The Value of Utilising External Consultants in the Pharmaceutical Business

Why would a successful business use external consultants? Surely, they would already have all the expertise onboard? That’s what you would think; however, the reality is somewhat different.

So why would a successful business use external expertise and consultants? What are the benefits, and how will it help a business develop faster and gain more traction in the marketplace?

Firstly, let's look at the typical areas that it might cover, specifically in the pharmaceutical industry. As we all know, this industry is highly complex in terms of regulations and relies on the latest technologies, sometimes disruptive ones.

So, it is unlikely that any one business is going to have the internal knowledge to navigate some pretty challenging waters.

Areas such as GMP and cGMP, analytical services and new regulations such as the recently introduced Annex 1 and now with the more disruptive elements of Pharma 4.0 and AI, let alone the advances in the more established technologies including Freeze Drying, Filling, Milling, Blending, Inhalations technologies and more.

This is where having access to an array of external experts that a business can call on at any time to support internal teams is incredibly important and, in today's world, perhaps critical.

To further emphasize this point, perhaps we should examine what regulators, such as the FDA, think of the use of external consultants. Their view seems very clear, as the examples below suggest.

Example 1

The Warning Letter dated February 2024 contains the following:

“Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements before resuming drug manufacturing operations.”

Thai Nakorn Patana Co., Ltd. - 672712 - 02/27/2024 | FDA (Verified as of 3/21/2024)

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/thai-nakorn-patana-co-ltd-672712-02272024

Example 2

The Warning Letter dated February 2024 contains the following:

“CGMP Consultant Recommended
Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit² of your entire operation for CGMP compliance and evaluate the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA”.

Bell International Laboratories, Inc. - 669736 - 02/15/2024 | FDA (verified as of 3/21/204) https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/bell-international-laboratories-inc-669736-02152024

Example 3

The Warning Letter dated February 2024 contains the following:
“CGMP Consultant Recommended
Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a (b)(4)-system audit¹ of your entire operation for CGMP compliance and evaluate the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA”.
Colgin, Inc. - 670332 - 01/25/2024 | FDA(verified as of 3/21/2024)

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/colgin-inc-670332-01252024

The above 3 Warning Letter examples were just from the month of February 2024. There are several other Warning Letters containing the statement for the utilization or use of consultants that can be searched in the US FDA Warning Letter Website:

Warning Letters | FDA(verified as of 4/01/2024)

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters

This makes it clear that any business without access to external consultants is likely to risk falling foul of the regulating authorities.

It is the view of the authors that this is true not only of the pharmaceutical manufacturers but also of any business that supplies equipment, processes, facilities, utilities, project management, and other services to the industry. Because they will be introducing all of these services into the same industry, there will be an expectation that they will have the same or better expertise than the pharmaceutical manufacturer in their specialist area.

How to select a consultant to support your business

So how would you even go about selecting an external consultant to support your business, well thankfully, there is some guidance and from a useful source, the FDA.

They suggest the following process for selecting a consultant.

GMP regulation “21 CFR 211.34” on consultant states that “Consultants advising on the manufacture, processing, packing, or holding of drug products shall have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained. Records shall be maintained stating the name, address, and qualifications of any consultants and the type of service they provide”.

eCFR :: 21 CFR 211.34 -- Consultants. (Verified as of 3/21/2024)

https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-B/section-211.34

Some points to consider when selecting the consultant(s) include:

1.Have a clear objective on what the consultant(s) needs to achieve and complete.

2.Have a timeline for when the objective needs to be completed. 

This includes:

Having the objective and timeline available will enable understanding of:

a. What type of consulting is needed (e.g., API, Drug Product (Small or Large Molecule), Medical Device, Food//Dietary Supplement, etc.)

b. Identify the skill and competency level of consultants to be selected (i.e., whether it’s technical and/or regulatory competency, whether the consultant can start and work immediately or need initial time for training (to understand the firm’s procedure, processes, and tools such as the Document Management System, etc.).

c. Estimate the number of resources needed and to be available (i.e., whether the consulting company has the appropriate amount of resources available).

3. Additional points to consider in selecting the consultant(s) will be whether the consultant(s) need to be working on-site or remotely and whether the consultant(s) need to have a local language (speaking and/or writing) capability.

4. The cost and budget should also be considered and understood, as it may impact the consultant selection.

5. Once the process of gathering information about potential consultants is completed, consider the process for deciding which consultant or companies to finally select. 

Other Reasons and Points to Consider in Utilizing Consultants may include:

1.Improving and maturing the Quality Management System (QMS)

The Quality Unit (e.g., Quality Assurance) ensure compliance with the GxP regulations by establishing a QMS.

A good QMS will include a process for improving the QMS, so that the QMS does not remain static.  Utilizing consultants can provide new perspectives on how to establish the proof to improve the QMS, as the consultants may have a wide perspective gained from their experiences at other business operations and also provide the understanding of the requirements of the evolving regulations and bringing good practices that can be leveraged by the firm (e.g., in the current version of EU GMP Annex 1, it states the need to establish Containment Control System - which is very challenging if you are starting from scratch).
https://health.ec.europa.eu/system/files/2020-02/2020_annex1ps_sterile_medicinal_products_en_0.pdf (verified as of 3/21/2024).

2.Ensuring companies have up-to-date cGMP regulation knowledge (know current expected practices) and provide technical and operational improvement for cost savings.

Compliance with GMP regulations is mandatory. Therefore, it is important for the company to be knowledgeable about up-to-date GMP regulations and their implementation expectations (note: the “c” in cGMP means “current”).

Having consultants is a good approach to measure the company's current practices compared to other companies' operations. It also keeps up with the ‘c’ in cGMP (as in being current and updated on what is going on in the industry and current industry practices). 

For example, thorough and effective on-site training can cover many personnel at once in the following aspects of GMPs:

2.1 Quality Management System (e.g., what trending needs to be done, whether it’s for measuring quality improvement, handling environmental excursions, comprehensiveness of deviation handling, etc.)

2.2 Organization and Personnel (e.g., providing annual or periodic cGMP training to update employees’ knowledge and quality culture, providing updates on regulation and current industry expected practices)

2.3 Building, Facilities, and Equipment (e.g., besides ensuring there’s no regulatory compliance gap, the consultant(s) can also provide and implement optimization of the utilities and equipment operation, such as optimizing the frequency of calibration program for cost-saving measures)

2.4 Control of Components and Drug Product Containers and Closures (e.g., ensuring and improving the compliance of raw material by identifying potential quality risks, such as partially returning it to the warehouse from production, using recycled solvents, etc.)

2.5 Production and Process Controls (e.g., optimizing the process to increase and maintain consistent production yield, narrowing the minimum and maximum range of the actual yield, implementing lean operation methodology to save costs while ensuring regulatory compliance, etc.

2.6 Packaging and Labeling Control (e.g., ensuring compliance with how the label and packaging materials are managed to ensure there are no regulatory compliance lapses, as an external set of eyes and expertise may identify areas and practices that are at risk and need to change).

2.7 Holdings and Distribution (e.g., understanding the MKT (Mean Kinetic Temperature) aspect of the warehouse operation, practicing or performing mock recall, etc.).

2.8 Laboratory Controls (Besides QMS, the laboratory is typically included in the regulatory authority inspection.  Hence, having a consultant to review laboratory operations on a periodic basis is recommended and needs to be highly considered, from sample life cycle management for each type of sample (Raw Material sample, Packaging sample, Intermediate sample, Finish/final product sample, Stability samples, one-off sample, logbooks management, standard management, instrument, see also Data Integrity section of this article).

2.9 Records and Reports

Although this topic may sound simple and straightforward, there are many nuances that some companies' operations may not realize, for example, handling the massive number of records and reports but also having a ‘knowledge management’ discipline in place. Good knowledge management can improve the efficiency of the company’s operation in terms of resources, materials, time, and cost.

2.10  Returned and Salvaged Drug Products

3.Data integrity, information protection for intellectual property, etc.

It’s been common knowledge that Data Integrity has been a significant issue in the industry and being a part of the FDA inspections.

A quick search on the internet using the keywords of Data Integrity and FDA will yield a lengthy result. A company that has always relied on internal resources for ensuring data integrity may benefit from an external set of eyes to review the data integrity program, as there are nuances that the company's internal resources may overlook, whether it’s in the IT operation, Manufacturing automation and control systems, Building management system, etc. There are too many details to be discussed in this short article; it is best for the company to contact an external consultant firm and have a review of their data integrity practices.

For companies that operate as CMOs (Contract Manufacturing Operations), good customer Intellectual Property (IP) control and handling needs to be considered. How should employees have access? How can the company ensure employees cannot walk out with a customer’s IP, etc.?

It is recommended that CMOs have consultants review their IT department’s operations and practices to ensure they are compliant with current regulations. Data is an asset, and IT departments are critical in managing, protecting, and maintaining it. Businesses should ensure their IT department, data privacy regulations (e.g., EU GDPR, HIPAA), and GXP, as well as robust cyber security along with any process data security pathways, including but not exclusively GAMP, GLP and GEP. There are many examples of inspections that demonstrate the lack of sufficient IT department operations and practices, which increases the risk of non-compliance in a business. It is unlikely that any company has all the expertise in this area so working with external consultants will very much help IT departments in the pharmaceutical industry, with all its nuances, to protect the business and develop plans for achieving or remaining compliant. Austar excels in this area not only with its own staff but also by having a network of some of the world’s leading consultants available to support their clients.

An example of this can be seen below from a recent inspection which states:

Interviews of current and former employees to identify the nature,scope, and root cause of data inaccuracies. We recommend that a qualified third party conduct these interviews.

For further clarification, click the link below, which will give full details:

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/kilitch-healthcare-india-limited-672956-03282024

4.Supporting the company’s search and selecting a CMO (Contract Manufacturing Operation) and the related activities (e.g., technology transfer).

Whether the firm is a new start-up firm, a firm that has been in operation for several years, or a firm that is searching for a contract manufacturer to support the firm’s operation, having consultants can help in the following aspects:

4.1 Selection of suppliers, contract manufacturers, contract laboratories, or other third-party services. Although the firm may already have a process in place, periodically having a consultant to support it may provide additional benefits. Consultants typically have the experience and competency gained from different organizations and can provide additional consideration that otherwise the firm may not realize. Hence, ensuring the supplier and any contract organization selection process is improved and up to date in meeting the expected regulations.

4.2 Supporting the technology transfer activities, whether the full technology transfer program (i.e., planning, managing, executing the completion of technology transfer project).

5.Supporting a one-off project (such as validation of utilities, technical competence and quality and regulatory compliance competence)

There are projects in the company that are better supported by the consultant(s). Also, having consultant(s) as temporary resources to supplement the current workforce will help the company's operations continue as usual. Since companies' resources typically already have been allocated to the daily operation, adding these employees' additional responsibilities for the one-off project may impact the daily operation and add more burden than an already stretched business can cope with.

Examples of these one-off projects may include the design of water systems, contamination control, qualification and validation of equipment, and automation of equipment, though we could have used many other examples.

Utilizing consultants who do not impact day-to-day operations is typically less expensive than hiring additional full-time employees to handle the project, as it is a resource that can be “turned on and off” as required.

6.Help reinforce management mandates and expectations and improve the quality of the culture.

Having a mature quality culture is integral to the success of GMP operation and compliance.  Bringing outside consultant(s) will help the management in voicing what they would like their employees to accomplish, as consultants can reinforce the message from other perspectives that help the employees understand and accept the company’s management expectations.

7.Provide technical updates and current technology knowledge.

The industry always advances and improves, from newly designed equipment capabilities and efficiencies to new approaches in operational practices, etc. It’s always beneficial to bring in consultant(s) to provide a technical update on the state of the industry. This provides the company with an understanding of the current available technology and ideas on how to improve and make the company’s operation more efficient.

The consultant(s) can also conduct an open session or forum whereby the consultant(s) can answer questions that employees might have. For example, how to improve product yield, how to decrease the cost of waste, and how to make the company a ‘green’ company.

The technical capability knowledge update provided by the consultant(s) will also keep the employees motivated, as they gain and learn something new and do not feel ‘left behind’ as they advance their knowledge.  

8.Preparation for inspection readiness

Previously, the article discussed the need for consultant(s) as recommended by regulatory authorities such as the FDA in issuing Warning Letters.

It is certainly better if the company can have consultants prior to an inspection by the regulatory authority. This would allow the consultant(s) to review the SOP to identify areas of improvement, ensure compliance with regulations, and pre-audit a facility.

Equally important is training employees to interact with regulatory authorities and properly manage the back room (a.k.a. the war room).

9.Support during an Inspection

Although the consultant may not be able to interact with the regulatory authority during an inspection, the consultant(s) can support the inspection in the background.

If a company has never been inspected before, it is strongly recommended that a consultant(s) support the company in hosting the inspection. 

Certain processes can be provided by consultants and set an example for handling future inspections. The consultant can, for example, manage the back room (a.k.a. the war room), prepare the subject matter expert, advise on the direction of the inspection, prepare for the next day of inspection, etc.

10.Supporting post-inspection activities

Typically, there are activities that a company may have to complete following an inspection.

For example, responding to the observation(s) that may have been issued during the inspection.

Many companies made the mistake of handling this response themselves, which often results in the regulatory authority's dissatisfaction and may prompt them to issue a Warning Letter to the company. 

There are nuances to providing a complete response to the regulatory authority that may not be realized by the company.

Even if the company did not receive any observations during the inspection, with the help of the consultant, the company can develop a lesson learned that can be moderated by the consultant and provide a future direction on what to do better in the next inspection.

11.What about the Supply Side?

Much can also be said about the supply side, as this article suggests that suppliers must also apply the same due diligence and knowledge to their offerings to the industry; any process must have a strong validation pack.

Yes, ultimately, it is the user's responsibility. However, the supplier must also be compliant with what you are providing as a service, equipment, process or facility.

In the same way that producers are unlikely to have all the answers, the same can be said of the suppliers, and there is an equally strong case for suppliers to use external consultants to support their businesses for exactly the same reasons.

Again, we could present as many examples as possible to support this, but the point has been made above: For your business to succeed in the pharmaceutical world, you need experts. You need people with a wide range of knowledge, probably gained over many years.

If used wisely, they will not only allow your business to flourish but also fast-track your growth and reduce the risk of falling foul of regulations. They will also give you industry-wide knowledge and experience, something you just cannot gain internally.

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/natco-pharma-limited-672564-04082024

12.Recommended by the Regulatory Authority

Finally, what do the regulators such as the FDA actually Recommend?

The example below is from a warning letter given to a producer. It clearly states that you really do need independent consultants, typically those that Austar can provide, to support your business.

They state in this example that the business must:

Provide an independent review by your consultant that determines the effectiveness of your CAPA, including but not limited to:

A list of all enhancements to cleaning and maintenance procedures, including specific frequencies and locations to be cleaned in all relevant equipment (e.g.,(b)(4)).

Identify any other sources of cross-contamination other than (b)(4) equipment,(b)(4)and(b)(4).

Determine the adequacy of your analytical methodology to identify residual carryover.

Your investigations into the unknown (unidentified) peaks detected in your reserve samples.

Supporting evidence to demonstrate that the challenges identified during your study, such as interference of product matrix and co-eluting peaks, were adequately resolved.

Adequacy of the scope of the investigation and its related CAPA.

For further details, click the link below:

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/natco-pharma-limited-672564-04082024

In Conclusion

We have discussed:

• Why the need to use consultant(s)

• Recommended by the Regulatory Authority

• Ensuring the company’s knowledge and practices expectations of cGMP

• Improving and maturing the Quality Management System

• Data integrity practices

• Enforce management mandate for the personnel.

• Quality culture maturity program

• Intellectual Property control and security

• Selecting CMO and Technology Transfer

• Perform one-off projects (validation, equipment qualification, automation, etc.)

• Providing technical updates and improving operations.

• Providing pre-inspection readiness

• Providing support during the inspection.

• Providing support for post-inspection activities and how to respond to regulatory authority observation.

• The supply side.

In summary, there are many points illustrated in this short article that outline what a company should consider when utilizing a consultant to support and improve its operations and compliance.

The use of external consultants will provide a pharmaceutical business, either a supplier to the industry or a pharmaceutical manufacturer, an edge in positioning itself better in the future arena of the pharmaceutical industry and complying with GMP and all the upcoming changes in the industry now and into the future. 

Written by

Ewart Richardson (Pharmaceutical and Process Engineering & Isolation Technologies) & Rory Budihandojo (Pharmaceutical Quality System & GMP/GDP Compliance), AUSTAR Senior Consultants