of sterile   products, including reference to  hygiene and to the basic elements of   microbiology. When outside staff who have not received such training   (e.g, building or maintenance contractors) need to  be brought in,   particular care shall be taken over their supervision.
 3.3 Entry restricted: Staff who have been engaged in the processing of    animal-tissue materials or of cultures of microorganisms other than   those used  in the current manufacturing process shall not enter   sterile-product areas  unless rigorous and clearly defined   decontamination procedures have been  followed.
 3.4 Hygiene and cleanliness: High standards of personal hygiene and   cleanliness  are essential and personnel involved in the manufacture of   sterile preparations  shall be instructed to report apparent illness or   open lesion. Periodic health  checks for such conditions are desirable,   and actions to be taken about  personnel who could be introducing undue   microbiological hazard shall be  decided by a designated competent   person.
 3.5 Use of protective garments: Outdoor clothing shall not be brought   into the  clean areas, personnel entering the changing rooms shall   already be clad in  standard factory protective garments and changing   and washing shall follow a  written procedure.
 3.6 Clothing requirements: The clothing and its quality shall be   appropriate  for the process in such a way so as to protect the product   from contamination.
 3.7 Protective garments in grade B room: For every worker in a grade B   room, clean  sterilized protective garments shall be provided at each   work session, or at  least once a day if monitoring results justify it,   the goes shall be regularly dis-infected during operations, masks and   gloves shall be changed at least at  every working session, and the use   of disposable clothing may be followed where  possible.
 3.8 Washing of clothing: Clothing used in clean areas shall be washed   or  cleaned in such a way that it does not gather additional particulate    contaminants that can later be shed. Separate laundry facilities for   such  clothing are desirable. If fibers are damaged by inappropriate   cleaning or  sterilization there may be an increased risk of shedding   particles. Washing and  sterilization operations shall follow standard   operating procedures.
 3.9 Prohibitions: Wrist-watches and jewelry shall not be worn in clean   areas,  and cosmetics that can shed particles shall not be used,   clothing shall be  appropriate to the air grade of the area where the   personnel will be working,  and the description of clothing required for   each grade is given below:
 
 Grade D: The hair and, where appropriate, beard shall be covered,   protective  clothing and appropriate shoes or long shoes shall be worn,   and appropriate  measures shall be taken to avoid any contamination   coming from outside the  clean area.
 Grade C: The hair and,  where appropriate, beard shall be covered, a   single or two-piece trouser suit,  gathered at the wrists and with a   high neck and appropriate shoes or overshoes,  shall be worn, and the   clothing shall shed virtually no fibers or particulate  matter.
 Grade B: Headgear shall  totally enclose the hair and, where   appropriate, beard it shall be tucked into  the neck of the suit; a face   mask shall be worn to prevent the shedding of  droplets; sterilized   non-powdered rubber or plastic gloves and sterilized or disinfected   footwear shall be worn; trouser-bottoms shall be tucked inside the    footwear and garment sleeves into the gloves, and the protective   clothing shall  shed virtually no fibers or particulate matter and shall   retain particles shed  by the body.
 
 SECTION – 2                  4 Maintenance of clean  area:
 4.1 General: Each manufacturing operation requires an appropriate air    cleanliness level in order to minimize the risks of particulate or   microbial  contamination of the product or materials being handled   Section 1.3 gives the  minimum air grades required for different   manufacturing operations. The  particulate and microbiological   conditions as prescribed shall be maintained in  the zone immediately   surrounding the product whenever the product is exposed to  the   environment. These conditions shall also be achieved throughout the    background environment if no personnel are present in the processing   area and  if the standards fall for any reason it shall be possible to   recover the conditions  after a short “clean-up” period. The utilization   of absolute-barrier technology  and automated systems to minimize human   interventions in processing areas can produce significant advantages   in ensuring the sterility of manufactured  products, and when such   techniques are used the recommendations relating to air  quality an   monitoring, still apply, with appropriate interpretations of the  terms   “workstation” and environment.
 4.2 Airlock system: The entry to the sterile production areas shall be   through  airlocks for personal and/or for materials. Airlock doors   shall not be opened  simultaneously, and an interlocking system and a   visual and/or audible warning  system where appropriate shall be   operated to prevent the opening of more than  one door at a time.
 4.3 Air supply system: A filtered air supply system of appropriate   efficiency  shall maintain a positive pressure relative to surrounding   area under all  operational conditions and flush the area effectively.   More over particular  attention shall be paid to the protection of the   zone of great risk that is,  the immediate environment to which the   product and the cleaned components in contact with it are exposed, and   the various recommendations regarding air  supplies and pressure   differentials may need to be modified if it become  necessary to contain   materials such as pathogenic, highly toxic, radioactive,  or live viral   or bacterial materials. Decontamination facilities and the  treatment   of air leaving a clean area may be necessary for some operations.
 4.4 Maintenance of equipment: When equipment maintenance is carried   out within  the clean area, clean instruments and tools shall be used,   and the area shall  be cleaned and dis-infected, where appropriate,   before processing recommences,  if the required standards of cleanliness   and/or asepsis have not been  maintained during the maintenance work.
 4.5 Water supply: Water treatment plants shall not be operated beyond   their  designed capacity and water shall be produced, stored and   distributed in manner  that prevents microbial growth for example by   constant circulation at 90ºC or  at temperature validated to keep   microbial count of water within the limit.
 
 
 SECTION – 3
 
 5. Equipment maintenance:
 5.1 Documentation: All equipment, including sterilizers, air-filtration  systems, and water-treatment systems including stills, shall be subject to  planed maintenance, validation and monitoring, and   its approved use, following  maintenance work, shall be documented.
 
 SECTION – 4 
 
 6. Sanitation
 6.1 Procedure: The sanitation of clean areas is particularly   important, they  shall be cleaned frequently and thoroughly in   accordance with a written program  approved by the quality control   department; where disinfectants are used, more  than one type shall be   employed with periodic alterations, the monitoring shall  be regularly   undertaken in order to detect the emergence of resistant strains  of   microorganism, and in view of its limited effectiveness, ultraviolet   light  shall not be used as a substitute for chemical disinfection.
 6.2 Use of disinfectants and detergents: Disinfectants and detergents   shall be  monitored for microbial contamination. Dilutions hall be kept   in previously  cleaned container and shall not be stored for long   periods unless sterilized,  and partly emptied containers shall not be   topped up.
 6.3 Fumigation: Fumigation of clean areas may be useful for reducing    microbiological contamination in inaccessible places, if required
 6.4 Monitoring of clean areas: Clean areas shall be monitored at   planned  intervals during operations by means of microbial counts of air   and surface,  where aseptic operations are performed, monitoring shall   be frequent to ensure  that the environment is within specifications,   the results of monitoring shall be considered when batches are assessed   for approval, air particulate quality  shall also be evaluated on a   regular basis, and additional monitoring is  sometimes desirable even   when there are no production operations such as after  validation of   systems, cleaning, and fumigation.
 SECTION – 5                  7. Processing:
 7.1 Precautions against contamination: Precautions to minimized   contamination  shall be taken during all processing stages including the   stage before  sterilization.
 7.2 Preparations of live organisms: Preparations containing live    microbiological organisms shall not be made or containers filled in   areas used  for the processing of other pharmaceutical products except   for validation  purposes however, vaccines of dead organisms or of   bacterial extracts may be  dispensed into containers after validated   inactivation and validated cleaning procedures in the same premises as   other sterile pharmaceutical products.
 7.3 Simulation of aseptic operations validation: The use of nutrient   media that  support microbial growth in trials to simulate aseptic   operations, sterile  media fills and broth fills, is a valuable part of   overall validation of an  aseptic process, and such trials shall have   the following characteristics,  namely: -
 (a) they shall simulate as closely as possible actual operations,   taking into  account such factors as complexity of operations, number of   personnel working,  and length of time;
 (b) the medium or media selected shall be capable of growing a wide   spectrum of  microorganisms, including those that would be expected to   be found in the  filling environment, and
 (c) they shall include a sufficient number of units of production to   give a  high degree of assurance that low levels of contamination, if   present, would be  detected,
 Note:- It is recommended that at least 3000 units of production be   included in  each broth-fill trial. The target shall be zero growth and   anything above 0.1%  of units contaminated shall be considered   unacceptable. Any contamination shall  be investigated. Broth fills   shall be repeated at regular intervals, and  whenever a significant   alteration in the product, premises, equipment or  process warrants   revalidation. Care shall be taken that validations do not harm  the   processes.
 7.4 Monitoring water supply sources: Water sources, water-treatment   equipment  and treated water shall be monitored regularly for chemicals,   biological  contamination and contamination with endotoxins to ensure   that the water  complies with the specifications appropriate to its use.   Records shall be  maintained of the results of the monitoring and of   any action.
 7.5 Activities in clean areas kept minimum: Activities in clean areas,    especially when aseptic operations are in progress, shall be kept to a   minimum  and the movement of personnel shall be controlled and   methodical to avoid  excessive shedding of particles and organisms due   to over-vigorous activity,  and the ambient temperature and humidity   shall not be uncomfortably high  because of the nature of the garments   worn.
 7.6 Care of starting materials: Micro-biological contamination   (bioburden) of  starting materials shall be minimal which shall be   monitored before  sterilization, and specifications shall included   requirements for  microbiological quality when the need for this has   been indicated by  monitoring.
 7.7 Care against  fibers: The presence of containers and materials   liable to generate fibers  shall be minimized in clean areas and avoided   completely while aseptic work is  in progress.
 7.8 Care after final cleaning of materials: Components, bulk-product   containers  and equipment shall be handled after the final cleaning   process in such a way  that they are not recontaminated, and the stage   of processing of components, bulk-product containers, and equipment   shall be properly identified.
 7.9 Interval between operations to be minimal: The interval between   the washing  and drying and the sterilization of components,   bulk-product containers, and  equipment, as well as between   sterilization and use, shall be as short as  possible and subject to a   time-limit appropriate to the validated storage conditions, similarly   the time between the start of the preparation of solution  and its   sterilization or filtration through a bacteria-retaining filter shall    be as short as possible, and maximum permissible time shall be set for   each  product that takes into account its composition and the prescribed   method of  storage.
 7.10 Sterilization of gases used: Any gas that is used to purge a   solution on  blanket a product shall pass through a sterilization   filter.
 7.11 Bioburden to be minimal: The microbiological contamination of   products  (bioburden) shall be minimal prior to sterilization, there   shall be a working  limit on contamination immediately before   sterilization that is related to the  efficiency of the method to be   used and the risk of pyrogens, all solutions, in particular   large-volume parenteral, shall be passed through a micro-organism    retaining filter, if possible immediately before the filling processes,   and  where aqueous solutions are held in sealed vessels, any   pressure-release  outlets shall be protected such as by hydrophobic   microbial air filter.
 7.12 Asepsis of articles in clean areas: Components, bulk-product   containers,  equipment and any other articles required in a clean area,   where aseptic work  is in progress, shall be sterilized and, wherever   possible, passed into the  area through double-ended sterilizers sealed   into the wall, and other  procedures that achieve the same end of not   introducing contamination, such as  triple wrapping, may be acceptable   in some circumstances.
 7.13 New processes to be validated: The efficacy of any new processing    procedure shall be validated and the validation shall be repeated at   regular  intervals thereafter or when any significant change is made in   the process or  equipment.
 
 SECTION – 6 
 
 8. Sterilization:
 8.1 General: Sterilization can be achieved by moist or dry heat, by   ethylene oxide  or other suitable gaseous sterilizing agent, by   filtration with subsequent  aseptic filling of sterile final containers,   or by irradiation with ionizing  radiation but not with ultraviolet   radiation unless the process is thoroughly  validated, each method has   its particular applications and limitations, and where possible and   practicable heat sterilization is the method of choice.
 8.2 Validation: All sterilization processes must be validated and   particular  attention shall be given when the adopted sterilization   method is not in  accordance with pharmacopoeial or other national   standards or when it is used  for a preparation that is not a simple   aqueous or oily solution.
 8.3 Suitability of process: Before any sterilization process is   adopted, its  suitability for the product and its efficacy in achieving   the desired  sterilizing conditions in all parts of each type of load to   be processed shall  be demonstrated and this work shall be repeated at   scheduled intervals, at  least annually, and whenever significant   modifications have been made to the  equipment, and records shall be   kept of the results.
 8.4 Care for biological indicators: Biological indicators shall be   considered  only as and additional method for monitoring the   sterilization, and if they are  used, strict precautions shall be taken   to avoid transferring microbial contamination from them.
 8.5 Sterilized not sterilized product differentiation: There shall be a   clear  means of differentiating products that have not been sterilized   from those that  have and each basket, tray, or other carrier of   products or components shall be  clearly labeled with the name of the   material, its batch number and an  indication of whether or not it has   been sterilized, and indicators such as autoclave tape may be used,   where appropriate, to indicate whether or not a  batch, or sub-batch,   has passed through a sterilization process, but they do  not give a   reliable indication that the lot is, in fact, sterilize.
 9. Sterilization by heat:
 9.1 Recording sterilization cycle: Each heat sterilization cycle shall   be  recorded by appropriate equipment with suitable accuracy and   precision such as  time and temperature chart with a suitably large   scale, the temperature shall  be recorded from a probe at the coolest   part of the load or loaded chamber having  been determined during the   validation. The temperature shall preferably be checked against a   second independent temperature probe located at the same  position, the   chart, or a photocopy of it, shall form part of the batch record,  and   chemical or biological indicators may also be used but shall not take   the  place of physical controls.
 9.2 Sufficient time allowed to reach required temperature: Sufficient   time must  be allowed for the whole of the load to reach the required   temperature before  measurement of the sterilizing time is started and   this time must be determined  for each type of load to be processed.
 9.3 Precautions during cooling: After the high-temperature phase of a   heat  sterilization cycle, precautions shall be taken against   contamination of a sterilized  load during cooling, and any cooling   fluid or gas in contact with the product shall be sterilized, unless it   can be shown that any leaking container would  not be approved for use.
 10. Sterilization by moist heat:
 10.1 General: Sterilization by moist heat is suitable only for   water-wettable  materials and aqueous solutions, both temperature and   pressure shall be used to  monitor the process, the temperature recorder   shall normally be independent of  the temperature regulator and there   shall be an independent temperature  indicator, the reading from which   is routinely checked against the chart recorder during the   steri8lization period, for sterilizers fitted with a drain  at the   bottom of the chamber, it may also be necessary to record the    temperature at this position, throughout the sterilization period, and   there  shall be regular leak tests on the chamber when a vacuum phase is   part of the  cycle.
 10.2 Wrapping materials: The items to be sterilized, other than   products in  sealed containers, shall be wrapped in a material that   allows removal of air  and penetration of steam but prevents   recontamination after sterilization and  all parts of the load shall be   in contact with water or saturated steam at the required temperature   for the required time.
 10.3 Care shall be taken to ensure that steam used for sterilization   is of  suitable quality and does not contain additives at a level that   could cause  contamination of the product or equipment.
 11. Sterilization by dry heat:
 The process used for sterilization by dry heat shall include air   circulation  within the chamber and the maintenance of a positive   pressure to prevent the  entry of non-sterile air, if air is supplied,   it shall be passed through a  microorganism-retaining filter, and where   this process of sterilization by dry  heat is also intended to remove   pyrogens, challenge tests using endotoxins  would be required as part of   the validation.
 12. Sterilization by radiation:
 12.1 General: Radiation sterilization is used mainly for the   sterilization of  heat-sensitive materials and products, many pharmaceutical products and some  packaging materials are radiation-sensitive, so this method is permissible only  when the absence of deleterious effect on the product has been confirmed experimentally, and ultraviolet irradiation is not acceptable method for terminal sterilization.
 12.2 Outside contractor: If radiation sterilizations is carried out by   an  outside contractor, the manufacturer has the responsibility of   ensuring that  the requirements of section 12.1 are met and that the   sterilization process is  validated and the responsibilities of the   radiation plant operator, such as the  right dose, shall also be   specified.
 
 12.3 Measurement of radiation: During the sterilization procedure the   radiation  dose shall be measured and for this purpose, dosimeters that   are independent of  dose rate shall be used giving a quantitative   measurement of the dose received  by the product itself, dosimeters   shall be inserted in the load in sufficient  number and close enough   together to ensure that there is always dosimeter in  the chamber: where   plastic dosimeters are used, they shall be used within the  time-limit   of their calibration, Biological indicators may be used only as an    additional control. Radiation – sensitive colour discs may be used to    differentiate between packages that have been subjected to irradiation   and  those that have not they are not indicators of successful   sterilization. The  information obtained shall constitute part of the   batch record, and the total  radiation dose shall be administered within   a predetermined time span.
 12.4 Validation: Validation procedures shall ensure that consideration   is given  to the effect of variations in the density to the packages.
 12.5 Handling procedures: Handling procedures shall prevent any mix-up   between  irradiated and non-irradiated materials. Each package shall   carry a  radiation-sensitive indicator to show whether or not it has   been subjected to  radiation treatment.
 
 13 Sterilization by ethylene oxide:
 13.1 General: Various gases and fumigants may be used for   sterilization,  ethylene oxide shall be used only when no other method   is practicable. During  process validation it shall be shown that the   gas has no damaging effect on the  product and that the conditions and   time allowed for degassing are such as to  reduce any residual gas and   re-action products to defined acceptable limits for the type of product   or material, and these limits shall be incorporated into  the   specifications.
 13.2 Ensure contact between gas and microbial cells: Direct contact   between gas  and microbial cells is essential, precautions shall be   taken to avoid the  presence of organisms likely to be enclosed in   material such as crystals or  dried protein, and the nature and quantity   of packaging materials can  significantly affect the process.
 13.3 Equilibrium with humidity and temperature: Before exposure to the   gas,  materials shall be brought into equilibrium with the humidity and   temperature  required by the process. The time required for this shall   be balanced against  the opposing need to minimize the time before   sterilization.
 13.4 Monitoring each cycle: Each sterilization cycle shall be   monitored with  suitable biological indicators, using the appropriate   number of test pieces  distributed throughout the load, and the   information so obtained shall form  part of the batch record.
 13.5 Biological indicators: Biological indicators shall be stored and   used  according to the manufacturer’s instructions and their performance   checked by  positive controls.
 13.6 Record maintenance: For each sterilization cycle, records shall   be made of  the time taken to complete the cycle of the pressure,   temperature, and humidity  within the chamber during the process and of   the gas concentration, the  pressure and temperature shall be recorded   throughout the cycle on a chart and  the records shall form part of the   batch record.
 13.7 Validation: After sterilization, the load shall be stored in a   controlled  manner under ventilated conditions to allow residual gas and   re-action products  to fall to the defined level, and this process   shall be validated.
 14 Filtration of pharmaceutical products that cannot be sterilized in   the final  container.
 14.1 General: Whenever possible, products shall be sterilized in the   final  container preferably by heat sterilization. Certain solutions and   liquids that  cannot be sterilized in the final container can be   filtered through a sterile  filter of nominal pore size 0.22um or less,   or with at least equivalent microorganism-retaining properties into a   previously sterilized container, such  filter can remove bacteria and   moulds, but not all viruses or mycoplasmas.
 14.2 Using double filter layer: Owing to the potential additional   risks of the  filtration method as compared with other sterilization   processes, a double  filter layer or second filtration via a further   sterilized  microorganism-retaining filter immediately prior to filling   may be advisable  and the final sterile filtration shall be carried out   as close as possible to  the filling point.
 14.3 Eliminate fibres: Filters that shed fibers shall not be used and   the use  of asbestos-containing filters shall be absolutely excluded.
 14.4 Checking integrity of filters: The integrity of the filter shall   be  checked by an appropriate method such as a bubble point test   immediately after  each use, it may also be useful to test the filter in   this way before use, the  time taken to filter a known volume of bulk   solution and the pressure  difference to be used across the filter shall   be determined during validation  and any significant differences from   this shall be noted and investigated.  Results of these checks shall be   recorded in the batch record.
 14.5 Frequency of use of filter: The same filter shall not be used for   more  than one working day unless such use has been validated.
 14.6 Filter safety: The filter shall not affect the product by removal   of  ingredients from it or by release of substances into it.
 15 Finishing of sterile products:
 15.1 General: Containers shall be closed by appropriately validated   methods,  and same shall be checked for integrity according to   appropriate procedures.
 15.2 Use of vacuum: Containers sealed under vacuum shall be  sampled   and the same tested for maintenance of that vacuum after and    appropriate pre-determined period.
 15.3 Inspection of containers: Filled containers of parenteral   products shall  be inspected individually, when inspection is done   visually it shall be done  under suitable and controlled conditions of   illumination and background,  operators doing the inspection shall pass   regular eyesight checks, with  spectacles if worn, and be allowed   frequent breaks from inspection, and where  other methods of inspection   are used, the process shall be validated and the  performance of the   equipment checked at intervals.
 
 SECTION – 7                  16. Quality control:
 16.1 Sterility testing: Samples taken for sterility testing shall be    representative of the whole of the batch but shall, in particular,   include  samples taken from parts of the batch considered to be most at   risk of  contamination, such as: -
 (a) for products that have been filled aseptically, samples shall   include  containers filled at the beginning and end of the batch and   after any  significant interruption of work; and
 (b) for products that have been heat sterilized in their final   containers, and  samples can be taken form any part of the load.
 16.2 Sterility test as the last measures: The sterility test applied   to the  finished product shall be regarded only as the last in a series   of control  measures by which sterility is assured and can be   interpreted only in  conjunction with the environmental and batch   processing records.
 16.3 Monitoring endotoxins: For injectable products, consideration   shall be  given to monitoring the water and the intermediate and   finished product for  endotoxins, using and established pharmacopoeial   method that has been validated  for each type of product, for large   –volume infusion solutions, such monitoring of water or intermediates   shall always be done, in addition to any test  required by the marketing   authorization on the finished product, and when a  sample fails a test,   the causes of failure shall be investigated and remedial  action taken   where necessary.
 Saving: This Schedule  B-II shall come into force with effect form the   date as may be notified by the  Federal Government and till such time   Schedule B-II as already provided in the  Rules shall remain in-force.
 After rule 20 the following new rule shall be inserted, namely: -
 “20A. Contract Manufacture. Manufacture or analysis on contract is   permissible  on behalf of a licensee or of a pharmaceutical company   whose products are  registered for import in Pakistan for sale subject   to the conditions laid down  in Schedule G”, as a special case and for   genuine reasons as approved by the Registration Board.
 SCHEDULE ‘G’
 1. Contract production and analysis:
 1.1 Contract of manufacture shall be undertaken only by a manufacturer   who  holds a valid drug manufacturing license, and the contract   acceptor shall/have  adequate facilities, knowledge, experience and   competent personnel to  satisfactorily carry out the work ordered by the   contract giver.
 1.2 General: Contract production and analysis shall be correctly   defined,  agreed and controlled in order to avoid misunderstandings that   could result in  a drug or work or analysis of unsatisfactory quality. A   written contract  between the contract giver and the contract acceptor   shall clearly establish  the duties of each party and state the way in   which the authorized person shall exercise his full responsibility in   releasing each batch of product for sale or  issuing the certificate of   analysis, and a copy of such a contract shall be  supplied to the   Central Licensing Board also.
 1.3 All arrangements for contract manufacture and analysis, including   any  proposed changes in technical or other arrangements, shall be in   accordance  with the registration of the drug concerned.
 1.4 There shall be a written contract covering the manufacture and or   analysis  arranged under contract and any technical arrangements made in   connection with  it.
 1.5 The contract shall permit the contract giver to audit the   facilities of the  contract acceptor.
 1.6 In the case of contract analysis, the final approval for release   must be  given by the authorized person(s).
 2. Contract Giver
 2.1 The contract giver shall be responsible for assessing the   competence of the  contract acceptor in successfully carrying out the   work or tests required and  for ensuring by means of the contract that   the principles of good manufacturing  practices are followed.
 2.2 The contract giver shall provide the contract acceptor with all   the  information necessary to carry out the contracted operations   correctly in  accordance with the registration and any other legal   requirement’s and the  contract giver shall ensure that the contract   acceptor is fully aware of any  problem associated with the product,   work, or tests that might pose a hazard to premises, equipment,   personnel, other material or other products.
 2.3 The contract giver shall ensure that all processed products and   material  delivered by the contract acceptor to comply with their   specifications or that the  product has been released by the authorized   person(s)
 3. Contract acceptor:
 3.1 The contract acceptor shall not pass to a third party any of the   work  entrusted to him or her under the contract without the written   consent of the  contract giver and prior evaluation and approval by the   arrangements of the  Central Licensing Board, and arrangements made   between the contract acceptor  and any third party shall ensure that the   manufacturing and analytical information is made available in the same   way as between the original contract  giver and contract acceptor.
 3.2 The contract acceptor shall refrain from any activity that may   adversely  affect the quality of the product manufactured and or   analyzed for the contract  giver.
 4. The contract:
 4.1 A contract shall be drawn up between the contract giver and the   contract  acceptor that specifies their respective responsibilities   relating to the  manufacture and control of the product, and technical   aspects of the contract  shall be drawn up by competent persons suitably   knowledgeable in pharmaceutical technology, analysis, and good   manufacturing practices. All arrangements for  production and analysis   must be in accordance with the registration and agreed  by both parties.
 4.2 The contract shall specify the way in which the authorized person   releasing  the batch for sale ensures that each batch has been   manufactured in, and  checked for, compliance with the requirements of   the marketing authorization.
 4.3 The contract shall describe clearly who is responsible for   purchasing, testing,  and releasing material and for undertaking   production and quality controls,  including in process controls, and who   has responsibility for sampling and  analysis, and in the case of   contract analysis, the contract shall state  whether or not the contract   acceptor shall take samples at the premises of the manufacture.
 4.4 Manufacturing, analytical distribution records and reference   samples shall  be kept by, or be available to, the contract giver, and   any records relevant to  assessing the quality of a product in the event   of complaints or a suspected  defect shall be accessible and specified   in the defect or recall procedures of  the contract giver.
 4.5 The contract shall describe the handling of stating material   intermediate  and bulk products and finished products if they are   rejected and it shall also  describe the processing of information if   the contract analysis shows that the  tested product must be rejected.