CMC Analytical Procedures and Methods Validation

Guidance for Industry: Analytical Procedures and Methods Validation—Chemistry, Manufacturing, and Controls Documentation

This draft guidance was released in August 2000 and is available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122858.pdf.

This guidance applies to applicants or sponsors who must file new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements to these applications, as well as those who file drug substance and drug product Type II drug master files (DMFs).

Laws and regulations referenced. Because this guidance relates to the broad areas of analytical procedures and methods validation to document the chemistry, manufacturing, and controls (CMC) section of applications, several laws and regulations are involved:

• 21 CFR 211.165(e)
• 21 CFR 211.194(a)(2) and (10)
• 21 CFR 312.23(a)(7)
• 21 CFR 314.50(d)(1) and (e)
• 21 CFR 314.94(a)(9)(i)
• 21 CFR 601.2 (a) and (c)(1)(iv)
• 21 CFR 610.20.

Broadly, this guidance refers to compliance with

• current Good Manufacturing Practices (cGMPs) (21 CFR part 211)
• Good Laboratory Procedures (GLPs) (21 CFR part 58)
• compendial procedures under section 501(g) of the Food, Drug, and Cosmetic Act.

The guidance also references other FDA guidances (among others listed in the References lines 1159 ff):

• Content and Format of Investigational New Drug Applications for Phase I Studies
• INDs for Phase 2 and 3 Studies of Drugs
• Validation of Chromatographic Methods.

The guidance references the International Conference on Harmonization (ICH) guidances (among other listed in the References lines 1190 ff):

• Q2 Text on Validation of Analytical Procedures
• Q2B Validation of Analytical Procedures: Methodology
• Q3Q Impurities in New Drug Substances.

Finally, by reference, the guidance cites the current version of the US Pharmacopeia–National Formulary (USP–NF).

Summary. Applicants, as defined above, must provide FDA with accurate and reliable documentation about analytical procedures and methods validation, along with samples, if appropriate, to ensure the identity, quality, purity, and potency of drug substances and drug products. Although this may at first seem straightforward, an applicant’s challenge is to show that, eg, clinical study batches of a drug substance and drug product used in 1-kg (or smaller) batches manufactured in, eg, New Jersey are equivalent to metric tons of hypothetically equivalent product manufactured years later in places as diverse as Puerto Rico, India, or China.

In order to achieve these goals, applicants use analytical procedures that comply with compendial guidelines (eg, chromatography, spectrophotometry, protein analysis, and others). These methods must be validated, which is defined as the “process of demonstrating that analytical procedures are suitable for their intended use.” Analytical procedures can include those specified in General Chapters of the current USP–NF, or they may be the applicant’s properly validated and approved methods. The former require only compliance, but the latter require full validation. That is, methods validation can be satisfied by demonstrating compliance with the current USP–NF methods or submission of a full validation package.

Rationale. In all cases, in the CMC sections of applications the applicant’s objective is to demonstrate that drug substances, drug products, excipients, and manufacturing are equivalent to or better than those identified in the applicant’s approved filing (NDA, ANDA, BLA, and so forth). If the applicant has changed materials, manufacturing site or procedures, or analytical technologies (among other changes), the applicant must demonstrate that drug substances and products retain acceptable identity, quality, purity, and potency.

Variations in a drug’s quality attributes can result from many factors (changes in active ingredient impurities, different excipients, different manufacturing equipment or procedures, and many others). After approval, clinical trials materials manufactured in small batches must be scaled up to production batches, and applicants must ensure that the approved product has at least the quality attributes of the approved product. This guidance helps applicants fulfill these requirements.

Resulting recommendations. Applicants must demonstrate that their analytical procedures and validation are under control and that their currently marketed products are equivalent to those in the approved application. Applicants can do so by showing compliance with regulatory/compendial procedures or validated alternative analytical procedures.

In effect, applicants may receive a bulk shipment of active pharmaceutical ingredient. This material must be tested by an assay to ensure its identity, quality, purity, and potency. The assay used is part of the sponsor’s application (NDA, ANDA, etc) and includes specification, defined as tests, procedures, and acceptance criteria. The tests may include, eg, chromatography carried out according to defined procedures involving type of column, reagents, and operating conditions, and predefined test criteria (eg, amount of active ingredient detected, impurity profile, and other characteristics).

If these tests follow the current USP–NF, the sponsor needs only to ensure that the assay was carried out in compliance with USP–NF. Such quality assurance is satisfied by documentation that analysts followed the compendial procedures. If the sponsor develops a new approach or varies from established compendial procedures, this sponsor must present detailed evidence, as outlined in this guidance, that the new assays or procedures are equivalent to or are better than USP–NF procedures.

An important component of demonstrating compliance with the approved application (NDA, ANDA, BLA, etc) is showing equivalence to a drug substance or drug product standard. The standard is either a sample of the sponsor’s reference material that, according to the guidance, is deposited with FDA and is also retained by the company as a house standard, or the applicant and FDA use a USP reference standard. In either case, the reference standard is a highly purified and qualified sample of the reference substance or product that is defined as the standard that shows drug substance or drug substance identity, quality, purity, and potency.

The guidance describes various quantitative tests for impurities, not all of which apply to a specific product. But the guidance is useful in helping applicants determine which tests they must perform, how often, and with what accuracy. In addition, because consistent quality is the objective, validation is an ongoing process that must be continuously monitored. Applicants must perform trend analysis to ensure that their processes, procedures, and activities are not drifting out of specification.

Impact. This guidance is a key document that shows applicants how they can demonstrate compliance with laws and regulations regarding analytical procedures and validated methods. Because each drug substance and drug product is unique, one can expect variation in types of analytical procedures, acceptance criteria, and validation from drug to drug (eg, innovator product vs generic drug or small molecules vs biotech products). As noted, the CMC section of applications helps ensure that regulators, manufacturers, and others can test drug substances and drug products meet standards of identity, quality, purity, and potency. This guidance does not speak to drug efficacy or mechanisms of action, but it does ensure that drug manufacturing is of consistent, well-defined quality.

[NOTE: This blog uses the terms test, procedure, and method loosely and often synonymously. In metrology they are distinct, as are accuracy, repeatability, intermediate precision, and robustness, which all are carefully defined components of measurement science. Those who are responsible for compliance with this guidance must be well versed in metrology.]

Stefan Schuber