GMP Compliance

GMP) controls and inspection, although where appropriate these requirements should be complied with. Manufacture of the finished dosage form should always be GMP compliant. There are also proposals for GMP compliance for active ingredient manufacture, which have been submitted for comment by the Enterprise Directorate General and under the auspices of the Pharmaceutical Inspection Convention-Pharmaceutical Inspection Co-operation Scheme (PIC-PIC/S) and the ICH process. 

Schedule Y of the Drugs and Cosmetics Rules sets up the requirements for clinical trials, and that of Schedule M for GMP compliance system. 

Most of the information sought is similar to the FDA s IND requirements. One major difference is that a Qualihed Person has to certify that the investigational medicinal product (IMP) is manufactured according to GMP The Competent Authority has the right to inspect the manufacturing facility for GMP compliance, the preclinical facility for GLP compliance, and the clinical trial sites for GCP compliance. 

Source Adapted from Hofmann FK. GMP Compliance, Centre for Continuous Education, Vista, CA, 2001. 

Australia and the EC have entered into a Mutual Recognition Agreement (MRA) on conformity assessment of medicinal products. The TGA will accept a certificate of GMP compliance of a manufacturer issued imder this MRA by the official inspection services of the EU countries. This follows on from Australia s work over many years with the Pharmaceutical Inspection Convention, now known as the PIC/S. 

Perform general GMP compliance inspection. Review the potential for contamination and mix-ups thoroughly. 

Solution preparation area clearance before compounding including checks for the processing materials for availability, completeness, release, and per the approved material requisition Area temperature, humidity, and pressure differential verihcation Nonviable particulate monitoring of the solution preparation room Other GMP compliance checks, per manufacturing site... 

Unless a firm has previous experience with such audits, it is highly recommended that the firm assign responsibilities for PAI readiness, determine the PAI schedule, anticipate FDA needs, verify application integrity, and verify GMP compliance on their own before the visit. 

Even though full GMP compliance may begin later than receipt of raw materials, it is important to treat raw materials in a GMP compliant manner. Raw materials should be purchased only from suppliers approved by the Quality Unit. For raw materials whose quality is important to conformance of the excipient to compendial or specification requirements, or to performance expectations, the supplier approval process should be a combination of site visit and an evaluation of raw material quality. For other raw materials, it would be adequate to confirm that the raw material supplier can meet the purchasing specification. 

From the point in the process where full GMP compliance begins, the excipient should be produced in qualified equipment using a validated manufacturing process and testing should be done using validated methods. Where production equipment is not dedicated, validated cleaning methods are also needed. Full GMP compliance is required no later than the final excipient purification step or the manufacturing step where the excipient molecule has been synthesized, whichever occurs later in the process. 

Usually the master validation plan covers the processing steps that impact excipient quality from the point in the process where full GMP compliance begins. 

This chapter is meant as a survey of the manufacturing issues in the production of pharmaceutical excipients. As such many important decision points have been discussed. It is a basic tenet of GMP compliance and a principle of auditing that... 

Auditing the contract API manufacturer is important in order to assess the quality systems used to determine the integrity and quality capability of the firm, to determine their level of GMP compliance, and assess the level of resources available to meet preapproval inspections (PAI) and GMP compliance readiness. 

Vina, B. GMP Compliance, Productivity, and Quality. Interpharm Press (1998). 

Good manufacturing practice regulations identify what controls must be in place and adhered to in order to be in compliance, but do not provide instruction on how to implement these controls. The methods used to ensure the product meets its defined requirements are the responsibility of the pharmaceutical manufacturer, who must be prepared to demonstrate GMP compliance with validated systems and formal records. 

Providing documented evidence to achieve and maintain the validated status and uphold GMP compliance requires a systematic approach and rigorous controls throughout all phases of the computer system validation life cycle. Formal testing at key stages in the life cycle will provide records to demonstrate that predefined requirements have been met and that the computer system is fully documented. 

GMP compliance and validation training—to an appropriate level commensurate with the individual s job function... 

Change control—to ensure any change to the system—or to other equipment that may affect system use—is properly assessed, documented, and progressed with regard to GMP compliance and system validation... 

The pharmaceutical manufacturer must establish effective policies and plans for regulatory compliance and validation to enable individuals to clearly understand the company commitment and requirements. Computer validation planning should ensure an appropriate training program, preparation of validation guidelines and procedures, system GMP compliance risk and criticality assessment, a documented validation strategy and rationale, clearly defined quality-related critical parameters and data for the manufacturing process. 

The pharmaceutical manufacturer must ensure that personnel are trained to an appropriate level in GMP and validation planning and requirements to enable them to adequately perform their function. This applies to any resource used in connection with GMP compliance and validation life-cycle activities and documentation. A training program should be in place and individual training records maintained. The records and suitability of external resources used by suppliers or contractors should also be examined. 

Description of process/environment Quality-related critical parameters Purpose and objectives of the system Major benefits of the system Special requirements Specific training needs System operating strategy Related GMP compliance/regulations Physical and logical boundaries System GMP risk assessment System validation rationale Life-cycle documentation Assumptions and prerequisites Limitations and exclusions Quality-related critical parameters/data Standard operating procedures System requirement specification Supplier and system history... 

All levels of development testing for the computer system must be fully documented and provide test records in the form of approved test procedures, signed-off test result sheets, and reports. For system parameters, data, and functions that are critical to product quality and GMP compliance it is beneficial that the test procedures align with qualification test requirements, and record... 

Periodic reviews may also be prompted by reported or suspected problems with GMP compliance. When a periodic review determines a deviation from approved conditions or practices this must be investigated and corrective action approved. If there is a need to redocument or retest the computer system, then the need for revalidation must be assessed and the resulting rationale documented. 

There was not as much overlap as the group had expected. Regulators in the United States and Europe have found it necessary to concentrate on different areas of GMP compliance. 

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