fda regulations

cGMP and FDA Regulations

Geoff Habiger, G Habiger Consulting, LLC

Topics

• Good Manufacturing Practices• Laws and Regulations

– Drugs– Devices

• FDA Expectations of Manufacturers– Drugs– Devices

• FDA Enforcement Tools• Questions

What are Good Manufacturing Practices (GMPs)?•Regulations enforced by the FDA.•System that assure proper design, monitoring, and control of manufacturing processes and facilities.•Adherence assures the identity, strength, quality, and purity of drug products.

– Requires that manufacturers adequately control manufacturing operations.•cGMPs are intended to be flexible to allow each manufacturer to decide how best to implement controls using scientifically sound design, processing, and testing. •cGMPS represent the minimum requirements a manufacturer must follow.

Good Manufacturing Practices

Good Manufacturing Practices (GMPs) are the main regulatory standard for ensuring pharmaceutical quality. Also abbreviated as cGMP, the small “c” meaning “current”.

• Consumers cannot tell on their own that a drug (or device) will be safe and that it will work.

• Testing alone is not adequate to ensure quality.– Most testing is destructive, so it’s not practical to test every tablet, pill, or

vial as there wouldn’t be anything left for patients to use.• Important that manufacturing happens under cGMP conditions to assure that

quality is built into the design and manufacturing process at every step.


Why are cGMPs important?

Complying with cGMP is a mandatory aspect of pharmaceutical manufacturing.

• cGMPs are spelled out in the Code of Federal Regulations (CFR).• The CFR is the codification of the rules and regulations published by the U.S.

federal government. The CFR represents areas subject to federal regulation.– Cover everything from Agriculture, Banking, Highways, Labor, and

Patents. There are 50 distinct chapters (titles) in the CFR.– Food & Drugs is covered in Title 21 and document the actions required

under federal law.• Title 21 is the FDAs interpretation of the Food, Drug, and Cosmetics Act and

related statutes.


Where do cGMPs come from?

Federal Food, Drug, and Cosmetic Act (FD&C Act)

• Signed into law on June 25, 1938 by President Franklin D. Roosevelt• Gives authority to the FDA to oversee safety of food, drugs, and cosmetics • Chapter 5 covers drugs and medical devicesSEC. 501. [21 USC §351] Adulterated Drugs and DevicesA drug or device shall be deemed to be adulterated—(a) Poisonous, insanitary, etc., ingredients; adequate controls in manufacture (1) If it consists in whole or in part of any filthy, putrid, or decomposed substance; or (2)(A) if it

has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health; or

(B) if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess

Laws & Regulations

Pertinent Sections of the CFR• Over 250 Parts in Title 21 of the CFR• Only 3 Parts pertain specifically to cGMP for drugs and medical devices

21 CFR 210: CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL21 CFR 211: CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS 21 CFR 820: QUALITY SYSTEM REGULATION (Subchapter H: Medical Devices)

• International Conference on Harmonisation (ICH) Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients has been recommended for adoption by regulatory agencies in Europe, Japan, and US.

Laws & Regulations

PART 210 -- CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL

Sec. 210.1 Status of current good manufacturing practice regulations. (a) The regulations set forth in this part and in parts 211 through 226 of this chapter contain the minimum current good manufacturing practice for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packing, or holding of a drug to assure that such drug meets the requirements of the act as to safety, and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess.

Laws & Regulations

PART 210 (continued)

Sec. 210.1 Status of current good manufacturing practice regulations. (b) The failure to comply with any regulation set forth in this part and in parts 211 through 226 of this chapter in the manufacture, processing, packing, or holding of a drug shall render such drug to be adulterated under section 501(a)(2)(B) of the act and such drug, as well as the person who is responsible for the failure to comply, shall be subject to regulatory action.

Laws & Regulations

Part 211: CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS

Sec. 211.1 Scope. (a) The regulations in this part contain the minimum current good manufacturing practice for preparation of drug products for administration to humans or animals.

Laws & Regulations

Part 820: QUALITY SYSTEM REGULATION

Sec. 820.1 Scope. (a) Applicability (1) Current good manufacturing practice (CGMP) requirements are set forth in this quality system regulation. The requirements in this part govern the methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices intended for human use.(c) Authority. Part 820 is established and issued under authority of sections 501, 502, 510, 513, 514, 515, 518, 519, 520, 522, 701, 704, 801, 803 of the act (21 U.S.C. 351, 352, 360, 360c, 360d, 360e, 360h, 360i, 360j, 360l, 371, 374, 381, 383). The failure to comply with any applicable provision in this part renders a device adulterated under section 501(h) of the act. Such a device, as well as any person responsible for the failure to comply, is subject to regulatory action.

Laws & Regulations

ICH Q7: GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS

Sec. 1.1 Objective. This document (guide) is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (API) under an appropriate system for managing quality.

•FDA considers the requirements in 21 CFR Parts 210 and 211 to be applicable to API manufacturing. •In 2001, FDA adopted the ICH Q7 guidance and represents FDA’s current thinking on cGMPs for APIs. •Manufacturers that follow ICH Q7 generally will be considered to comply with the statutory cGMP requirement.(Ref. FDA Compliance Program Guidance Manual 7356.002F “Active Pharmaceutical Ingredient (API) Process Inspection”)

Laws & Regulations

The following slides show some of the specific provisions of 21 CFR 211 and 21 CFR 820 related to the areas of cGMP that the FDA looks at during inspections. Include with each are examples of the types of evidence that might be used to support a manufacturer’s assertion that they are meeting the requirement.

(Please note, having the evidence suggested will not guarantee that the FDA will not cite a company for being in violation of the regulation. These are guidelines to show what could be provided to support meeting the requirement and is not an exhaustive list, focusing on the quality unit and training as related to cGMP. The manufacturer must still prove to the inspector that they are in compliance with the regulations.)

FDA Expectations

Sec. 211.22 Responsibilities of quality control unit. • Requirement:(a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.

• Evidence to support:–Organizational Charts–Procedures

FDA Expectations

Sec. 211.22 Responsibilities of quality control unit. • Requirement:(b) Adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to the quality control unit.

• Evidence to support:–In-house testing results–Contract testing results–Certificate of Analysis results

FDA Expectations

Sec. 211.22 Responsibilities of quality control unit. • Requirement:(c) The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.• Evidence to support:–Procedures–Quality Assurance review and approval of documents:

• Batch Records• Investigation/CAPA approval• Specifications• SOPs/Methods• Validation Protocols• Other (Change controls, etc.)

FDA Expectations

Sec. 211.22 Responsibilities of quality control unit. • Requirement:(d) The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed.

• Evidence to support: –SOPs–Policies (Quality Manual)

FDA Expectations

Sec. 211.25 Personnel qualifications. • Requirement:(a) Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee's functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.(b) Each person responsible for supervising the manufacture, processing, packing, or holding of a drug product shall have the education, training, and experience, or any combination thereof, to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess.

• Evidence to support:–Training Records (individual and annual cGMP)–CVs–Job Descriptions

FDA Expectations

Sec. 820.20 Management responsibilities•Requirement:

(a) Quality policy. Management with executive responsibility shall establish its policy and objectives for, and commitment to, quality. Management with executive responsibility shall ensure that the quality policy is understood, implemented, and maintained at all levels of the organization.(c) Management review. Management with executive responsibility shall review the suitability and effectiveness of the quality system at defined intervals and with sufficient frequency according to established procedures to ensure that the quality system satisfies the requirements of this part and the manufacturer’s established quality policy and objectives. The dates and results of quality system reviews shall be documented.

•Evidence to support:–Quality manual/Quality policy–Training records–Meeting minutes from Quality Management Review (QMR) meetings

FDA Expectations

Sec. 820.22 Quality audit•Requirement:

Each manufacturer shall establish procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system. Quality audits shall be conducted by individuals who do not have direct responsibility for the matters being audited. Corrective action(s), including a reaudit of deficient matters, shall be taken when necessary. A report of the results of each quality audit, and reaudit(s) where taken, shall be made and such reports shall be reviewed by management having responsibility for the matters audited. The dates and results of quality audits and reaudits shall be documented.

•Evidence to support:–SOPs–Audit log/Audit history

FDA Expectations

Sec. 820.25 Personnel•Requirement:

(a) General. Each manufacturer shall have sufficient personnel with the necessary education, background, training, and experience to assure that all activities required by this part are correctly performed.(b) Training. Each manufacturer shall establish procedures for identifying training needs and ensure that all personnel are trained to adequately perform their assigned responsibilities. Training shall be documented.(1) As part of their training, personnel shall be made aware of device defects which may occur from the improper performance of their specific jobs. (2) Personnel who perform verification and validation activities shall be made aware of defects and errors that may be encountered as part of their job functions.

•Evidence to support:–SOPs–Training records/training on specific CAPAs

FDA Expectations

• Inspections• FDA Form 483• Establishment Inspection Report• Regulatory Actions• Warning Letters• Recalls• Consent Decree

FDA Enforcement Tools

Inspections

Inspections by the FDA are performed:•To determine whether a manufacturer is in compliance with cGMP requirements, and if not, to provide the evidence for actions to prevent adulterated products from entering the market and remove adulterated products from the market, and take actions against the person(s) responsible. •To provide cGMP assessment to determine acceptability of manufacturer in pre-approval review.•To provide input to manufacturers to improve their compliance with regulations.•To continue FDAs expertise in drug manufacturing in determining the adequacy of cGMP requirements.

(Source: FDA Compliance Program Guidance Manual 7356.002 “Drug Manufacturing Inspections”)


Inspections

Inspections follow a system based approach.The inspection covers 2 or more systems, with mandatory coverage of Quality System. Inspecting the minimum number of systems, or more as necessary, will provide the basis for an overall cGMP decision.•Quality System•Facilities and Equipment System•Materials System•Production System•Packaging and Labeling System•Laboratory Control System



Inspections: Surveillance InspectionsFull Inspection•Performed to provide deep and broad evaluation of manufacturer’s cGMP. Covers at least 4 systems, one of which is Quality System•New manufacturers•Doubt about cGMP compliance•Follow up to previous regulatory action

Abbreviated Inspection•Performed to provide documentation for continued satisfactory cGMP compliance. Covers at least 2 systems, one of which is Quality System•A record of satisfactory cGMP compliance•No significant recall, product defects, alert incidents•Little shift in manufacturing profiles for the company



Inspections: Compliance Inspections

•Performed to evaluate or verify compliance corrective actions after a regulatory actions was taken. •Covers areas found deficient and subjected to corrective action.•Also covers other systems to make a determination on overall compliance status after corrective actions. •Uses the Full Inspection option.•Includes For Cause Inspections to investigate a specific problem that has come to the attention of the FDA. (Field Alerts, complaints, recalls, defective product, etc.)



FDA Form 483

•At the conclusion of the inspection, the inspectors may issue a FDA Form 483.•Form 483 is issued to management when observations of conditions, that in the inspector’s judgement, are violations for the FD&C Act. •Observations are made when conditions or practices observed indicate that the food, drug, device, cosmetic has been adulterated, may become adulterated, or injurious to health.•Purpose is to notify management of objectionable conditions.•Is not an all-inclusive list of every possible deviation from the laws and regulations.•Is not a final FDA determination of whether any condition is in violation of the FD&C Act.


Establishment Inspection ReportAfter the FDA receives the 483 observations, and the firm’s responses to the observations, they will issue an Establishment Inspection Report (EIR).•The report provides the inspection conclusion and the FDAs decision from the inspection:

• No Action Indicated (NAI): No objectionable conditions found, or conditions do not justify further action.

• Correction Indicated (CI): Objectionable conditions/practices found, and firm failed to meet regulatory/administrative requirements.

• Referred to Center (RTC): Temporary conclusion indicating the EIR should be referred to the appropriate Center for final decision.


Establishment Inspection Report (continued)

Based upon the Inspection Conclusion reached the FDA district office will issue its decision that it will take or recommend. •Decision Type:

• No Action Indicated (NAI): No objectionable conditions/practices found during the inspection.

• Voluntary Action Indicated (VAI): Objectionable conditions found and documented, but FDA is not prepared to take or recommend any regulatory actions since the conditions do not meet the threshold for regulatory action.

• Official Action Indicated (OAI): Objectionable conditions found and regulatory action should be recommended.

• Referred to State (RTS): Referred to state, local, or federal office. Used when no federal jurisdiction over the violation, or state action is most efficient method of obtaining compliance.

• Referred to Center (RTC): Can only be used when objectionable conditions are for a compliance area which no clear policy has been established or significant technical issues exist.


Regulatory ActionsThere are several types of regulatory actions that the FDA can pursue based on the results of the inspection and EIR.


The most common type of action taken by the FDA is the Warning Letter. The warning letter is issued when the FDA determines that a company’s response to a 483 is insufficient and additional actions are required.


Note: The large increase in total warning letters starting in 2011 is due to letters for Tobacco products.

RecallsAnother common enforcement tool is the product recall. Recalls are often performed voluntarily by a company, but the FDA can also require a recall if significant cGMP violations for a company are identified.There are three classes of recalls:•Class I: A situation in which there is a reasonable probability that the use of or exposure to a violative product will cause serious adverse health consequences or death.•Class II: A situation in which use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.•Class III: A situation in which use of or exposure to a violative product is not likely to cause adverse health consequences.


Consent Degree•An order issued by a judge that represents a voluntary agreement by all participants in a lawsuit. Consent decrees are usually issued after one side in a lawsuit voluntarily agrees to cease a specific action without admitting that the action was illegal.•It is often applied in cases where a company is sued by government organizations. •It is legally binding and must be recognized by a court and is enforced by the courts.•Generally used when a company has repeated cGMP violations that have not been resolved. •Will include fines, reimbursements for inspection costs, due dates for specific actions, and penalties for non-compliance. •It is usually permanent, and a company can petition to remove the consent decree if they demonstrate compliance.


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