FDA 483's,EIR & Warning Letter's

 

FDA 483’s,EIR & WARNING LETTER’s

 

FDA 483’s - (Notice of inspectional observations)

483 is a form issued by an FDA investigator to a company at the conclusion of a GMP, GCP or GLP inspection (or any inspection) setting forth the observations the FDA employee finds objectionable, and considers to be possible violations of the law.

They are inspectional observations, and do not represent a final Agency determination regarding firms compliance.” The FDA-483 can be amended after an inspection by the investigator who issued it and re-issued.

Objective of form 483 is to fix the problem areas and bring the firm in to compliance.

The FDA Form 483 is a report which does not include observations of questionable or unknown significance at the time of the inspection. There may be other objectionable conditions that exist at the firm that are not cited on the FDA Form 483. FDA investigators are instructed to note only what they saw during the course of the inspection. Companies are responsible to take corrective action to address the cited objectionable conditions and any related non-cited objectionable conditions that might exist.

The FDA established a policy concerning written responses to FDA-483 observations. The policy gives companies 15 days to respond in writing to the FDA after a 483 is issued, if they wish their comments to be taken into consideration when the FDA is deciding whether or not to issue a warning letter.

Companies are not required to reply at all, but nearly everyone does, and it is expected. Failure to respond is unusual, and could be taken as a sign of indifference by the FDA. A prompt, proper response is essential to avoid further action by the FDA. In fact, the vast majority of 483s do not lead to warning letters. Warning letters are sent when the FDA feels the observations made during the inspection are significant, and a stronger warning than the 483 itself is warranted.

FDA 483 lists only significant observations. Observations of lesser significance will be included in narrative report (EIR).

 

EIR - (Establishment inspection Report)

After departing, the FDA inspector(s) prepare a detailed ‘Establishment Inspection Report (EIR)’ .The EIR becomes FDA’s primary comprehensive record of inspector’s  visit to the firm, and it may be reviewed by FDA compliance officers looking for violations of law. EIR’s are subject to release under the freedom of information act (FOI) to any member of public, including competitors.EIR includes

Ø Brief history of prior inspectional findings, including any action taken by FDA or corrective action taken by the firm in response to a previous inspection.

Ø The investigator’s narrative report.

Ø Any refusals, voluntary corrections, or promises made by the firm’s management.

Ø Copies of forms the FDA issued to the firm during the inspection, including the FDA Form 483.

Warning Letters

The Warning Letter is a document that usually originates from the FDA-483 observations (a critical 483 observation may leads to a warning letter) that have been linked to citations by one or more legal reviews within the Compliance and legal branch of the FDA. A Warning Letter is informal and advisory. It communicates the agency's position on a matter, but it does not commit FDA to taking enforcement action. For these reasons, FDA does not consider Warning Letters to be final agency action on which it can be sued. The Warning Letter is issued by the agency and not the investigator.

The warning letter generally represents FDA's first official notification to a firm or individual that FDA has found that one or more products, practices, processes, or other activities are in violation of the Food, Drug, and Cosmetic Act. The warning letter affords firms the opportunity to voluntarily take corrective action prior to the initiation of formal enforcement action.

There are two purposes: (1) obtain prompt, voluntary correction of the issues cited by the FDA and (2) establish a background of prior warning so that if the FDA has to seek court intervention, they can show that they exhausted their administrative options before asking the court to intervene through formal litigation.

The primary consequences of a warning letter are the publicity (since warning letters are posted on FDA’s web site), and the time and expense to take the necessary corrective actions, and deal with the FDA.

 

FDA 483’s VS Warning Letter

FDA 483’s	Warning Letter
The Form 483 is issued for inspectional observations. It lists the alleged deficiencies or issues of non-compliance in the manufacturer’s quality system.	Warning letters are issued for violations of “regulatory significance” (Significant violations are those violations that may lead to enforcement action if not promptly and adequately corrected).
The Form 483 is issued by the inspection team alone.	The warning letter is issued from a higher level FDA official or officials.
Bad inspections lead to Form 483s.	Warning letters usually result from multiple lacking responses to issued 483s, or other issues much more serious that require quick attention/escalation.

 

Reference

•        Investigators Operations Manual

http://www.fda.gov/ora/inspect_ref/iom/iomoradir.html

•        Regulatory Procedures Manual

    http://www.fda.gov/ora/compliance_ref/rpm/default.htm




 

FDA Inspection Classification- NAI,VAI,OAI & Establishment inspection Report (EIR)

If regulatory non compliance observed during FDA inspection, the FDA inspector issues “Form 483” (Notice of Inspectional Observations) to the facility. The contents of the 483 comprise inspectional observations but do not represent a final Agency determination regarding compliance.

The company which receives a 483 should respond to the FDA addressing each item within 15 working days. A response is not compulsory but a good response can help the company avoid receiving a warning letter, or stronger enforcement actions including withholding of product approval or even a plant shutdown.

FDA provides initial classification of the inspection based on the observations noted during the inspection, the investigator’s report, and FDA District Office supervisory personnel review. With the exception of instances where procedures indicate that the relevant product center has the right of final classification, the final classification of the inspection is made by the FDA District Office. An inspection classification reflects the compliance status of the establishment at the time of the inspection, based on the observations documented. The conclusions of the inspection are reported as Official Action Indicated (OAI), Voluntary Action Indicated (VAI), or No Action Indicated (NAI).

An OAI inspection classification occurs when significant objectionable conditions or practices were found and regulatory action is warranted to address the establishment's lack of compliance with statute(s) or regulation(s).

A VAI inspection classification occurs when objectionable conditions or practices were found that do not meet the threshold of regulatory significance. Inspections classified with VAI violations are typically more technical violations of the FDCA (The United States Federal Food, Drug, and Cosmetic Act).

An NAI inspection classification occurs when no objectionable conditions or practices were found during the inspection or the significance of the documented objectionable conditions found does not justify further actions.

If no enforcement action is contemplated, or after enforcement action is concluded, FDA provides inspected establishments with a final inspection report, called an Establishment Inspection Report (EIR), which includes:

• Brief history of prior inspectional findings, including any action taken by FDA or corrective action taken by the firm in response to a previous inspection
• The investigator’s narrative report
• Any refusals, voluntary corrections, or promises made by the firm’s management
• Copies of forms the FDA issued to the firm during the inspection, including the FDA Form 483.

Inuse (Open Bottle) Stability Testing for Multidose Containers

 

INUSE (OPEN BOTTLE) STABILITY TESTING FOR MULTIDOSE CONTAINERS

 

The continued integrity of products in multidose containers after the first opening is an important quality issue. Repeated opening and closing, can pose a risk to its content with regard to microbiological contamination, proliferation and/or physicochemical degradation once the closure system has been breached.

 

The purpose of in use stability testing is to establish a period of time during which a multidose product may be used following the removal of the first dose of product from the container without adversely affecting the integrity of the product. 

The registration dossier for a multi-dose product should include either the in-use stability data on which the in-use shelf life is based or a justification why no in-use shelf life is established.This justification can also be based on experimental results. 

Selection of batches

A minimum of two batches, at least pilot scale batches, should be subjected to the test. At least one of the batches should be chosen towards the end of its shelf life. If such results are not available, one batch should be tested at the final point of the submitted stability studies. 

If the product is to be supplied in more than one container size or in different strengths, the inuse stability test should be applied to the product which presents the greatest susceptibility to change. The choice of the tested product should always be justified.

 

Test Design

As far as possible the test should be designed to simulate the use of the product in practice taking into consideration the filling volume of the container and any dilution/reconstitution before use. At intervals comparable to those which occur in practice appropriate quantities should be removed by the withdrawal methods normally used and described in the product literature. Sampling should take place under normal environmental conditions of use. The appropriate physical, chemical and microbial properties of the product susceptible to change during storage should be determined over the period of the proposed in-use shelf life. If possible, testing should be performed at intermediate time points and at the end of the proposed in-use shelf life on the final remaining amount of the product in the container. 

Test storage conditions

The product should be stored under the conditions as recommended in the product literature throughout the in-use stability test period. Any other storage conditions should be justified. 

Test parameters

The appropriate physical, chemical and microbial properties of the product susceptible to change during use should be monitored. The tests used must be appropriate to individual dosage forms, however, examples of parameter types which may need to be studied are given below:

Physical: colour, clarity, closure integrity, particulate matter, particle size

Chemical: active substance assay(s), antimicrobial preservative and antioxidant content(s), degradation product level(s), pH

Microbial: Total viable count, sterility 

In-use stability data should be used to determine whether or not a declaration of an in-use shelf life and additional storage conditions are necessary. 

Labelling of the primary container

The in-use shelf life should be stated on the label. In addition (if space allows) there should be a space for the user to write the date of opening or the "use-by" date.

Brevundimonas (Pseudomonas) diminuta - Sterile Filter challenging organism

Brevundimonas (Pseudomonas) diminuta - Sterile Filter Challenging Organism

 

Sterilizing grade filter is one that will produce a sterile effluent after being challenged by microorganisms at a challenge level of greater than or equal to 1x107/cm2 of effective filtration area.

 

Until the late 1960’s, 0.45 μm-rated membranes were considered “sterilizing grade” filters, and were used successfully in the sterilizing filtration of parenterals. In the mid-1960’s Dr. Frances Bowman observed a 0.45 μm “sterile-filtered” culture medium to be contaminated with a micro-organism, subsequently shown to penetrate 0.45 μm-rated membranes repeatedly in small numbers.

 

Brevundimonas diminuta is a standard organism for validation of sterilizing-grade membrane filters.

Brevundimonas diminuta (formerly known as Pseudomonas diminuta)  is a gram negative 0.5x1.0 -4.0 μm,motile rod with one polar flagellum.

A Medicinal Product shall not be used beyond its expiry date why?

 

A Medicinal Product shall not be used beyond its expiry date why?

 

The expiration date is the final day that the manufacturer guarantees the full potency and safety of a medication. The expiration date of a drug is determined by stability testing. An expired medicine is not safe for human consumption because of the following reasons.

v Some drugs losses potency over time due to degradation, and become less effective at treating the intended condition (i.e in an expired medication, the drug has limited or no therapeutic effect).

vOn expiration, the active pharmaceutical ingredient of the medicinal product starts degrading and the degradation product (impurity) may be more toxic than parent product, which can create harmful effects in patients.

FAQ on stability studies

FAQ on stability studies

           

 

1.What is stability?

The term “stability” with respect to a drug dosage form, refers the physical and chemical integrity of dosage unit. When appropriate, the ability of the dosage unit to maintain protection against microbial contamination.

2.What are the factors, which affect stability of a drug?

Stability parameters of a drug dosage form can be influenced by environmental conditions of storage (temperature, light, air & humidity) as well as packaging components.

3. What is  shelf life/expiration period?

The time period during which a drug substance or drug product is expected to remain within the approved shelf-life specification, provided that it is stored under the conditions defined on the container label.            

4. What is the purpose of stability study? 

a.          Provide evidence, to how the quality of the drug product varies with time.

b.          Establish shelf life for the product.

c.          To recommend storage conditions

d.          To determine container suitability.

 5.What is accelerated stability testing?

Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies. Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical effects at non-accelerated conditions and to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping.

6.What are climatic zones in stability testing?

The four zones in the world that are distinguished by their characteristic prevalent annual climatic conditions. This is based on the concept described by W. Grimm.

 Type of Climate Zone

Zone I

Temperate zone

Zone II

Mediterranean/subtropical zone

Zone III

Hot dry zone

Zone IVa

Hot humid/tropical zone

Zone IVb

Hot/very humid (ASEAN testing conditions)                

 7.What is the testing frequency for accelerated stability study?

At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where an expectation (based on development experience) exists that results from accelerated studies are likely to approach significant change criteria, increased testing should be conducted either by adding samples at the final time point or by including a fourth time point in the study design.

 8.What is the testing frequency for long term (drug product) stability study?

The  recommended frequency of testing at the long term storage condition is normally every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed shelf life.

 9.What is bracketing & matrixing in stability study?

Bracketing & matrixing are reduced designs, where the testing frequency is reduced or certain factor combinations are not tested at all.

10.What is “significant change” for drug product

In general, “significant change” for a drug product is defined as:

1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures;

2. Any degradation product’s exceeding its acceptance criterion;

3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation)

4. Failure to meet the acceptance criterion for pH; or

5. Failure to meet the acceptance criteria for dissolution for 12 dosage units.

 

Change control procedure in Pharmaceuticals

Change Control System

Change control is a CGMP concept that focuses on managing change to prevent unintended consequences. Certain manufacturing changes (i.e changes that alter specifications, a critical product attribute or bioavailability) require regulatory filings and prior regulatory approval.

Change is an inherent part of the life cycle of a pharmaceutical product. A change can be an addition to, deletion of, or modification to manufacturing facility, utilities, process, material, product, procedures or equipment (including software) which impacts quality or regulatory requirements.

Change control is a procedure that ensures changes are implemented in a controlled and coordinated manner. The  change control program evaluate all changes that could affect the production and control of the drug product, intermediate or API. It is the most critical element in the overall quality management of pharmaceutical industry. A change control system provides checks and balances in the quality system by tracking, reviewing and approving the changes. In adequate change control procedures ends up in regulatory non compliance.

The purpose of change control is to prevent the unintended consequences that are sometimes encountered when making a change to a product or system.

Benefits of change control system

• Structured and systematic approach for change management with proper change evaluation
• Documenting & tracking  the details of change
• Routing of change requests to appropriate individuals/team for approvals
• Demonstrate compliance to regulatory agencies

Change control Process flow

Changes can happen anytime during a product’s  life cycle.

 

Change proposal

 

Change Evaluation/review

 

Change Classification

 

Identification of impacted systems/documents & risk assessment

 

Change Approval

 

Change implementation

 

Verification of change implementation

 

Change control close out

Change control Procedure

A formal change control procedure always begins with a change proposal, which is initiated by user department personnel with proper justification. The change proposal then, evaluated by an expert team (change control committee) contributing the appropriate expertise and knowledge from relevant areas.

After change evaluation, quality unit will classify the change (i.e minor/major/critical).Benefits of change classification includes

v Classification can help in assessing the impact of change in a reliable way.

v Change classification can be used to identify risk associated with each change request.

v Change classification can help to determine the change acceptability (i.e reject or approve changes).

Change classification triggers impact analysis of the proposed change  for identification of impacted systems and documents. There are several risk associated with each change proposal, including  reduced product quality. Risk assessment in changing requirements of existing systems is an important aspect of producing the desired result of a change.

After impact analysis and risk reduction, quality unit will approve or reject the change proposal based on the criticality of the proposed change. The change can be implemented after change approval by quality unit. After implementation, quality unit verify the effectiveness of implemented changes, to confirm the change objectives were achieved and that there was no deleterious impact on product quality. After verification of change implementation, the change control can be closed.

Change control procedure should ensure that the level of documentation and effort is matched to the risk associated with the change. It should be ensured that

v The change control is linked to other quality system such as CAPA, customer complaints, validation etc.

v Includes criteria to evaluate whether changes affects regulatory filings.

v Includes evaluation criteria for determining if changes are technically justified.

GMP deficiencies related to change control

v Inadequate review & approval of the change by quality control unit.

v Failure to file the changes with regulatory.

v Failure to evaluate/justify the changes.

v Excluding "like-for-like" changes from change control program.

Change controls for like to like changes

‘Like to like’ change – replacement of a piece of equipment by another with ideal characteristics and function.

A pump on a spray dryer system must be managed to control product flow rate to the dryer. Because the product is sensitive to even minor changes in this rate, the pump is considered a critical element of the process. The pump recently failed. A new pump of the same model, same manufacturer and same design was purchased to replace it --- a like-for-like change. However, the new pump operates more efficiently than the "old" pump and generates 10% higher RPMs than the old one. Thus, product flow rate (i.e, injection pressure) is different and results in failing particle size distribution of the final product.

Let us consider another example of like-for-like change

A company performed a routine replacement of the filling pump pistons, without taking a change request because it was a “like to like” replacement (which has been a typical industry practice). Although the replacement pistons had the same part number as the original pistons, they were slightly longer. This longer dimension caused the pistons to come into contact with the bottom of the filling blocks, resulting in the generation of metal particles, which contaminated the product batches.This metal contamination resulted in the recall of several product batches.

In both the case, a like-for-like change impacted product quality. Thus, even for like-for like changes, an assessment is needed to determine if pre-use testing, assessment,qualification or other verification is needed before use. In short, some truly like-for like changes are innocuous and should be implemented without change control assessment. BUT, equipment, processes or controls that could impact product quality should receive additional scrutiny prior to use.