GMP IN PERMISES: DESIGN,CONSTRUCTION, MAINTENANCE & EQUIPMENT

YUB RAJ NEUPANE M.PHARMA,SEM II PHARMACEUTICS JAMIA HAMDARD,NEW DELHI

GMP is.
.. that part of Quality Assurance which ensure that products are consistently produced and controlled to the quality standards appropriate to their use. GMP is an integral part of Quality Assurance

QA

GMP

QC

Basic Principle of GMP

Quality, safety and efficacy must be designed and built in the product. Testing alone cannot be relied on to ensure quality. Each step in the manufacturing process must be controlled to ensure that the final product lies within limits and specifications.

Why is GMP necessary?

Customer Protection & Satisfaction

Employee Protection
Fulfilling Legal Requirements Good Business Practice Pride in Workplace

Basic Requirements for GMP

Clearly defined and systematically reviewed processes. Critical steps validated. Appropriate resources: personnel, buildings, equipment, materials. Clearly written procedures. Trained operators. Complete records, failure investigations. Recall system. Complaint handling.

Food and Drug Administration : GMP

Code of Federal Regulations (Title 21)
Title 21, Code of Federal Regulations (21 CFR) is updated April 1 of each year.

The current edition contains nine volumes.

1) 21 CFR 1-99. General regulations for enforcement of the FFDC (Federal Food, Drug and Cosmetic ) Act and the Fair Packaging and Labeling Act. Color additives.

2) 21 CFR 100-169. General regulations for food labeling (contains the new regulations for nutrition labeling). Infant formula quality control procedures and labeling. Food standards and quality standards for bottled drinking water. The CGMP regulations for food, bottled drinking water, low-acid canned foods, and acidified foods.

3) 21 CFR 170-199. Food additives.

4) 21 CFR 200-299. General regulations for drugs.

5) 21 CFR 300-499. Drugs for human use. 6) 21 CFR 500-599. Animal drugs, feeds, and related products. 7) 21 CFR 600-799. Biologics and cosmetics.

8) 21 CFR 800-1299. Medical devices, radiological health, and control of communicable diseases. Import Milk Act, Federal Tea Importation Act, and Federal Caustic Poison Act.
9) 21 CFR 1300-End. Regulations implementing the Controlled Substances Act and the Controlled Substances Import and Export Act.

Under the 4 th volume:

Part 210: GMP in Manufacturing, Processing, Packing, or Holding of Drugs; General

Part 211: GMP for Finished Pharmaceuticals.

INTRODUCTION
A draft of GMP regulations was prepared in 1975 which was implemented in 1988 in the form of amended Schedule M. GMPs form the heart of quality. GMPs comprises a set of practices that ensures quality at every level of operation in an industry. GMPs provide quality assurances that off-the-shelf testing cant.

GMPs are more immediate and consistent way to control quality.

Virtually every manufacturer adheres to in-house GMP std. but now embracing on industrial std GMPs.

Subparts of Schedule-M
Subpart: A Finished Pharmaceuticals: General Provision B Organization and Personnel C Building and Facilities D Equipments E Control of Components and Drug Product Container and Closure F Production and Process Control G Packaging and Labeling Control H Holding and Distribution I Laboratory Control J Records and Report

SUBPART-C and D

Premises
Principle Principle PremisePrinciple Premises must be loPrinciple Premiseslocated, designed, constructed, adapted and maintained forconstructed, Premises must be must be located, designed, the operations: Minimize risks of errors and cross-contamination adapted and maintained for the operations: Permit effective cleaning Permit effective maintenance Minimize build-up dirt and dust Minimizeofrisks on quality Eliminate any adverse effects of errors and cross cated, designed, constructed, adapted and maintained for the operations: contamination and cross-contamination Minimize risks of errors Permit effective cleaning Permit effective maintenance Permit effective cleaning Minimize build-up of dirt and dust Eliminate any adverse effects on quality s must be located, designed, constructed, adapted and maintained for the operations: Permit effective maintenance Minimize risks of errors and cross-contamination Permit effective cleaning Minimize build-up of dirt and dust Permit effective maintenance Minimize build-up of dirt and dust Eliminate any adverse effects on quality Eliminate any adverse effects on quality

Principle Premises must be located to minimize risks of crosscontamination; e.g. not located next to a malting factory with high airborne levels of yeast

Location

Geography, climate, noise and economic factors Neighbours

What do they do? What impact can they have on the business?

Pollution/effluent control

Premises should be built to: Facilitate sanitation. Be maintained and cleaned easily Services availability Protection against entry of insects or other animals

Specific areas
Storage areas

Weighing areas
Production areas

Quality control areas

Ancillary areas (change rooms, toilet facilities, sampling, Rest and refreshment rooms )

Storage areas Appropriate temperature and relative humidity conditions within defined limits Provided, controlled, monitored and recorded Good storage conditions: clean, dry and appropriate lights Separate area for narcotics in locked room.

Weighing areas:
Weighing operations in separated areas Appropriate design (see also training material on HVAC) Provision for dust control Smooth, impervious, durable, easy-to-clean finishes

Cleaning procedures and records

Documentation, e.g. SOPs, logs and records

Design of areas for weighing of materials

Proper air supply Dust control measures (including extraction of dust and air) Easily cleanable surfaces No areas for dust accumulation Protection of material, product and operator

Manufacturing and Packaging I

Dedicated and self-contained facilities for: Logical flows of materials and people Adequacy of working space and orderly and logical positioning of equipment Interior surfaces smooth/crackfree/easy to clean

 Aseptic processing, which includes as appropriate:

(i) floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable; (ii) temperature and humidity controls; (iii) an air supply filtered through high-efficiency particulate air (HEPA) filters under positive pressure, regardless of whether flow is laminar or nonlaminar; (iv) system for monitoring environmental conditions; (v) system for cleaning and disinfecting the room and equipment to produce aseptic conditions; (vi) system for maintaining any equipment used to control the aseptic conditions.

 Operations relating to the manufacture, processing, and packing of penicillin shall be performed in facilities separate from those used for other drug products for human use.

Other Areas Personnel rest areas/cafeterias/changing rooms

away from operating areas prevention of cross-contamination prevention of operators going outside in work clothes provision of access control prevention of visitors access to operating areas

Maintenance service areas

separated from production areas whenever possible

Finish of Floors, Walls and Ceilings

Difficult but not impossible to get right, smooth, impervious, hardwearing, easy to clean; but not bricks, tiles, wood or sliding doors!

Not These

Finishing of floors, walls and ceilings

These pictures illustrate a much better approach to achieving smooth, impervious durable surfaces for floors, walls and ceilings. The light fixtures fit flush with the ceiling, the floor uses welded vinyl which is covered to the wall face are very smooth and easy to clean and there are no gaps

 Methods to reduce cross-contamination : 1. 2. 3. 4. 5. 6. 7. 8. Segregated areas Airlocks and pressure differentials Treatment of re-circulated air Protective clothing Effective cleaning procedures Closed production systems Residue testing Status labelling

Manufacturing and Packaging I Pipe work and other fittings sited to avoid recesses Drain design:
equipped to prevent backflow open channels avoided

Effective air handling to suit product

temperature humidity filtration monitoring

Manufacturing and Packaging II Specifically designed and laid out to avoid mixups and cross-contamination
Changing facilities to provide segregated access

Prevention of cross-contamination Suitable lighting levels

MAINTENANCE
Cracks and holes in walls, floors, or ceilings can provide access for insects, rodents, birds, dirt, or microorganisms. Adequately drain areas that may contribute to contamination of food by food borne filth, or provide conditions for nesting and breeding of for pests;

Operate systems for waste treatment and disposal in an adequate manner.

In-Process and QC laboratories

Located separate from but near manufacturing
prevention of cross-contamination
separate biological , microbiological, radioisotopic areas

Designed for the operations being carried out

suitable storage space

Equipment (Subpart D)
EQUIPMENT DESIGN, SIZE, AND LOCATION: used shall be of: appropriate design, adequate size, suitably located constructed materials shouldnt be reactive, additive, absorptive

 lubricants or coolants, shall not come into contact with components, drug product containers, closures, in-process materials, Records shall be kept for maintenance, cleaning, sanitizing, and inspection as specified in 211.180 and 211.182.

References
Good manufacturing practices for pharmaceutics. A Plan for total quality control 4th edition, Revised & Expanded Vol. 78, Sidney H. willing James R Stoker, page 33-51 Quality assurance of pharmaceuticals A compendium of guidelines and related materials Volume 2, 2nd updated edition Good manufacturing practices and inspection-WORLD HEALTH ORGANISATION
Encyclopedia of PHARMACEUTICAL TECHNOLOG Third Edition VOLUME 1, James Swarbick, page 1941 http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/ CurrentGoodManufacturingPracticesCGMPs