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Laboratory Quality

Q: I am a quality control (QC) manager of a contract test laboratory. I am going to be upgrading the lab testing environment and would like to know if you have any advice on how I should approach this activity?
 
A: Upgrading the laboratory quality of a contract pharma manufacturer is an exciting activity. It needs to be approached with a thoughtful, well-constructed plan that does not interrupt the lab testing business needs of your clients.
 

Contract Laboratory

 

laboratory qualityYou mentioned that you are QC for the contract test laboratory quality, which would imply the products you test could include clinical trial material, final product dosage forms, and potentially, APIs. Regardless of the testing you are performing, the first step of this process should be to notify your clients of your intention to upgrade laboratory quality programs. 
 

Stability Testing

 

In addition, pharmaceutical contract manufacturing often includes performing final product release and stability testing. This is important because some clients may not wish you to perform their analyses on new equipment (e.g. API contract manufacturing). You will need to work with these clients closely to make sure you understand their concerns and that you address them before decommissioning any equipment used to analyze their materials.
 

Risk Assessment

 

The next process step for laboratory quality is to take inventory of the equipment you have. Start making some risk-based decisions on a project plan that will define what should be replaced, in what order, and what the requirements are for each. Regardless of which piece of contract labs equipment you decide to tackle first, there are several issues you must address with every replacement.
 
When contract drug manufacturing companies upgrade to a new piece of equipment to replace an aging piece (i.e., like for like), the requirements are straightforward. If you are replacing an existing technology with a significant upgrade or different technology, a more comprehensive approach will be necessary. In all cases, you will need to make sure the current equipment is performing adequately and is still capable of generating reliable results. 
 

Product Validation

 

For a simple like-for-like replacement, you should perform installation qualifications (IQ) and operational qualifications (OQ) on the new equipment.

 

The next step in the laboratory quality process would be to execute a performance qualification (PQ) and a comparison protocol. Any pharma contract manufacturing teams should be able to demonstrate the results obtained with new equipment are the same from both an efficacy and quality perspective.

 

In many cases, the PQ and comparison may be combined into one document. If the results from the protocol match up, you can decommission the old contract lab testing equipment and start using the new equipment. 

 

Manufacturing Operations

 

When changing from one laboratory quality technology to a different, more sensitive technology, there are more decisions to be considered. You need to work closely with your client on the lab testing specifics of their product so you can perform the transition with minimal disruption to their and your product flow.

 

These more complex upgrades require a lot of upfront planning. As with the like-for-like replacement, you need to make sure the current contract laboratory equipment is operating appropriately.

 

Comparison Protocol

 

As before, you need to perform the IQ and PQ on the new equipment. It is in the PQ and comparison protocol where attention to detail will be crucial to execution. For instance, when changing from high-performance liquid chromatography (HPLC) to the more sensitive ultra-high pressure liquid chromatography (UHPLC), you need to be prepared to address the possibility that you could see some unknown peaks during the analysis.

 

These contract testing peaks need to be identified and characterized before you can continue with the transfer. While this investigation is underway, you need to determine the suitability of the contract pharma product for release. This includes understanding the potential impact the peaks might have on stability of the item being analyzed.

 

Compendial Method

 

If the method being converted is a US Pharmacopeial Convention (USP) method, you need to be sure that the new methodology generates results that are equivalent or better than the results obtained using the compendial method. The comparability protocol details will help you address the unforeseen circumstances should they occur during the execution of the overall laboratory quality protocol.

 

The issues arising from the conversion of one method to a more sensitive method need to be fully addressed and explained before decommissioning the obsolete equipment.

 

Product Stability

 

There may be situations where you will need to maintain both the new and the old lab testing equipment operational at the same time. For instance, you may want to continue to monitor the stability of a product on the equipment the analysis was started on and not change to the new equipment until the last stability time point has been analyzed.

 

In this case, you will want to maintain the old equipment while utilizing the new equipment for release and future stability monitoring. These situations need to be discussed with your client and included in the laboratory timeline for transitioning the laboratory.

 

GMP Training 

 

Another important element of transitioning a contract test laboratory is making sure your analysts are properly trained on the new equipment while maintaining expertise on the old equipment until the transition is complete. Many companies selling analytical equipment have experts to perform the necessary training and to help address issues that may come up as the analysts become more familiar with the equipment.

 

It is important for the laboratory and your clients that analysts are properly trained so they can deal more effectively with problems that occur during the transition period. The more training and familiarity the analysts have in running the new equipment, the less disruption there will be to operations.

 

Clinical Labs

 

When introducing new contract laboratory equipment and new methodologies, it is important to have a comprehensive implementation plan that discusses what equipment you will introduce. The lab testing timeline for the introduction of the equipment and how you will investigate unexpected analytical results are important during the transition. Additionally, how you will make sure your analysts are appropriately trained is essential to cause minimal interruptions to operations.

 

Putting your contract laboratory plan down in writing and discussing it with your clients up front will save you a lot of time and minimize delays as you implement your plan.

 

Article Details

 

laboratory quality

 

Pharmaceutical Technology
Vol. 41, No. 6
Pages: 74-73

 

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Pharmaceutical Manufacturing

Q: I work for a contract manufacturing organization (CMO) and our pharmaceutical manufacturing team has dedicated capital funds to update some of our manufacturing lines. I need to work with my clients to get approval to make the necessary changes. Many of my clients feel any changes to the manufacturing line would require a prior approval supplement (PAS). Do you have any compliance advice regarding a regulatory strategy that I could propose to my clients that would satisfy them and minimize downtime?
 
 
A:  This is a great question and a complicated issue. pharmaceutical manufacturing teams have been trying to become more efficient from both manufacturing and regulatory perspectives. The challenge is to improve processes, quality systems, and manufacturing capabilities while operating efficiently and in a manner that ensures safe, effective, and cost-efficient medicines to patients. Many updates to processes and quality systems can be easily and readily implemented with little or no impact on regulatory filings.
 
 
When non compliance impacts regulatory filings, it has the potential to disrupt the supply chain if it is not handled appropriately and as efficiently as possible. FDA seems to recognize these situations and has been working to help lessen the regulatory filing burden to companies while not affecting the quality of the products. In the past three years, FDA has issued three important guidelines to help facilitate the dialog between clients and CDMO and expedite the regulatory post approval change.

 

Quality Agreements

 

The first step in the process of upgrading your facility is to get the agreement, or at least, an acknowledgment from your clients that they are aware that you intend to upgrade the facility. Any mass produced pharmaceutical in this scenario needs to communicate that it may affect the client’s regulatory filing. The first guideline that helps you facilitate the dialog with your client is the quality agreement guidance issued.
 
This guideline states:
 
“… FDA recommends that owners and contracted facilities implement written quality agreements as a tool to define communications, delineate responsibilities, and assure the quality, safety, and effectiveness of drug products.”
 
If you have a quality agreement, then you need to check and see whether the contract manufacturing organization or the client has the responsibility to maintain the facility. For example, if you have relegated this responsibility to your clients and they are hesitant to implement a needed capsule filling machine upgrade, remind them that the quality agreement guideline gives you the authority to maintain your facility (including necessary equipment upgrades):
 
“A quality agreement does not exempt contracted facilities from CGMP requirements related to the operations they perform, regardless of whether such CGMP requirements are specifically discussed in the quality agreement.”
 
Bottom line, both you and your client(s) may have responsibilities outlined in the quality agreement regarding maintaining and upgrading the facility but you, as the CMO, need to adhere to CGMPs and make sure your facility is maintained per 21 Code of Federal Regulations (CFR) 211.58 requirements that “any building used in the manufacture, processing, packaging, or holding of a drug product shall be maintained in a good state of repair.”
 

CMC Post-Approval Changes

 

The second guideline that helps in updating your facility in a timely manner is the chemistry, manufacturing, and controls (CMC) post-approval manufacturing changes that can be documented in an annual report that was issued in 2014.
 
This new revision reiterates the concept of like-for-like replacement while expanding some of the facility changes that can be made as an annual report. For instance, the new guidance states:
 
For equipment used in aseptic manufacturing processes (e.g., new filling line, new lyophilizer), replacement of equipment with that of the same design and operating principle, when there is no change in the approved process methodology or in-process control limits” … and … “In the sterile manufacturing of products, the addition of barriers within a conventional fill area to prevent routine in-process human intervention in an existing filling or compounding area that is qualified and validated by established procedures”
 
Many pharmaceutical facility compliance professionals would have considered these changes as needing prior approval before being implemented. Be cautious, though; just because these improvements comply with regulations, you still need to do all the necessary work to ensure the change is appropriate and does not impact product quality.
 

Comparability Protocol 

 

You may still have pharma company clients wary of the change even when you notify them of the change. The facility compliance guidelines support making the compliancy change without going through the PAS process. This is where the third guidance comes into play, and it is the updated guidance on comparability protocols for human drugs and biologics (3). A comparability protocol has the potential to decrease the filing category.

 

Engineering Data

 

For instance, items that would normally be handled as a PAS have the potential to be considered as a changes-being-effected-in-30-days supplement. By employing the use of a comparability protocol within production scheduling,  you are making sure your facility compliance client understands the change you will be implementing. The production engineering data you will be collecting and reviewing to assess that the upgrade was successful can demonstrate changes did not affect product quality.

 

The comparability protocol is a pharmaceutical science compromise when you have clients insisting on a PAS and others who are comfortable with the annual reportable strategy. It allows you to file the protocol as a PAS and build the inventory needed in preparation for the anticipated shutdown period.

 

Contract Manufacturing

 

There are no right or wrong answers when recommending filing strategies to a client. Regardless of what the contract manufacturing organization says, the client can always choose an alternative design for manufacturing. The best way to convince a client of a filing strategy is to make sure you have a robust quality agreement in place that gives you the responsibility for maintaining your facility.

 

Become familiar with the regulations and use them to justify your recommendation. Finally, use a comparability protocol for proving like-to-like equivalency, and present the recommendation to the client in a documented manner. These facility compliance steps should help you implement a facility upgrade in a timely manner while reducing your downtime to make the improvement.

 

Published by:

 

pharmaceutical manufacturing

 

Pharmaceutical Technology
Vol. 40, No. 8
Pages: 82, 81
 

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Transitioning to the EU In Vitro Diagnostic Devices Regulation

 

The application date of May 26, 2022 for the EU In Vitro Diagnostic Medical Devices Regulation (2017/746), commonly referred to as IVDR, has come and gone.  IVDR has created challenges for in vitro diagnostic (IVD) medical device firms planning to introduce or continue to market their products to the European Union.

 

IVD Device Classifications

 

One of the biggest changes from the in vitro diagnostic directives (IVDD) to IVDR is the move from list-based IVD device classifications to a rule-based IVD medical device classification. The new classification results in four new device classes: class A (lowest risk) to class D (highest risk), where class B, C, and D would require Notified Body (NB) involvement.

 

This change requires a large number of NBs, and the increased workload is cause for concern. Moreover, it is estimated that the quantity of medical device products will increase from 20% under the Medical Devices Directive (MDD) to approximately 80% under IVDR. As of this writing, there are only four IVDR designated NBs, which highlights the shortage.

 

IVD Scheduling Delays

 

Proactive strategic planning and effective resource allocation are critical for the timely execution and implementation of a comprehensive IVDR implementation plan. IVDR manufacturers must consider and prepare for potential delays. Scheduling bottlenecks for NB conformity assessment activities can impact planned commercialization efforts for existing and/or new IVDR products. It is necessary for IVDR manufacturers to establish contingency plans to mitigate these potential challenges.

 

regulatory compliance

Additional nuances from IVDD to IVDR are based on a medical device life cycle approach and include:

 

  • Requirements for medical device manufacturers to establish and demonstrate effective quality management systems (QMS).
  • More stringent requirements for clinical evidence demonstrating conformity.
  • New requirements for postmarket performance monitoring and reporting.
  • Greater supply chain oversight and device traceability, including giving NBs discretionary authority to monitor supplier audits and subcontractor compliance.

 

IVD Timing

 

The move from IVDD to IVDR can be a time-consuming process, and many medical device companies are still in the process of making the transition.

 

Timing is an issue because companies need to:

 

  • Evaluate if their current NB is still the right partner to work with.
  • Plan the regulatory strategy of the current medical device in the field.
  • Know the IVDD certificate expiration date and prioritize the products that need immediate attention.
  • Classify devices according to the new IVDR classification rules.

 

No matter the size of your company, if you have not already started your transition, you will need to start preparing for the IVDR deadline now as it is quickly approaching. Timely compliance to IVDR requires a dedicated team of subject matter experts.

 

For example, the goal is to properly implement and execute the deliverables as laid out in your IVDR implementation plan. These deliverables may require extensive updates to a manufacturer’s existing QMS and technical documentation. Likewise, establishing or enhancing a manufacturer’s body of objective evidence of clinical performance is validation for the product lifecycle.

 

Having the Proper Team of IVD Experts

 

Organizations have a better chance of a successful transition by having a team of subject matter experts with intimate familiarity of the implementation of IVDR.

 

The subject matter experts should identify the intended purpose and inherent risks associated with your device(s). This will determine the device classification and help create technical documentation in compliance with IVDR.

 

Robust procedures for postmarket surveillance and postmarket performance follow-up must be put in place to successfully transition to IVDR.

 

Conclusion

 

If you are planning to introduce or continue to market your IVD products to any of the EU member states you must identify the new classifications your devices fall under. This includes anticipating potential scheduling delays caused by the limited number of NBs capable of reviewing IVD device classifications. Above all, plan carefully for the entire process. Putting together the right team to handle the work can ease the transition.

 

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