Sterility Test Failure Investigation

                      

How to Perform a Sterility Test Failure Investigation

Sterility test is a mandatory product release criteria for aseptically – filled products. Sterility test failure of a drug product/substance is a stressful event, because it will  raise concerns about manufacturers  control over the process, practices and clean room environment and finally it will landed up with customer and revenue losses.

All sterility failures in pharmaceuticals should thoroughly investigated, because inadequately investigated sterility failures can trigger regulatory action as it is evident from many of the FDA’s warning letters to the manufacturers.

Investigating a sterility failure is just like connecting the dots. The first challenge in a sterility failure investigation is to confirm the reported result is real or false positive.

As a part of investigation clean room data, such as differential pressures, microbial monitoring, videos, gowning records, cleaning records, maintenance records, sterilizer records, etc. are to be verified to find evidence of contamination. Firms should review all recent sterilization, depyrogenation, and decontamination cycle re-validations and compare them to the original qualification experiments performed.

While performing a sterility failure investigation it is important to find out how the microbes  goes in to the product rather than merely finding the source of contamination.

A sterility failure investigation must be conducted in two phases

1. Laboratory Investigation (Sterility test &testing environment)

2. Manufacturing Investigation (manufacturing & filling Process)

In the event of a sterility failure following activities to be initiated immediately parallel to the investigation program.

Immediate Action

As and when a sterility failure is reported, the batch in question must immediately be put in quarantine, and a decision must be taken to set the boundaries of the investigation and identify other batches which may also be affected.  Production activities shall be stopped in the manufacturing and filling area where the contaminated batch was manufactured until the identification of root cause and CAPA implementation.

Impact Analysis

Impact analysis is equally important as failure investigation, because regulatory inspectors pay more attention to the pitfalls in such assessments. In the event of sterility failure, a detailed impact analysis to be performed by giving consideration to other batches filled on the same filling line, filled in the same suite, using the same sterilizers, using equipment sterilized in the same manner, sharing the same air handling system, or using the same materials in formulation. A formalized risk assessment to be initiated to evaluate the impacts of sterility failure in these batches with rationale and scientific justification, because these are key area of focus in regulatory inspections. These decisions may need to be reviewed in the light of further information gained through subsequent investigation.

Investigation Procedure

1. Laboratory Investigation (Sterility test &testing environment)

·       Verify the negative control. If growth observed invalidate test and repeat the analysis. If negative control does not showing growth proceed with investigation.

·       Carry out identification of the organism. The nature of the organisms recovered in the sterility test may give some direction to potential source, but care should be taken to ensure that the investigation remains sufficiently broad to include all potential sources.

·       Verify analyst technique, If possible interview the analyst and gather the information about his knowledge and technique. Also verify the results of finger dabs and personnel monitoring of the persons involved in testing.

·       Verify autoclaving record for sterilization accessories used for the test like glass ware, garments, gloves to confirm that correct load pattern and sterilization parameters were followed.

·       Verify the deviations, which reported during the performance of sterility test.

·       Verify testing environment, be it a UDAF unit or isolator. If an isolator was used, the leak testing and gassing process should be reviewed. Validation, maintenance and cleaning status will need to be confirmed as part of this review.

2. Manufacturing Investigation (manufacturing & filling Process)

·       Review trend analysis of viable and nonviable count in the critical area immediately adjacent to it.

·       Verify if processing batches involved in any deviations.

·       Verify the trend of personnel monitoring results to find any adverse trend.

·       Verify if any untoward event occurred during processing & was not reported earlier.

·       Verify if there was any failure of utility, while batch was being processed.

·       Verify if there was any drop in differential pressure during processing.

·       Verify for the manufacturing history of the product or similar product for any changes for process, personnel and equipment.

·       Verify gowning records, cleaning records, maintenance records, sterilizer records etc. to find evidence of contamination.

·       Verify operator’s technique, If possible interview the operator and gather the information about his knowledge and technique.

·       Data from the most recent media fill to be verified. If the investigation indicates that any interventions may have been the cause, consideration should be made as to whether the interventions were included and simulated during the media fill or if there were any concerns when the intervention was simulated.

·       Cleaning & disinfection records pertaining to the filling room and filling zone to be evaluated. Such review should consider the effectiveness of cleaning techniques and the expiry time of disinfectants used for cleaning.

At the completion of the initial investigations of both the manufacturing and laboratory phases, it is not unusual to still not have identified a definitive root cause. Additional testing or monitoring may be required to do this. It certain causes investigation may conclude with more than one root cause also.Under normal conditions sterility failure can happen due to following reasons

·       Poor personnel practice

·       Loss of environmental control

·       Flawed operational design

Based up on the arrived root cause, a media fill study may required to be performed  before resuming production activities to establish that the clean room is under control.
 

WHO Inspection Findings – NOC (Notice of concern)

WHO Inspection Findings –  NOC (Notice of concern)

The WHO prequalification team plans and coordinates the performance of inspections (announced or unannounced) of the site(s) of manufacture of selected Active Pharmaceutical Ingredients API(s), the Finished Pharmaceutical Product (FPP), and of selected clinical testing units or Contract Research Organization (CRO). The inspection report listing all the observations and findings is prepared after the inspection (WHOPIR – WHO Public Inspection Report) and provided to the manufacturer or CRO as relevant. The manufacturer and or CRO has to take appropriate corrective and preventive action and submit a response to the inspection report for assessment by the inspectors.

NOC (Notice of concern) is a letter that is issued to a firm (i.e manufacturer, contract research organization or quality control laboratory), by the WHO Prequalification of Medicines Programme, if WHO has concerns regarding compliance of the site with specified standards such as Good Manufacturing Practices (GMP), Good Clinical Practices (GCP) or Good Laboratory Practices (GLP). In other words an NOC contains the factual observations made during an inspection.

NOC was introduced in Jun 2008 by the WHO Prequalification of Medicines Programme.The WHO Notices of Concern are very similar to FDA Warning Letters.  Like FDA Warning Letters, NOC  is also published on the internet.

An NOC states observations made during an inspection that are considered to be "critical" or "major" non-compliances with WHO norms and standards, that are of concern in relation to quality management or quality assurance; or "critical" or "major" non-compliances with WHO norms and standards that were not satisfactorily addressed in the response from the company to an inspection. 

If there are immediate public health concerns or if the inspection observations relate to misrepresentation of data, falsification or manipulation of data with the intent to deceive, the NOC will be immediately published on the Prequalification of Medicines Programme web site. In other cases the NOC will be published after the corrective actions described in the response to the observations noted in the NOC have been reviewed and the review determines that the corrective actions are unsatisfactory (which may include not providing suitable objective evidence of corrective actions, if applicable).  It may also be published if a response to the observations noted in the NOC is not received within 30 days from the date of the NOC, as requested. In addition, an NOC may be issued if a manufacturer refuses inspection of their manufacturing site.

An NOC will remain active on the WHO Prequalification of Medicines Programme web site until WHO is satisfied with firms CAPA.

During the period that an NOC is in place the PQ Team Inspection Services will perform additional and more frequent inspections if the site is still supplying prequalified product. If the site has been suspended then the next inspection will be performed when the company advises that it considers that it has adequately dealt with the matters that led to the NOC. Following such follow up inspections and if satisfied that sufficient improvements have been made by the site, PQT Inspection Services will recommend the lifting of the NOC and that the site inspected may be named/continue to be named in the relevant dossiers under prequalification or already prequalified. If the NOC has been published on the website then the NOC is then removed from the website and placed in the archive.

WHO Enforcement Actions

If WHO identifies a public health risk, appropriate additional steps are taken to safeguard public health.  These steps may include:

• Suspension of products on the "List of prequalified products"; (Notice of Suspension)
• Recall of batches of products on the "List of prequalified products" that had been supplied by a manufacturer;
• Rejection of applications submitted for assessment to the Prequalification Programme.

ICH Announces Organisational and Name changes

ICH Announces Organisational Changes

As a part of reformation, on 23 October 2015 “International Conference on Harmonisation” (ICH) has changed its name as “International Council for Harmonisation" (ICH)

ICH was established in April 1990.An agreement between European Union, Japan and United states resulted the inception of ICH. The motive was to bringing together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration.

On the occasion of its 25 years of existence, ICH has announced to reinforce its foundations to make it better-equipped to face the challenges of global pharmaceutical development and regulation.

The reforms will mean that ICH is expanding beyond the current ICH members. More involvement from regulators around the world is welcomed and expected, as they will be invited to join counterparts from Europe, Japan, USA, Canada and Switzerland as ICH regulatory members.

The changes give ICH a more stable operating structure through the establishment of an ICH association, a legal entity under Swiss law. The association establishes the new Assembly as the over-arching governing body that will be instrumental in facilitating future growth through the participation of new members.

FDA INSPECTION AND ENFORCEMENT ACTIONS

FDA INSPECTION AND ENFORCEMENT ACTIONS

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)’ .This should be done in 30 working dates. 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. The company must respond within 15 days and explained in detail how to resolve the deficiencies on the one hand and how a recurrence can be prevented on the other hand.

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 Enforcement Actions

As an outcome of noncompliance, following unpleasant events can happen.

1.Influence on product approval:

Temporary Denial of Approval: FDA can withhold approvals of generic drug applications if the firm is under active criminal investigation for dishonest conduct involving its drug applications (for example, bribery or material misrepresentations).
Withdrawal of Approval: For a generic drug that's already been approved, FDA may withdraw that approval if the company used bribery or fraud to get approval or if the company can't produce the drug properly.

2.FDA Import Alert:

The company's product (or products) may no longer be imported into the United States. The goods remain at customs. An import alert allows FDA to detain, without physically exam­ining; products that either have or potentially could violate the Food, Drug, and Cosmetic Act. 

3.Debarment of Individuals and Firms:

Permissive Debarment of Individuals: FDA has the option to debar, for up to five years, individuals convicted of certain crimes, described in the act, that are related to the regulation of drugs but do not require mandatory debarment. In January 1997, FDA used this authority for the first time, debarring the head of a blood plasma facility convicted of falsifying blood records.

Debarment of Firms: Firms are also subject to mandatory or permissive debarment. They can be prohibited from submitting applications for generic drug approval (in this case, the law lives up to its name and only applies to generics) for certain crimes relating to the development or approval of generic drug applications. They can be debarred for up to 10 years, depending on the seriousness of the crime and other factors, and they can be debarred permanently if they are convicted a second time while debarred.

4.Civil Penalties:

Besides fines for violating a debarment, fines of up to $1 million may also be imposed on a company for bribery, false statements, or other wrongful conduct involving a generic drug application.

5.Suspension of Distribution:

FDA can suspend marketing of some or all of a company's drug products if the company is under investigation for certain conduct that may influence the safety or effectiveness of a drug.

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