1 the compatibility of other manufacturing operations that may be carried out in the same or adjacent premises 2 allow the production to take place in areas connected in a logical order according to the sequence of the operations and to the requisite cleanliness levels 3 the adequacy of the working space, which shall allow orderly and logical placement of equipment and materials to suit the operation, efficient flow of work, effective communication and supervision to avoid crowding and disorder 4 avoid the use of production areas as a general traffic for personnel or materials or for storage other than the materials in process.

The layout of rooms, corridors, and spaces shall provide for logical movements of materials and personnel with minimal traffic for operations to be carried out in defined areas and to avoid cross contamination. The design and layout of premises shall fulfill the following requirements:

1 the risk of mix-up between different drugs or their components, the possibility of cross-contamination by other drugs or substances and the risk of omission of any production step shall be prevented 2 penicillins shall be produced only in separate buildings, with separate air handling facilities dedicated to these products using dedicated equipment, including dedicated packaging lines. 3 cephalosporins shall be produced in separate buildings, with separate air handling facilities dedicated to these products using dedicated equipment, including dedicated packaging lines 4 cross contamination of products should be prevented

Cross contamination of products by live biologicals, or by drug products, such as certain steroids or cytotoxic agents which in trace amounts may produce physiological effects should be prevented by the following methods:

1 carrying out production operations in separate buildings or adequately isolating the operations by total enclosure 2 controlling airborne contaminants by the use of an appropriate air pressure differential in processing areas and adequate exhaust systems and filters, together with control of recirculated air 3 the setting and shielding of production equipment, and wherever possible, the use of equipment solely for one type of drug/product; 4 containment of contaminant-transfer by means of airlocks, clothing change and decontamination of containers and other articles prior to their removal from the isolated area 5 separate cleaning area for contaminated clothing 6 periodic testing of the environment around the production areas for the presence of the therapeutic substance being processed and 7 validation of cleaning procedures.

Separate space for:

1 Cleaning mobile equipment 2 Storage of cleaning materials

Defined areas for the following operations are required:

1 gowning/change rooms for all personnel 2 receiving of starting materials 3 incoming goods quarantine 4 sampling room for sampling of deliveries of starting materials 5 storage for approved materials (chemical & packaging) 6 storage of reject materials 7 laboratories 8 weighing / dispensing of materials 9 processing operations 10 equipment washing 11 storage of cleaned, idle/non-functional equipment 12 major repair and maintenance activities 13 storage of cleaning tools and supplies 14 staging/storage of bulk products 15 packaging / labeling operations (+5 MORE)

Storage areas shall be of adequate space, provided with suitable lighting, arranged and equipped to allow dry, clean and orderly placement of stored materials and products. :

1 Special and secured areas shall be available for storage of flammable and explosive substances, highly toxic substances, narcotics and other dangerous drugs. 2 Storage areas shall be laid-out to permit effective and orderly segregation of the various categories of materials stored to allow FIFO system. 3 Segregated storage shall be provided for rejected, recalled or returned goods. 4 Storage arrangements shall permit separation of different labels, as well as other printed materials to avoid mix-up. 5 Materials require special storage conditions such as temperature and/or humidity controls. These conditions should be monitored and records of the monitoring retained.

A complete set of activities to produce drugs from start to finish to produce a product

Manufacturing

Manufacturing vs Compounding

Manufacturing is a LARGE SCALE production Compounding is a SMALL SCALE production Both produces drugs

Any substance used for treatment, mitigation & diagnosis

Drugs

Any organization involved in manufacturing, importing, packaging and distribution of drugs

Drug Establishment

Included here are prescription drugs (google: achieved when the manufacturing process prioritizes good health for all parties involved, including the environment, workers, and consumers)

Ethical manufacturing

Included here are vaccines, toxoids, serums (google: the use of biological systems that have been engineered, or that are used outside their natural context, to produce a product)

Biological manufacturing

Included here are Branded or generic drugs

Proprietary/Generic Manufacture

Included here are Medicinal products

Medicinal manufacture

Included here are Animal drug products

Veterinary manufacture

Sole owner of products.

Traders

Hired manufacturing firm by traders – sole owner of products.

Toll / Contract Manufacturing

Drug Establishments:

1 Drug manufacture 2 Drug importer 3 Drug exporter 4 Drug traders 5 Drug supplier 6 Drug distributor/wholesale time sd

Drugs transported from outside countries to the Philippines

Drug importer

Local drugs transported internationally

Drug exporter

Transports raw materials to local places.

Drug distributor/wholesale

Departments of Drug Establishments

1 Marketing Department 2 Research Department 3 Production Department 4 Quality Control Department: SARS 5 Engineering Department 6 Purchase Department 7 Medical Department

Main role is PRODUCT POSITIONING (put products in consumers’ minds ) - Spying other company - Promotes products; Responsible of marketing products - Ads; conventions

Marketing Department

- Main role: formulate, improve drug products - Facilities: library, pilot plant, animal house

Research Department

Main roles:  Manufacture and production  Warehousing  Acceptance of new materials

Production Department

- Ensures public safety - Areas: Raw Materials QC, Intermediate Products QC, Finished Products QC - Sampling

Quality Control Department: SARS

Role: Purchase; inventory

Purchase Department

- Preclinical and clinical studies - Physical exams of employees - Treatment of employees - Make package inserts

Medical Department

Drug Discovery Process

1 New chemical entity -> 2 Preclinical studies -> 3 IND application -> 4 Clinical trials and Preclinical studies (continued) -> 5 NDA (New Drug Application) application -> 6 Post-marketing

- Initial synthesized entity tested on animals - Study of the ADME

Preclinical Studies

Start of approval for clinical trials

IND Application

Phase 1

- 20-100 healthy individuals - Test: Safety and dosage - Know how the treatment is given - Period: Months - 1 year

Phase 2

- 100-200 individuals with diseases - Test: Efficacy and side-effects – degree on how a drug can prevent or treat a disease - Know the route and dosage form of drug

Phase 3

- 1000+ individuals with the target disease - Test: Efficacy in a normal clinical condition - Know how to achieve better bioavailability

Phase 4

Post-marketing

Final drug product without the packaging

Intermediate product

Final drug product with the packaging

Finished product

Current Good Manufacturing Practices for Drugs What Law?

(A.O. 43, Series of 1999)

Part of QA which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use (WHO, 2007). System of QA aimed at ensuring that products are consistently manufactured to a quality appropriate for their intended use and is concerned with both manufacture and QC processes and procedures (A.O. 43, s. 1999).

Good Manufacturing Practices

Sulfonilamide Elixir tragedy year

1937

US FDA year

1939

Thalidomide tragedy year

1952

GMP year

1956

BFAD year

1974

1 Why is cGMP important? 2 What is the objective of cGMP?

1) 1 To preserve the identity, strength, quality and purity of drugs. 2 To ensure the safety of personnel and patients. 2) 1 Prescribe standard guidelines in the manufacture of drug products. 2 Ensure that no person or establishment shall manufacture drugs under substandard conditions

Equipment used in the manufacturing of drug products shall be of appropriate __, __ and suitably __ in order to assure product quality and process reproducibility and to facilitate its cleaning and maintenance.

1 design and construction 2 adequate size 3 located

The design and construction of equipment shall fulfill the following requirements:

1 the equipment surfaces coming in contact with any material shall not be reactive, additive or absorptive so as to alter safety, strength, identity, quality or purity of the drug beyond the established limits 2 equipment shall not adversely affect the product through leaking valves, lubricant drips, inappropriate repairs, maintenance, modifications or adaptations 3 materials required for specific operations, such as lubricants or coolants shall not come into contact with any in-process materials as to alter the strength, safety, identity, quality, or purity of raw material, intermediate, bulk or the finished product 4 equipment shall be easily and conveniently cleanable 5 all equipment designated for use with flammable substances or chemicals shall be explosion proof 6 equipment employed for weighing, measuring, testing and recording shall be regularly checked for accuracy and calibrated according to an appropriate program and procedure; records shall be maintained. 7 filters for liquid filtration used in the processing of products shall not release fibers or substances into such products.

Installation and Location

1 Equipment shall be suitably installed and located to eliminate cross-contamination 2 Equipment shall be located at a sufficient distance from other equipment to avoid congestion and to ensure that products do not become admixed or confused with one another. 3 All open mechanical belts and pulleys shall be equipped with safety guards. Water, steam and pressure or vacuum lines shall be installed so as to be easily accessible during all phases of operation. These shall be adequately labeled and marked to be easily recognized. 4 Each piece of equipment shall be clearly marked with an identifying number. 5 All pipes, tanks, jackets for steam or coolant shall be properly insulated to prevent possible injury and to minimize energy loss. 6 Piping to equipment designated for use with the pressurized steam shall be properly trapped and drained. 7 Heating, ventilation, air conditioning, potable water, purified water, distilled water, clean steam, compressed air, gases and other support systems must undergo validation.

The complete set of activities to produce a drug that comprise production and quality control from dispensing of materials to the release for distribution of the finished product.

Manufacture or Manufacturing

Instrument, apparatus, or contrivances, including their components, parts and accessories, intended (1) for use in the diagnosis, cure, mitigation, or prevention of disease in man and animals; or (2) to affect the structure or any function of the body of man or animal.

Device

A date fixed for each individual batch on or before which the batch is expected to meet the standard specifications for quality, safety and efficacy.

Expiration Date

For Blood Products: Any area used for the collection, processing, compatibility testing, storage or distribution of blood and blood components. For Other Products (drugs, medical devices, bulk chemical material and others): This refers to the building, premises and equipment necessary in the manufacture of drugs.

Facilities

A product which has UNDERGONE ALL STAGES of manufacturing operations.

Finished Product

It is the SYSTEM of quality assurance aimed at ensuring that products are CONSISTENTLY MANUFACTURED to a quality appropriate for their intended use. It is thus concerned with both manufacturing and quality control processes and procedures.

Good Manufacturing Practice (GMP)

Contaminated with extraneous biological agents and therefore capable of spreading infection.

Infected ( Man or Animal)

CHECKS AND TESTS instituted and carried out IN THE COURSE OF THE MANUFACTURE of a drug to assure identity, strength, quality and purity.

In-Process Control