Siegfried Schmitt, PhD, is Vice President Technical at Parexel International, Siegfried.Schmitt@parexel.com.

Siegfried Schmitt

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Q: We are revising our audits and inspections programs and wanted some advice on best practices. How can we limit the number of on-site audits or inspections?

A: Companies need to find the right balance between the different types of audits, be it a questionnaire, a remote (virtual) or an on-site audit, or a combination of these. A number of reasons have to be taken into consideration, including criticality of the product or service, the feasibility of the type of audit, the regulatory expectations, and others. Here, the company is in charge of the decision making.

This is different in the case of inspections. It is at the discretion of the inspecting authority what type of inspection they will perform. The inspected company can greatly help such an inspection succeed if they are suitably prepared for the various scenarios, especially with regards to remote inspections.

Let us first address the audit program. It is essential to understand that there are fundamental differences between the different types of audits. The following examples shall exemplify this.

A third-party logistics (3PL) company with its own warehouses and fleet of transport vehicles is to be audited. The 3PL fills in a questionnaire sent by the customer. According to the answers, the company is in full compliance with all good distribution practice requirements. The customer decides to perform a virtual audit of the 3PL. This allows for a review of the actual documentation and a virtual site tour. Everything is clean, and there is sufficient space for performing the work. All seems to be fully compliant. However, the customer decides to perform an on-site audit. The documentation is the same; although, it is now possible to have several documents next to each other and cross-reference easily. Importantly, the premises and operations can now be seen firsthand, making it possible to see problems such as cracks in the concrete floor of the warehouse, paint peeling off the wall, insect traps that hadn’t been cleaned for too long, aisles blocked by pallets because there actually isn’t enough space, and electronic access controls being bypassed by doors that were propped open. Just be aware.

In reverse, if you the customer get inspected, you do not want to be the one who isn’t open and honest. You want to present truthfully what you do and how you do it. And this you want to do equally well, whether it is a virtual or an on-site inspection. Plenty has been published about preparing for on-site inspections, and companies are usually well prepared. The issues are still with preparing best for virtual audits. Specifically, can you share all documents electronically, including logbooks or other paper documentation? Can you show live video of all areas without a wobbling (handheld) camera? These are the two most challenging aspects of such inspections.

Updating your audits and inspections program gives you a chance to make sure you are as prepared for inspections as you would want your suppliers to be prepared for your audits.

Siegfried Schmitt is vice president, Technical at Parexel.

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Vol. 48, No. 9
September 2024
Pages: 34

When referring to this article, please cite it as Schmitt, S. Keeping Audit and Inspection Programs Current. 

Articles

Updating your audits and inspections program ensures inspection preparedness, says Siegfried Schmitt, vice president, Technical at Parexel.

Keeping Audit and Inspection Programs Current

Q: We received a warning letter (WL) from FDA, to which we provided a written response. Although we are confident that our reply is comprehensive, we would like to get confirmation from FDA. Is there a way to ask FDA to give us this feedback?

A: It is understandable that you want to be certain that your response to FDA is complete and acceptable. You should stay in contact with the person(s) mentioned in your WL and to who you addressed your response letter. In addition, under the Generic Drug User Fee Amendments (GDUFA or GDUFA III Commitment Letter) (1), your facility may be eligible for a Post-Warning Letter Meeting, as described in section VII(D)(1) of the GDUFA III commitment letter (2).

You can only be granted such a meeting if you have “submitted to FDA a thorough and complete corrective action and preventive action (CAPA) plan that addresses all items cited in the warning letter, and reasonable progress has been made toward remediation” (2). As mentioned above, your facility needs to keep FDA informed regularly about progress with the remediation effort as detailed in the CAPA plan. As FDA must see what progress you made, they cannot grant a meeting earlier than six months from the date of a company’s initial response to a WL. In fact, you should be certain that you have reached significant milestones in your remediation program before applying for a Post-Warning Letter Meeting, or FDA may deny you such a meeting.

What can you expect from such a meeting with FDA? The meeting will allow you to present the remediation progress to date and the projected completion dates for any remaining CAPA activities. FDA will voice any concerns they may have regarding your roadmap back into compliance. The agency will tell you if you are on the right track or if additional efforts are needed. It will give you assurance that your planning schedule is appropriate. It should be noted that FDA’s advice is not binding. Furthermore, agreeing to a Post-Warning Letter Meeting “does not preclude FDA from taking any regulatory actions necessary, including a follow-up inspection at any time” (2). You can request a maximum of two Post-Warning Letter Meetings.

Success depends very much on good preparation. You should, therefore, study the FDA’s draft guidance (3) that provides information on how to prepare the Meeting Package and the Meeting Package Content. Should you be eligible for such a meeting, it is recommended that you include this in your overall communication plan with FDA. Returning to a compliant state of operations at your facility has highest priority. Leveraging all available tools to inform and convince the agency of your sincere intentions, actual progress, and estimated fulfillment dates of all commitments is a sensible and logical approach.

FDA. Post-Warning Letter Meetings Under GDUFA. September 2023, 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/post-warning-letter-meetings-under-gdufa

GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027

. https://www.fda.gov/media/153631/download

Post-Warning Letter Meetings Under GDUFA Guidance for Industry

https://www.fda.gov/media/171785/download

When referring to this article, please cite it as Schmitt, S. Post-Warning Letter Interaction with FDA. 

Communication and meetings with FDA after receiving a warning letter 
demonstrates a serious response, says Siegfried Schmitt, vice president, Technical at Parexel.


Post-Warning Letter Interaction with FDA

Q: We read in an article (1) that there are no specific good manufacturing practice (GMP) regulations for emerging therapies in the United States, yet we wish to bring our emerging therapy products to the US market. How can we make sure our products comply with current regulations?

A: In the absence of specific regulations for your products, the existing generic regulations, such as 21 Code of Federal Regulations (CFR), 600 Biological Products (2), will apply as appropriate. Also, international harmonized guidelines, such as International Council for Harmonisation (ICH) Q9(R1) Quality Risk Management and ICH Q10 Pharmaceutical Quality System (3,4) need to be followed and complied with. However, these are not the only sources of regulatory information available. FDA has published guidance on cellular and gene therapy products (5), which includes guidance and information on “Regenerative Medicine Advanced Therapy Designation” and on “Interactions with Office of Tissues and Advanced Therapies”.

Companies, especially developers of new types of drugs, are encouraged to interact with the regulatory authorities early on in the drug development cycle, and FDA is no exception. There are multiple opportunities for formal as well as informal meetings with FDA, and FDA’s website provides an excellent overview, including links to further information (6).

There is more information out there, free of charge, and most likely relevant to the products your company is currently developing. Though international regulations are only harmonized to some degree, there is generally a broad consensus on the basic principles of GMP, be it for traditional drug products or novel, emerging therapy products. Therefore, companies should look at regulations from other regions (e.g., the European Union [EU]) and guidance from key agencies, such as the European Medicines Agency (EMA). The EU have issued specific regulations for advanced therapy medicinal products (7), recognizing the need to address compliance for these products separately. The GMP requirements detailed in here will broadly be the same that FDA expects. Aspects that require further guidance and clarification are often covered in “Questions & Answers” documents published by EMA. An EMA Q&A document published in 2011 (8) discusses, for example, how to identify the minimum GMP requirements for starting materials, considering quality management, quality risk management, product development, production, and quality control.

These are just a few pieces of information in response to your question. There is much more information available online, from specialist publications, subject matter experts, and not least directly from the regulatory agencies through their consultation mechanisms.

Thomas, F. Optimizing the Manufacture of Emerging Therapies. 

FDA. Interactions with Office of Therapeutic Products. 

EC. Part IV, GMP requirements for Advanced Therapy Medicinal Products. 

Questions and Answers on the Principles of GMP for the Manufacturing of Starting Materials of Biological Origin Used to Transfer Genetic Material for the Manufacturing of ATMPs,

When referring to this article, please cite it as Schmitt, S. GMPs for Emerging Therapies.

Guidance documents and interaction with FDA can help manufacturers stay in GMP compliance, says Siegfried Schmitt, VP Technical, at Parexel.

Emerging Therapies and GMPs

Q. We understand that as the marketing authorization holder we are accountable for the storage and distribution of our products when we send them to the market. How can we enforce good distribution practice (GDP) with the shipping companies that we contract with?

A. The number of contractors and subcontractors involved in the supply chain for finished goods can be high, and their relationships very complex, particularly when goods are shipped by air or sea. Depending on the scope of the activity (e.g., whether the shipping company is performing transport by land, air, or sea only; whether the company is also a wholesaler; or whether they store the products in their warehouses), and depending on the applicable regulations, these companies may or may not have to comply with GDP regulations. This is probably why you found it difficult to assure that the shipping organizations follow and adhere to GDP.

Transport companies in general are knowledgeable in handling delicate goods, goods that need to be kept at certain temperatures (e.g., foodstuff), and goods of a high value. Thus, many will have a certain level of control for the safe and controlled transport of goods in place. Some companies have already established either pharma-specific transportation services or at least have some experience with transporting pharmaceuticals. These are the companies to look out for in the first place.

Typically, the key issues with regards to GDP concern the maturity of the contractors’ quality systems, their documentation (completeness and trustworthiness), the correct and careful handling, and traceability (knowing where your goods are at any time in the supply chain). The recommended approach is, therefore, for the license holder to negotiate, educate, contract, and then oversee the transportation contractor.

As already mentioned, many of these companies are not required by law to adhere to GDP, so they are unlikely to be aware of the GDP regulations, or how they should implement and adhere to these. Support from the contract giver is called for. Establishing a partnership will provide a win-win situation. This support may include GDP training, support with the upgrade of the contractor’s quality system to include the relevant GDP elements, supplying suitable transport containers, etc.

The relationship must be documented in a quality/technical agreement (1), which should be as granular and detailed as possible, covering all aspects of the outsourced transportation services. For example, rather than merely saying: “the contractor will transport products in table A in temperature controlled vehicles”, this could be detailed as:

“products in table A will be transported:

in dedicated (pharmaceuticals only) temperature-controlled vehicles.

the vehicles are equipped with automatic temperature recording devices.

the temperature logs are automatically transferred to a printout in the vehicles and transferred electronically to a data center.

the vehicles are equipped with automatic GPS locators.”

This agreement should also include key performance indicators, such as time to notification in case of deviations (e.g., temperature excursions), the expected frequency of routine audits by the contract giver, and any other oversight activities deemed necessary.

It is through these measures that you should be able to assure your contractors are as compliant as possible with GDP. It may not be an easy and immediate success, but it will certainly be so in the long term.

EudraLex Volume 4, Chapter 7, Outsourced Activities

When referring to this article, please cite it as Schmitt, S. Ensuring Contractors Perform Good Distribution Practices. 

The license holder should negotiate, educate, contract, and then oversee 
the transportation contractor, says Siegfried Schmitt, vice president, Technical at Parexel. 

Ensuring Contractors Perform Good Distribution Practices

Q. We are planning to market a new drug (film coated tablets of the biotech product in nine different blister pack sizes) in the United States and the European Union. In support of the application, we must perform process validation and we will need to have stability data. To minimize the number of batches, we intend to manufacture three commercial-size batches of the tablets, then split each batch into three to create nine sub batches (one batch for each blister pack size). We will then take samples from each blister pack size to test stability. Is this a compliant approach?

A. You correctly state that you need to perform process validation and collect stability data for the various pack sizes. The question to answer is whether your batch sizes are in compliance with the regulations. Though the batch size for the tablets is at commercial scale, the batch size for each of the nine packaging runs is only a third of commercial scale.

The globally accepted standard for stability testing is International Council for Harmonisation (ICH) Q1A(R2) Stability Testing of New Drug Substances and Products (1). Herein, the minimum batch size requirement is, “The batches should be manufactured to a minimum of pilot scale.”

FDA confirms this requirement (2), stating that these batches can be “either pilot scale or a small scale batch.”

The European Medicines Agency (EMA) refers to the ICH guidance on their “quality: stability” website (3) and mentions “pilot scale” as the minimum batch size in their variation guidance listed on this website.

The Parenteral Drug Association’s (PDA) Technical Report 60-2 Process Validation: A Lifecycle Approach–1 Oral Solid Dosage/Semisolid Dosage Forms Annex (4), which reflects industry best practices, refers to batches for stability testing at 10–15% of commercial batch volume.

Your batch size of a third (i.e., 33%) of commercial batch size, with the aim to demonstrate the appropriate quality of the drug product on stability, is thus compliant with regulatory expectations and the laws.

At this scale, however, these batches cannot be used for process validation for a drug product to be approved for marketing in either the US or the EU. Process validation for a drug product, even a generic-drug product, has to be done with commercial scale (packaging) batches.

The reason is that process validation has to cover all the unit operations involved in the packaging process at the commercial scale. If the same batch is split at the packaging stage into sub-batches for different pack sizes, then validation of the packaging step will be incomplete. For example, sampling during blister packaging needs to be done at different time points (including beginning, middle, and end) of packaging of a commercial size batch. Full-scale manufacturing may take so long that shift changes may be required, or new rolls of foil may be required. These interventions may not happen during the manufacture at the reduced batch size. Process validation is defined as follows:

EMA definition of process validation (5): “The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to product a medicinal product meeting its predetermined specifications and quality attributes.”

FDA definition of process validation (6): “The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products.”

Although the definition of process validation differs somewhat between the EU and US, the requirements for commercial batch size for process validation do not. The details can be found in the two documents referenced above.

Stability Testing of New Drug Substances and Products

Questions and Answers on Quality-Related Controlled

Technical Report 60-2 Process Validation: A Lifecycle

Approach - 1 Oral Solid Dosage/Semisolid Dosage Forms Annex

Guideline on Process Validation for Finished Products–Information and Data to be Provided in Regulatory Submissions,

 EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1,Corr.1, Nov. 21, 2016.

Guidance for Industry, Process Validation: General Principles and Practices

When referring to this article, please cite it as S. Schmitt, “Which Batch Size for Validation and Stability Studies?,” 

Process validation for a drug product must be done with commercial scale batches, says Siegfried Schmitt, vice president, Technical at Parexel.


Which Batch Size for Validation and Stability Studies?

In February 2020, travel ceased as the COVID-19 pandemic began to emerge. Since that time, we have come a long way with stay-at-home orders, social distancing, testing, tracing, and quarantine. Countries that implemented aggressive public health measures have had fewer cases and fewer deaths. The regulatory authorities also ceased to travel and were forced to utilize alternative mechanisms to assess industry compliance and review and approve new applications. This article discusses select industry experience with regulatory authorities utilizing alternative mechanisms for assessing compliance as part of their review and approval of existing marketing authorizations or new applications.

Until the time of the pandemic, the norm was that inspections would be performed as in-person on-site inspections. In the case of the European Union, Amended Directive 2001/83/EC, article 46(f) (1) explicitly states, “the holder of the manufacturing authorisation shall verify compliance by the manufacturer and distributors of active substances with good manufacturing practice and good distribution practices by conducting audits at the manufacturing and distribution sites…” [emphasis added by author].

Pharmaceutical Technology’s Quality and Regulatory Sourcebook eBook

James Stumpff, RPh, is principal consultant at Parexel International. Siegfried Schmitt, PhD, is vice president Technical at Parexel International.

When referring to this article, please cite it as J. Stumpff, S. Schmitt, “Remote Inspections - Lessons Learned," 

This article discusses select industry experience with regulatory authorities utilizing alternative mechanisms for assessing compliance as part of their review and approval of existing marketing authorizations or new applications.