𝐒 𝐉 𝐄𝐗𝐈𝐌 𝐒𝐞𝐫𝐯𝐢𝐜𝐞𝐬

Dated: 20.08.2019

GOOD MANUFACTURING PRACTICE IN COSMETICS

“The Drugs & Cosmetics Act, 1940” and “The Drugs & Cosmetics Rules, 1945” of India is the primary law which regulates the Manufacture/Production and Sales including EXIM trade with respect to Cosmetics.

This chapter has been conceived on the best of our experience and interaction with the Drugs Controller office (CDSCO). This chapter extensively deals with the provisions of “The Drugs &Cosmetics Act, 1940”. This chapter also gives a detailed process of good manufacturing practices and requirements of premises, plant and equipment for pharmaceutical products.

The understanding of the compliance for manufacturing Cosmetics is very much essential to carry on with the best manufacturing practices. This in turn will certainly help the manufacturers in improving on their quality aspects to cater to the global demand for good quality products. The Standard Operating Procedures enshrined in this chapter is a best practice methodology defined by the Drugs controller of India under the Food & Drug Administration (FDA).

CONTENTS

Good Manufacturing Practice in Cosmetics

 

[See Rules 71, 74, 76 and 78]

GOOD MANUFACTURING PRACTICES AND REQUIREMENTS OF PREMISES, PLANT AND EQUIPMENT FOR PHARMACEUTICAL PRODUCTS.

Note:  –  To  achieve  the  objectives  listed  below,  each  licensee  shall  evolve  appropriate methodology,  systems  and  procedures  which  shall  be  documented  and  maintained  for inspection and reference; and the manufacturing premises shall be used exclusively for production of drugs and no other manufacturing activity shall be undertaken therein.

GOOD MANUFACTURING PRACTICES FOR PREMISES AND MATERIALS

1. GENERAL REQUIREMENTS
   • Location and surroundings – The factory building(s) for manufacture of drugs shall be so situated and shall have such measures as to avoid risk of contamination from external environmental including open sewage, drain, public lavatory or any factory which  product  disagreeable  or  obnoxious  odour,  fumes,  excessive  soot,  dust,  smoke, chemical or biological emissions.
   • Building and  premises –  The  building(s)  used  for  the  factory  shall  be designed, constructed, adapted and maintained to suit the manufacturing operations so as to  permit  production  of  drugs  under  hygienic    They shall  conform  to  the conditions laid down in the Factories Act, 1948 (63 of 1948)

The premises used for manufacturing, processing, warehousing, packaging labeling and testing purposes shall be

• Compatible with other drug manufacturing operations that may be carried out in the same or adjacent area / section;
• Adequately provided  with  working  space  to  allow  orderly  and  logical placement of equipment, materials and movement of personnel so as to:
• Avoid the risk of mix-up between different categories of drugs or with raw materials, intermediates and in-process material;
• Avoid the  possibilities  of  contamination  and  cross-  contamination by providing suitable mechanism;
• Designed /  constructed  /  maintained  to  prevent  entry  of  insects,  pests, birds,  vermin,  and    Interior  surface  (walls,  floors  and  ceilings) shall be smooth and free from cracks, and permit easy cleaning, painting and disinfection;
• Air-conditioned, where prescribed for the operations and dosage from under production. The  production  and  dispensing  areas  shall  be  well lighted,  effectively  ventilated,  with  air  control  facilities  and  may  have proper  Air  Handling  Units  (wherever  applicable)  to  maintain  conditions including temperature  and,  wherever  necessary,  humidity,  as  defined  for the relevant product. These conditions shall be appropriate to the category of drugs and nature of the operation.  These  shall  also  be  suitable  to  the comforts  of  the  personnel  working  with  protective  clothing,  products handled,  operations  undertaken  within  them  in  relation  to  the  external environment.  These areas  shall  be  regularly  monitored  for  compliance with required specifications;
• Provided with drainage system, as specified for the various categories of products, which shall be of adequate size and so designed as to prevent back flow and/or prevent insets and rodents entering the premises. Open channels  shall  be  avoided  in  manufacturing  areas  and,  where  provided, these shall be shallow to facilitate cleaning and disinfection;
• The walls  and  floors  of  the  areas  where  manufacture  of  drugs  is  carried out  shall  be  free  from  cracks  and  open  joints  to  avoid  accumulation  of dust. These shall be smooth, washable, covered and shall permit easy and effective cleaning and dis-infection.  The interior surfaces shall not shed particles.  A periodical record of cleaning and painting of the premises shall be maintained.
  • Water System  –  There  shall  be  validated  system  for  treatment  of  water drawn  from own  or  any other source  to render  it potable in accordance  with standards specified by the Bureau of Indian Standards or Local Municipality, as the case may be, so as to produce Purified Water conforming to Pharmacopoeial specification. Purified Water so produced shall only be used for all operations except washing and cleaning operations where potable water may be used. Water shall be stored in tanks, which do not adversely affect quality of water and ensure freedom from microbiological growth. The tank shall be cleaned periodically and records maintained by the licensee in this behalf.

• Disposal of waste –

The disposal of sewage and effluents (solid, liquid and gas) from the manufactory shall be in conformity with the requirements of Environment Pollution Control Board.

1996. All bio-medical waste shall be destroyed as per the provisions of the Bio-Medical Waste (Management and Handling) Rules, 1996.
1997. Additional precautions shall be taken for the storage and disposal of rejected drugs. Records shall be maintained for all disposal of waste.

• Provisions shall be made for the proper and safe storage of waste materials awaiting      Hazardous, toxic   substances   and flammable  materials  shall  be  stored  in  suitably  designed  and segregated,  enclosed  areas  in  conformity  with  Central  and  State Legislations.

2. Warehousing Area –
   • Adequate areas   shall   be   designed   to   allow   sufficient   and   orderly warehousing of various categories of materials and products like starting and packaging materials,  intermediates,  bulk  and  finished  products,  products  in  quarantine,  released, rejected, returned or recalled, machine and equipment spare parts and change items.
   • Warehousing areas shall be designed and adapted to ensure good storage conditions. They shall be clean, dry and maintained with acceptable temperature limits, where special storage conditions are required (e.g. temperature, humidity), these shall be provided, monitored and recorded. Storage  areas  shall  have  appropriate  house-keeping and  rodent,  pests  and  vermin  control  procedures  and  records    Proper racks, bins and platforms shall be provided for the storage of materials.
   • Receiving and dispatch bays shall protect materials and products from adverse weather conditions.
   • Where quarantine status is ensured by warehousing in separate earmarked areas in the same warehouse or store, these areas shall be clearly demarcated. Any system replacing the physical quarantine, shall give equivalent assurance of segregation. Access to these areas shall be restricted to authorized persons.
   • There shall be a separate sampling area in the warehousing area for active raw materials and excipients. If  sampling  is  performed  in  any  other  area,  it  shall  be conducted in such a way as to prevent contamination, cross-contamination and mix-up.
   • Segregation shall  be  provided  for  the  storage  of  rejected,  recalled  or returned materials or products. Such areas, materials or products shall be suitably marked and secured. Access to these areas and materials shall be restricted.
   • Highly hazardous,  poisonous  and  explosive  materials  such  as  narcotics, psychotropic drugs and substances presenting potential risks of abuse, fire or explosion shall  be  stored  in  safe  and  secure    Adequate fire protection measures shall be provided in conformity with the rules of the concerned civic authority.
   • Printed packaging materials shall be stored in safe, separate and area
   • Separate dispensing   areas   for   β   (Beta)   lactum,   Sex   Hormones   and Cytotoxic  substances  or  any  such  special  categories  of  product  shall  be  provided  with proper   supply   of   filtered   air   and   suitable   measures   for   dust   control   to   avoid contamination. Such areas shall be under differential pressure.
   • Sampling and dispensing of sterile materials shall be conducted under aseptic conditions conforming to Grade A, which can also be performed in a dedicated area within the manufacturing facility.
   • Regular checks shall be made to ensure adequate steps are taken against spillage, breakage and leakage of containers.
   • Rodent treatments  (Pest  control)  should  be  done  regularly  and  at  least once in a year and record maintained.
3. Production area –
   • The production area shall be designed to allow the production preferably in uni-flow and with logical sequence of operations.
   • In order to avoid the risk of cross-contamination, separate dedicated and self-contained facilities   shall   be   made   available   for   the   production   of sensitive pharmaceutical products like penicillin or biological preparations with live micro- organisms.  Separate   dedicated   facilities   shall   be   provided   for   the   manufacture   of contamination  causing  and  potent  products  such  as  Beta-Lactum,  sex  hormones  and cytotoxic substances.
   • Working and  in-process  space  shall  be  adequate  to  permit  orderly  and logical  positioning  of  equipment  and  materials  and  movement  of  personnel  to  avoid cross-contamination  and  to  minimize  risk  of  omission  or  wrong  application  of  any manufacturing and control measures.
   • Pipe-work, electrical fittings, ventilation openings and similar services lines shall be designed, fixed and constructed to avoid creation of recesses. Services lines shall preferably be identified by colours and the nature of the supply and direction of the flow shall be marked/indicated.
4. Ancillary Areas –
   • Rest and refreshment rooms shall be separate from other areas. These areas shall not lead directly to the manufacturing and storage areas.
   • Facilities for changing, storing clothes and for washing and toilet purposes shall be  easily  accessible  and  adequate  for  the  number  of    Toilets,  separate  for males  and  females,  shall  not  be  directly  connected  with  production  or  storage  areas. There shall be written instructions for cleaning and disinfection of such areas.
   • Maintenance workshops shall be separate and away from production areas. Whenever spares, changed parts and tools are stored in the production area, these shall be kept in dedicated rooms or lockers. Tools and spare parts for use in sterile areas shall be disinfected before these are carried inside the production areas.
   • Areas housing animals shall be isolated from other areas. The other requirements regarding animal houses shall be those as prescribed in Rule 150-C(3) of the Drugs and Cosmetics Rules, 1945 which shall be adopted for production purposes.
5. Quality Control Area –
   • Quality Control Laboratories shall be independent of the production areas. Separate areas shall be provided each for physico-chemical, biological, microbiological or radio-isotope analysis. Separate instrument room with adequate area shall be provided for sensitive and sophisticated instruments employed for analysis.
   • Quality Control Laboratories shall be designed appropriately for the operations to be carried out in them. Adequate space shall be provided to avoid mix-ups and cross-contamination. Sufficient and suitable storage space shall be provided for test samples, retained samples, reference standards, reagents and records.
   • The design  of  the  laboratory  shall  take  into  account  the  suitability  of construction materials and ventilation. Separate air handling units and other requirements shall be provided for biological, microbiological and radioisotopes testing areas.  The laboratory  shall  be  provided  with  regular  supply  of  water  of  appropriate  quality  for cleaning and testing purpose.
   • Quality Control Laboratory shall be divided into separate sections i.e. for chemical, microbiological and wherever required, biological testing. These shall have adequate area for basis installation and for ancillary purposes. The microbiology section shall  have  arrangements  such  as  airlocks  and  laminar  air  flow  work  station,  wherever considered necessary.
6. Personnel –
   • The manufacture  shall  be  conducted  under  the  direct  supervision  of competent  technical  staff  with  prescribed  qualifications  and  practical  experience  in  the relevant dosage and / or active pharmaceutical products.
   • The head  of  the  Quality Control  Laboratory shall  be  independent  of  the manufacturing    The testing shall be conducted under the direct supervision of competent technical staff who shall be whole time employees of the licensee.
   • Personnel for Quality Assurance and Quality Control operations shall be suitably qualified and experienced.
   • Written duties of technical and Quality Control personnel shall be laid and following strictly.
   • Number of personnel employed shall be adequate and in direct proportion to the workload.
   • The licensee shall ensure in accordance with a written instruction that all personnel in production area or into Quality Control Laboratories shall receive training appropriate to the duties and responsibility assigned to them. They shall be provided with regular in-service training.
7. Health, clothing and sanitation of workers –
   • The personnel   handling   Beta-lactum   antibiotics   shall   be   tested   for Penicillin  sensitivity  before  employment  and  those  handling  sex  hormones,  cytotoxic substances  and  other  potent  drugs  shall  be  periodically examined  for  adverse  These personnel should be moved out of these sections (except in dedicated facilities), by rotation, as a health safeguard.
   • Prior to  employment,  all  personnel,  shall  undergo  medical  examination including   eye   examination,   and   shall   be   free   from   Tuberculosis,   skin   and   other communicable  or  contagious    Thereafter, they should be medically examined periodically, at least once a year. Records shall be maintained thereof. The licensee shall provide the services of a qualified physician for assessing the health status of personnel involved in different activities.
   • All persons prior to and during employment shall be trained in practices which ensure personnel hygiene. A high level of personal hygiene shall be observed by all those engaged in the manufacturing processes. Instructions to this effect shall be displayed in change rooms and other strategic locations.
   • No person  showing,  at  any time,  apparent  illness  or  open  lesions  which may adversely affect the quality of products, shall be allowed to handle starting materials, packing materials, in-process materials, and drug products until his condition is no longer judged to be a risk.
   • All employees shall be instructed to report about their illness or abnormal health condition to their immediate supervisor so that appropriate action can be taken.
   • Direct contact   shall   be   avoided   between   the   unprotected   hands   of personnel and raw materials, intermediate or finished, unpacked products.
   • All personnel shall wear clean body coverings appropriate to their duties. Before entry into the manufacturing area, there shall be change rooms separate for each sex with  adequate  facilities  for  personal  cleanliness  such  as  wash  basin  with  running water,  clean  towels,  hand  dryers,  soaps,  disinfectants,    The change room shall be provided with cabinets for the storage of personal belongings of the personnel.
   • Smoking, eating,  drinking,  chewing  or  keeping  plants,  food,  drink  and personal  medicines  shall  not  be  permitted  in  production,  laboratory,  storage  and  other areas where they might adversely influence the product quality.
8. Manufacturing Operations and Controls –
   • All manufacturing operations shall be carried out under the supervision of technical staff approved by the Licensing Authority. Each critical step in the process relating to the selection, weighing and measuring of raw material addition during various stages shall be performed by trained personnel under the direct personal supervision of approved technical staff.

The contents of all vessels and containers used in manufacture and storage during the  various  manufacturing  stages  shall  be  conspicuously  labeled  with  the  name  of  the product,  batch  number,  batch  size  and  stage  of  manufacture.  Each label should be initialed and dated by the authorised technical staff.

Products  not  prepared  under  aseptic  conditions  are  required  to  be  free  from pathogens like Salmonella, Escherichia coli, Pyocyanea, etc.

• Precautions against mix-up and cross-contamination-
  • The licensee   shall   prevent   mix-up   and   cross-contamination   of drug material  and  drug  product  (from  environmental  dust)  by  proper  air-handling  system, pressure  differential,  segregation,  status  labeling  and    Proper records and Standard Operating Procedures thereof shall be maintained.
  • The licensee shall ensure processing of sensitive drugs like Beta-Lactum antibiotics, sex  hormones  and  cytotoxic  substances  in  segregated  areas  or  isolated production  areas  within  the  building  with  independent  air-handling  unit  and  proper pressure differential. The effective segregation of these areas shall be demonstrated with adequate records of maintenance and services.
  • To prevent  mix-ups  during  production  stages,  materials  under  process shall  be  conspicuously  labeled  to  demonstrate  their    All equipment used for production shall be labeled with their current status.
  • Packaging lines shall be independent and adequately segregated. It  shall be  ensured  that  all  left-overs  of  the  previous  packaging  operations,  including  labels, cartons and caps are cleared before the closing hour.
  • 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 and spillages. The line clearance shall be performed according to an approximate check-list and recorded.
  • The correct  details  of  any  printing  (for  example  of  batch  numbers  or expiry  dates)  done  separately  or  in  the  course  of  the  packaging  shall  be  rechecked  at regular intervals. All printing and overprinting shall be authorized in writing.
  • The manufacturing environment shall be maintained at the required levels of temperature, humidity and cleanliness.
  • Authorised persons shall ensure change-over into specific uniforms before undertaking any manufacturing operations including packaging.
  • There shall be segregated enclosed areas, secured for recalled or rejected material and for such materials which are to e reprocessed or recovered.

9. Sanitation in the Manufacturing Premises –
   • The manufacturing premises shall be cleaned and maintained in an orderly manner, so that it is free from accumulated waste, dust, debris and other similar material. A validated cleaning procedure shall be maintained.
   • The manufacturing areas shall not be used for storage of materials, except for the material being processed. It shall not be used as a general thoroughfare.
   • A routine sanitation program shall be drawn up and observed, which shall be properly recorded and which shall indicate–

• Specific areas to be cleaned and cleaning intervals;
• Cleaning procedure to be followed, including equipment and materials to be used for cleaning; and
• Personnel assigned to and responsible for the cleaning operation.
  • The adequacy of the working and in-process storage space shall permit the orderly and logical positioning of equipment and materials so as to minimize the risk of mix-up between  different  pharmaceutical  products  or  their  components  to  avoid  cross contamination, and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.
  • Production areas   shall   be   well   lit,   particularly where   visual   on-line controls are carried out.

10. Raw Materials –
    • The licensee shall keep an inventory of all raw materials to be used at any stage of manufacture of drugs and maintain records as per Schedule U.
    • All incoming materials shall be quarantined immediately after receipt or processing. All materials shall be stored under appropriate conditions and in an orderly fashion to permit batch segregation and stock rotation by a first in/first expiry first- out principle. All incoming materials shall be checked to ensure that the consignment corresponds to the order placed.
    • All incoming materials shall be purchased from approved sources under valid purchase vouchers. Wherever possible, raw materials should be purchased directly from the producers.
    • Authorized staff  appointed  by  the  licensee  in  this  behalf,  which  may include personnel from the Quality Control Department, shall examine each consignment on  receipt  and  shall  check  each  container  for  integrity  of  package  and    Damaged containers shall be identified, recorded and segregated.
    • If a single delivery of material is made up of different batches, each batch shall be considered as a separate batch for sampling, testing and release.
    • Raw materials in the storage area shall be appropriately labeled. Labels shall be clearly marked with the following information:

• Designated name of the product and the internal code reference, where applicable, and analytical reference number;
• Manufacturer’s name, address and batch number;
• The status of   the   contents (e.g.   quarantine, under   test,   released, approved, rejected); and
• The manufacturing date, expiry date and re-test date.
  • There shall   be   adequate   separate   areas   for   materials   under   test, approved  and  rejected  with  arrangements  and  equipment  to  allow  dry,  clean  and orderly placement of stored materials and products, wherever necessary, under controlled temperature and humidity.
  • Containers from which samples have been drawn shall be identified.
  • Only raw  materials  which  have  been  released  by  the  Quality  Control Department  and which  are within their shelf-life shall be used.  It  shall be ensured that shelf life of formulation product shall not exceed with that of active raw materials used.
  • It shall be ensured that all the containers of raw materials are placed on the raised platforms/racks and not placed directly on the floor.

11. Equipment –
    • Equipment shall be located, designed, constructed, adapted and maintained to suit the operations to be carried out. The  layout  and  design  of  the equipment  shall  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. Each equipment shall be provided with a logbook, wherever necessary.
    • Balances and other measuring equipment of an appropriate range, accuracy and precision shall be  available  in  the  raw  material  stores,  production  and  in process control operations and these shall be calibrated and checked on a scheduled basis in accordance with Standard Operating Procedures and records maintained.
    • The parts  of  the  production  equipment  that  come  into  contact  with  the product  shall  not  be  reactive,  additive  or  adsorptive  to  an  extent  that  would  affect  the quality of the product.
    • To avoid  accidental  contamination,  wherever  possible,  non-toxic/edible grade  lubricants  shall  be  used  and  the  equipment  shall  be  maintained  in  a  way  that lubricants do not contaminate the products being produced.
    • Defective equipment shall be removed from production and Quality Control areas or appropriately labeled.
12. Documentation and Records – Documentation is an essential part of the Quality assurance system  and,  as  such,  shall  be  related  to  all  aspects  Good  Manufacturing Practices  (GMP).  Its  aim  is  to  define  the  specifications  for  all  materials,  method  of manufacture and control, to ensure that all personnel concerned with manufacture know the information necessary to decide whether or not to release a bath of drug for sale and to  provide  an  audit  trail  that  shall  permit  investigation  of  the  history of  any suspected defective batch.
    • Documents designed,   prepared,   reviewed   and   controlled,   wherever applicable, shall comply with these rules.
    • Documents shall be approved, signed and dated by appropriate and authorized persons.
    • Documents shall specify the title, nature and purpose. They shall be laid out in an orderly fashion and be easy to check. Reproduced documents shall be clear and legible. Documents shall be regularly reviewed and kept up to date. Any alteration made in the entry of a document shall be signed and dated.
    • The records shall be made or completed at the time of each operation in such a  way that  all  significant  activities  concerning the  manufacture  of  pharmaceutical products  are    Records and associated Standard  Operating  Procedures  (SOP) shall be retained for at least one year after the expiry date of the finished product.
    • Data may  be  recorded  by  electronic  data  processing  systems  or  other reliable  means,  but  Master  Formulae  and  detailed  operating  procedures  relating  to  the system in use shall also be available in a hard copy to facilitate checking of the accuracy of the    Wherever  documentation  is  handled  by  electronic  data  processing methods,  authorized  persons  shall  enter  modify  data  in  the  computer.  There shall be record of changed and deletions. Access shall be restricted by passwords or other means and  the  result  of  entry  of  critical  data  shall  be  independently  checked.  Batch  records electronically  stored  shall  be  protected  by  a  suitable  back-up.  During the period of retention, all relevant data shall be readily available.
13. Labels and other Printed Materials – Labels are absolutely necessary for identification of the drugs and their use. The Printing shall be done in bright colours and in a legible manner. The label shall carry all the prescribed details about the product.
    • All containers and equipment shall bear appropriate labels. Different colour coded tablets shall be used to indicate the status of a product (for example under test, approved, passed, rejected).
    • To avoid chance mix-up of printed packaging materials, product leaflets, relating to different products, shall be stored separately.
    • Prior to  release,  all  labels  for  containers,  cartons  and  boxes  and  all circulars, inserts and leaflets shall be examined by the Quality Control Department of the licensee.
    • Prior to  packaging  and  labeling  of  a  given  batch  of  a  drug,  it  shall  be ensured by the licensee that samples are drawn from the bulk and duly tested, approved and released the quality control personnel.
    • Records of  receipt  of  all  labeling  and  packaging  materials  shall  be maintained for each shipment received indicating receipt, control reference numbers and whether accepted or rejected. Unused coded and damaged labels and packaging materials shall be destroyed and recorded.
    • The label or accompanying document of reference standards and reference culture shall indicate concentration, lot number, potency, date on which containers was first opened and storage conditions, where appropriate.
14. Quality Assurance – This is a wide-ranging concept concerning all matters that individually or collectively influence the quality of a product. It is the totality of  the  arrangements  made  with  the  object  of  ensuring  that  products  are  of  the  quality required for their intended use.
    • The system   of   quality   assurance   appropriate   to   the   manufacture   of pharmaceutical products shall ensure that: –

• The pharmaceutical products are designed and developed in a way that takes  account  of  the  requirement  of  Good  Manufacturing Practices (herein referred as GMP) and other associated codes such as  those  of  Good  Laboratory  Practices  (hereinafter  referred  as GLP) and Good Clinical Practices (herein after referred as GCP);
• Adequate arrangements are made for manufacture, supply and use of the correct starting and packaging materials.
• Adequate controls on starting materials, intermediate products, and bulk products  and  other  in-process  controls,   calibrations,  and validations are carried out.
• The finished   product   is   correctly   processed   and   checked   in accordance with established procedures;
• The pharmaceutical products are not released for sale or supplied before authorized persons have certified that each production batch as been produced and controlled in accordance with the requirements of the label claim and any other provisions relevant to production, control and release of pharmaceutical products.

15. Self-Inspection and Quality audit – It may be useful to constitute a self- inspection team supplemented with a quality audit procedure for assessment of all or part of a system with the specific purpose of improving it.
    • To evaluate  the  manufacturer’s  compliance  with  GMP  in  all  aspects  of production   and   quality  control,   concept   of   self-inspection   shall   be      The manufacturer shall constitute a team of independent, experienced, qualified persons from within  or  outside  the  company,  who  can  audit  objectively  the  implementation  of methodology   and   procedures   evolved.   The   procedure   for   self-inspection   shall   be documented indicating self-inspection results; evaluation, conclusions and recommended corrective actions with effective follow up program. The recommendations for corrective action shall be adopted.
    • The program shall be designed to detect           shortcomings in the implementation  of  Good  Manufacturing  Practice  and  to  recommend  the  necessary corrective   Self-inspections shall be  performed   routinely and on specific occasions, like when product recalls or repeated rejections occur or when an inspection by the licensing authorities is announced. The team responsible for self-inspection shall consist  of  personnel  who  can  evaluate  the  implementation  of  Good  Manufacturing Practice objectively; all recommendations for corrective action shall be implemented.
    • Written instructions for  self-inspection  shall  be  drawn  up  which  shall include the following: –

• Personnel
• Premises including personnel facilities.
• Maintenance of buildings and equipment
• Storage of starting materials and finished products
• Equipment
• Production and in-process controls
• Quality control
• Documentation
• Sanitation and hygiene
• Validation and revalidation programmes
• Calibration of instruments or measurement systems.
• Recall procedures
• Complaints management
• Labels control
• Results of previous self-inspections and any corrective steps taken.

16. Quality Control  System  –  Quality  control  shall  be  concerned  with  sampling, specifications, testing, documentation, release procedures which ensure that the necessary and relevant tests are actually carried and that the materials are not released for use, nor products released for sale or supply until their quality has been judged to be satisfactory. It is not confined to laboratory operations but shall be involved in all decisions concerning the quality of the product.  It shall be ensured  that  all  quality control  arrangements  are effectively and reliably carried out the department as a whole shall have other duties such as  to  establish  evaluate,  validate  and  implement  all  Quality  Control  Procedures  and methods.
    • Every manufacturing establishment shall establish its own quality control laboratory manner by qualified and experience staff.
    • The area of the quality control laboratory may be divided into Chemical, Instrumentation, Microbiological and Biological testing.
    • Adequate area having the required storage conditions shall be provided for keeping reference samples. The quality control department shall evaluate, maintain and store reference samples.
    • Standard operating procedures shall be available for sampling, inspecting and testing of raw materials, intermediate bulk finished products and packing materials and, wherever necessary, for monitoring environmental conditions.
    • There shall  be  authorized  and  dated  specifications  for  all  materials, products,  reagents  and  solvents  including  test  of  identity,  content,  purity  and  These shall include specifications for water, solvents and reagents used in analysis.
    • No batch  of  the  product  shall  be  released  for  sale  or  supply until  it  has been certified by the authorized person(s) that it is in accordance with the requirements of the standards laid down.
    • Reference/retained samples from each batch of the products manufactured shall be maintained in quantity which is at least twice the quantity of the drug required to conduct all the tests, except sterility and pyrogen/Bacterial Endotoxin Test performed on the active material and the product manufactured. The retained product shall be kept in its final pack or simulated pack for a period of three months after the date of expiry.
    • Assessment of  records  pertaining  to  finished  products  shall  include  all relevant factors, including the production conditions, the results of in process testing, the manufacturing (including  packaging) documentation,  compliance  with  the  specification for  the  finished  product,  and  an  examination  of  the  finished    Assessment  records should  be  signed  by  the  in-charge  of  production  and  countersigned  by  the  authorised quality control personnel before a product is released for sale or distribution.
    • Quality control personnel shall have access to production areas for sampling and investigation, as appropriate.
    • The quality control department shall conduct stability studies of the products to ensure and assign their shell life at the prescribed conditions of storage. All records of such studies shall be maintained.
    • The in-charge of Quality Assurance shall investigate   all   product complaints and records thereof shall be maintained.
    • All instruments shall be calibrated and testing procedures validated before these are adopted for routine testing. Periodical calibration of instrument and validation of procedures shall be carried out.
    • Each specification for raw materials, intermediates, final products, and packing materials shall be approved and maintained by the Quality Control Department. Periodic revisions  of  the  specifications  shall  be  carried  out  wherever  changes  are necessary.
    • Pharmacopoeia, reference   standards,   working   standards,   references, spectra, other reference materials and technical books, as required, shall be available in the Quality Control Laboratory of the license.
17. Specification-
    • For raw materials and packaging materials. – They shall include-

• The designated name and internal code reference;
• Reference, if any, to a pharmacopoeial monograph;
• Qualitative and quantitative requirements with acceptance limits;
• Name and address of manufacturer or supplier and original manufacturer of the material;
• Specimen of printed material;
• Directions for sampling and testing or reference to procedures;
• Storage conditions; and
• Maximum period of storage before re-testing.
  • For product containers and closures. –
    • All containers and closures intended for use shall comply with the pharmacopoeial requirements. Suitable validated test methods, sample sizes, specifications, cleaning procedure and sterilization procedure, wherever indicated, shall be strictly followed to ensure that these are not reactive, additive, absorptive, or leach to an extent that significantly affects the quality or purity of the drug. No second hand or used containers and closures shall be used.
    • Whenever bottles are being used, the written schedule of cleaning shall be laid down and followed. Where bottles are not dried after washing, they should be rinsed with de-ionised water or distilled water, as the case may be.
  • For in-process and bulk products. – Specifications for in-process material, intermediate and bulk products shall be available. The specifications   should   be authenticated.
  • For finished products. – Appropriate specifications for finished products shall include: –

1. The designated name of the product and the code reference;
2. The formula   or   a   reference   to   the   formula   and   the   pharmacopoeial reference;
3. Directions for sampling and testing or a reference to procedures;
4. A description of the dosage form and package details;
5. The qualitative  and  quantitative  requirements,  with  the  acceptance  limits for release;
6. The storage conditions and precautions, where applicable, and The shelf-life.
   • For preparation of containers and closures. – The requirements mentioned in the  Schedule  do  not  include  requirements  of  machinery,  equipment’s  and  premises required  for  preparation  of  containers  and  closures  for  different  dosage  forms  and categories  of    The suitability and adequacy  of  the  machinery,  equipment  and premises shall be examined taking into consideration the requirements of each licensee in this respect.

18. Master Formula Records-

There shall be Master Formula records relating to all manufacturing procedures for each product and batch size to be manufactured. These shall be prepared and endorsed by the competent technical staff i.e. head of production and quality control. The master

Formula shall include: –

1. The name  of  the  product  together  with  product  reference  code  relating  to  its specifications;
2. The patent or proprietary name of the product along with the generic name, a description of the dosage form, strength, composition of the product and batch size;
3. Name, quantity, and reference number of all the starting materials to be used.

Mention shall be made of any substance that may disappear in the courts of processing.

1. A statement  of  the  expected  final  yield  with  the  acceptable  limits,  and  of relevant intermediate yields, where applicable.
2. A statement of the processing location and the principal equipment to be used.
3. The methods, or reference to the methods, to be used for preparing the critical equipment’s including cleaning, assembling, calibrating, sterilizing.
4. Detailed stepwise processing instructions and the time taken for each step;
5. The instructions for in-process control with their limits;
6. The requirements   for   storage   conditions   of   the   products,   including   the container, labeling and special storage conditions where applicable;
7. Any special precautions to be observed; and
8. Packing details and specimen labels.
9. Packing Records –

There shall be authorised packaging instructions for each product, pack size and type. These shall include or have a reference to the following: –

1. Name of the product;
2. Description of the dosage form, strength and composition;
3. The pack size expressed in terms of the number of doses, weight or volume of the product in the final container;
4. Complete list of all the packaging materials required for a standard batch size, including quantities,  sizes  and  types  with  the  code  of  reference  number relating to the specifications of each packaging material.
5. Reproduction of   the   relevant   printed   packaging  materials   and   specimens indicating  where  batch  number  and  expiry  date  of  the  product  have  been applied;
6. Special precautions to be observed, including a careful examination of the area and equipment  in  order  to  ascertain  the  line  clearance  before  the  operations begin.
7. Description of  the  packaging  operation,  including  any  significant  subsidiary operations and equipment to be used;
8. Details of  in-process  controls  with  instructions  for  sampling  and  acceptance; and
9. Upon completion of the packing and labeling operation, a reconciliation shall be made between number of labeling and packaging units issued, number of units labeled,  packed  and  excess  returned  or    Any  significant  or unusual  discrepancy  in  the  numbers  shall  be  carefully  investigated  before releasing the final batch.
10. Batch Packaging Records-
    • A batch  packaging  record  shall  be  kept  for  each  batch  or  part  batch processed. It shall be based on the relevant parts of the packaging instructions, and the method of preparation of such records shall be designed to avoid transcription errors.

• Before any packaging operation begins, check shall be made and recorded that the equipment and the work stations are clear of the previous products, documents or materials not  required  for  the  planned  packaging operations,  and  that  the  equipment  is clean and suitable for use.

21. Batch Processing Records-
    • There shall be Batch Processing Record for each product. It shall be based on the relevant parts of the currently approved Master Formula. The method of preparation of such records included in the Master Formula shall be designed to avoid transcription errors.
    • Before any processing begins, check shall be performed and recorded to ensure that the equipment and work station are clear of previous products, documents or materials not required for the planned process are removed and the equipment is clean and suitable for use.
    • During processing, the following information shall be recorded at the time each action is taken and the record shall be dated and signed by the person responsible for the processing operations: –
22. The name of the product
23. The number of the batch being manufactured,
24. Dates and  time  of  commencement,  of  significant  intermediate  stages  and  of completion of production,
25. Initials of the operator of different significant steps of production and where appropriate, of the person who checked each of these operations,
26. The batch number and/or analytical control number as well as the quantities of each starting material actually weighed,
27. Any relevant processing operation or event and major equipment used,
28. A record  of  the  in-process  controls  and  the  initials  of  the  person(s)  carrying them out, and the results obtained,
29. The amount   of   product   obtained   after   different   and   critical   stages   of manufacture (yield),
30. Comments or explanations for significant deviations from the expected yield limits shall be given.
31. Notes on special problems including details, with signed authorization, for any deviation from the Master Formula.
32. Addition of any recovered or reprocessed material with reference to recovery or reprocessing stages,
33. Standard Operating Procedures (SOPs) and Records, regarding –

 

• Receipt of materials:
  • There shall be written Standard Operating Procedures and records for the receipt of each delivery of raw, primary and printed packaging material.
  • The records of the receipts shall include;

1. The name  of  the  material  on  the  delivery  note  and  the  number  of containers;
2. The date of receipt;
3. The manufacturer’s and/ or supplier’s name;
4. The manufacturer’s batch or reference number;
5. The total quantity, and number of containers, quantity in each container received;
6. The control reference number assigned after receipt;
7. Any other relevant comment or information.
   • There shall be written standard operating procedures for  the  internal labeling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate.
   • There shall   be   Standard   Operating   Procedures   available   for   each instrument and equipment and these shall be placed in close proximity to the related instrument and equipment.

• Sampling: –
  • There shall be written Standard Operating Procedures for sampling which include the person(s) authorized to take the samples.
  • The sampling instruction shall include:
• The method of sampling and the sampling plan,
• The equipment to be used,
• Any precautions  to  be  observed  to  avoid  contamination  of  the material or any deterioration in its quality,
• The quantity of samples to be taken,
• Instructions for any required sub-division or poling of the samples,
• The types of sample containers to be used,
• Any specific  precautions  to  be  observed,  especially  in  regard  to sampling of sterile and hazardous materials.
  • Batch Numbering. –
    • There shall be Standard Operating Procedures describing the details of the batch (lot) numbering set up with the objective of ensuring that each batch of intermediate, bulk or finished product is identified with a specific batch number.
    • Batch numbering Standard Operating Procedures applied to a processing stage and to the respective packaging stage shall be same or traceable to demonstrate that they belong to one homogenous mix.
    • Batch number allocation shall be immediately recorded in a logbook or by electronic data processing system. The record shall include date of allocation, product identity and size of batch.
  • Testing:
    • There shall  be  written  procedures  for  testing  materials  and  products  at different stages of manufacture, describing the methods and equipment to be used. The tests performed shall be recorded.
  • Records of Analysis. –
    • The records shall include the following data:

1. Name of the material or product and the dosage form
2. Batch number and, where appropriate the manufacturer and/ or supplier,
3. Reference to the relevant specifications and testing procedures,
4. Test results, including observations and calculations, and reference to any specifications (limits),
5. Dates of testing,
6. Initials of the persons who performed the testing,
7. Initials of   the   persons   who   verified   the   testing   and   the   detailed calculations,
8. A statement of release or rejection, and
9. Signature and date of the designated responsible person
   • There shall  be  written  standard  operating  procedures  and  the  associated records of actions taken for:
10. Equipment assembly and validation
11. Analytical apparatus and calibration,
12. Maintenance, cleaning and sanitation;
13. Personnel matters including qualification, training, clothing, hygiene
14. Environmental monitoring;
15. Pest control;
16. Complaints;
17. Recalls made; and
18. Returns received.

1.  Reference Samples. –

• Each lot of every active ingredient, in a quality sufficient to carryout all the tests, except sterility and pyrogens / Bacterial Endotoxin Test, shall be retained for a period of 3 months after the date of expiry of the last batch produced from that active ingredient.
• Samples of finished formulations shall be stored in the same or simulated containers in which the drug has been actually marketed.

1.  Reprocessing and Recoveries. –

• Where reprocessing  is  necessary,  written  procedures  shall  be  established and  approved  by the  Quality Assurance  Department  that  shall  specify the conditions and      limitations of repeating chemical reactions. Such reprocessing shall be validated.
• If the product batch has to be reprocessed, the procedure shall be authorized and    An   investigation   shall   be   carried out   into   the causes necessitating re-processing and appropriate corrective measures shall be taken for prevention of recurrence. Re-processed batch shall be subjected to stability evaluation.
• Recovery of the product residue  may  be  carried  out,  if  permitted,  in  the master  production  and  control records by incorporating it in  subsequent batches of the product.

1.  Distribution records:

• Prior to distribution or dispatch of given batch of a drug, it shall be ensure that the  batch  has  been  duly tested,  approved  and  released  by the  quality control    Pre-dispatch  inspection  shall  be  performed  on  each consignment  on  a  random  basis  to  ensure  that  only the  correct  goods  are dispatched.  Detailed  instructions  for  warehousing  and  stocking  of  Large Volume Parenterals, if stocked, shall be in existence and shall be complied with   after   the   batch   is   released   for   distribution.   Periodic   audits   of warehousing practices  followed at distribution centers shall be  carried out and  records  thereof  shall  be  maintained.  Standard  Operating  Procedures shall be developed for warehousing of products.
• Records for distribution shall be maintained in a manner such that finished batch of  a  drug  can  be  traced  to  the  retain  level  to  facilitate  prompt  and complete recall of the batch, if and when necessary.

1.  Validation and process validation. –

• Validation studies   shall   be   an   essential   part   of   Good   Manufacturing Practices and shall b conducted as per the pre-defined protocols. These shall include validation of processing, testing and cleaning procedures.
• A written report summarizing recorded results  and  conclusions  shall  be prepared, documented and maintained.
• Processes and  procedures  shall  be  established  on  the  basis  of  validation study and undergo periodic revalidation to ensure that they remain capable of  achieving  the  intended    Critical processes shall  be  validated, prospectively for retrospectively.
• When any new Master Formula or method of preparation is adopted, steps shall be taken to demonstrate its suitability for routine processing. The defined process, using the materials  and  equipment  specified  shall  be demonstrated to yield a product consistently of the required quality.
• Significant changes to the manufacturing process, including any changes in equipment or   materials   that   may   affect   product   quality   and/or   the reproducibility of the process, shall be validated.

1. Product Recalls. –

• A prompt and effective product recall system of defective products shall be devised for timely information of all concerned stockists, wholesalers, suppliers, upto the retail level within the shortest period. The licensee may make use of both print and electronic media in this regard.
• There shall  be  an  established  written  procedure  in  the  form  of  Standard Operating  Procedure  for  effective  recall  of  products  distributed  by  the licensee. Recall operations shall be capable of being initiated promptly so as to effectively reach at the level of each distribution channel.
• The distribution  records  shall  be  readily  made  available  to  the  persons designated for recalls.
• The designated   person   shall   record   a   final   report   issued,   including reconciliation between the delivered and the recovered quantities of the products.
• The effectiveness  of  the  arrangements  for  recalls  shall  be  evaluated  from time to time.
• The recalled products shall be stored separately in a secured segregated area pending final decision on them.

1.  Complaints and Adverse Reactions.

• All complaints   thereof   concerning   product   quality   shall   be   carefully reviewed and recorded according to written procedures.  Each  complaint shall be investigated /evaluated by the designated personnel of the company and  records  of  investigation  and  remedial  action  taken  thereof  shall  be maintained.
• Reports of serious adverse drug reactions resulting from the use of a drug along with comments and documents shall be forthwith reported to the concerned licensing authority.
• There shall be written procedure describing the action to be taken, recall to be made of the defective product.

1.  Site Master File. –The licensee shall prepare a succinct document in the form of Site Master File containing specific and factual Good Manufacturing Practices about the production and/or control of pharmaceutical manufacturing preparations carried out at the licensed premises. It shall contain the following: –

• General information, –

1. Brief information of the firm;
2. Pharmaceutical manufacturing   activities   as   permitted   by   the   licensing authority;
3. Other manufacturing activities, if any, carried out on the premises;
4. Type of  product  licensed  for  manufacture  with  flow  charts  mentioning procedure and process flow;
5. Number of  employees  engaged  in  the  production,  quality  control,  storage and distribution;
6. Use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis;
7. Short description of the Quality Management System of the firm; and
8. Products details registered with foreign countries.
9. Organizational chart   showing   the   arrangement   for   quality   assurance including production and quality control;
10. Qualification, experience and responsibilities of key personnel;
11. Outline for  arrangements  for  basic  and  in-service  training  and  how  the records are maintained;
12. Health requirements for personnel engaged in production; and
13. Personal hygiene requirements, including clothing.
14. Simple plan or description of manufacturing areas drawn to scale;
15. Nature of construction and fixtures/fittings;
16. Brief description  of  ventilation    More  details  should  be  given  for critical  areas  with  potential  risk  of  airborne  contamination  (schematic drawing of systems). Classification of the rooms used for the manufacture of sterile products should be mentioned;
17. Special areas for the handling of the highly toxic, hazardous and sensitizing materials;
18. Brief description   of   water   system   (schematic   drawings   of   systems), including sanitation; and
19. Description of planned preventive maintenance programs for premises and of the recording system.
20. Brief description  of  major  equipment  used  in  production  and  Quality Control Laboratories (a list of equipment required);
21. Description of planned preventive maintenance programs for equipment and of the recording system; and
22. Qualification and calibration including the recording systems and arrangements for computerized systems validation
    • –

• Availability of written specifications and procedures for cleaning manufacturing areas and equipment

            Documentation. –

1. Arrangements for the preparation, revision and distribution of;
2. Necessary documentation for the manufacture;
3. Any other  documentation  related  to  product  quality  that  is  not  mentioned elsewhere (e.g. microbiological controls about air and water).
4. Brief description of production operations using, wherever possible, flow sheets and charts specifying important parameters;
5. Arrangements for  the  handling  of  starting  materials,  packaging  materials, bulk  and  finished  products,  including  sampling,  quarantine,  release  and storage;
6. Arrangements for the handling of rejected materials and products; and
7. Brief description of general policy for process validation
   • Quality Control. –

• Description of the quality control system and of the activities of the Quality Control Department. Procedures for the release of the finished products.
  • Loan licence manufacture and licensee. –

1. Description of the   way  in  which   compliance   of  Good  Manufacturing
2. Practices by the loan licensee shall be assessed.
   • Distribution, complaints and product recall. –
3. Arrangements and recording system for distribution; and
4. Arrangements for handling of complaints and product recalls
   • Self-inspection. –

• Short description  of   the  self-inspection  system  indicating  whether   an outside,  independent  and  experienced  external  export  was  involved  in evaluating   the   manufacturer is   compliance   with   Good   manufacturing Practices in all aspects of production.
  • Export of drugs. –

1. Products exported to different countries; and
2. Complaints and product recall, if any.

Source: CDSCO, Ministry of Health and Family Welfare, Govt. of India

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