The development of a drug product is a lengthy process involving drug discovery, laboratory testing, animal studies, clinical trials and regulatory registration.To further enhance the effectiveness and safety of the drug product after approval, many regulatory agencies such as the United States Food and Drug Administration (FDA) also require that the drug product be tested for its identity, strength, quality, purity and stability before it can be released for use. For this reason, pharmaceutical validation and process controls are important in spite of the problems that may be encountered1. Process controls include raw materials inspection, in-process controls and targets for final product. The purpose is to monitor the on-line and off-line performance of the manufacturing process and then validate it. Even after the manufacturing process is validated, current good manufacturing practice also requires that a well written procedure for process controls is established to monitor its performance2. This paper provides an overview of pharmaceutical validation and process controls in drug development. The validation concept can be applied to new drugs, new dosage forms and generic drug development.
Essentials of Pharmaceutical ValidationValidation is an integral part of quality assurance; it involves the systematic study of systems, facilities and processes aimed at determining whether they perform their intended functions adequately and consistently as specified. A validated process is one which has been demonstrated to provide a high degree of assurance that uniform batches will be produced that meet the required specifications and has therefore been formally approved. Validation in itself does not improve processes but confirms that the processes have been properly developed and are under control3. Adequate validation is beneficial to the manufacturer in many ways:
- It deepens the understanding of processes; decreases the risk of preventing problems and thus assures the smooth running of the process.
- It decreases the risk of defect costs.
- It decreases the risk of regulatory noncompliance.
- A fully validated process may require less in-process controls and end product testing.
- Totally new process
- New equipment
- Process and equipment which have been altered to suit changing priorities and
- Process where the end-product test is poor and an unreliable indicator of product quality.
Major Phases in ValidationThe activities relating to validation studies may be classified into three:
Phase 1:This is the Pre-validation Qualification Phase which covers all activities relating to product research and development, formulation pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions and storage, and handling of in-process and finished dosage forms, equipment qualification, installation qualification, master production document, operational qualification and process capacity.
Phase 2:This is the Process Validation Phase. It is designed to verify that all established limits of the critical process parameter are valid and that satisfactory products can be produced even under the worst conditions.
Phase 3:Known as the Validation Maintenance Phase, it requires frequent review of all process related documents, including validation of audit reports, to assure that there have been no changes, deviations, failures and modifications to the production process and that all standard operating procedures (SOPs), including change control procedures, have been followed. At this stage, the validation team comprising of individuals representing all major departments also assures that there have been no changes/deviations that should have resulted in requalification and revalidation. A careful design and validation of systems and process controls can establish a high degree of confidence that all lots or batches produced will meet their intended specifications. It is assumed that throughout manufacturing and control, operations are conducted in accordance with the principle of good manufacturing practice (GMP) both in general and in specific reference to sterile product manufacture5. The validation steps recommended in GMP guidelines can be summarized as follows:
- As a pre-requisite, all studies should be conducted in accordance with a detailed, pre-established protocol or series of protocols, which in turn is subject to formal – change control procedures.
- Both the personnel conducting the studies and those running the process being studied should be appropriately trained and qualified and be suitable and competent to perform the task assigned to them.
- All data generated during the course of studies should be formally reviewed and certified as evaluated against pre-determined criteria.
- Suitable testing facilities, equipment, instruments and methodology should be available.
- Suitable clean room facilities should be available in both the ‘local’ and background environment. There should be assurance that the clean room environment as specified is secured through initial commissioning (qualification) and subsequently through the implementation of a programme of re-testing – in-process equipment should be properly installed, qualified and maintained.
- When appropriate attention has been paid to the above, the process, if aseptic, may be validated by means of “process simulation” studies.
- The process should be revalidated at intervals and
- Comprehensive documentation should be available to define support and record the overall validation process6.
Process ValidationProcess validation is the means of ensuring and providing documentary evidence that processes (within their specified design parameters) are capable of repeatedly and reliably producing a finished product of the required quality5. It would normally be expected that process validation be completed prior to the release of the finished product for sale (prospective validation). Where this is not possible, it may be necessary to validate processes during routine production (concurrent validation). Processes, which have been in use for some time without any significant changes, may also be validated according to an approved protocol (retrospective validation) 6-13.
Pre-requisites for Process ValidationBefore process validation can be started, manufacturing equipment and control instruments as well as the formulation must be qualified. The information on a pharmaceutical product should be studied in detail and qualified at the development stage, i.e., before an application for marketing authorization is submitted. This involves studies on the compatibility of active ingredients and recipients, and of final drug product and packaging materials, stability studies, etc. Other aspects of manufacture must be validated including critical services (water, air, nitrogen, power supply, etc.) and supporting operations such as equipment cleaning and sanitation of premises. Proper
training and motivation of personnel are prerequisites to successful validation14-16.
Process validation decisionThe following model may be useful in determining whether or not a process should be validated:
Figure 1 - Process validation decision tree
The model shown describes a decision tree that a manufacturer can follow when deciding on whether a process needs to be validated. The process under consideration in this model is the simplest possible - many processes may be large and/or a complex set of sub-processes.
Each process should have a specification describing both the process parameters and the output desired. The manufacturer should consider whether the output can be verified by subsequent monitoring or measurement (A). If the answer is positive, then the consideration should be made as to whether or not verification alone is sufficient to eliminate unacceptable risk and is a cost effective solution (B). If yes, the output should be verified and the process should be appropriately controlled (C). If the output of the process is not verifiable then the decision should be to validate the process (D); alternatively, it may become apparent that the product or process should be redesigned to reduce variation and improve the product or process (E). Also, a change in a manufacturing process may result in the need for process validation even though the process formerly only required verification and control. The risk or cost may also be reduced by redesigning the product or process to a point where simple verification is an acceptable decision (E).
The Pharmaceutical Process EquipmentThe key idea of validation is to provide a high level of documented evidence that the equipment and the process conform to a written standard. The level (or depth) is dictated by the complexity of the system or equipment. The validation package must provide the necessary information and test procedures required to provide that the system and process meet specified requirements. Validation of pharmaceutical process equipment involves the following:
- Component Operational Qualification, of which calibration can be considered a large part.
- System Operational Qualification to determine if the entire system operates as an integrated whole.
Process Performance Qualification
Conclusion:It is necessary, before approval of a new drug, that an accurate and reliable assessment for its effectiveness and safety for the intended indication and target patient population is demonstrated. Pharmaceutical validation which includes assay validation, cleaning validation, equipment validation as well as the overall process validation is crucial in stability analysis, animal studies and early phases of clinical development such as bioavailability/bioequivalence studies. After the drug is approved, pharmaceutical validation and process control are necessary to ensure that the drug product will meet/set pharmaceutical standards for identity, strength, quality, purity, stability, evaluation safety and efficacy. In general, pharmaceutical validation and process control provide a certain assurance of batch uniformity and integrity of the product manufactured.
References:1. Sharp JR. The Problems of Process Validation. Pharm J 1986; 1:43-5.
2. Chow S. Pharmaceutical Validation and Process Controls in Drug Development. Drug Inf J 1997; 31: 1195-201.
3. Committee on Specifications for Pharmaceutical Preparations. Good Manufacturing Practices for Pharmaceutical Products. WHO Technical Report Series no. 82. Geneva: World Health Organization, 1992, pp 14-79.
4. South African Guide to Good Manufacturing Practice. Pretoria: Medicines Control Council, 1996. http://www.pharmanet.co.za/mcc /inpectorate/ins-71998.htm .
5. Guide to Inspections of Oral Solid Dosage Forms Pre/Post Approval Issued for Development and Validation. WashingtonDC: US Food and Drug Administration, 1994.
6. Therapeutics Products Programme. Process Validation: Aseptic Processes for Pharmaceuticals. http://www.hc-sc.gc.ca/hpbdgps/ therapeutic; downloaded March 30, 2001.
7. Rosendale DM. Process Equipment 1990. www.vectorcorporation.com/download/val_in terphex.
8. Cleaning Validation in Active Pharmaceutical Ingredient Manufacturing Plants. Brussels: Active Pharmaceutical Ingredients Committee. http://www.apic.cefic.org/pub4cleaningval/1999pdf; downloaded September 1999.
9. Guide to Inspections Validation of Cleaning Processes. WashingtonDC: US Food and Drug Administration. http://www.fda.gov/ora/inspect _ref/igs/valid.html.
10. Cleaning Validation Guidelines. Ottawa, Canada: Health Products and Food Branch Inspectorate, Health Canada, May 2000, p 11.
11. Harder SW. The Validation of Cleaning Procedures. Pharm Technol 1984; 8(5): 29-34.
12. Jenkins KM, Vanderwielen AJ. Cleaning Validation: An Overall Perspective. Pharm Technol 1994; 18(4): 60-74.
13. United States Pharmacopoeia and the National Formulary XXIII, 18th ed,. Rockville, MD: The United States Pharmacopoeia Convention Inc., 1995, pp 1982 – 1984.
14. Chapman GM, Amer G, Boyce C, Brower G, Green C, Hall WE, Harpaz D, Mullendore B. Proposed Validation Standard VS1: Non-aseptic Pharmaceutical Processes. J Val Technol 2000; 6:502-20.
15. LeBlane DA. Establishing scientifically justified acceptance criteria for cleaning validation of finished drug product. Pharm Technol 1998; 23(10): 136-48.
16. WHO Expert Committee on Specifications for Pharmaceutical Preparations, 34th Report. WHO Technical Report Series no. 863, Annex 6, Geneva: WHO, 1966, pp 80-96.
17. Good Manufacturing Practices for Pharmaceutical Products, WHO/Pharm./93.562/Annex: Guidelines on Validation of Manufacturing Process. Geneva: WHO.