Validation
has become one of the pharmaceutical industry’s most recognized and
discussed subjects. It is a critical success factor in product approval
and ongoing commercialization. This article provide brief introduction
about the pharmaceutical process validation and its importance according
to regulatory provision, also provide the answer
of question like why to do, when to do and how to do it. This work is
to present an introduction and general overview on process validation of
pharmaceutical manufacturing
process. Quality is always an imperative prerequisite when we consider
any product. Therefore, drugs must be manufactured to the highest
quality levels. End-product testing by itself does not guarantee the
quality of the product. Quality assurance techniques must be used to
build the quality into the product at every step and not just tested for
at the end. In pharmaceutical industry, Process Validation performs
this task to build the quality into the product because according to ISO 9000:2000, it had proven to be an important tool for quality management of pharmaceuticals.
THE REGULATORY BASIS FOR PROCESS VALIDATION
Once the concept of being able to predict process performance to meet user requirements evolved, FDA regulatory officials established that there was a legal basis for requiring process validation. The ultimate legal authority is Section 501(a)(2)(B) of the FD&C Act, which states that a drug is deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or were not operated or administrated in conformity with CGMP. Assurance must be given that the drug would meet the requirements of the act as to safety and would have the identity and strength and meet the quality and purity characteristics that it purported or was represented to possess. That section of the act sets the premise for process validation requirements for both finished pharmaceuticals and active pharmaceutical ingredients, because active pharmaceutical ingredients are also deemed to be drugs under the act.
The CGMP regulations for finished pharmaceuticals, 21 CFR 210 and 211, were promulgated to enforce the requirements of the act. Although these regulations do not include a definition for process validation, the requirement is implicit in the language of 21 CFR 211.100, which states: “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.”
Once the concept of being able to predict process performance to meet user requirements evolved, FDA regulatory officials established that there was a legal basis for requiring process validation. The ultimate legal authority is Section 501(a)(2)(B) of the FD&C Act, which states that a drug is deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or were not operated or administrated in conformity with CGMP. Assurance must be given that the drug would meet the requirements of the act as to safety and would have the identity and strength and meet the quality and purity characteristics that it purported or was represented to possess. That section of the act sets the premise for process validation requirements for both finished pharmaceuticals and active pharmaceutical ingredients, because active pharmaceutical ingredients are also deemed to be drugs under the act.
The CGMP regulations for finished pharmaceuticals, 21 CFR 210 and 211, were promulgated to enforce the requirements of the act. Although these regulations do not include a definition for process validation, the requirement is implicit in the language of 21 CFR 211.100, which states: “There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.”
THE REGULATORY HISTORY OF PROCESS VALIDATION
Although the emphasis on validation began in the late 1970s, the requirement has been around since at least the 1963 CGMP regulations for finished pharmaceuticals. The Kefauver-Harris Amendments to the FD&C Act were approved in 1962 with Section 501(a) (2) (B) as an amendment. Prior to then, CGMP and process validation were not required by law. The FDA had the burden of proving that a drug was adulterated by collecting and analyzing samples. This was a significant regulatory burden and restricted the value of factory inspections of pharmaceutical manufacturers. It took injuries and deaths, mostly involving cross-contamination problems, to convince Congress and the FDA that a revision of the law was needed. The result was the Kefauver–Harris drug amendments, which provided the additional powerful regulatory tool that FDA required to deem a drug product adulterated if the manufacturing process was not acceptable. The first CGMP regulations, based largely on the Pharmaceutical Manufacturers Association’s manufacturing control guidelines, were then published and became effective in 1963. This change allowed FDA to expect a preventative approach rather than a reactive approach to quality control. Section 505(d)(3) is also important in the implementation of process validation requirements because it gives the agency the authority to withhold approval of a new drug application if the “methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity.”
Another requirement of the same amendments was the requirement that FDA must inspect every drug manufacturing establishment at least once every 2 years. At first, FDA did this with great diligence, but after the worst CGMP manufacturing situations had been dealt with and violations of the law became less obvious, FDA eased up its pharmaceutical plant inspection activities and turned its resources to more important problems.
The Drug Product Quality Assurance Program of the 1960s and 1970s involved first conducting a massive sampling and testing program of finished batches of particularly important drugs in terms of clinical significance and dollar volume, then taking legal action against violative batches and inspecting the manufacturers until they were proven to be in compliance. This approach was not entirely satisfactory because samples are not necessarily representative of all batches. Finished product testing for sterility, for example, does not assure that the lot is sterile. Several incidents refocused FDA’s attention to process inspections. The investigation of complaints of clinical failures of several products (including digoxin, digitoxin, prednisolone, and prednisone) by FDA found significant content uniformity problems that were the result of poorly controlled manufacturing processes. Also, two large-volume parenteral manufacturers experienced complaints despite quality control programs and negative sterility testing. Although the cause of the microbiological contamination was never proven, FDA inspections did find deficiencies in the manufacturing process and it became evident that there was no real proof that the products were sterile. What became evident in these cases was that FDA had not looked at the process itself—certainly not the entire process—in its regulatory activities; it was quality control- rather than quality assurance-oriented. The compliance officials were not thinking in terms of process validation. One of the first entries into process validation was a 1974 paper presented by Ted Byers, entitled “Design for Quality”. The term validation was not used, but the paper described an increased attention to adequacy of processes for the production of pharmaceuticals. Another paper—by Bernard Loftus before the Parenteral Drug Association in 1978 entitled “Validation and Stability”—discussed the legal basis for the requirement that processes be validated.
The May 1987 Guideline on General Principles of Process Validation was written for the pharmaceutical, device, and veterinary medicine industries. It has been effective in standardizing the approach by the different parts of the agency and in communicating that approach to manufacturers in each industry.
Although the emphasis on validation began in the late 1970s, the requirement has been around since at least the 1963 CGMP regulations for finished pharmaceuticals. The Kefauver-Harris Amendments to the FD&C Act were approved in 1962 with Section 501(a) (2) (B) as an amendment. Prior to then, CGMP and process validation were not required by law. The FDA had the burden of proving that a drug was adulterated by collecting and analyzing samples. This was a significant regulatory burden and restricted the value of factory inspections of pharmaceutical manufacturers. It took injuries and deaths, mostly involving cross-contamination problems, to convince Congress and the FDA that a revision of the law was needed. The result was the Kefauver–Harris drug amendments, which provided the additional powerful regulatory tool that FDA required to deem a drug product adulterated if the manufacturing process was not acceptable. The first CGMP regulations, based largely on the Pharmaceutical Manufacturers Association’s manufacturing control guidelines, were then published and became effective in 1963. This change allowed FDA to expect a preventative approach rather than a reactive approach to quality control. Section 505(d)(3) is also important in the implementation of process validation requirements because it gives the agency the authority to withhold approval of a new drug application if the “methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity.”
Another requirement of the same amendments was the requirement that FDA must inspect every drug manufacturing establishment at least once every 2 years. At first, FDA did this with great diligence, but after the worst CGMP manufacturing situations had been dealt with and violations of the law became less obvious, FDA eased up its pharmaceutical plant inspection activities and turned its resources to more important problems.
The Drug Product Quality Assurance Program of the 1960s and 1970s involved first conducting a massive sampling and testing program of finished batches of particularly important drugs in terms of clinical significance and dollar volume, then taking legal action against violative batches and inspecting the manufacturers until they were proven to be in compliance. This approach was not entirely satisfactory because samples are not necessarily representative of all batches. Finished product testing for sterility, for example, does not assure that the lot is sterile. Several incidents refocused FDA’s attention to process inspections. The investigation of complaints of clinical failures of several products (including digoxin, digitoxin, prednisolone, and prednisone) by FDA found significant content uniformity problems that were the result of poorly controlled manufacturing processes. Also, two large-volume parenteral manufacturers experienced complaints despite quality control programs and negative sterility testing. Although the cause of the microbiological contamination was never proven, FDA inspections did find deficiencies in the manufacturing process and it became evident that there was no real proof that the products were sterile. What became evident in these cases was that FDA had not looked at the process itself—certainly not the entire process—in its regulatory activities; it was quality control- rather than quality assurance-oriented. The compliance officials were not thinking in terms of process validation. One of the first entries into process validation was a 1974 paper presented by Ted Byers, entitled “Design for Quality”. The term validation was not used, but the paper described an increased attention to adequacy of processes for the production of pharmaceuticals. Another paper—by Bernard Loftus before the Parenteral Drug Association in 1978 entitled “Validation and Stability”—discussed the legal basis for the requirement that processes be validated.
The May 1987 Guideline on General Principles of Process Validation was written for the pharmaceutical, device, and veterinary medicine industries. It has been effective in standardizing the approach by the different parts of the agency and in communicating that approach to manufacturers in each industry.
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