Regulatory and Quality Considerations for Raw Material Identification by Portable, Handheld, and Miniature Spectrometers in the Manufacture of Drug Products and Compounded Sterile Preparations

Abstract

Portable, handheld, and miniature spectrometers are ubiquitous in the marketplace now. The possibility of instituting a raw material identification and verification system in your supply chain management system that meets regulatory and quality requirements is now possible for every large, medium, and small pharmaceutical manufacturer and compounding pharmacy. Cost considerations are no longer a barrier as the costs for these devices are very affordable such that the return on investment can be realized in a years’ time. Furthermore, the complexities typically associated with processing and managing the data is no longer an issue. Many, if not most, systems are now easily deployable “out of the box” with very little or no extensive training in multivariate, spectral matching routines, or other complex algorithms that have prevented employing such tools in the past.

With all of this being said, the biggest barrier to overcome and the most time consuming from the time the decision is made to purchase these devices to site deployment, is complying with the evolving regulations, guidances, and your company’s quality organization. This paper will present and review regulatory and quality issues that must be understood, fashioned into a policy and executed according to well-designed protocols. Hopefully, for those who have delayed making the decision to proceed with these time-proven systems that have saved millions of dollars globally and more importantly have provided increased assurance in the identity and purity of active pharmaceutical ingredients and excipients and have lowered the risk of poor quality medicines to patient safety, these considerations will emphasize the importance of adopting the use of portable, handheld, and miniature spectroscopic approaches for managing the safety, security, and quality of pharmaceutical raw materials.

Regulatory Considerations

The place to begin when considering whether or not to use a portable, handheld, or miniature spectrometer is the user system requirement (USR). This document should be used to answer the requirements stated in [21CFR211.63]:

Sec. 211.63 Equipment Design, Size, and Location

Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance. The elements of the user system requirement documents consists of a purpose, scope, traceability numbering, requirements, specifications, user and technical support documentation, and revision history The purpose should describe what the spectrometer must do in the quality control laboratory for the identification of raw material and will indicate the functional, operational, and data requirements that are controlled by the software to obtain, analyze, archive, and retrieve spectra. The scope of a user requirement should specify the spectrometers applicability, hardware, and software design operation specifications with other systems (e.g. computers, servers), location, and range of operation.

Traceability numbering aligns vendor instrument design specifications with the user requirements. A matrix is constructed for instrument qualifications and software validation tests performed to prove the requirements have been met. This document can be used to create a traceability matrix that serves as an auditing tool to document other requirements such as conformance to instrument qualifications, 21 CFR Part 11 Electronic Signatures, computer validation, risk assessment and method validations.

A number of facilities practice several types of procedures in controlling the reception of active pharmaceutical ingredients (APIs) and excipients collectively referred to as raw materials. In lieu of testing every lot received for identification and any other attribute called for from either a compendial monograph or other specification, reduced testing is used in combination with a quality review of certificates of analysis (CoA). The implementation of a rapid, non-invasive, non-destructive testing of incoming raw materials for identification provides analytical evidence of the chemical and physical properties for conformance to the CoA acceptance criteria. In many instances other quality attributes can be tested for simultaneously such as moisture and particle size.

Based on the user requirements, once the desired equipment has been obtained, the following rule must be adhered to and fulfilled based on the rational for quality control has been established [21CFR211.84]:

Sec. 211.84 Testing and Approval or Rejection of Components, Drug Product Containers, and Closures

(a) Each lot of components, drug product containers, and closures shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit.

(b) Representative samples of each shipment of each lot shall be collected for testing or examination. The number of containers to be sampled, and the amount of material to be taken from each container, shall be based upon appropriate criteria such as statistical criteria for component variability, confidence levels, and degree of precision desired, the past quality history of the supplier, and the quantity needed for analysis and reserve where required by 211.170.

(c) Samples shall be collected in accordance with the following procedures:

1. The containers of components selected shall be cleaned when necessary in a manner to prevent introduction of contaminants into the component.
2. The containers shall be opened, sampled, and resealed in a manner designed to prevent contamination of their contents and contamination of other components, drug product containers, or closures.
3. Sterile equipment and aseptic sampling techniques shall be used when necessary.
4. If it is necessary to sample a component from the top, middle, and bottom of its container, such sample subdivisions shall not be composited for testing.
5. Sample containers shall be identified so that the following information can be determined: name of the material sampled, the lot number, the container from which the sample was taken, the date on which the sample was taken, and the name of the person who collected the sample.
6. Containers from which samples have been taken shall be marked to show that samples have been removed from them.

(d) Samples shall be examined and tested as follows:

1. At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used.
2. Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals.
3. Containers and closures shall be tested for conformity with all appropriate written specifications. In lieu of such testing by the manufacturer, a certificate of testing may be accepted from the supplier, provided that at least a visual identification is conducted on such containers/closures by the manufacturer and provided that the manufacturer establishes the reliability of the supplier’s test results through appropriate validation of the supplier’s test results at appropriate intervals.
4. When appropriate, components shall be microscopically examined.
5. Each lot of a component, drug product container, or closure that is liable to contamination with filth, insect infestation, or other extraneous adulterant shall be examined against established specifications for such contamination.
6. Each lot of a component, drug product container, or closure with potential for microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use.

(e) Any lot of components, drug product containers, or closures that meets the appropriate written specifications of identity, strength, quality, and purity and related tests under paragraph (d) of this section may be approved and released for use. Any lot of such material that does not meet such specifications shall be rejected.

In rule 211.84 are all of the action items that become the basis of control of raw materials using portable, handheld and miniature spectrometers. They are, in order of appearance in the rule:

• Holding of materials
• Releasing of materials
• Statistical sampling
• Sampling of material
• Facility and state of sanitary conditions
• Aseptic procedure
• Use of appropriate container and closures
• Microscopic examination
• Labeling
• Testing
• Identity
• Microbiological testing
• Acceptance or rejection of materials

Note: 211.84 is frequently cited by the FDA in Form 483 inspection observations (See Table 1). In 2016, the FDA reported that this rule was cited 20 times.

Table 1. FY 2016 Inspectional Observation Summaries

Quality Considerations

The International Conference on Harmonization (ICH) Guidance for Industry Q10 Pharmaceutical Quality System consists of several tenants that provide a framework for manufacturing controls for product lifecycle. With respect to this paper that focuses on the use of portable, handheld and miniature spectrometers as controls for raw material, several key points emerge that require special attention from a quality perspective if full compliance to the regulations previously discussed are to be realized.

As the initial step in the manufacture of a pharmaceutical drug product or compounded sterile preparations is to receive, store, test, and dispense the material for manufacturing or compounding; the quality control unit must provide assurance that the material is the correct material; that it has been packaged, transported, and stored under the stated labeled requirements. While a CoA may be suitable for demonstrating the identity, source and analytical tests of conformity, the handling of the material during the packaging, transporting and storage may negatively impact the chemical and physical attributes attested to on the CoA. Analysis upon receipt may not occur again for days or weeks before processing. The delay in testing could affect the performance of the material the longer it is quarantined before use. In fact, the stability of materials is a key analytical indicator for the usefulness of the material. Analytical testing alone for potency may not be sufficient if during handling of the materials prior to use the material was prone to degrading.

Product Lifecycle Management is the Theme that Underpins ICH Q10

ICH Q10 as a framework for a robust and effective quality management system to augment current good manufacturing practice (CGMP) 21 CFR Part 210 and 211 while also providing an effective model to mitigate the risk of producing poor drug product or compounded sterile preparations.

The four key quality elements for controlling incoming raw materials at the initial stage of a product and preparation lifecycle are:

1. Process performance and product quality monitoring system
2. Corrective action and preventive action (CAPA) system
3. Change management system
4. Management review of process performance and product quality

A well designed raw material identification should incorporate practices from all four lifecycle elements such as from 1. A quality risk management system to establish the control strategy inherent in the use of portable, handheld or miniature spectrometers, 2. To paraphrase ICHQ10, a system for implementing corrective actions and preventive actions resulting from the investigation of [raw material] complaints, rejections, nonconformance’s, recalls, deviations, audits, regulatory inspections and findings, and trends from process performance and [raw material quality monitoring, 3. A change management system is necessary to maintain the equipment and associated procedures in a validated state. Quality risk management should be utilized to evaluate proposed changes, and 4. Management review should provide assurance that process performance and product quality are managed over the lifecycle. Depending on the size and complexity of the company, management review can be a series of reviews at various levels of management and should include a timely and effective communication and escalation process to raise appropriate quality issues to senior levels of management for review.

Conclusion

The Department of Health and Human Services US Food and Drug Administration September 2004 PHARMACEUTICAL CGMPS FOR THE 21ST CENTURY—A RISK-BASED APPROACH FINAL REPORT laid out and initiative to enhance and modernize the regulation of pharmaceutical manufacturing and product quality — to bring a 21st century focus to this critical FDA responsibility. More recently, the FDA has been mandated to enforce the Compounded Quality Act (Drug Quality Security Act, 2013). These two taken together allow for CGMP to be applied across the supply chain ensuring that the FDA’s mission to protect the public health by providing a safe and secure supply chain are met and that drug products are pure, safe and effective.

The adoption of a low-cost value-added analytical solution for meeting the regulatory requirements in today’s global market is not only a smart business move for sustainability, it is a requisite for compliance to an ever-changing regulatory landscape. The paradigm shift from a paper based quality control strategy to an electronic based control strategy has taken place and is well under way. Incorporating digital information that provides instantaneous empirical evidence for the chemical and physical properties desirable for manufacturing or compounding fills the need for a strategy that is both scientific and risk-based for a modern quality system.

The use of electronic digital spectra extends the utility of the requirement for accepting raw material on the basis of certificates of analysis and provides further proof that is evidence base, providing immediate information about the quality of the material in real time during receiving. The result of having such information instantly available is an enhanced quality system that controls the decision making process for acceptance or rejection of the material utilizing risk management, change management, corrective and preventative action systems and electronic computer based instrument management assessments to ensure data integrity.

Author Biography

Gary Ritchie was an advisor in the formative years of Dynalabs and later a consultant. He was present on the early discussions that eventually led to the creation of the DVx and later he help lay the groundwork for adapting good manufacturing practices that are the basis of the quality and operation unit practices at Dynalabs today. With over 30 years’ experience, Gary joined Dynalabs in 2015 as their Director of Operations responsible for aligning the operational and quality departments, with the goal of improving quality, efficiencies and costs. As Regulatory Affairs Analyst, Gary has refocused his efforts in assessing the impact of the FDA guidance’s on compounding on clients and laboratory operations to ensure compliance and continuous improvements in laboratory and quality operations. As an internationally recognized expert with a focus on vibrational spectroscopy and multivariate analysis, process analytics and quality assurance, Gary’s experience includes increasing responsibilities in quality control, technical services, research and development and new technologies with Schein Pharmaceuticals and Purdue Pharma. Gary served as Scientific Fellow for Process Analytical Technology and Liaison to the General Chapters, Pharmaceutical Waters and Statistics Expert Committee’s from 2003 through 2008 for the United States Pharmacopeia (USP). Gary also served as Consultant with his own company, Garton Consulting, providing analytical and quality solutions for various large pharmaceutical and biopharmaceutical firms from 2009 through 2015 and as Director of Scientific Affairs for InfraTrac. Gary has more than twenty-five peer reviewed papers and book chapter contributions; four issued patents, numerous industry journal articles and has been invited to give conference and symposia presentations worldwide. He was President of The Council for NearInfrared Spectroscopy (2012-2014).

Gary’s combined experience in industry and regulatory agencies has allowed him to quickly see through problems and provide solutions. Gary has a deep appreciation for pharmaceutical regulatory science. This coupled with his hands on experience in pharmaceutical and process analysis allows him to provide solutions that are both practical and compliant. Gary has demonstrated leadership and organization skills at both the domestic and international levels, having led a 47 member consortium of pharmaceutical industry and regulatory bodies to revise a national standard for the USP. He has chaired committees for the ASTM International and the International Diffuse Reflectance Conference (IDRC).

Previous employment includes:

Schein Pharmaceutical (Senior Scientist), Purdue Pharma (Principal Scientist), InfraTrac (Director of Scientific Affairs) and Consultant to Merck, Schering Plough, Sandoz, Novartis and Roche.

Gary received his Bachelor of Arts and Masters of Science in Biology at the University of Bridgeport, Bridgeport, Connecticut.