TGA introduces shorter Surveillance Inspections

From 1 July 2024, the Australian TGA will introduce, at least temporarily, new regulations for GMP inspections of domestic and foreign manufacturers of medicinal products, active pharmaceutical ingredients (APIs), biological products and blood products, so-called surveillance inspections.

These are repeat inspections of manufacturers with a shorter duration, but according to the TGA with full scope. This means that the inspection should cover all aspects of the pharmaceutical quality system (PQS) and the operations, but be reduced by around 50 % of the usual inspection time.

The GMP certificates issued after the inspection will then state that a surveillance inspection has been carried out.

Who is eligible for this?

Both domestic and foreign manufacturers who received a "good" or "satisfactory" rating (A1 or A2) in their last TGA inspection. However, there are also clearly defined exceptions where shortened inspections are not possible.

Objectives

The primary aim is to reduce overdue re-inspections to a level commensurate with the manufacturer's risk and to reduce business disruption caused by delays in re-inspections

Is it possible to remove a Biofilm in pharmaceutical Water Systems?

advantage is that the increased temperature also reaches areas that are difficult to access, such as branch pipes, if the duration of the thermal sanitization is long enough. Temperatures of 70-80 °C are common. Hot systems are therefore self-sanitizing.

Conclusion

The removal of biofilms from pharmaceutical water systems is difficult. Therefore, the measure should not be the removal of a biofilm, but the prevention of such a biofilm. An appropriate system design is essential for this (no dead leg, stub lines, cold spots, etc.). Ozonization of the system is very helpful in preventing biofilm. Regular heating of the entire system is also a good prevention strategy. The most important aspect, however, is to avoid stagnant water. This applies to the entire system as well as to individual components, which should be able to be drained. The water system should therefore not be left standing over the weekend, but should rather be producing water in the design. The motto is: "keep it running!"

Change Control and (Re)Validation - The FDA Perspective

The topic of revalidation is rarely mentioned in the regulations. Ongoing/continued process verification has replaced regular revalidation (with exceptions in the sterile area). But what can happen after a change control? Read the FDA's opinion below.

In a Warning Letter, the FDA describes what it expects in the event of a change in the process. What is it about?

The lack of sufficient validation was criticised. In addition, as a result of customer complaints regarding the viscosity of the product, the company changed two ingredients without change control. The new process was not (re)validated. The FDA does not explicitly refer to revalidation here, but only validation. With reference to its process validation guideline, the FDA then explains what it understands by process validation.

The company's response that it had initiated a structured approach to process validation was not sufficient for the FDA. The authority requires the demonstration of appropriate process validation procedures and plans. Furthermore, the FDA would like to see a timeline for the implementation of CAPA measures or risk assessments on products that have been released without appropriate validation or testing.

The FDA further requires

A plan to ensure that there is continuous monitoring throughout the manufacturing lifecycle of all medicinal products. 

A data-driven and science-based programme to identify process variability and ensure that the necessary parameters and product quality are maintained. 

A summary of the validation programme to ensure that a state of control is maintained throughout the product life cycle, together with the associated procedures. 

A description of the Process Performance Qualification (PPQ) programme 

A description of the monitoring activities to assess intra-batch and inter-batch variability to ensure state of control 

A schedule for the implementation of the PPQ for each of the marketed medicinal products 

A detailed programme for the development, validation, maintenance, control and monitoring of each manufacturing process, with regard to intra- and inter-batch variability to ensure a state of control 

A programme for the qualification of plant and equipment.

Conclusion: Process changes can trigger an event-related (re)validation, whereby the FDA does not use the term revalidation, but only refers to validation.

Containment: What is the Difference between OEB and OEL

In manufacturing, where potentially hazardous substances are handled, concepts such as Occupational Exposure Bands (OEB) and Occupational Exposure Limits (OEL) play a crucial role in employee safety. The two terms, OEB and OEL, are often used interchangeably, but there are clear differences.

What does OEB mean?

OEB stands for Occupational Exposure Bands (OEB). This is a method of classifying substances based on their hazard potential or toxicity, particularly in relation to inhalation exposure. OEBs are usually classified on a scale of 1 to 5, with OEB 1 representing substances with the lowest hazard potential and OEB 5 representing substances with the highest hazard potential. The OEB bands are not standardized, but are defined by companies themselves. So, there can be deviations, which is important for external employees who deal with containment areas of different companies. OEBs should actually be better called iOEBs, for internal Occupational Exposure Bands.

In practice, by specifying the OEBs, a quick and simple classification is possible, which is immediately understandable for the employees. This is safer than, for example, specifying 10-100 µg/m3 when a new product comes into the company and protective measures are explained. "We are receiving an OEB 4 product" is easier than a '1-10 µg/m3 product'.

What does OEL mean?

Occupational Exposure Limits (OEL) are quantified limit values for the permissible exposure of employees to hazardous substances during their work. These limits are usually expressed in ppm or µg/m3 or mg/m3 and are based on the toxic data of the substance and the current state of knowledge about possible health effects. OELs are set by various organizations and authorities, such as the American Conference of Governmental Industrial Hygienists (ACGIH), the European Medicines Agency (EMA) or the Occupational Safety and Health Administration (OSHA).

Differences between OEB and OEL

Although OEBs and OELs are both used to control employee exposure to hazardous substances, there are important differences:

Classification vs. quantification: OEBs classify substances according to their hazard potential, while OELs set quantified exposure limits. 

Subjectivity vs. objectivity: The classification of a substance according to an OEB can be more subjective and based on a comprehensive assessment of various factors, whereas an OEL is based on objective scientific data and threshold values. 

Scope: OEBs are often used to assess the risk of exposures at early stages of development or when information is limited, while OELs serve as specific guidelines to meet exposure limits in practice.

Example

Here is an example to illustrate this: a new active substance in development is provisionally classified as OEB 4 based on limited toxicological data, indicating a high hazard potential and the associated protective measures. Based on subsequent studies and analysis, an OEL of 1 ppm is set to limit employee exposure based on the specific toxicity data.

So, while OEBs classify substances according to their hazard potential in bands or areas, OELs set quantified limits for the permissible exposure of employees. Both concepts complement each other and are crucial to ensure the health and safety of employees through adequate exposure control

FDA Warning Letter on Data Integrity Issues Dominican company Laboratorio Magnachem

On June 18, 2024, the FDA issued a Warning Letter to the Dominican company Laboratorio Magnachem International regarding CGMP violations. The Warning Letter is based on an FDA inspection in November 2023. The company's responses dated December 1, 2023 to the complaints listed in the Form 483 were insufficient in the FDA's view. FDA Warning Letters always reference the GMP requirements set out in 21 CFR Part 211, in this case for data integrity complaints:

"Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(a))"

In general, comprehensive control of CGMP data is expected to ensure that all changes, deletions and additions of information to electronic records are authorized and documented.

Observations

The laboratory equipment used to generate analytical data for the release of finished medicinal products has no access protection and no further controls.

There are no adequate controls to prevent data deletion and record alteration

There is no definition of unique user names and passwords

Laboratory staff have administrator rights that allow uncontrolled access to delete or modify HPLC files

There is no way to track individuals who have deleted or modified data generated by the IT system

There are no adequate backup copies of the data generated by the laboratory equipment

Response from the company

The company's responses to this observation were inadequate. Why?

The company stated that it had found a supplier for the management of equipment data and that the HPLC management system was being assessed by this supplier. They had a process in place to address data integrity issues. The FDA was not satisfied with these statements. No interim measures were taken to protect patients and ensure drug quality, e.g.

Notification of customers

Recall of products

Conducting additional tests

Inclusion of batches in the stability program

Increased monitoring of complaints

What does the FDA expect when responding to this Warning Letter?

A complete assessment of the documentation systems used throughout the manufacturing and laboratory operations to determine where documentation procedures are inadequate

A detailed CAPA plan that comprehensively corrects the company's documentation practices to ensure that the company maintains assignable, legible, complete, original, accurate and timely records throughout the operation

A comprehensive, independent assessment and CAPA plan for the security and integrity of the computer system

Interim controls should also be described and details provided of when the procedures for the CAPAs will be implemented

FDA Warning Letter to a Manufacturer of an Athlete Muscle Maintenance Creme

On 9 July, the FDA issued a Warning Letter to a Korean manufacturer registered as a manufacturer of over-the-counter drugs. With the Warning Letter, the FDA is responding to the documents it received from this manufacturer in response to two requests in 2022 and 2024. Since the methods, facilities or controls described in the company's response for the manufacture, processing, packaging or storage of drugs do not comply with CGMP, they are automatically considered adulterated and non-compliant.

Content

The Warning Letter lists a number of violations:

1. Lack of an adequate and written testing programme to assess stability properties. Only 3 months of data were available, with a shelf life of 2 years. There was therefore a lack of sufficient chemical and microbiological tests and data. This meant that there was no proof of compliance with the defined specifications and quality over the shelf life period.

2. The raw materials used had not been sufficiently tested with regard to identity and conformity, e.g. purity, starch and quality. This also included the error frequently identified in recent months that the batches of glycerine used were not tested for the limit values of diethylene glycol (DEG) and ethylene glycol. The FDA points this out again in its Warning Letter:

"The use of glycerin contaminated with DEG and EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for DEG or EG contamination at https://www.fda.gov/media/167974/download.."

FDA Warning Letter to a Manufacturer of an Athlete Muscle Maintenance Creme

On 9 July, the FDA issued a Warning Letter to a Korean manufacturer registered as a manufacturer of over-the-counter drugs. With the Warning Letter, the FDA is responding to the documents it received from this manufacturer in response to two requests in 2022 and 2024. Since the methods, facilities or controls described in the company's response for the manufacture, processing, packaging or storage of drugs do not comply with CGMP, they are automatically considered adulterated and non-compliant.

Content

The Warning Letter lists a number of violations:

1. Lack of an adequate and written testing programme to assess stability properties. Only 3 months of data were available, with a shelf life of 2 years. There was therefore a lack of sufficient chemical and microbiological tests and data. This meant that there was no proof of compliance with the defined specifications and quality over the shelf life period.

2. The raw materials used had not been sufficiently tested with regard to identity and conformity, e.g. purity, starch and quality. This also included the error frequently identified in recent months that the batches of glycerine used were not tested for the limit values of diethylene glycol (DEG) and ethylene glycol. The FDA points this out again in its Warning Letter:

"The use of glycerin contaminated with DEG and EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for DEG or EG contamination at https://www.fda.gov/media/167974/download.."

Conclusion

Since the company could not demonstrate that adequate testing of the manufactured products and starting materials was performed, e.g., the certificates of analysis you submitted for dermaFIT Athlete Muscle Maintenance Cream did not include adequate assay testing for active ingredient content or microbiological testing.

Accordingly, the FDA recommends that a GMP consultant be consulted and advises that the FDA may withhold approval of new applications or supplements until all violations are fully corrected and compliance with CGMP is confirmed.

FDA describes detailed CAPA Procedure in Warning Letter

An FDA Warning Letter is a formal communication from the US Food and Drug Administration (FDA) notifying a company or individual of regulatory violations. These typically describe observations made during an inspection and list violations found (referencing the specific sections of the FD&C Act, the Code of Federal Regulations (CFR), and other applicable laws as appropriate). In addition, specific measures are listed that the recipient must take to remedy the violations. It does not go into great detail, especially not with regard to instructions on the desired procedure.

In a Warning Letter issued to Sun Pharmaceutical Industries Limited (India) at the beginning of July, this is now different. It describes in great detail what the FDA considers to be appropriate CAPA measures in a specific case.

What happened?

The company was criticised for not adequately cleaning and maintaining the equipment used to manufacture drug products. According to the company's response, a defective valve was the cause of the observed liquid build-up. This was discovered in the course of investigating the cause following the inspector's observation. Affected batches were recalled, but this was not enough for the FDA, which now lists very specifically what to expect:

A comprehensive, independent retrospective evaluation of the effectiveness of cleaning measures, including consideration of production equipment that may have been improperly cleaned.

A corrective and preventive action plan (CAPA) based on the retrospective assessment of the cleaning programme, including appropriate corrective actions for cleaning procedures and practices and a timeline for completion.

A detailed summary of weaknesses in the process for the life cycle management of equipment cleaning.

Identification of improvement actions to the cleaning programme, cleaning effectiveness and improved ongoing verification of proper performance.

Among other things, the CAPA plan should ensure that potential problems with equipment are recognised immediately so that, for example, repairs are carried out effectively. The plan should also ensure that appropriate action is taken across the organisation's network.

The CAPA plan must comprehensively address any gaps identified by an external consultant when assessing the maintenance programme.

The review of the effectiveness of the CAPA measures must include at least the following:

Evaluation of improvements to cleaning and maintenance procedures, including determining the specific frequency and locations to be cleaned at all relevant facilities

Adequacy of maintenance and repair history analysis

Assessment of all major production facilities for other sources of cross-contamination

Adequacy of improvements to the method of analysis to identify residual carryover

Adequacy of investigations of other unknown (unidentified) peaks

Assessment of whether the scope of the investigation and the associated CAPA were sufficient

However, the FDA was also not satisfied with the measures taken in the investigation of OOS results: "Your investigations of out-of-specification (OOS) results were inadequate because they lacked scientific rationale for root cause determinations."

FDA Warning Letter - Missing incoming Control Tests

In June 2024, the U.S. FDA issued a Warning Letter to the Portuguese company "Fancystage Unipessoal, LDA" after having inspected its site in January 2024.

The significant violations of CGMP regulations for drug products, which are mentioned in the Warning Letter, are listed as follows:

"Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier's test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2))."

"Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a))."

"Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b))."

"Your firm's quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22)."

According to U.S. FDA Warning Letter, the firm failed to do proper incoming control tests to identify the goods. Testing and sampling of incoming goods are mandatory to verify the identity of the received materials and CGMP qualified suppliers are required. "ICH Q7 Good manufacturing practice for active pharmaceutical ingredients" guideline clearly describes these requirements in chapter 7.3 "Sampling and Testing of Incoming Production Materials".

The observed findings resulted in a long list of remediation activities and CAPA measurements requested.

Coming to the final conclusion mentioned in the Warning Letter, the U.S. FDA has issued an import alert for this company. Engaging a consultant to ensure that the company will be CGMP compliant from now on is highly recommended in the Warning Letter.

Fancystage Unipessoal, LDA WL

In June 2024, the U.S. FDA issued a Warning Letter to the Portuguese company "Fancystage Unipessoal, LDA" after having inspected its site in January 2024.

The significant violations of CGMP regulations for drug products, which are mentioned in the Warning Letter, are listed as follows:

"Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier's test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2))."

"Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a))."

"Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b))."

"Your firm's quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22)."

According to U.S. FDA Warning Letter, the firm failed to do proper incoming control tests to identify the goods. Testing and sampling of incoming goods are mandatory to verify the identity of the received materials and CGMP qualified suppliers are required. "ICH Q7 Good manufacturing practice for active pharmaceutical ingredients" guideline clearly describes these requirements in chapter 7.3 "Sampling and Testing of Incoming Production Materials".

The observed findings resulted in a long list of remediation activities and CAPA measurements requested.

Coming to the final conclusion mentioned in the Warning Letter, the U.S. FDA has issued an import alert for this company. Engaging a consultant to ensure that the company will be CGMP compliant from now on is highly recommended in the Warning Letter.