required gmp standards and inspections alain kupferman workshop on who prequalification requirements...

Required GMP Standards and Inspections

Alain Kupferman

Workshop on WHO prequalification requirements for reproductive health medicines ,

Jakarta, October 2009

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 20092 |

Drugmeeting

requirements

Equipment Personnel

MethodsPremisesDefinition of conditions under

which drugs are manufactured, packed, tested, held

State of Control:a drug firm is considered

to be operating in a state of control when it can guarantee

a finished drug product for which quality, strength and

purity has been assured throughout production and

that the product is compliant with its registration

STATE OF CONTROL


ELEMENTS OF COMPLIANCEELEMENTS OF COMPLIANCE

EQUIPMENT COMPONENTS PERSONNEL FACILITIES PROCESS

QUALIFICATION ANALYSIS TRAINING QUALIFICATIONDEVELOPMENT

VALIDATION

PRODUCT

APPROVAL BY AUTHORITIES


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MONITORING OF COMPLIANCEMONITORING OF COMPLIANCE


DEFINITIONSDEFINITIONS

Compliance The state of conformity of a regulated party (including a corporation, institution, individual or other legal entity) or a product with a legislative or regulatory requirement.

Compliance Monitoring Actions planned to maintain regular surveillance in order to evaluate compliance with applicable requirements of the National Regulatory Authority (NRA) and its associated Regulations. This includes a wide variety of fact gathering and assessment activities such as inspections, market surveys and a product sampling program.

Compliance Verification Actions taken to verify compliance in response to information regarding known or suspected non-compliance with the applicable requirements of the NRA and its associated Regulations. This includes actions such as information gathering either off-site or via on-site visits.


DEFINITIONSDEFINITIONS

Enforcement Actions that may be taken to induce, encourage or compel compliance with the NRA and its associated Regulations.

Inspection On-site monitoring and assessment against the applicable requirements of the NRA and its associated Regulations. Inspections are routinely conducted on a predetermined cycle or as required to assess compliance.

Inspector Any person designated as an inspector for the purpose of the enforcement of the NRA

Investigation Actions taken to gather evidence to support a case referral for potential judicial determination regarding specific violations of the NRA and its associated regulations .


REASONS FOR INSPECTIONREASONS FOR INSPECTION

• Regular schedule based on general GMP’s

• Pre-approval inspections • Submission of a variation

• Submission of an NDA

• New products and/or manufacturing changes

• Site changes

• For cause inspections• Recalls or significant complaint

• Past inspection history


• Focus on Risk and Quality Systems

• Doctrine of Liability for Executives

• Process Analytical Technology

TRENDSTRENDS


FOCUS ON QUALITY SYSTEMS & RISKFOCUS ON QUALITY SYSTEMS & RISK

Quality Systems Inspection Program

Assess Firm's State of ControlSystems Approach (6 systems)Executive Management

Expected to Establish Effective Procedures and Controls to Ensure:

Timely Investigations Supportable Decisions Are Documented


The idea underlying this approach is that deficiencies in one system

will affect all other systems as well.

FDA Systems Approach (6 systems)Quality SystemFacilities SystemEquipment SystemMaterials SystemProduction SystemPackaging & Labeling System

FOCUS ON QUALITY SYSTEMSFOCUS ON QUALITY SYSTEMS


“Risk Based Pharmaceutical cGMP Initiative” Goals

(GMPs for 21st Century)

the most up-to-date concepts of risk management and quality systems approaches should be incorporated while continuing to ensure product quality (PAT); the latest scientific advances in pharmaceutical manufacturing and technology should be encouraged; the submission review program and the inspection program should operate in a coordinated and synergistic manner; regulation and manufacturing standards should be applied consistently; management of the program encourages innovation in the pharmaceutical manufacturing sector; and FDA resources should be used most effectively and efficiently to address the most significant health risks

FDA FOCUS ON QUALITY SYSTEMS & RISK


• Increased number of pharmaceutical products and a greater role of medicines in health care

• Decreased frequency of FDA (NRA) manufacturing inspections as a result of

fewer resources available for pharmaceutical manufacturing inspections

• FDA’s (NRA’s) accumulation of experience with, and lessons learned from, various approaches to the regulation of product quality

• Advances in the pharmaceutical sciences and manufacturing technologies

• Application of biotechnology in drug discovery and manufacturing

• Advances in the science and management of quality

• Globalization of the pharmaceutical industry

WHY A NEW FOCUS?


RISK ASSESSMENT


RISK ASSESSMENT COMPONENTSRISK ASSESSMENT COMPONENTS

PRODUCT COMPONENT

PROCESS COMPONENT

FACILITY COMPONENT


1 .Intrinsic factorsFactors such as sterility, medical gas, and the determination of prescription (Rx) versus over the counter (OTC) are crude methods to distinguish between products with higher and lower potential for public health consequence should there be a drug defect. If there is a quality defect, sterile drugs would have a higher public health consequence than nonsterile drugs; hence, sterile drugs should be given a higher weight.Specific products where there is a heightened risk of cross-contamination, such as sites manufacturing highly sensitizing agents (e.g., penicillin) and at least one other product using similar processing methods should be taken into account.

2 .Past recalls for quality defects / ComplaintsDrug recall data provide information on past recalls for quality defects with potential for human health hazard .

PRODUCT COMPONENT


Some processes are more complex and more susceptible to problems than others.A primary goal of CGMP inspections is to ensure that processing operations are in a state of control .

Two types of process-related factors were identified for inclusion in the risk-ranking model:

1 .Factors associated with maintaining process control2 .Factors associated with potential vulnerability to product or

environmental contamination

PROCESS COMPONENT


It is important to arrive to a risk-ranking (i.e., from high to low) of the probability of a loss of a state of control and, independently, the vulnerability of the process to contamination for a product category and processing operations associated with that product category .

It is necessary to survey on risks associated with commonly employed manufacturing operations (e.g., measuring, mixing, compression, and filling) and for a variety of product categories (e.g., immediate and modified release solid-oral drugs, sterile liquids, metered dose inhalers, and active ingredients by chemical and fermentation processes).

PROCESS COMPONENT


PROCESS COMPONENT: RISK MANAGEMENT

ICH Q9


The facility component of the US FDA risk ranking model includes 4 factors:

1 .History of violation (e.g., CGMP deficiencies have higher weights)

2 .History of inspection (e.g., no prior inspection, newly registered/ licensed or no CGMP inspection in the past 2 years have higher weights than those with recent CGMP inspection)

3 .Estimated volume of production output (surrogate for exposure, e.g., higher volume and production output, higher weights)

4 .Type of establishment (e.g., manufacturer, repacker, contract lab)

FACILITY COMPONENT


MANAGEMENT CONTROLSMANAGEMENT CONTROLS

Strict Liability Requires Diligence & Management Controls to:• Prevent Violations• Detect Problems When They Occur• Correct Root Cause Issues

Corporations Act Through Individuals

Individuals Can Be Held Accountable

The FD&C Act

…“dispenses with the conventional requirement for criminal conduct -- awareness of some wrongdoing “.

…“ a positive duty to seek out and remedy violations when they occur … and …, a duty to implement measures that wil ensure that violations will not occur”.

…“and permits conviction of responsible corporate officials, who … have the power to prevent or correct violations”


PAT is considered to be a system for• designing ,

• analyzing, and • controlling manufacturing

through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final

product quality”.

PROCESS ANALYTICAL TECHNOLOGYPAT


1 .PAT Tools

2 .Process Understanding

3 .Risk-Based Approach

4 .Integrated Systems Approach

5 .Real Time Release

PROCESS ANALYTICAL TECHNOLOGY


1 .PAT Tools• Multivariate data acquisition and analysis tools

• Modern process analyzers or process analytical chemistry tools • Process and endpoint monitoring and control tools

• Continuous improvement and knowledge management tools

2 .Process Understanding A process is generally considered well understood when

• all critical sources of variability are identified and explained;• variability is managed by the process; and ,

• product quality attributes can be accurately and reliably predicted over the ranges of acceptance criteria established for materials used, process parameters, and manufacturing environmental and other conditions .The ability to predict reflects a high degree of process understanding .

Although retrospective process capability data are indicative of a state of control, these alone may be insufficient to gauge or communicate process understanding



3 .Risk-Based Approach Within an established quality system and for a particular manufacturing process, there is an inverse relationship between the level of process understanding and the risk of producing a poor quality product

4 .Integrated Systems ApproachDevelopment, manufacturing, quality assurance, and information/knowledge management functions

5 .Real Time ReleaseReal time release is the ability to evaluate and ensure the acceptable quality of in-process and/or final product based on process analytical data



PROCESS ANALYTICAL TECHNOLOGY and ICH


Error PrecursorsError Precursors


Human ErrorsHuman Errors

Organizational / systemic: For example, when the work culture priority in the company is efficiency and productivity.Of course, efficiency and productivity are important, but so is quality. So there has to be a balance. Some companies put quite too much emphasis on productivity; managers lead by example and people are just cutting corners the same as the managers, and they are therefore taking product and regulatory risks to reduce cost and increase profits. Some companies have gone so far as to say that they would take the risk of doing this or that, because they don’t expect the NRA to catch them doing it.

Procedural (SOPs): Sometimes SOPS are not clear, or the instructions are contradictory. It was not the operator’s fault, it is the company’s fault, because the SOPs are not clear in the first place. How do you train someone in SOPs that are not clear?

Careless work: That is another type of human error, where people are forgetful. They are not paying attention to what they are doing, or they are careless. Sometimes people have serious personal problems, they have a lot of stuff in their minds. This happens. But also the work environment may have an influence on these types of errors. For example if you have an operation where you have to rely on the person’s memory to execute some steps correctly, you [may be] setting that person up for failure.

Voluntary / intentional: The SOP is inadequate and the employees know the SOP is wrong and they just don’t follow it.Many times we see that employees do backdating, sometimes following instructions from managers.

Involuntary: Errors due to human variability. We know there are going to be errors. We are just human. We are all human. But what can we do to minimize them?


FINDINGS FROM INSPECTIONSFINDINGS FROM INSPECTIONS

Source:MHRA (MCA)



Source:MHRA (MCA)


FINDINGS FROM FDA INSPECTIONSFINDINGS FROM FDA INSPECTIONS


Buildings and Facilities

• Not of adequate size or capacity for intended activities• Failure to provide separate or defined areas to prevent contamination, cross-contamination or

mix-ups• No appropriately cleaned or maintained

• Effectiveness of sanitation has not been established• Poorly designed air handling systems or not appropriate for intended activities

• Not monitored for temperature or humidity• Poorly designed water systems

• Poor hygienic zone system• Use of low quality building fabrics leading to easily damaged walls and doors which become

difficult to clean •Incorrect airflows and pressure differentials to prevent cross contamination

•Sterile area changing rooms insufficient in size or bqd lqyout •Goods receipt areas of insufficient size

INSPECTION RESULTS


Equipment

• No or improperly maintained cleaning and usage logs• No expiration dating of cleaned equipment

• No or inadequate cleaning validation• Not identified as to use or status

• No or insufficient SOP for use• Not or incorrectly identified in batch record

• Inadequate calibration program• Preventative maintenance program not in existence or inadequate

INSPECTION RESULTS


Raw Materials and Components

• Poor labeling or mislabeling• Poor segregation to prevent mix-ups

• Inadequate sampling conditions and testing procedures• Incomplete SOPs for receipt, storage, sampling and disposition

• No or inaccurate inventory system or log •Insufficient assurance of supplier adequacy

•No evidence that APIs have been manufactured to GMP •TSE risks inadequately controlled

•No vendor recertification or secondary/backup to suppliers •No system to address problems with suppliers, e.g. audit or increased testing

•Poor sampling facilities •Insufficient identification testing (Annex 8)

INSPECTION RESULTS


Quality Management Systems, Records and Reports

• Incomplete batch and test records: - Steps not verified

- Laboratory results not included - Equipment not identified

• Not reviewed or revised periodically• Inadequate documentation of deviations and OOS

• Incomplete or tardy recording and investigation of complaints and incidents •No regular management review of quality indicators

•Lack of quality improvement / CAPA processes •Insufficient change control

•Ineffective self-inspection systems •Recall systems incomplete and untested

•Non-compliance with previous inspection commitments• Inadequate recording of training and effectiveness

• Insufficient documentation of maintenance and calibration activities

INSPECTION RESULTS


Laboratory Controls

• Not based on scientifically sound and appropriate (specific) specifications

• Test methods not appropriately validated

Standard Operating Procedures (SOP)

• Not in existence.• Incomplete or not in sufficient detail

• Not followed or deviations not justified• Not periodically reviewed and updated

INSPECTION RESULTS


Procedures and Process Controls

• Aseptic processing principles not applied or validated: - Not all aseptic processes are included in challenge studies.

- Product exposed to environment that is not properly controlled. - Failure to validate aseptic connection.

- Failure to follow SOP.• Investigations following excursions not performed, documented or

are inadequate: - Do not include other batches associated with failure.

- Are not completed in timely manner.

INSPECTION RESULTS


Procedures and Process Controls

• In-process hold times not validated or incorporated into stability program• Sterilization procedures not appropriately validated or revalidated• No or inadequate process validation studies or in-process testing

• Inadequate changeover procedures for multi-purpose areas• No time limits for completion of time-sensitive production phases

INSPECTION RESULTS


Environmental Monitoring

• Not performed during manufacturing operations• Appropriate limits: - Not based on trends

- Do not consider nature of the product• Inadequate monitoring frequencies

• Improper location of sampling devices or monitoring locations not identified No viable monitoring close to point of fill for aseptic products Poor handling and positioning of settle plates in critical zones

Poor or no continuous particle monitoring in critical zones• Inadequate personnel monitoring

• Wash bays, cold stores and water systems not monitored microbiologically •No monitoring during or following building work •No assessment of recovery or growth promotion

• Sampling procedures not representative of usage procedures• Data not linked to manufacturing process

• Investigation following excursions are no performed,not documented, or inadequate: - Are not complete, do not consider impact on product, are not completed in timely manner

• Procedures allow for consecutive out of specification results before taking action

INSPECTION RESULTS


CONCLUSIONCONCLUSION

Adopt the mindset

Be prepared and compliant all the time, NOT just at the time of the inspection

Conduct at regular intervals

Inspection Readiness Training

Self Audits

Integrate audit program with overall system based GMP program.

required gmp standards and inspections alain kupferman workshop on who prequalification requirements...

Documents

prequalification requirements

applicable requirements

reproductive health

compliance monitoring

definitions compliance

associated regulations

nra investigation actions

cause inspections