Qualification of Raw Materials for Biopharmaceutical Use

Quality assurance for finished pharmaceuticals, biopharmaceuticals, medical devices, and active pharmaceutical ingredients (APIs) includes the specification and control of those components that have product contact during manufacturing, that is, the raw materials (RMs).^1-6

An RM qualification and control program is considered a key factor in assuring the quality of medicinal drugs, yet it is often deemed of secondary importance at a busy firm. Usually, RM testing is not considered scientifically challenging or exciting - until, of course, the supply chain is imperiled by a single failure. At this point, a great deal of scientific and compliance information must be quickly sifted through and presented to an investigation team, then both short-term and long-term actions initiated. The data are often not readily accessible or transparent and require the collaboration of subject matter experts to integrate and interpret.

GMP REQUIREMENTS

GMP regulations and good business practices require that pharmaceutical RMs and their suppliers be qualified both initially and periodically.

^1-3,6,7

Similar requirements can be found in the US Code of Federal Regulations, ICH guidance documents, European GMP regulations, and within ISO.

Patient safety is a key reason for this requirement, dating back to several unfortunate events within the pharmaceutical and food industries. In one incident, the use of an unsuitable RM led to widespread toxicity, resulting in hallucinations and other severe symptoms.⁸ Mix-ups and errors of identity have also occurred. For example, the accidental use of ethylene glycol instead of propylene glycol resulted in morbidity and mortality.

Legally, a pharmaceutical firm takes on full responsibility for the quality of the RMs it purchases and uses in a cGMP manufacturing process. Consequently, it is in the business interest of a firm to exercise reasonable oversight of suppliers and test laboratories and to characterize RMs appropriately.^9,10

Table 1. References to regulatory requirements

Regulatory requirements in the pharmaceutical industry have evolved over time to reduce the probability, or risk, of such events. Some of the most important actions a firm takes to reduce risk include setting specifications that define and control the RMs, testing to verify identity and quality, and establishing systems to prevent the use of unsuitable materials.³

RM qualification should be carefully defined in GMP procedures and placed under strict change control. Both the chemical entity and suppliers must be qualified, usually in tandem. RMs deemed "critical" require testing of more supplier lots for more attributes and extensive supplier evaluation before qualification is achieved. The critical status of an RM is related directly to its intended use in the process and to the potential risk created by a quality deficit in the RM that may adversely impact the product's identity, purity, potency, toxicity, or efficacy.^11,12 An RM may be critical to one process but not to another. Each firm must identify which materials are critical and justify the choices made and the additional oversight required.

Table 1 summarizes the applicable regulations for pharmaceutical products of various types, and summarizes some of the differences between US and European regulations. These differences may create complex challenges for the firm that manufactures multiple profile classes of products for worldwide sale. Considering the rapid rate of change to these regulations, sustaining a compliant, effective program requires a strategic approach.

PRACTICAL CONCERNS

A firm faces the practical challenge of establishing and operating an efficient, compliant system that assures continuous supply of quality RMs that are sampled, tested, and then released for manufacturing needs on time. A properly sized and managed warehouse provides a buffer zone where unpredictable RM problems (back orders, late deliveries, and items failing to meet specifications) can be resolved without delaying manufacturing. However, it is undesirable to build large warehouses and store huge inventories if materials must be discarded because they expire before use. Therefore, it is important for supply chain management to reduce the probability of receiving RMs that fail to meet specifications. This is part of the payoff of a robust and sustainable vendor and RM qualification program.

^7,9,10

Table 2. List of procedures needed for RM qualification program

Table 2. Continued: List of procedures needed for RM qualification program

Business needs. In establishing an RM qualification program, first determine your internal business requirements. A development organization will usually need a rapid, flexible RM qualification process that can quickly assess up to 100 or more new materials and suppliers and approve them for at least provisional use. Furthermore, changes in RMs and suppliers are expected during development.^5,6 Therefore, full qualification of an RM may proceed in parallel with its use and should be completed at a defined project milestone.

In contrast, an organization with a mature, marketed product is unlikely to have frequent changes in RMs, and long-term supplier relationships are commonly in place. Any changes may require overcoming regulatory hurdles and are highly undesirable. Consequently, all RMs are likely to be fully qualified before use and the quality program will focus on maintenance and monitoring of the qualified state.

Table 3. Master plan items

System procedures. In order to qualify new RMs from new or existing suppliers, several GMP procedures and systems are needed (see Table 2). In writing these procedures, consider compliance as well as efficiency. Check that the different documents link with each other appropriately and do not contradict each other. Avoid the extremes of lumping many procedures into one document or splitting integrated procedures into different documents. Check that the procedures are clearly written and can be consulted and followed while on the floor.

A master plan is an invaluable document for both new and existing programs. This document may be "live" (subject to periodic revision) or static (created at one moment in time). Some firms archive master plans within a quality manual, while others place the information within a standard operating procedure.²

A master plan records basic decisions and assumptions, codifying company philosophies and corporate policies related to quality. Since the document is kept centrally, it can be used to archive organizational history, assumptions, and knowledge. It will be retrievable long after meeting minutes are lost, and can be cited by other documents. The master plan can include references, discussion of any interpretation issues, and the company's formal commitment to quality.

Table 4. Compliance concerns

Table 4. Continued - Compliance concerns

Creating a master plan has a further, indirect benefit. By documenting key assumptions, roles, and responsibilities, cross-functional dialogue occurs and team members can improve their alignment, engage in continuous improvement, and better understand their customers' needs. Inconsistencies in the strategy or gaps in team assignments are exposed and can be addressed before issues arise.⁷

Table 3 lists typical sections of a master plan. This information also may be captured in other documents, such as quality manuals or system SOPs. Regardless of the document's name, be sure that it is linked to cGMP systems and the information is accurate, archived, and traceable.

Quality concerns. The program also needs to have built-in responses when quality issues are discovered by QC testing or by QA audits. One common disconnect, particularly in firms where QC and QA are each part owners of the RM control system, is that the system does not respond quickly to new information. As described in the ANSI/ASQ standard Z1.4 for sampling, switching rules should be defined to permit increased testing (and other oversight actions such as auditing) when an RM lot fails to meet specifications.¹³ Switching rules also can define when reduced testing is appropriate - and save the firm money without significantly increasing risks. Similarly, an appropriate response to adverse audit findings may include increased QC testing and an adjustment in the frequency of follow-up audits. To make this happen reliably, the nonconforming materials control system, the audit program, and the RM testing programs must include linkages and notifications. A review of several FDA warning letters and 483s (issued to firms at the end of inspections), suggests that some firms' systems are not sufficiently agile to respond to new RM issues in a timely way, creating compliance risk and negative findings. Table 4 summarizes recent deficiencies that were cited by FDA from 2001 to 2003.^14-16

Figure 1.

A STEP-BY-STEP PROCESS

Process thinking is especially helpful in setting up the system for RM and supplier qualification. Often, a specialized team member conducts a single step in the qualification process and then hands off the data to the next team member. Process engineers know that errors and miscommunications occur at interfaces between people and organizations; compliance auditors tend to look for deficiencies at these points.

¹⁰

Therefore, creating a committee of key members involved in RM processes facilitates communication, helps ensure that information is not lost or garbled during transfers, and establishes a structure that can handle RM non-conformances.

Figure 1 shows a flow chart for the RM qualification process. The tasks listed are documented in and driven by SOPs or other GMP documents. Depending on the organization, several different work units (such as QC, purchasing, shipping and receiving, manufacturing, and QA) may participate. Both the quality and manufacturing units approve suppliers and RMs. However, in order to maintain objectivity and minimize conflicts of interest, regulations require that the quality unit has oversight and the sole authority to disposition RMs for release or rejection.

The following elements should be part of an RM qualification exercise. Note that some steps may be combined and several are concurrent.

Step 1. Collect information regarding the RM: What grades are available, and what do suppliers test for and set specifications upon? Is the material listed in a compendium such as the US Pharmacopeia, European Pharmacopeia, or Japanese Pharmacopeia? (Compendial materials are well defined and accepted as suitable for finished pharmaceutical use.)^17-19 How do the stated specifications compare to actual values reported for a single lot? Is this RM critical or noncritical, based on its intended use? (See Table 5 for examples of critical RMs.)

Table 5. Examples of materials defined as critical

Step 2. Determine the qualification strategy and set your acceptance criteria for this RM. The purpose of qualification is to generate evidence that your firm can rely on the supplier's certificate of analysis and start defining the quality profile of the RM.

The quality profile includes those chemical, biochemical, or microbiological characteristics consistently possessed by the RM and those attributes required by your process. Therefore, it may extend beyond those tests reported on the certificate of analysis. For a critical material, all tests included on the certificate of analysis should be performed.⁹ Similarly, compendial materials should be tested against the full, current compendium since this is the claim being verified. Use the data to "qualify" the supplier's testing program (that is, show that their results are believable).

Some firms defer qualification activity for noncritical RMs until later in clinical development and accept the low risk that unknown, untested attributes could impact their product.⁷ Noncritical RMs (for example, lipids added to cell culture media) are often accepted on certificate of analysis plus identity confirmation, after at least one lot has undergone full testing. A "paperwork" review of the actual test values reported on each supplier's certificate against the written specification verifies that each lot received meets the specification. Remember, however, that if you do not perform all testing, it will not be possible to detect some problems. Most regulatory authorities expect that full qualification is completed prior to pivotal clinical trials.5 During periodic review of specifications, such risk-based decisions should be reviewed. This is also the time to decide whether a second source should be, or can be, qualified.

Step 3. Analyze the test results and any information derived from audits or supplier evaluations. Determine the nature of information provided by each test. Some are obvious, such as purity, activity, and identity. Others, such as impurities, moisture, bioburden, or country of origin, may be less directly related to your immediate use of the material, yet still important. Do these tests directly relate to suitability for use, safety to the patient, cross-contamination or mix-up detection, or stability of the material?

Step 4. Based on the data obtained during qualification, approve the final selection of the tests you will perform on each incoming lot for routine release. The data may show that some tests do not provide useful information or that tests not listed on the certificate of analysis are quality-indicating and should be performed routinely. These will be listed on the RM release specification. The test results should be compared with the specifications as well as to the results that were reported by the supplier on the certificate of analysis. Investigate discrepancies between your test results and the suppliers' even if both values are within release specifications.

The regulations require identity confirmation on every receipt of each RM.^1-3,6 European regulations differ for excipients and currently require sampling every container for identity. A new WHO draft document - with major cost implications if implemented - suggests that this should also be applied to in-process RMs, although it is likely eclipsed by existing EU and FDA regulations for pharmaceuticals.²⁰ Appearance testing should always be done, since it is an inexpensive and useful way to spot several types of quality problems. Other tests may be added based on the results of your qualification testing, your process and its requirements, and other knowledge that you have. For example, it may be useful to watch for particles or heavy metals if you know that the container or closure used for the RM - or the equipment used for its manufacture - has the potential to shed such materials or if you have seen such a problem in the past.

Step 5. Analyze the data obtained during qualification. Did the RM and the supplier both meet acceptance criteria that were defined in Step 2? If so, document the successful qualification in your cGMP records as a status change, add the RM to the qualified list, and put it into the periodic review program to be overseen by the RM committee. This list should be used to control all ordering of cGMP RMs to ensure that unqualified RMs are not accidentally used. If the data are not satisfactory, consider other actions that can mitigate risk, including vendor follow-ups and testing of other grades, other sources, or both to find suitable materials. Note that it is possible to qualify the RM as suitable for use in the process, while not qualifying the supplier (usually based on audits). Suppliers may be given status labels such as: provisional, qualified, certified, or "avoid using." When the supplier's status is not ideal, a major goal of the committee is to work with the supplier on addressing the concerns, with the long-term goal of upgrading status.¹⁰

Step 6. Finalize the frequency of requalification - when you will next put a lot (or lots) of this RM from this supplier through full testing. This lot is called the skip lot. Firms themselves decide the frequency of requalification (no guidance on suitable periods is provided in the regulations). The frequency may be based on calendar dates, set as a skip-lot system (every ten supplier lots, for example), or both. Ensure that your GMP system will notify QC and QA when a skip lot is coming up because the testing will take longer, and the lot's release will be delayed. When the skip lot is approaching, consider that the QC laboratory may be out of practice in performing some tests; a training period may be useful.

SUSTAINABILITY

Once an RM and its supplier are qualified, it is necessary to maintain that qualification. Suppliers may change their processes, facilities, or equipment. Corporate entities may merge or divest, changing their approaches to and control over quality. Process scale-up often results in changed requirements for RM containers and closures that affect RM quality, stability, and performance as well as sampling methods. Sampling and testing methods change, for example, when a solvent is received in a railroad tank car instead of in a bottle or carboy.

To respond to unexpected issues with RMs, suppliers, or the entire system, ensure that adequate checks and monitoring systems are in place. This area is the most important in keeping a quality operation in running order - and one that is most cited by FDA during inspections.¹⁴ Activities undertaken to sustain qualification include audits or other supplier evaluation activities such as trending of test data from the QC lot-testing program and periodic full testing of representative lots of the RM.^9,10 Consider if you will be able to detect a new problem in a timely manner and whether the systems require that your team investigates problems with appropriate urgency and depth, finds the root causes, and follows up appropriately. Follow-up must address both any product lots affected by the current situation and whether preventive action is warranted to reduce the probability that the event will recur.

To ensure a sustainable RM qualification program:

• Allocate resources or set aside capacity for working with exceptions, as with any maintenance activity. Feed the results back into the testing program.

• Be proactive. Studies show that preventive action is less expensive than corrective action. For example, according to an unpublished benchmarking study conducted by Margaret Hauter, purchasing manager at Genentech, the labor cost of a single-issue RM failure was over 120 person-hours by the time the material was shipped back to the supplier and all paperwork completed. The cost of qualification, including performing full certificate testing on one to three lots of material and performing a supplier audit, is comparable to experiencing a single lot failure, making it cost effective.

• Aggressively investigate negative patterns or trends in QC test data. Out-of-trend items may show a material is close to failure, indicating follow-up is needed to prevent a potential problem. Firms often have the ability to generate large amounts of data but lack capacity to assess it thoroughly.

• Schedule a periodic audit of the RM quality system using QSIT techniques.2 Do not rely only on a traditional lab-by-lab audit, since the program will be fragmented across many groups. Check whether similar materials are treated consistently and determine where the risks and potential risks lie. Determine if the company's money is being spent wisely.

• Commission a permanent committee that includes purchasing, finance, QC, QA, warehousing, and production personnel. This group should meet regularly to discuss the tactical and strategic issues related to RM sourcing, timing of audits, and testing glitches. Transparency of information is the key goal. A second goal is to make committee members aware of each department's requirements and issues. If the purchasing department is aware of minimum quality requirements, it is unlikely to pursue low-cost items at the expense of compendial status. And if QC is aware of the impact of testing delays on other groups, they will communicate issues in a timely manner.

CONCLUSION

Controlling the quality of RMs used during manufacturing by qualifying the materials and their suppliers helps ensure that a firm's final product is well-defined, consistent, and suitable for its intended use. Without qualification, product batches can be lost, production schedules can be delayed, and the supply chain can become unpredictable. Qualification provides documented assurance - enabling a firm to perform risk analysis when it accepts the legal and regulatory responsibilities that go with producing pharmaceutical products.

References

1. FDA. Current good manufacturing practices for finished pharmaceuticals.

Code of Federal Regulations, Title 21, Part 211.80-94, 211.101, 211.184

as amended 1 Apr 2003.

2. FDA. Quality system regulation. Code of Federal Regulations, Title 21, Part 820 revised 1 Apr 2003.

3. EMEA. Medicinal products for human and veterinary use. GMP Guide (Volume 4) 1998.

4. EMEA. Sampling of starting and packaging materials. GMP Guide (Volume 4) Annex 8 1999.

5. EMEA. Manufacture of investigational medicinal products. GMP Guide (Volume 4) Annex 13 revised 2003 Jul.

6. ICH. Good manufacturing practice for active pharmaceutical ingredients. Q7A. Geneva; 2000.

7. Del Tito BJ, Tremblay M, Shadle P. Qualification of raw materials for clinical biopharmaceutical manufacturing. BioPharm 1996; 9(10).

8. Thereapeutic Goods Administration. TGA reminds Australians of the potential danger of Pan Pharmaceuticals [press release]. Woden, Australia: TGA; 2003 Aug 24.

9. Lubiniecki AS, Shadle PJ. Raw material considerations. Dev. Biol. Standard 1997; 91:65-72.

10. Dolecek G. Vendor audit and certification programs. Pharmaceutical Engineering 1997; 17:24.

11. ICH. Specifications: test procedures and acceptance criteria for new drug substances and new drug products - chemical substances. Q6A. Geneva; 1999.

12. ICH. Specifications: test procedures and acceptance criteria for biotechnological/biological products. Q6B. Geneva; 1999.

13. ANSI/ASQC Z1.4-1993. Sampling procedures and tables for inspection by attributes. Milwaukee (WI): ASQC Quality Press.

14. Recent inspection findings. Excerpted from BioQuality: i2i Corporation. Idyllwild (CA); 2001-2003.

15. FDA. FDA's electronic freedom of information reading room - warning letters and responses. Available from URL: http://www.fda.gov/foi/warning.htm.

16. ICH. Validation of analytical procedures: methodology. Q2B. Geneva; 1995.

17. USP. The United States pharmacopeia. 27th ed. Rockville (MD): United States Pharmacopeial Convention; 2004.

18. European Pharmacopeia Commission. European pharmacopeia. 5th ed. Strasbourg, France: The Commission; 2004.

19. EMEA. Note for guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products. London; 2001 May 31.

20. WHO. Guideline for sampling of pharmaceutical and related materials. Draft 2003. Avaliable from URL: http://www.who.int/medicines/organization/qsm/activities/qualityassurance/gmp/gmptwo.html.

21. CPMP. Note for guidance on viral validation. In: Commissions of the EC, rules governing medicinal products in the EC, Vol 3, Addendum 2. Luxembourg: Office for Official Publications of the EC; 1992.

22. Seely RJ, Wight HD, Fry HH, Rudge, Slaff, GF. and Rudge. Validation of chromatography resin useful life. BioPharm 1994; 7(7).